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[1]

TÍTULO / TITLE:  - Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Lancet. 2013 Jan 4. pii: S0140-6736(12)61424-X. doi: 10.1016/S0140-6736(12)61424-X.

            ●● Enlace al texto completo (gratuito o de pago) 1016/S0140-6736(12)61424-X

AUTORES / AUTHORS:  - Burmester GR; Blanco R; Charles-Schoeman C; Wollenhaupt J; Zerbini C; Benda B; Gruben D; Wallenstein G; Krishnaswami S; Zwillich SH; Koncz T; Soma K; Bradley J; Mebus C

INSTITUCIÓN / INSTITUTION:  - Charite-University Medicine Berlin, Berlin, Germany. Electronic address: gerd.burmester@charite.de.

RESUMEN / SUMMARY:  - BACKGROUND: Rheumatoid arthritis is a heterogeneous chronic disease, and no therapeutic agent has been identified which is universally and persistently effective in all patients. We investigated the effectiveness of tofacitinib (CP-690,550), a novel oral Janus kinase inhibitor, as a targeted immunomodulator  and disease-modifying therapy for rheumatoid arthritis. METHODS: We did a 6-month, double-blind, parallel-group phase 3 study at 82 centres in 13 countries, including North America, Europe, and Latin America. 399 patients aged  18 years or older with moderate-to-severe rheumatoid arthritis and inadequate response to tumour necrosis factor inhibitors (TNFi) were randomly assigned in a  2:2:1:1 ratio with an automated internet or telephone system to receive twice a day treatment with: tofacitinib 5 mg (n=133); tofacitinib 10 mg (n=134); or placebo (n=132), all with methotrexate. At month 3, patients given placebo advanced to either tofacitinib 5 mg twice a day (n=66) or 10 mg twice a day (n=66). Primary endpoints included American College of Rheumatology (ACR)20 response rate, mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI), and rates of disease activity score (DAS)28-4(ESR) less than 2.6 (referred to as DAS28<2.6), all at month 3. The full analysis set for the primary analysis included all randomised patients who received at least one dose of study medication and had at least one post-baseline assessment. This trial is registered with www.ClinicalTrials.gov, number NCT00960440. FINDINGS: At month 3, ACR20 response rates were 41.7% (55 of 132 [95% CI vs placebo 6.06-28.41]; p=0.0024) for tofacitinib 5 mg twice a day and 48.1% (64 of 133; [12.45-34.92]; p<0.0001) for tofacitinib 10 mg twice a day versus 24.4% (32 of 131) for placebo. Improvements from baseline in HAQ-DI were -0.43 ([-0.36 to -0.15]; p<0.0001) for 5 mg twice a day and -0.46 ([-0.38 to -0.17]; p<0.0001) for 10 mg twice a day tofacitinib versus -0.18 for placebo; DAS28<2.6 rates were 6.7% (eight of 119; [0-10.10]; p=0.0496) for 5 mg twice a day tofacitinib and 8.8% (11 of 125 [1.66-12.60]; p=0.0105) for 10 mg twice a day tofacitinib versus 1.7% (two of 120) for placebo. Safety was consistent with phase 2 and 3 studies. The most common adverse events in months 0-3 were diarrhoea (13 of 267; 4.9%), nasopharyngitis (11 of 267; 4.1%), headache (11 of 267; 4.1%), and urinary tract infection (eight of 267; 3.0%) across tofacitinib groups, and nausea (nine of 132; 6.8%) in the placebo group. INTERPRETATION: In this treatment-refractory population, tofacitinib with methotrexate had rapid and clinically meaningful improvements in signs and symptoms of rheumatoid arthritis  and physical function over 6 months with manageable safety. Tofacitinib could provide an effective treatment option in patients with an inadequate response to  TNFi. FUNDING: Pfizer.

 

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[2]

TÍTULO / TITLE:  - Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Lancet. 2012 Dec 4. pii: S0140-6736(12)61963-1. doi: 10.1016/S0140-6736(12)61963-1.

            ●● Enlace al texto completo (gratuito o de pago) 1016/S0140-6736(12)61963-1

AUTORES / AUTHORS:  - Davies C; Pan H; Godwin J; Gray R; Arriagada R; Raina V; Abraham M; Alencar VH; Badran A; Bonfill X; Bradbury J; Clarke M; Collins R; Davis SR; Delmestri A; Forbes JF; Haddad P; Hou MF; Inbar M; Khaled H; Kielanowska J; Kwan WH; Mathew BS; Muller B; Nicolucci A; Peralta O; Pernas F; Petruzelka L; Pienkowski T; Rajan B; Rubach MT; Tort S; Urrutia G; Valentini M; Wang Y; Peto R

INSTITUCIÓN / INSTITUTION:  - Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, UK. Electronic address: atlas@ctsu.ox.ac.uk.

RESUMEN / SUMMARY:  - BACKGROUND: For women with oestrogen receptor (ER)-positive early breast cancer,  treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess  the further effects of continuing tamoxifen to 10 years instead of stopping at 5  years. METHODS: In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. FINDINGS: Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0.002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0.01), and reduced overall mortality (639 deaths vs 722 deaths, p=0.01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0.90 [95% CI 0.79-1.02] during years 5-9 and 0.75 [0.62-0.90] in later years; breast cancer mortality RR 0.97 [0.79-1.18] during years 5-9 and 0.71 [0.58-0.88] in later years). The cumulative risk of recurrence during years 5-14 was 21.4% for women allocated to continue versus 25.1% for controls; breast cancer mortality during years 5-14 was 12.2% for women allocated to continue versus 15.0% for controls (absolute mortality reduction 2.8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12 894 women, mortality without recurrence from causes other than breast cancer was little affected (691  deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0.99 [0.89-1.10]; p=0.84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1.87 (95% CI 1.13-3.07, p=0.01 [including 0.2% mortality in both treatment groups]), stroke 1.06 (0.83-1.36), ischaemic heart disease 0.76 (0.60-0.95, p=0.02), and endometrial cancer 1.74 (1.30-2.34, p=0.0002). The cumulative risk of endometrial cancer during years 5-14 was 3.1% (mortality 0.4%) for women allocated to continue versus 1.6% (mortality 0.2%) for controls (absolute mortality increase 0.2%). INTERPRETATION: For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. FUNDING: Cancer Research UK, UK Medical Research Council, AstraZeneca  UK, US Army, EU-Biomed.

 

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[3]

TÍTULO / TITLE:  - Prognostic and Predictive Value of Tumor-Infiltrating Lymphocytes in a Phase III  Randomized Adjuvant Breast Cancer Trial in Node-Positive Breast Cancer Comparing  the Addition of Docetaxel to Doxorubicin With Doxorubicin-Based Chemotherapy: BIG 02-98.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2011.41.0902

AUTORES / AUTHORS:  - Loi S; Sirtaine N; Piette F; Salgado R; Viale G; Van Eenoo F; Rouas G; Francis P; Crown JP; Hitre E; de Azambuja E; Quinaux E; Di Leo A; Michiels S; Piccart MJ; Sotiriou C

INSTITUCIÓN / INSTITUTION:  - Sherene Loi, Nicolas Sirtaine, Roberto Salgado, Francoise Van Eenoo, Ghizlane Rouas, Stefan Michiels, Martine J. Piccart, and Christos Sotiriou, Institut Jules Bordet, Brussels; Fanny Piette and Emmanuel Quinaux, International Drug Development Institute, Louvain-la-Neuve, Belgium; Giuseppe Viale, University of Milan, Milan; Angelo Di Leo, Hospital of Prato, Prato, Italy; Prudence Francis, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australian and New Zealand Breast Cancer Trials Group, Newcastle, New South Wales, Australia, and International Breast Cancer Study Group, Bern, Switzerland; John P.A. Crown, Irish Clinical Oncology Research Group, Dublin, Ireland; and Erika Hitre, National Institute of Oncology, Budapest, Hungary.

RESUMEN / SUMMARY:  - PURPOSEPrevious preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case, anthracycline-only CT-in selected BC subtypes. PATIENTS AND METHODSWe investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years.ResultsThere was no significant prognostic association in the global nor estrogen receptor (ER) -positive/human epidermal growth factor receptor 2 (HER2) -negative population. However, each 10% increase  in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018). CONCLUSIONIn node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted. Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes.

 

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[4]

TÍTULO / TITLE:  - Re: Intracutaneous and Intravesical Immunotherapy with Keyhole Limpet Hemocyanin  Compared with Intravesical Mitomycin in Patients with Non-Muscle-Invasive Bladder Cancer: Results from a Prospective Randomized Phase III Trial.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Urol. 2013 Feb;189(2):483-4. doi: 10.1016/j.juro.2012.10.103. Epub 2012 Oct 29.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.juro.2012.10.103

AUTORES / AUTHORS:  - Wood DP

 

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[5]

TÍTULO / TITLE:  - Health-related quality of life outcomes of lenalidomide in transfusion-dependent  patients with Low- or Intermediate-1-risk myelodysplastic syndromes with a chromosome 5q deletion: Results from a randomized clinical trial.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Res. 2013 Mar;37(3):259-65. doi: 10.1016/j.leukres.2012.11.017. Epub 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.leukres.2012.11.017

AUTORES / AUTHORS:  - Revicki DA; Brandenburg NA; Muus P; Yu R; Knight R; Fenaux P

INSTITUCIÓN / INSTITUTION:  - United BioSource Corporation, Bethesda, MD, USA. Electronic address: Dennis.Revicki@unitedbiosource.com.

RESUMEN / SUMMARY:  - We report health-related quality of life (HRQL) outcomes assessed using the Functional Assessment of Cancer Therapy-Anemia (FACT-An) among 167 RBC transfusion-dependent patients with IPSS Low-/Intermediate-1-risk del5q31 MDS treated with lenalidomide versus placebo in a randomized phase 3 clinical trial,  MDS-004. Mean baseline to 12 week changes in FACT-An Total scores improved following treatment with lenalidomide 5 and 10mg (+5.7 and +5.7, respectively) versus placebo (-2.8) (both p<0.05). Clinically important changes in HRQL from baseline were observed at weeks 12, 24, 36, and 48 among RBC-TI>/=26 week responders in both treatment groups. Lenalidomide treatment may be effective in improving HRQL outcomes.

 

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[6]

TÍTULO / TITLE:  - The BCR-ABL1 T315I mutation and additional genomic abberations are dominant genetic lesions associated with disease progression in chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitor therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2012.762649

AUTORES / AUTHORS:  - Malcikova J; Razga F; Jurcek T; Dvorakova D; Zackova D; Toskova M; Sebejova L; Smardova J; Oltova A; Vankova G; Jurackova L; Trbusek M; Pospisilova S; Mayer J; Racil Z

 

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[7]

TÍTULO / TITLE:  - Prognostic and predictive value of tumor VEGF gene amplification in metastatic breast cancer treated with paclitaxel with and without bevacizumab; results from  ECOG 2100 trial.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-3029

AUTORES / AUTHORS:  - Schneider BP; Gray R; Radovich M; Shen F; Vance GH; Li L; Jiang G; Miller KD; Gralow J; Dickler MN; Cobleigh M; Perez EA; Shenkier TN; Nielsen KV; Muller S; Thor AD; Sledge GW; Sparano JA; Davidson NE; Badve S

INSTITUCIÓN / INSTITUTION:  - Medicine, Indiana University Melvin and Bren Simon Cancer Center.

RESUMEN / SUMMARY:  - Purpose Clinically validated biomarkers for anti-angiogenesis agents are not available. We have previously reported associations between candidate VEGFA SNPs  and overall survival (OS) in E2100. The associations between tumor VEGFA amplification and outcome are evaluated here. Patients and Methods E2100 was a phase III trial comparing paclitaxel with or without bevacizumab for patients with metastatic breast cancer. Fluorescence in situ hybridization to assess gene  amplification status for VEGFA was performed on paraffin embedded tumors from 363 patients in E2100. Evaluation for association between amplification status and outcomes was performed. Results ER+ or PR+ tumors were less likely to have VEGFA  amplification compared with ER/PR- tumors (p=0.020). VEGFA amplification was associated with worse OS (20.2 vs. 25.3 months; p=0.013) in univariate analysis with a trend for worse OS in multivariate analysis (p=0.08). There was a significant interaction between VEGFA amplification, hormone-receptor status, and study arm. Patients with VEGFA amplification and triple negative breast cancers (TNBCs) or HER2 amplification had inferior OS (p=0.047); amplification did not affect OS for those who were ER+ or PR+ and HER2-. Those who received bevacizumab with VEGFA amplification had inferior PFS (p=0.010) and OS (p=0.042); no association was seen in the control arm. Test for interaction between study arm and VEGFA amplification with OS was not significant. Conclusion VEGFA amplification in univariate analysis was associated with poor outcomes; this was  particularly prominent in HER2+ or TNBCs. Additional studies are necessary to confirm the trend for poor OS seen on multivariate analysis for patients treated  with bevacizumab.

 

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[8]

TÍTULO / TITLE:  - Minimal residual disease detectable by quantitative assessment of WT1 gene before allogeneic stem cell transplantation in patients in first remission of acute myeloid leukemia has an impact on their future prognosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Transplant. 2013 Jan;27(1):E21-9. doi: 10.1111/ctr.12046. Epub 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 1111/ctr.12046

AUTORES / AUTHORS:  - Valkova V; Polak J; Markova M; Vitek A; Hajkova H; Salek C; Prochazka B; Cetkovsky P; Trneny M

INSTITUCIÓN / INSTITUTION:  - Department of Bone Marrow Transplantation, Institute of Haematology and Blood Transfusion, Prague, Czech Rep; Institute of Experimental Haematology, First Faculty of Medicine, Charles University, Prague, Czech Rep.

RESUMEN / SUMMARY:  - Overall 42 patients (pts) transplanted in hematological CR1 were retrospectively  analyzed. Median follow-up was 15 months (range 2-77). The expression of WT1 gene was measured according to the European Leukaemia Net recommendations. At the time of allogeneic stem cell transplantation (allo-SCT) 29 pts were WT1-negative and 13 pts were WT1-positive. In the univariate analysis, significantly better results were observed in the group of WT1 neg in terms of progression-free survival (in three yr 77% vs. 27%, p = 0.001). In multivariate analysis, the only significant feature in terms of better OS was WT1 negativity (p = 0.029). Our results show that minimal residual disease status measured by quantitative assessment of WT1 gene in acute myeloid leukemia pts in CR1 significantly affects their future prognosis after allo-SCT.

 

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[9]

TÍTULO / TITLE:  - Somatic Mutations and Deletions of the E-Cadherin Gene Predict Poor Survival of Patients With Gastric Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.44.4612

AUTORES / AUTHORS:  - Corso G; Carvalho J; Marrelli D; Vindigni C; Carvalho B; Seruca R; Roviello F; Oliveira C

INSTITUCIÓN / INSTITUTION:  - Giovanni Corso, Daniele Marrelli, and Franco Roviello, University of Siena and Instituto Toscano Tumori; Carla Vindigni, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Giovanni Corso, Joana Carvalho, Raquel Seruca, and Carla Oliveira, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP); Giovanni Corso, Joana Carvalho, Raquel Seruca, and Carla Oliveira, University of Porto, Portugal; Beatriz Carvalho, VU University Medical  Center, Amsterdam, the Netherlands.

RESUMEN / SUMMARY:  - PURPOSEThe prognosis of gastric cancer (GC) is poor, and the molecular pathogenesis players are vastly unknown. Surgery remains the primary option in GC treatment. The aim of this study was to investigate the impact of somatic CDH1 alterations in prognosis and survival of patients with GC. PATIENTS AND METHODSA  series of patients with sporadic and familial GC (diffuse and intestinal; n = 246) were analyzed for somatic CDH1 mutations, promoter hypermethylation, and loss of heterozygosity (LOH) by polymerase chain reaction sequencing. E-cadherin  protein expression was determined by immunohistochemistry. Associations between molecular, clinicopathologic, and survival data were analyzed.ResultsCDH1 somatic alterations were found in approximately 30% of all patients with GC. Both histologic types of sporadic GC displayed LOH in 7.5%, mutations in 1.7%, and hypermethylation in 18.4% of patients. Primary tumors from hereditary diffuse GC, lacking germline CDH1 alterations, showed exclusively CDH1 promoter hypermethylation in 50% of patients. Familial intestinal GC (FIGC) tumors showed  LOH in 9.4% and hypermethylation in 17.0%. CDH1 alterations did not associate with a particular pattern of E-cadherin expression. Importantly, the worst patient survival rate among all GCs analyzed was seen in patients with tumors carrying CDH1 structural alterations, preferentially those belonging to FIGC families. CONCLUSIONCDH1 somatic alterations exist in all clinical settings and histotypes of GC and associate with different survival rates. Their screening at  GC diagnosis may predict patient prognosis and is likely to improve management of patients with this disease.

 

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[10]

TÍTULO / TITLE:  - Angioedema in a Patient With Renal Cell Cancer Treated With Everolimus in Combination With an Angiotensin-Converting Enzyme Inhibitor.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 7.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.44.5106

AUTORES / AUTHORS:  - Rothermundt C; Gillessen S

INSTITUCIÓN / INSTITUTION:  - Kantonsspital St Gallen, St Gallen, Switzerland.

 

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TÍTULO / TITLE:  - Factors predicting the response to oral fluoropyrimidine drugs: a phase II trial  on the individualization of postoperative adjuvant chemotherapy using oral fluorinated pyrimidines in stage III colorectal cancer treated by curative resection (ACT-01 Study).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):437-44. doi: 10.3892/or.2012.2177. Epub 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2177

AUTORES / AUTHORS:  - Mori T; Ohue M; Takii Y; Hashizume T; Kato T; Kotake K; Sato T; Tango T

INSTITUCIÓN / INSTITUTION:  - Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Tokyo, Japan. m.takeo@cick.jp

RESUMEN / SUMMARY:  - We evaluated the predictive relevance of several biomarkers on the survival of patients with stage III colorectal cancer treated with adjuvant chemotherapy of oral fluoropyrimidines. This was a multicenter phase II trial on adult patients with histologically confirmed resected stage III (Dukes’ C) colorectal cancer. Patients received oral doxifluridine (800 mg/m2/day) in 3 divided doses, or oral  uracil/tegafur (UFT) (400 mg/m2/day) in 2 divided doses for 5 days, every 7 days  for 12 months with a 5-year follow-up. Outcome measures were disease-free survival and tissue markers [thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) protein levels and TP, DPD, thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT) mRNA levels in tumor samples and TS tandem-repeat type in blood samples]. There was a significant association between the intratumoral TP/DPD enzyme ratio and disease-free survival when the model included the drug, the parameter and the interactions between them [hazard ratio  (HR)=2.76; P=0.00469]. The 5-year disease-free survival rate was statistically significantly higher in patients with high TP/DPD ratios [median >/=2.63: 71.9%;  95% confidence interval (CI) 61.4-80.0] compared to patients with low TP/DPD ratios (<2.63: 57.0%; 95% CI 46.3-66.3) (log-rank P=0.0277) following adjuvant therapy with oral fluoropyrimidines. No significant association was observed between the intratumoral TP/DPD enzyme ratio (cut-off value 2.0) and the disease-free survival rate in the doxifluridine group; primary endpoint (log-rank P=0.6850). The magnitude of the intratumoral TP/DPD enzyme ratio may be a potential indicator for the individualization of postoperative adjuvant chemotherapy with oral fluoropyrimidines for stage III colorectal cancer.

 

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[12]

TÍTULO / TITLE:  - Outcome of azacitidine treatment in patients with therapy-related myeloid neoplasms with assessment of prognostic risk stratification models.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Res. 2013 Jan 16. pii: S0145-2126(12)00483-3. doi: 10.1016/j.leukres.2012.12.012.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.leukres.2012.12.012

AUTORES / AUTHORS:  - Duong VH; Lancet JE; Alrawi E; Al-Ali NH; Perkins J; Field T; Epling-Burnette PK; Zhang L; List AF; Komrokji RS

INSTITUCIÓN / INSTITUTION:  - H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

RESUMEN / SUMMARY:  - Azacitidine’s efficacy in therapy-related myeloid neoplasms (t-MN) has not been well-studied. In our retrospective review of 84 t-MN patients treated with azacitidine, median overall survival (OS) was 14.5 months and overall response rate was 43%, including 11% complete remission, 4% marrow complete remission, and 11% partial remission. In patients who underwent allogeneic transplant (25%), median OS was 19.2 versus 12.8 months (P=0.023) for those who did not. Response rates were comparable to those reported for de novo myelodysplastic syndrome. When we analyzed outcomes according to five scoring systems, only the Global MD Anderson Risk Model predicted survival with statistical significance.

 

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[13]

TÍTULO / TITLE:  - STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1267-72. doi: 10.1073/pnas.1211805110. Epub 2013 Jan 3.

            ●● Enlace al texto completo (gratuito o de pago) 1073/pnas.1211805110

AUTORES / AUTHORS:  - Timofeeva OA; Tarasova NI; Zhang X; Chasovskikh S; Cheema AK; Wang H; Brown ML; Dritschilo A

INSTITUCIÓN / INSTITUTION:  - Departments of Oncology and Radiation Medicine, and Drug Discovery Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057.

RESUMEN / SUMMARY:  - Activation of STAT3 in cancers leads to gene expression promoting cell proliferation and resistance to apoptosis, as well as tumor angiogenesis, invasion, and migration. In the characterization of effects of ST3-H2A2, a selective inhibitor of the STAT3 N-terminal domain (ND), we observed that the compound induced apoptotic death in cancer cells associated with robust activation of proapoptotic genes. Using ChIP and tiling human promoter arrays, we found that activation of gene expression in response to ST3-H2A2 is accompanied by altered STAT3 chromatin binding. Using inhibitors of STAT3 phosphorylation and a dominant-negative STAT3 mutant, we found that the unphosphorylated form of STAT3 binds to regulatory regions of proapoptotic genes and prevents their expression in tumor cells but not normal cells. siRNA knockdown confirmed the effects of ST3-HA2A on gene expression and chromatin binding to be STAT3 dependent. The STAT3-binding region of the C/EBP-homologous protein (CHOP) promoter was found to be localized in DNaseI hypersensitive site of chromatin in  cancer cells but not in nontransformed cells, suggesting that STAT3 binding and suppressive action can be chromatin structure dependent. These data demonstrate a suppressive role for the STAT3 ND in the regulation of proapoptotic gene expression in cancer cells, providing further support for targeting STAT3 ND for  cancer therapy.

 

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[14]

TÍTULO / TITLE:  - BCR-ABL1 transcript at 3 months predicts long-term outcomes following second generation tyrosine kinase inhibitor therapy in the patients with chronic myeloid leukaemia in chronic phase who failed Imatinib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Haematol. 2012 Dec 24. doi: 10.1111/bjh.12187.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bjh.12187

AUTORES / AUTHORS:  - Kim DD; Lee H; Kamel-Reid S; Lipton JH

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.

RESUMEN / SUMMARY:  - The BCR-ABL1 transcript level at 3 months can predict long-term outcomes following frontline therapy with Imatinib or Dasatinib in chronic myeloid leukaemia (CML) patients. However, data is lacking for second-generation tyrosine kinase inhibitor (2GTKI) therapy after Imatinib failure. A total of 112 patients  with CML in chronic phase receiving 2GTKI after Imatinib failure were reviewed. Treatment outcomes including complete cytogenetic (CCyR), major molecular (MMR) and molecular response 4.5 (4.5 log reduction of BCR-ABL1 transcript level, MR(4.5) ), treatment failure, progression-free and overall survival (OS) were compared according to BCR-ABL1 transcript levels at 3 or 6 months, divided into <1%(IS) , 1-10%(IS) and >/=10%(IS) . BCR-ABL1 transcript level at 3 months showed better correlation with OS (P < 0.001) than that at 6 months (P = 0.147). Better  OS was also observed in the patients achieving <1%(IS) (100%) and 1-10%(IS) (100%) than those with >/=10%(IS) at 3 months (70.6%, P < 0.001). Those with <1%(IS) showed the best CCyR, MMR and MR(4.5) rates; 1-10%(IS) , intermediate; and >/=10%(IS) , the lowest CCyR, MMR and MR(4.5) rates. The group with <1%(IS) at 3 months maintained significantly lower BCR-ABL1 transcript level compared to  other two groups. In conclusion, the BCR-ABL1 transcript level at 3 months is the most relevant surrogate for outcomes following 2GTKI therapy after Imatinib failure.

 

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[15]

TÍTULO / TITLE:  - Predicting infections in high-risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: Aretrospective multicenter study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Hematol. 2013 Feb;88(2):130-4. doi: 10.1002/ajh.23368.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ajh.23368

AUTORES / AUTHORS:  - Merkel D; Filanovsky K; Gafter-Gvili A; Vidal L; Aviv A; Gatt ME; Silbershatz I; Herishanu Y; Arad A; Tadmor T; Dally N; Nemets A; Rouvio O; Ronson A; Herzog-Tzarfati K; Akria L; Braester A; Hellmann I; Yeganeh S; Nagler A; Leiba R; Mittelman M; Ofran Y

INSTITUCIÓN / INSTITUTION:  - Division of Hematology, Sheba Medical Center, Tel-Hashomer, Tel Aviv University,  Israel.

RESUMEN / SUMMARY:  - Hypomethylating agents have become the standard therapy for patients with high-risk myelodysplastic syndrome (MDS). In Israel, azacitidine (AZA) is routinely used. Yet, infectious complications are common during AZA therapy. The  current study was aimed to evaluate the incidence and predisposing risk factors for infections in AZA-treated patients. This retrospective study included patients treated with AZA in 18 Israeli medical institutions between 2008 and 2011. Data on 184 patients [157 high-risk MDS and 27 acute myeloid leukemia (AML)], with a median age of 71.6 (range 29-92) were recorded. Overall, 153 infectious events were reported during 928 treatment cycles (16.5%) administered  to 100 patients. One hundred fourteen, 114/153 (75%) events required hospitalization and 30 (19.6%) were fatal. In a univariate analysis, unfavorable  cytogenetics, low neutrophil, hemoglobin (Hb) and platelet (PLT) counts were found to be associated with infections (24.4% vs. 12.9%, P < 0.0001; 27% vs. 13.5%, P < 0.0001; 20.4% vs. 11%, P < 0.0001 and 29.2% vs. 14.2%, P < 0.0001, respectively). In multivariate analysis, only low Hb level, low PLT count, and unfavorable cytogenetics remained significant. Prior to therapy, poor cytogenetics, PLT count below 20 x 10(9) /L and neutrophil count below 0.5 x 10(9) /L were predictive of the risk of infection during the first two cycles of  therapy. In conclusion, patients with unfavorable cytogenetics, presenting with low neutrophil and PLT counts, are susceptible to infections. Evaluation of infection risk should be repeated prior to each cycle. Patients with poor cytogenetics in whom AZA is prescribed despite low PLT count are particularly at  high risk for infections and infection prophylaxis may be considered. Am. J. Hematol. 88:130-134, 2013. © 2012 Wiley Periodicals, Inc.

 

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[16]

TÍTULO / TITLE:  - High expression of crystallin alphaB represents an independent molecular marker for unfavourable ovarian cancer patient outcome and impairs TRAIL- and cisplatin-induced apoptosis in human ovarian cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Cancer. 2012 Dec 6. doi: 10.1002/ijc.27975.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.27975

AUTORES / AUTHORS:  - Volkmann J; Reuning U; Rudelius M; Hafner N; Schuster T; V Rose AB; Weimer J; Hilpert F; Kiechle M; Durst M; Arnold N; Schmalfeldt B; Meindl A; Ramser J

INSTITUCIÓN / INSTITUTION:  - Clinic of Gynecology and Obstetrics, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich, Germany.

RESUMEN / SUMMARY:  - Dysregulated apoptotic pathways are regarded as major reasons for chemoresistance development as a particular challenge in ovarian cancer therapy. In search of molecular factors affecting human ovarian cancer cell apoptosis and, consequently, patient survival, we examined tumors of 103 platinum-/taxane-treated ovarian cancer patients by mRNA-array hybridization, qPCR, and immunohistochemistry. We identified high expression of crystallin alphaB (CRYAB), a proposed negative regulator of tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. By Kaplan Meier analysis, this factor turned out to be significantly associated with poor patient outcome [overall survival (OS) p = 0.001, recurrence-free survival (RFS) p = 0.003]. Elevated hazard ratios (HR) were estimated with regard to OS (HR = 2.11, 95% CI 1.10-4.06) and RFS (HR = 1.92, 95% CI 1.07-3.47) in multivariable analyses. These associations were confirmed in independent, publicly available mRNA data comprising 431 patients for OS (p < 0.001) and 413 for RFS (p < 0.001)(.) Our findings were validated by studying apoptotic events in cultured human ovarian cancer cells which were stably transfected to express elevated CRYAB levels. These data emphasized the crucial role of CRYAB in human ovarian cancer biology since TRAIL- as well as cisplatin-induced apoptosis was significantly impaired as a function of enhanced CRYAB expression. Taken together, we identified CRYAB as an independent biomarker for unfavourable outcome of human ovarian cancer patients. Since TRAIL is currently tested as anti-cancer drug and large proportions of the present patient cohort displayed low CRYAB levels in their tumors, CRYAB may enable the selection of patient subgroups benefiting most from  TRAIL-containing therapy.

 

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[17]

TÍTULO / TITLE:  - Phase I clinical trial of a peptide vaccine combined with tegafur-uracil plus leucovorin for treatment of advanced or recurrent colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar;29(3):951-9. doi: 10.3892/or.2013.2231. Epub 2013 Jan 10.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2231

AUTORES / AUTHORS:  - Matsushita N; Aruga A; Inoue Y; Kotera Y; Takeda K; Yamamoto M

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan.

RESUMEN / SUMMARY:  - Recently, analysis of tumor antigens using micro-arrays has revealed upregulation of cancer-testis antigens RNF43 and TOMM34 and vascular endothelial growth factor receptors VEGFR1 and VEGFR2 in colorectal cancer. A phase I clinical trial of peptide vaccine therapy together with oral anticancer drugs was conducted to treat advanced colorectal cancer using synthesized peptides of these tumor antigens in order to confirm the safety, immunogenicity and activity of this treatment. The subjects were patients with a human leukocyte antigen (HLA) type of A2402 who had inoperable colorectal cancer but had failed to respond to or were unable to undergo standard chemotherapy. Four peptides (RNF43, TOMM34, VEGFR1 and VEGFR2) were emulsified with incomplete Freund’s adjuvant (Montanide), and the resulting solution was administered subcutaneously once a week. Patients  received the oral anticancer drug tegafur-uracil plus leucovorin for four weeks continuously as part of one course followed by one week of rest. The primary endpoint of the trial was observation of adverse events as determined by the NCI-CTCAE criteria, and the secondary endpoints were the size of the tumor and the number of cytotoxic T lymphocytes (CTLs) in the peripheral blood after treatment. Vaccine therapy was administered 148 times to 10 patients from July 2008 to December 2009. The adverse events were grade 1 redness and induration, a  grade 2 skin ulcer at the vaccination site and grade 1 pyrexia. All patients tolerated treatment. Tumor imaging revealed that after 1 course of treatment 1 patient had partial response (PR), 7 had stable disease (SD) and 2 had progressive disease. A CTL assay of 10 patients revealed an increase in peptide-specific CTLs in patients with PR and SD, and the clinical responses of those patients were observed. KaplanMeier analysis indicated that patients who had a strong CTL reaction had a tendency to have longer progressionfree survival  and overall survival.

 

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[18]

TÍTULO / TITLE:  - Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 10;31(2):181-6. doi: 10.1200/JCO.2012.43.3383. Epub 2012 Dec 3.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.43.3383

AUTORES / AUTHORS:  - Choueiri TK; Vaishampayan U; Rosenberg JE; Logan TF; Harzstark AL; Bukowski RM; Rini BI; Srinivas S; Stein MN; Adams LM; Ottesen LH; Laubscher KH; Sherman L; McDermott DF; Haas NB; Flaherty KT; Ross R; Eisenberg P; Meltzer PS; Merino MJ; Bottaro DP; Linehan WM; Srinivasan R

INSTITUCIÓN / INSTITUTION:  - Urologic Oncology Branch, National Cancer Institute, 9000 Rockville Pike, Bldg 10, Room 1-5940, Bethesda, MD 20892; ramasrin@mail.nih.gov.

RESUMEN / SUMMARY:  - PURPOSE Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC. PATIENTS AND METHODS Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5  every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). Results Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3  months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli. CONCLUSION Foretinib demonstrated activity in patients with advanced PRCC with a  manageable toxicity profile and a high response rate in patients with germline MET mutations.

 

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[19]

TÍTULO / TITLE:  - Clinical outcomes in elderly patients administered gefitinib as first-line treatment in epidermal growth factor receptor-mutated non-small-cell lung cancer: retrospective analysis in a Nagano Lung Cancer Research Group Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):450. doi: 10.1007/s12032-012-0450-2. Epub 2013 Jan 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0450-2

AUTORES / AUTHORS:  - Tateishi K; Ichiyama T; Hirai K; Agatsuma T; Koyama S; Hachiya T; Morozumi N; Shiina T; Koizumi T

INSTITUCIÓN / INSTITUTION:  - First Department of Internal Medicine, Shinshu University, Matsumoto City, Japan.

RESUMEN / SUMMARY:  - The clinical efficacy and outcomes of gefitinib therapy as a first-line treatment for elderly patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations were analyzed retrospectively. We analyzed chemotherapy-naive NSCLC patients aged 75 years or older who had EGFR mutations (exon 19 deletion mutation or L858R), who were initially treated with gefitinib (250 mg) once daily in Nagano Prefecture. A total of 55 patients (16 men, 39 women) with a median age of 81.1 years (range; 75-94 years) treated between April 2007 and July 2012 were analyzed. The overall response rate and disease control rate were 72.7 % (95 % confidence interval (CI); 59.5-82.9 %) and 92.7 % (95 % CI; 82.0-97.6 %), respectively. Median progression-free survival and overall survival from the start of gefitinib treatment were 13.8 months (95 % CI; 9.9-18.8 months) and 29.1 months (95 % CI; 22.4 months-not reached), respectively. Two-year survival rate was 59.5 % (95 % CI; 41.0-78.0 %). Major grade 3 toxicities were skin rash (1.8 %) and increased levels of aspartate aminotransferase or alanine aminotransferase (7.3 %). First-line treatment with gefitinib for elderly EGFR-mutated NSCLC patients was effective and well tolerated. The results suggest that first-line gefitinib should be considered as  a preferable standard treatment in elderly patients with advanced NSCLC harboring EGFR mutations.

 

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[20]

TÍTULO / TITLE:  - Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal a breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 10;31(2):203-9. doi: 10.1200/JCO.2012.43.4134. Epub 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.43.4134

AUTORES / AUTHORS:  - Prat A; Cheang MC; Martin M; Parker JS; Carrasco E; Caballero R; Tyldesley S; Gelmon K; Bernard PS; Nielsen TO; Perou CM

INSTITUCIÓN / INSTITUTION:  - Vall d’Hebron Institute of Oncology (VHIO), Pg Vall d’Hebron, 119-129, 08035, Barcelona, España; aprat@vhio.net.

RESUMEN / SUMMARY:  - PURPOSE Current immunohistochemical (IHC)-based definitions of luminal A and B breast cancers are imperfect when compared with multigene expression-based assays. In this study, we sought to improve the IHC subtyping by examining the pathologic and gene expression characteristics of genomically defined luminal A and B subtypes. PATIENTS AND METHODS Gene expression and pathologic features were collected from primary tumors across five independent cohorts: British Columbia Cancer Agency (BCCA) tamoxifen-treated only, Grupo Español de Investigacion en Cancer de Mama 9906 trial, BCCA no systemic treatment cohort, PAM50 microarray training data set, and a combined publicly available microarray data set. Optimal cutoffs of percentage of progesterone receptor (PR) -positive tumor cells to predict survival were derived and independently tested. Multivariable Cox models  were used to test the prognostic significance. Results Clinicopathologic comparisons among luminal A and B subtypes consistently identified higher rates of PR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and histologic grade 1 in luminal A tumors. Quantitative PR gene and protein expression were also found to be significantly higher in luminal A tumors. An empiric cutoff of more than 20% of PR-positive tumor cells was statistically chosen and proved significant for predicting survival differences within IHC-defined luminal A tumors independently of endocrine therapy administration. Finally, no additional prognostic value within hormonal receptor (HR) -positive/HER2-negative disease was observed with the use of the IHC4 score when  intrinsic IHC-based subtypes were used that included the more than 20% PR-positive tumor cells and vice versa. CONCLUSION Semiquantitative IHC expression of PR adds prognostic value within the current IHC-based luminal A definition by improving the identification of good outcome breast cancers. The new proposed IHC-based definition of luminal A tumors is HR positive/HER2 negative/Ki-67 less than 14%, and PR more than 20%.

 

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[21]

TÍTULO / TITLE:  - High expression of the Ets-related gene (ERG) is an independent prognostic marker for relapse-free survival in patients with acute promyelocytic leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Hematol. 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00277-012-1648-2

AUTORES / AUTHORS:  - Hecht A; Nowak D; Nowak V; Hanfstein B; Faldum A; Buchner T; Spiekermann K; Sauerland C; Lengfelder E; Hofmann WK; Nolte F

INSTITUCIÓN / INSTITUTION:  - Department of Hematology and Oncology, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

RESUMEN / SUMMARY:  - In acute promyelocytic leukemia (APL), relapse occurs in about 15 % of cases and  is a major cause for death. Molecular markers identifying patients at high risk for relapse are not well established. High expression of the transcription factor Ets-related gene (ERG) is associated with inferior overall survival (OS) and disease-free survival in different types of hematologic malignancies. There are no data available about the impact of ERG expression in APL. ERG expression levels were analyzed in bone marrow samples of 86 APL patients at initial diagnosis. High ERG expression was significantly associated with an inferior OS in patients who had reached first complete remission. It was also significantly correlated with inferior relapse-free survival (RFS) and time to relapse (i.e., relapse-free interval, RFI). In multivariate analysis, high ERG expression had an independent negative impact on RFS and RFI. High ERG expression was significantly associated with inferior OS, RFS, and RFI. Moreover, in multivariate analysis, it maintained its value as an independent negative prognostic factor with regard to  RFS and RFI. Therefore, ERG expression might serve as a molecular marker for risk stratification in APL and might identify patients who could benefit from intensified treatment regimens.

 

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[22]

TÍTULO / TITLE:  - Higher Expression of Receptor Tyrosine Kinase Axl, and Differential Expression of its Ligand, Gas6, Predict Poor Survival in Lung Adenocarcinoma Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Surg Oncol. 2012 Dec 16.

            ●● Enlace al texto completo (gratuito o de pago) 1245/s10434-012-2795-3

AUTORES / AUTHORS:  - Ishikawa M; Sonobe M; Nakayama E; Kobayashi M; Kikuchi R; Kitamura J; Imamura N; Date H

INSTITUCIÓN / INSTITUTION:  - Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan, mishi@kuhp.kyoto-u.ac.jp.

RESUMEN / SUMMARY:  - BACKGROUND: Downstream activation through receptor tyrosine kinases (RTKs) plays  important roles in carcinogenesis. In this study, we assessed the clinical involvement of Axl, an RTK, and its ligand, Gas6, in surgically treated lung adenocarcinoma. METHODS: Axl and Gas6 mRNA and protein expression levels were quantified using quantitative real-time polymerase chain reaction and immunohistochemistry, respectively, in completely resected lung adenocarcinoma tissues (n = 88) and were evaluated for correlation with clinicopathologic features and patient survival. RESULTS: Higher expressions of Axl mRNA/protein and Gas6 protein were significantly related to worse clinicopathological features and prognosis (5-year overall survival rates: Axl mRNA low: 72.3 %, high: 49.7 %, P = 0.047; Axl protein low: 77.5 %, high: 38.6 %, P < 0.001; and Gas6 protein low: 70.5 %, high: 48 %, P = 0.042). On the contrary, higher Gas6 mRNA expression was related to better clinicopathological features and prognosis (5-year overall  survival rates: Gas6 mRNA low: 59.2 %, high: 81.8 %, P = 0.054). Multivariate analysis suggests that high Axl mRNA expression may be an independent factor for  poor patient prognosis (P = 0.04). CONCLUSIONS: In lung adenocarcinoma, Axl and Gas6 expression levels were associated with tumor advancement and patient survival, thus rendering them as reliable biomarkers and potential targets for treatment of lung adenocarcinoma.

 

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[23]

TÍTULO / TITLE:  - Cancer therapy combination: green tea and a phosphodiesterase 5 inhibitor?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Invest. 2013 Jan 25:1-3. doi: 10.1172/JCI67589.

            ●● Enlace al texto completo (gratuito o de pago) 1172/JCI67589

AUTORES / AUTHORS:  - Yang CS; Wang H

RESUMEN / SUMMARY:  - The major constituent of green tea, (-)-epigallocatechin-3-O-gallate (EGCG), has  been shown to have cancer-preventive and therapeutic activities. Numerous molecular targets for EGCG have been proposed, but the mechanisms of its anticancer activities are not clearly understood. In this issue of the JCI, Kumazoe et al. report that EGCG activates 67-kDa laminin receptor (67LR), elevates cGMP levels, and induces cancer cell apoptosis. Furthermore, a phosphodiesterase 5 inhibitor, vardenafil, synergizes with EGCG to induce cancer  cell death. This is a provocative observation with important implications for cancer therapy. It also raises several issues for further investigation, such as  the mechanism by which EGCG specifically activates 67LR.

 

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[24]

TÍTULO / TITLE:  - IL-21R gene polymorphisms and serum IL-21 levels predict virological response to  interferon-based therapy in Asian chronic hepatitis C patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Antivir Ther. 2013 Jan 7. doi: 10.3851/IMP2502.

            ●● Enlace al texto completo (gratuito o de pago) 3851/IMP2502

AUTORES / AUTHORS:  - Hsu CS; Hsu SJ; Liu WL; Liu CH; Chen CL; Liu CJ; Chen PJ; Chen DS; Kao JH

INSTITUCIÓN / INSTITUTION:  - Division of Gastroenterology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Taipei Branch.

RESUMEN / SUMMARY:  - BACKGROUND: IL-21R polymorphisms have been identified as potential predictors of  virologic outcomes in Western chronic hepatitis C (CHC) patients receiving interferon-based treatment. We aimed to examine the associations of IL-21R genotypes and serum IL-21 levels with virologic responses to interferon-based treatment in Asian CHC patients. METHODS: Genomic and clinical data were collected from 178 consecutive Taiwanese HCV genotype 1 patients who received interferon-based therapy and 72 non-HCV healthy subjects. Among them, serum IL-21 levels, IL-21R and IL28B genotypes were determined in 124 CHC patients and healthy controls. RESULTS: Among patients with IL28B rs8099917 non-TT genotypes,  patients with IL-21R rs3093390 CC genotype had a higher SVR rate than those with  non-CC genotypes (CC vs. non-CC: 14/24 vs. 0/4, P=0.031). Compared to non-HCV controls, CHC patients had higher serum IL-21 levels [HCV vs. non-HCV: 377.8+/-780.9 vs. 70.5+/-33.2(pg/mL), P=0.001]. Patients with SVR had higher pretreatment serum IL-21 levels than those without (Adjusted Odds Ratio, 95%CI: 0.23, 0.07-0.80, P=0.021). CONCLUSIONS: CHC patients have higher serum IL-21 levels than healthy adults. Higher pretreatment serum IL-21 levels and IL-21R polymorphisms may serve as potential factors predictive of treatment outcomes in  CHC patients with interferon-based therapy.

 

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[25]

TÍTULO / TITLE:  - Combined analysis of intratumoral human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) expression is a powerful predictor of survival in patients with pancreatic carcinoma treated with adjuvant gemcitabine-based chemotherapy after operative resection.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Surgery. 2012 Dec 17. pii: S0039-6060(12)00628-9. doi: 10.1016/j.surg.2012.10.010.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.surg.2012.10.010

AUTORES / AUTHORS:  - Nakagawa N; Murakami Y; Uemura K; Sudo T; Hashimoto Y; Kondo N; Sueda T

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan. Electronic address: naoyaman423@hiroshima-u.ac.jp.

RESUMEN / SUMMARY:  - BACKGROUND: Although postoperative adjuvant chemotherapy for pancreatic carcinoma improves survival in some patients, its efficacy varies among individuals. The aim of this study was to determine the usefulness of intratumoral expression of human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) as predictive markers of the efficacy of adjuvant gemcitabine-based chemotherapy for pancreatic carcinoma after operative resection. METHODS: The expression of intratumoral hENT1 and RRM1 was examined immunohistochemically in 109 patients with pancreatic carcinoma who received adjuvant gemcitabine-based chemotherapy after operative resection. Relationships  between clinicopathologic factors, including hENT1 and RRM1 expression, and disease-free and overall survival (DFS and OS) were evaluated by univariate and multivariate analyses. RESULTS: The 5-year DFS and OS rates for the 109 patients  were 26% and 31%, respectively. In univariate analysis, both hENT1 and RRM1 expression were significantly associated with DFS (hENT1, P = .004; RRM1, P = .011) and OS (hENT1, P = .001; RRM1, P = .040). In multivariate analysis, both were independent factors for DFS (hENT1, P = .001; RRM1, P = .009) and OS (hENT1, P = .001, RRM1, P = .019). Evaluation of the combination analysis of both was also identified as a powerful independent predictor of DFS (P < .001) and OS (P < .001). CONCLUSION: Expression of hENT1 and RRM1 is predictive of the efficacy of  adjuvant gemcitabine-based chemotherapy for pancreatic carcinoma after operative  resection. In addition, their combined analysis has greater predictive value than either factor alone.

 

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[26]

TÍTULO / TITLE:  - Prognostically relevant gene signatures of high-grade serous ovarian carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Invest. 2013 Jan 2;123(1):517-25. doi: 10.1172/JCI65833. Epub 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 1172/JCI65833

AUTORES / AUTHORS:  - Verhaak RG; Tamayo P; Yang JY; Hubbard D; Zhang H; Creighton CJ; Fereday S; Lawrence M; Carter SL; Mermel CH; Kostic AD; Etemadmoghadam D; Saksena G; Cibulskis K; Duraisamy S; Levanon K; Sougnez C; Tsherniak A; Gomez S; Onofrio R; Gabriel S; Chin L; Zhang N; Spellman PT; Zhang Y; Akbani R; Hoadley KA; Kahn A; Kobel M; Huntsman D; Soslow RA; Defazio A; Birrer MJ; Gray JW; Weinstein JN; Bowtell DD; Drapkin R; Mesirov JP; Getz G; Levine DA; Meyerson M

RESUMEN / SUMMARY:  - Because of the high risk of recurrence in high-grade serous ovarian carcinoma (HGS-OvCa), the development of outcome predictors could be valuable for patient stratification. Using the catalog of The Cancer Genome Atlas (TCGA), we developed subtype and survival gene expression signatures, which, when combined, provide a  prognostic model of HGS-OvCa classification, named “Classification of Ovarian Cancer” (CLOVAR). We validated CLOVAR on an independent dataset consisting of 879 HGS-OvCa expression profiles. The worst outcome group, accounting for 23% of all  cases, was associated with a median survival of 23 months and a platinum resistance rate of 63%, versus a median survival of 46 months and platinum resistance rate of 23% in other cases. Associating the outcome prediction model with BRCA1/BRCA2 mutation status, residual disease after surgery, and disease stage further optimized outcome classification. Ovarian cancer is a disease in urgent need of more effective therapies. The spectrum of outcomes observed here and their association with CLOVAR signatures suggests variations in underlying tumor biology. Prospective validation of the CLOVAR model in the context of additional prognostic variables may provide a rationale for optimal combination of patient and treatment regimens.

 

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[27]

TÍTULO / TITLE:  - Differential effect of adjuvant taxane-based and taxane-free chemotherapy regimens on the CK-19 mRNA-positive circulating tumour cells in patients with early breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 17. doi: 10.1038/bjc.2012.597.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2012.597

AUTORES / AUTHORS:  - Xenidis N; Perraki M; Apostolaki S; Agelaki S; Kalbakis K; Vardakis N; Kalykaki A; Xyrafas A; Kakolyris S; Mavroudis D; Georgoulias V

INSTITUCIÓN / INSTITUTION:  - 1] Department of Medical Oncology, University Hospital of Heraklion, PO Box 1352, 711 10 Heraklion, Crete, Greece [2] Department of Medical Oncology, University Hospital of Alexandroupolis, Alexandroupolis, Greece.

RESUMEN / SUMMARY:  - Background:To determine the effect of adjuvant taxane-free and taxane-based chemotherapy regimens on the elimination of circulating tumour cells (CTCs) in patients with early breast cancer.Methods:The presence of CK-19 mRNA-positive CTCs in the peripheral blood was evaluated before and after chemotherapy, using a real-time RT-PCR assay, in a historical comparison of two cohorts of women with stage I-III breast cancer treated with adjuvant taxane-free (N=211; FE(75)C or E(75)C) and taxane-based (N=334; T/E(75)C or T/E(75)) chemotherapy.Results:Taxane-based chemotherapy resulted in a higher incidence of  CTCs’ elimination than taxane-free regimens since 49.7% (74 of 149) and 33.0% (29 of 88) of patients with detectable CTCs before chemotherapy, respectively, turned negative post-chemotherapy (P=0.015). Patients treated with taxane-free regimens  had a significantly lower disease-free survival (DFS) (P=0.035) than patients treated with taxane-based regimens; this difference was observed in patients with but not without detectable CTCs before chemotherapy (P=0.018 and P=0.481, respectively). The incidence of deaths was significantly higher in the taxane-free cohort of patients with but not without detectable CTCs before chemotherapy compared with that of the taxane-based cohort (P=0.002). Multivariate analysis revealed that the chemotherapy regimen was significantly associated with prolonged DFS (HR: 2.00; 95% CI=1.20-3.34).Conclusion:Elimination of CK-19 mRNA-positive CTCs during adjuvant chemotherapy seems to be an efficacy  indicator of treatment and is associated with a favourable clinical outcome of patients with detectable CTCs before chemotherapy.British Journal of Cancer advance online publication, 17 January 2013; doi:10.1038/bjc.2012.597 www.bjcancer.com.

 

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[28]

TÍTULO / TITLE:  - mRECIST and EASL responses at early time point by contrast-enhanced dynamic MRI predict survival in patients with unresectable hepatocellular carcinoma (HCC) treated by doxorubicin drug-eluting beads transarterial chemoembolization (DEB TACE).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Oncol. 2012 Dec 5.

            ●● Enlace al texto completo (gratuito o de pago) 1093/annonc/mds605

AUTORES / AUTHORS:  - Prajapati HJ; Spivey JR; Hanish SI; El-Rayes BF; Kauh JS; Chen Z; Kim HS

INSTITUCIÓN / INSTITUTION:  - Departments of Interventional Radiology and Image Guided Medicine.

RESUMEN / SUMMARY:  - BackgroundWe analyzed the magnetic resonance imaging (MRI) responses by world health organization (WHO), response evaluation criteria in solid tumor (RECIST),  European Association for the Study of Liver (EASL), and modified RECIST (mRECIST) guidelines and correlated with survival after doxorubicin (Adriamycin; Pharmacia  & Upjohn, Peapac, NJ). drug-eluting beads transarterial chemoembolization (DEB TACE) in patients with unresectable hepatocellular carcinoma (HCC).Patients and methodsThe early target and overall imaging responses were studied in 120 consecutive patients treated with DEB TACE for unresectable HCC, using RECIST, WHO, EASL, and mRECIST guidelines on contrast-enhanced dynamic liver MRI. The median period between the DEB TACE and assessment scan was 33.50 days. Survival analyses were carried out with the Kaplan-Meier method and the Cox proportional model.ResultsWHO and RECIST1.1 had poor correlation with survival. mRECIST and EASL had significant correlation with survival with target lesion response rates  of 63.3% and 48.3% and with overall response rates of 52.5% and 39.2%, respectively. The responders of EASL and mRECIST had significant median survival  (P </= 0.0001). Moreover, mRECIST was better than EASL in predicting survival, because the survival difference between responders and non-responders of overall  response was statistically significant (P = 0.013) for mRECIST, but not for EASL  (P = 0.064).ConclusionsEASL and mRECIST responses measured on MRI at an early time point after DEB TACE predicted survival. mRECIST response demonstrated higher survival correlation than EASL.

 

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[29]

TÍTULO / TITLE:  - Time from Prior Chemotherapy Enhances Prognostic Risk Grouping in the Second-line Setting of Advanced Urothelial Carcinoma: A Retrospective Analysis of Pooled, Prospective Phase 2 Trials.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur Urol. 2012 Nov 26. pii: S0302-2838(12)01417-0. doi: 10.1016/j.eururo.2012.11.042.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.eururo.2012.11.042

AUTORES / AUTHORS:  - Sonpavde G; Pond GR; Fougeray R; Choueiri TK; Qu AQ; Vaughn DJ; Niegisch G; Albers P; James ND; Wong YN; Ko YJ; Sridhar SS; Galsky MD; Petrylak DP; Vaishampayan UN; Khan A; Vogelzang NJ; Beer TM; Stadler WM; O’Donnell PH; Sternberg CN; Rosenberg JE; Bellmunt J

INSTITUCIÓN / INSTITUTION:  - University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL,  USA.

RESUMEN / SUMMARY:  - BACKGROUND: Outcomes for patients in the second-line setting of advanced urothelial carcinoma (UC) are dismal. The recognized prognostic factors in this context are Eastern Cooperative Oncology Group (ECOG) performance status (PS) >0, hemoglobin level (Hb) <10g/dl, and liver metastasis (LM). OBJECTIVES: The purpose of this retrospective study of prospective trials was to investigate the prognostic value of time from prior chemotherapy (TFPC) independent of known prognostic factors. DESIGN, SETTING, AND PARTICIPANTS: Data from patients from seven prospective trials with available baseline TFPC, Hb, PS, and LM values were used for retrospective analysis (n=570). External validation was conducted in a second-line phase 3 trial comparing best supportive care (BSC) versus vinflunine  plus BSC (n=352). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox proportional hazards regression was used to evaluate the association of factors, with overall  survival (OS) and progression-free survival (PFS) being the respective primary and secondary outcome measures. RESULTS AND LIMITATIONS: ECOG-PS >0, LM, Hb <10g/dl, and shorter TFPC were significant prognostic factors for OS and PFS on multivariable analysis. Patients with zero, one, two, and three to four factors demonstrated median OS of 12.2, 6.7, 5.1, and 3.0 mo, respectively (concordance statistic=0.638). Setting of prior chemotherapy (metastatic disease vs perioperative) and prior platinum agent (cisplatin or carboplatin) were not prognostic factors. External validation demonstrated a significant association of TFPC with PFS on univariable and most multivariable analyses, and with OS on univariable analyses. Limitations of retrospective analyses are applicable. CONCLUSIONS: Shorter TFPC enhances prognostic classification independent of ECOG-PS >0, Hb <10g/dl, and LM in the setting of second-line therapy for advanced UC. These data may facilitate drug development and interpretation of trials.

 

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[30]

TÍTULO / TITLE:  - Low p14ARF expression in neuroblastoma cells is associated with repressed histone mark status, and enforced expression induces growth arrest and apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hum Mol Genet. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1093/hmg/ddt020

AUTORES / AUTHORS:  - Dreidax D; Gogolin S; Schroeder C; Muth D; Brueckner LM; Hess EM; Zapatka M; Theissen J; Fischer M; Ehemann V; Schwab M; Savelyeva L; Westermann F

INSTITUCIÓN / INSTITUTION:  - Division of Tumor Genetics B030, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

RESUMEN / SUMMARY:  - The TP53 tumor suppressor pathway is abrogated by TP53 mutations in the majority  of human cancers. Increased levels of wildtype TP53 in aggressive neuroblastomas  appear paradox but are tolerated by tumor cells due to co-activation of the TP53  ubiquitin ligase, MDM2. The role of the MDM2 antagonist, p14(ARF), in controlling the TP53-MDM2 balance in neuroblastoma is unresolved. In the present study, we show that conditional p14(ARF) expression substantially suppresses viability, clonogenicity and anchorage-independent growth in p14(ARF)-deficient or MYCN-amplified neuroblastoma cell lines. Furthermore, ectopic 14(ARF) expression  induced accumulation of cells in the G1 phase and apoptosis, which was paralleled by accumulation of TP53 and its targets. Comparative genomic hybridization analysis of 193 primary neuroblastomas detected one homozygous deletion of CDKN2A (encoding both p14(ARF) and p16(INK4A)) and heterozygous loss of CDKN2A in 22% of tumors. Co-expression analysis of p14(ARF) and its transactivator, E2F1, in a set of 68 primary tumors revealed only a weak correlation, suggesting that further regulatory mechanisms govern p14(ARF) expression in neuroblastomas. Intriguingly, analyses utilizing chromatin immunoprecipitation revealed different histone mark-defined epigenetic activity states of p14(ARF)in neuroblastoma cell lines that correlated with endogenous p14(ARF) expression but not with episomal p14(ARF) promoter reporter activity, indicating that the native chromatin context serves to epigenetically repress p14(ARF) in neuroblastoma cells. Collectively, the data pinpoint p14(ARF) as a critical factor for efficient TP53 response in neuroblastoma cells and assign p14(ARF) as a neuroblastoma suppressor candidate that is impaired by genomic loss and epigenetic repression.

 

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[31]

TÍTULO / TITLE:  - Human NK Cells Selective Targeting of Colon Cancer-Initiating Cells: A Role for Natural Cytotoxicity Receptors and MHC Class I Molecules.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Immunol. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 4049/jimmunol.1201542

AUTORES / AUTHORS:  - Tallerico R; Todaro M; Di Franco S; Maccalli C; Garofalo C; Sottile R; Palmieri C; Tirinato L; Pangigadde PN; La Rocca R; Mandelboim O; Stassi G; Di Fabrizio E; Parmiani G; Moretta A; Dieli F; Karre K; Carbone E

INSTITUCIÓN / INSTITUTION:  - Department of Experimental and Clinical Medicine, University of “Magna Graecia,”  88100 Catanzaro, Italy;

RESUMEN / SUMMARY:  - Tumor cell populations have been recently proposed to be composed of two compartments: tumor-initiating cells characterized by a slow and asymmetrical growth, and the “differentiated” cancer cells with a fast and symmetrical growth. Cancer stem cells or cancer-initiating cells (CICs) play a crucial role in tumor  recurrence. The resistance of CICs to drugs and irradiation often allows them to  survive traditional therapy. NK cells are potent cytotoxic lymphocytes that can recognize tumor cells. In this study, we have analyzed the NK cell recognition of tumor target cells derived from the two cancer cell compartments of colon adenocarcinoma lesions. Our data demonstrate that freshly purified allogeneic NK  cells can recognize and kill colorectal carcinoma-derived CICs whereas the non-CIC counterpart of the tumors (differentiated tumor cells), either autologous or allogeneic, is less susceptible to NK cells. This difference in the NK cell susceptibility correlates with higher expression on CICs of ligands for NKp30 and NKp44 in the natural cytotoxicity receptor (NCR) group of activating NK receptors. In contrast, CICs express lower levels of MHC class I, known to inhibit NK recognition, on their surface than do the “differentiated” tumor cells. These data have been validated by confocal microscopy where NCR ligands and MHC class I molecule membrane distribution have been analyzed. Moreover, NK cell receptor blockade in cytotoxicity assays demonstrates that NCRs play a major role in the recognition of CIC targets. This study strengthens the idea that biology-based therapy harnessing NK cells could be an attractive opportunity in solid tumors.

 

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[32]

TÍTULO / TITLE:  - 67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Invest. 2013 Jan 25. pii: 64768. doi: 10.1172/JCI64768.

            ●● Enlace al texto completo (gratuito o de pago) 1172/JCI64768

AUTORES / AUTHORS:  - Kumazoe M; Sugihara K; Tsukamoto S; Huang Y; Tsurudome Y; Suzuki T; Suemasu Y; Ueda N; Yamashita S; Kim Y; Yamada K; Tachibana H

RESUMEN / SUMMARY:  - The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in  various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCdelta/acid sphingomyelinase (PKCdelta/ASM) pathway. Furthermore, upregulation  of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5 (PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.

 

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[33]

TÍTULO / TITLE:  - Circulating tumor cells as therapy-related biomarkers in cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Immunol Immunother. 2013 Jan 12.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00262-012-1387-1

AUTORES / AUTHORS:  - Gorges TM; Pantel K

INSTITUCIÓN / INSTITUTION:  - Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany, t.gorges@uke.de.

RESUMEN / SUMMARY:  - Carcinomas (tumors of epithelial origin) are responsible for most of all new cancers in the industrialized countries. Due to the high mortality rate caused by the metastatic spread of aggressive cancer cells, there is an urgent demand in finding new biomarkers, which should detect early formation of metastases and monitor efficacy of systemic adjuvant therapy in a timely manner. It has been considered that the molecular analysis of cells which are shed from tumors into the blood system (circulating tumor cells (CTCs)) might provide new insights for  the clinical management of cancer, probably far earlier than using traditional high-resolution imaging technologies. Clinical trials indicated that CTCs can be  deployed for diagnostic, monitoring, and prognostic purposes. Furthermore, these  cells are discussed to be suitable as predictive markers. In any case, identification of CTCs requires innovative and challenging technologies as detection methods should be specific, sensitive, standardized, and highly reproducible. Although many different approaches have been developed until now, only the CellSearch method has been cleared by the American Food and Drug Administration. Although the detection of CTCs has already shown to have a prognostic impact in many tumor entities including breast, prostate, lung and colon cancer, ongoing and future studies are aimed to explore whether CTCs can be used for an individual therapy decision making including novel immunotherapeutic  approaches. This review discusses (1) different detection strategies for CTCs, (2) their clinical impact, and (3) the potential use of CTCs guiding the treatment of individual cancer patients.

 

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[34]

TÍTULO / TITLE:  - Risk Model and Nomogram for Dysphagia and Xerostomia Prediction in Head and Neck  Cancer Patients Treated by Radiotherapy and/or Chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Dysphagia. 2013 Jan 26.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00455-012-9445-6

AUTORES / AUTHORS:  - Teguh DN; Levendag PC; Ghidey W; van Montfort K; Kwa SL

INSTITUCIÓN / INSTITUTION:  - Radiation Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands, d.teguh@erasmusmc.nl.

RESUMEN / SUMMARY:  - In our randomized trial on hyperbaric oxygen (HBO), it was shown that HBO could reduce dysphagia and xerostomia, which are frequently encountered after (chemo-)  radiotherapy (RT) and/or surgery for head and neck cancer (HNC). A risk model and nomogram are developed to select those patients who most likely will respond to HBO treatment. A total of 434 HNC patients treated from 2000 to 2008 were analyzed and filled out the EORTC QLQC-30 and H&N35 questionnaires. Age, gender,  chemotherapy, T and N stages, site, radiotherapy technique, RT boost, surgery of  the primary tumor and neck, bilateral RT, and dose were analyzed in a statistical model. The discriminative value of the model was evaluated based on receiver operating characteristics (ROC), the area under the curve (AUC), sensitivity, specificity, and proportion of correctly classified measures. Significant factors in predicting swallowing problems are age, follow-up duration, tumor site, chemotherapy, surgery of the primary tumor and neck, and dose. For dry mouth, the significant factors are age, gender, tumor site, N stage, chemotherapy, and bilateral irradiation. For dysphagia and xerostomia, the area under the ROC curve is 0.7034 and 0.7224, respectively, with a specificity of 89/77 %, sensitivity of 27/58 %, and a positive predictive value of 83/67 % for dysphagia and xerostomia, respectively. The developed predictive risk model could be used to select patients for costly hyperbaric oxygen treatment to prevent or reduce severe late  side effects of HNC treatment. Our model serves as a guideline for the Department of Radiation Oncology to reduce costs by excluding patients not amenable to hyperbaric oxygen protocols. The nomogram presented is a useful tool for clinicians in assessing patient risks when deciding on follow-up strategies (e.g., hyperbaric oxygen treatment) after RT or surgery for HNC.

 

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[35]

TÍTULO / TITLE:  - High FAK combined with low JWA expression: clinical prognostic and predictive role for adjuvant fluorouracil-leucovorin-oxaliplatin treatment in resectable gastric cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Gastroenterol. 2013 Jan 11.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00535-012-0724-7

AUTORES / AUTHORS:  - Chen Y; Xia X; Wang S; Wu X; Zhang J; Zhou Y; Tan Y; He S; Qiang F; Li A; Roe OD; Zhou J

INSTITUCIÓN / INSTITUTION:  - Department of Molecular Cell Biology and Toxicology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People’s Republic of China.

RESUMEN / SUMMARY:  - BACKGROUND: The multifunctional protein JWA was previously identified as a novel  regulator of focal adhesion kinase (FAK/PTK2) in suppressing cancer cell adhesion, invasion and metastasis. JWA is downregulated in gastric cancer (GC) and a prognostic and predictive biomarker for resectable GC. However, the value of FAK combined with JWA for GC patients as a biomarker has not been studied. Here we evaluated the roles of FAK alone and combined with JWA in GC patients treated with surgery alone or combined with adjuvant platinum-based chemotherapy. METHODS: Two tissue microarrays were constructed of specimens from resected GC (n = 709 in total) for detection of FAK and JWA expression by immunohistochemistry.  Correlations between both proteins and clinicopathological features as well as prognostic and predictive values were evaluated. RESULTS: Compared with adjacent  non-cancerous tissues, FAK protein levels were remarkably up-regulated in GC lesions (P < 0.001). High FAK alone or combined with low JWA expression significantly correlated with worse overall survival (OS) (both P < 0.001 in two  cohorts). Simultaneously, JWA plus FAK expression was a more valuable prognostic  biomarker than JWA or FAK alone. Moreover, the patients with high FAK only or combined with low JWA had significant benefit from adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) therapy compared with those with surgery alone (P = 0.003); however, the cases with adjuvant fluorouracil-leucovorin-cisplatin (FLP) therapy did not show these effects. CONCLUSION: FAK plus JWA may serve as a more prognostic and predictive biomarker  for GC than each separately with a potential clinical application.

 

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[36]

TÍTULO / TITLE:  - Human Leukocyte Antigen-G Is Frequently Expressed in Glioblastoma and May Be Induced in Vitro by Combined 5-Aza-2’-Deoxycytidine and Interferon-gamma Treatments: Results from a Multicentric Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Pathol. 2013 Feb;182(2):540-52. doi: 10.1016/j.ajpath.2012.10.021. Epub 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ajpath.2012.10.021

AUTORES / AUTHORS:  - Wastowski IJ; Simoes RT; Yaghi L; Donadi EA; Pancoto JT; Poras I; Lechapt-Zalcman E; Bernaudin M; Valable S; Carlotti CG Jr; Flajollet S; Jensen SS; Ferrone S; Carosella ED; Kristensen BW; Moreau P

INSTITUCIÓN / INSTITUTION:  - Commissariat a l’Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Therapies Innovantes, Service de Recherches en Hemato-Immunologie, Hopital Saint-Louis, Paris, France; Universite Paris-Diderot, Sorbonne Paris-Cite, UMR E5, Institut Universitaire d’Hematologie, Hopital Saint-Louis, Paris, France.

RESUMEN / SUMMARY:  - Human leukocyte antigen-G (HLA-G) is a nonclassical major histocompatibility complex (MHC) class I molecule involved in immune tolerance processes, playing an important role in the maintenance of the semi-allogeneic fetus. Although HLA-G expression is restricted in normal tissues, it is broadly expressed in malignant  tumors and may favor tumor immune escape. We analyzed HLA-G protein and mRNA expression in tumor samples from patients with glioblastoma collected in France,  Denmark, and Brazil. We found HLA-G protein expression in 65 of 108 samples and mRNA in 20 of 21 samples. The absence of HLA-G protein expression was associated  with a better long-term survival rate. The mechanisms underlying HLA-G gene expression were investigated in glioma cell lines U251MG, D247MG, and U138MG. Induction of HLA-G transcriptional activity was dependent of 5-aza-2’-deoxycytidine treatment and enhanced by interferon-gamma. HLA-G protein  expression was observed in U251MG cells only. These cells exhibited a permissive  chromatin state at the HLA-G gene promoter and the highest levels of induced HLA-G transcriptional activity following 5-aza-2’-deoxycytidine treatment. Several antigen-presenting machinery components were up-regulated in U251MG cells after demethylating and IFN-gamma treatments, suggesting an effect on the up-regulation of HLA-G cell surface expression. Therefore, because of its role in tumor tolerance, HLA-G found to be expressed in glioblastoma samples should be taken into consideration in clinical studies on the pathology and in the design of therapeutic strategies to prevent its expression in HLA-G-negative tumors.

 

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[37]

TÍTULO / TITLE:  - Methylation of breast cancer susceptibility gene 1 (BRCA1) predicts recurrence in patients with curatively resected stage I non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer. 2013 Jan 18. doi: 10.1002/cncr.27754.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cncr.27754

AUTORES / AUTHORS:  - Harada H; Miyamoto K; Yamashita Y; Nakano K; Taniyama K; Miyata Y; Ohdan H; Okada M

INSTITUCIÓN / INSTITUTION:  - Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; Institute for Clinical Research, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan; Department of Respiratory Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan.

RESUMEN / SUMMARY:  - BACKGROUND: Even after early detection and curative resection of early stage non-small cell lung cancer (NSCLC), a significant fraction of patients develop recurrent disease. Molecular biomarkers that can predict the risk of recurrence thus need to be identified to improve clinical outcomes. METHODS: Using the methylation-specific polymerase chain reaction assay, promoter methylation of the breast cancer susceptibility gene 1 (BRCA1) was assessed in cancer tissues from 70 patients with curatively resected stage I NSCLC. The clinical relevance of BRCA1 methylation status was evaluated in terms of outcome of the disease. RESULTS: Methylation of the BRCA1 promoter was detected in 13 of 70 patients (18.6%). Multiple logistic regression analysis revealed that BRCA1 methylation was an independent risk factor for recurrence (P = .0197) and that patients with  BRCA1 methylation demonstrated significantly poorer recurrence-free survival compared to those without (P = .0139). Cox’s proportional hazard regression analysis revealed that BRCA1 methylation was an independent risk factor for recurrence-free survival (P = .0155). CONCLUSIONS: Methylated BRCA1 can be a potential biomarker that predicts the prognosis after curative resection of stage I NSCLC. Considering that BRCA1 plays a role in chemotherapy-induced apoptosis, it is plausible that identification of methylated BRCA1 could provide information that is clinically relevant to tailored adjuvant therapy. Cancer 2013. © 2013 American Cancer Society.

 

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[38]

TÍTULO / TITLE:  - Clinical and safety profile of high-dose interleukin-2 treatment in elderly patients with metastatic melanoma and renal cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncology. 2013;84(2):123-6. doi: 10.1159/000342764. Epub 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000342764

AUTORES / AUTHORS:  - Clark JM; Kelley B; Titze J; Fung H; Maciejewski J; Nathan S; Rich E; Basu S; Kaufman HL

INSTITUCIÓN / INSTITUTION:  - Department of General Surgery, Rush University Medical Center, Chicago, Ill., USA.

RESUMEN / SUMMARY:  - Objective: High-dose interleukin-2 (IL-2) is effective immunotherapy for the treatment of metastatic melanoma and renal cell carcinoma (RCC) but has been contraindicated in elderly patients. This study assessed the safety and therapeutic efficacy of high-dose IL-2 in patients >/=65 years of age with metastatic melanoma and RCC. Methods: A prospectively collected clinical database of 104 consecutive melanoma or RCC patients treated with high-dose IL-2 between 2009 and 2012 was used to compare clinical outcomes and adverse events in patients >/=65 years of age with those of younger patients. Results: There were 22 (21%) patients >/=65 years and 82 (79%) patients <65 years of age. The mean number of IL-2 doses was lower in older patients during cycle 1 of treatment (7.2 vs. 8.6, p = 0.012). There were no other differences in dosing pattern by age group. There was a higher rate of selected cardiac, constitutional, hematologic,  metabolic and renal toxicities in younger patients (p < 0.05). Overall, objective responses and survival were not affected by age, though older patients had a higher partial response rate (p = 0.04). Conclusions: IL-2 is safe and has comparable therapeutic effectiveness in patients >/=65 years. Age should not be considered a contraindication to treatment with IL-2 in otherwise eligible patients.

 

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[39]

TÍTULO / TITLE:  - Tetrahydropyrroloquinolinone type dual inhibitors of aromatase/aldosterone synthase as a novel strategy for breast cancer patients with elevated cardiovascular risks.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Med Chem. 2013 Jan 24;56(2):460-70. doi: 10.1021/jm301408t. Epub 2013 Jan 3.

            ●● Enlace al texto completo (gratuito o de pago) 1021/jm301408t

AUTORES / AUTHORS:  - Yin L; Hu Q; Hartmann RW

INSTITUCIÓN / INSTITUTION:  - Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus C2-3, D-66123 Saarbrucken, Germany.

RESUMEN / SUMMARY:  - The application of aromatase inhibitors to postmenopausal breast cancer patients  increases the risk of cardiovascular diseases (CVD), which is believed to be caused by the abnormally high concentrations of aldosterone as a consequence of the estrogen deficiency. Dual inhibitors of aromatase (CYP19) and aldosterone synthase (CYP11B2) are therefore proposed as a novel strategy for the adjuvant therapy to reduce the CVD risk for these patients. By combining decisive structural features of CYP11B2 and CYP19 inhibitors into a common template, a series of pyridinylmethyl substituted 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-ones were designed and synthesized. Interestingly, the substituents on the methylene bridge showed strong influences on the inhibitory activities leading to opposite effects, that  is, a given substituent showed an increase in inhibition of one enzyme, while it  led to a decrease for the other enzyme. The compromise of this conflict led to compounds 3j, 3k, 3n, and 3p as potent and selective dual inhibitors of CYP19 and CYP11B2, especially compound 3p, which exhibited IC(50) values of 32 and 41 nM for CYP19 and CYP11B2, respectively, and a high selectivity toward CYP17 and CYP11B1. This compound is considered as a candidate for further evaluation in vivo.

 

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[40]

TÍTULO / TITLE:  - ABT-737 Resistance in B-Cells Isolated from Chronic Lymphocytic Leukemia Patients and Leukemia Cell Lines is Overcome by the Pleiotropic Kinase Inhibitor Quercetin Through Mcl-1 Down-regulation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Jan 24. pii: S0006-2952(13)00048-8. doi: 10.1016/j.bcp.2013.01.011.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2013.01.011

AUTORES / AUTHORS:  - Russo M; Spagnuolo C; Volpe S; Tedesco I; Bilotto S; Russo GL

INSTITUCIÓN / INSTITUTION:  - Institute of Food Sciences, National Research Council, 83100 Avellino, Italy.

RESUMEN / SUMMARY:  - Chronic Lymphocytic Leukemia (CLL) is the most frequent form of leukemia in adult population and despite numerous studies, it is considered an incurable disease. Since CLL is characterized by overexpression of pro-survival Bcl-2 family members, treatment with their antagonists, such as ABT-737, represent a promising new therapeutic strategy. ABT-737 is a BH3 mimetic agent which binds Bcl-2, Bcl-X(L) and Bcl-w with high affinity, while weakly interacts with Mcl-1 and Bfl-1. Previous studies demonstrated that quercetin, a flavonoid naturally present in food and beverages, was able to sensitize B-cells isolated from CLL patients to apoptosis when associated with death ligands or fludarabine, through  a mechanism involving Mcl-1 down-regulation. Here, we report that the association between ABT-737 and quercetin synergistically induces apoptosis in B-cells and in five leukemic cell lines (Combination Index <1). Peripheral blood mononuclear cell from healthy donors were not affected by quercetin treatment. The molecular  pathways triggered by quercetin have been investigated in HPB-ALL cells, characterized by the highest resistance to both ABT-737 and quercetin when applied as single molecules, but highly sensitivity to the co-treatment. In this  cell line, quercetin down-regulated Mcl-1 through the inhibition of PI(3)K/Akt signaling pathway, leading to Mcl-1 instability. The same mechanism was confirmed in B-cells. These results may open new clinical perspectives based on a translational approach in CLL therapy.

 

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[41]

TÍTULO / TITLE:  - Outcome of allogeneic SCT in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Hematol. 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00277-012-1650-8

AUTORES / AUTHORS:  - Oyekunle A; Zander AR; Binder M; Ayuk F; Zabelina T; Christopeit M; Stubig T; Alchalby H; Schafhausen P; Lellek H; Wolschke C; Muller I; Bacher U; Kroger N

INSTITUCIÓN / INSTITUTION:  - Department for Stem Cell Transplantation, University Cancer Center Hamburg (UCCH), Martinistr. 52, 20246, Hamburg, Germany.

RESUMEN / SUMMARY:  - The introduction of tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) led to a dramatic change in the role of allogeneic stem cell transplantation (SCT) with a rapid decline in the number of patients receiving SCT in first chronic phase (CP1). We evaluated 68 consecutive patients in all phases of CML (male/female = 39:29, 27 in CP1), who received SCT from related/unrelated donors (related/unrelated = 23:45) under myeloablative or reduced intensity conditioning (MAC/RIC = 45:23). Forty-eight patients (71 %) received TKIs pre-SCT, 20 patients post-SCT (29 %). Overall survival (OS) of CP1  patients achieved a plateau of 85 % at 10 months. Relapse-free survival (RFS) of  CP1 patients was 85 % at 1 and 2 years, and 81 % at 5 years. Multivariate analysis showed adverse OS and RFS for patients transplanted >CP1 (hazard ratio (HR) = 6.61 and 4.62) and those who had grade III-IV aGvHD (HR = 2.45 and 1.82).  Patients with advanced CML had estimated OS of 65 and 47 %; and RFS of 41 and 32  % at 1 and 2 years respectively. Therefore, for patients with advanced CML phases, allogeneic SCT provides an acceptable chance of cure. Transplant research should focus on improving conditioning regimens and post-SCT management for this  subgroup of CML patients.

 

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[42]

TÍTULO / TITLE:  - Dual inhibition of Bcl-2 and Bcl-xL strikingly enhances PI3K inhibition-induced apoptosis in human myeloid leukemia cells through a GSK3- and Bim-dependent mechanism.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-1365

AUTORES / AUTHORS:  - Rahmani M; Aust MM; Attkisson E; Williams DC Jr; Ferreira-Gonzalez A; Grant S

INSTITUCIÓN / INSTITUTION:  - Internal Medicine, Virginia Commonwealth University.

RESUMEN / SUMMARY:  - Effects of concomitant inhibition of the PI3K/AKT/mTOR pathway and Bcl-2/Bcl-xL (BCL2L1) were examined in human myeloid leukemia cells. Tetracycline-inducible Bcl-2 and Bcl-xL dual knockdown sharply increased PI3K/AKT/mTOR inhibitor lethality. Conversely, inducible knockdown or dominant-negative AKT increased whereas constitutively active AKT reduced lethality of the Bcl-2/Bcl-xL inhibitor ABT-737. Furthermore, PI3K/mTOR inhibitors (e.g., BEZ235, PI-103) synergistically increased ABT-737-mediated cell death in multiple leukemia cell lines and reduced colony-formation in leukemic but not normal CD34+ cells. Notably, increased lethality was observed in 4/6 primary AML specimens. Responding, but not non-responding, samples exhibited basal AKT phosphorylation. PI3K/mTOR inhibitors markedly down-regulated Mcl-1 but increased Bim binding to Bcl-2/Bcl-xL; the latter effect was abrogated by ABT-737. Combined treatment also markedly diminished Bax/Bak binding to Mcl-1, Bcl-2 or Bcl-xL. Bax, Bak, or Bim (BCL2L11)  knockdown, or Mcl-1 over-expression significantly diminished regimen-induced apoptosis. Interestingly, pharmacologic inhibition or shRNA knockdown of GSK3alpha/beta significantly attenuated Mcl-1 down-regulation and decreased apoptosis. In a systemic AML xenograft model, dual tet-inducible knockdown of Bcl-2/Bcl-xL sharply increased BEZ235 anti-leukemic effects. In a subcutaneous xenograft model, BEZ235 and ABT-737 co-administration significantly diminished tumor growth, down-regulated Mcl-1, activated caspases, and prolonged survival. Together, these findings suggest that anti-leukemic synergism between PI3K/AKT/mTOR inhibitors and BH3 mimetics involves multiple mechanisms, including Mcl-1 down-regulation, release of Bim from Bcl-2/Bcl-xL as well as Bak and Bax from Mcl-1/Bcl-2/Bcl-xL, and GSK3alpha/beta, culminating in Bax/Bak activation and apoptosis. They also argue that combining PI3K/AKT/mTOR inhibitors with BH3-mimetics warrants attention in AML, particularly in the setting of basal AKT  activation and/or addiction.

 

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[43]

TÍTULO / TITLE:  - Chronic lymphocytic leukemia cells induce defective LFA-1-directed T cell motility by altering Rho GTPase signaling that is reversible with lenalidomide.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Blood. 2013 Jan 16.

            ●● Enlace al texto completo (gratuito o de pago) 1182/blood-2012-08-448332

AUTORES / AUTHORS:  - Ramsay AG; Evans R; Kiaii S; Svensson L; Hogg N; Gribben JG

INSTITUCIÓN / INSTITUTION:  - Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, United Kingdom;

RESUMEN / SUMMARY:  - T lymphocytes have an essential role in adaptive immunity and rely on the activation of integrin lymphocyte function-associated antigen-1 (LFA-1) to mediate cell arrest and migration. In cancer, malignant cells modify the immune microenvironment to block effective host anti-tumor responses. Here we show for the first time that CD4 and CD8 T cells from patients with chronic lymphocytic leukemia (CLL) exhibit globally impaired LFA-1-mediated migration and that this defect is mediated by direct tumor cell contact. We show that following coculture of previously healthy T cells with CLL cells, subsequent LFA-1 engagement leads to altered Rho GTPase activation signaling by down-regulating RhoA and Rac1, while up-regulating Cdc42. Of clinical relevance, repair of this T cell defect was demonstrated using the immunomodulatory drug lenalidomide that completely rescued adhesion and motility function by restoring normal Rho GTPase activation  signaling. Our report identifies a novel cancer immune evasion mechanism whereby  tumor cells induce Rho GTPase signaling defects in T cells that prevent appropriate LFA-1 activation and motility. We believe these findings identify important biomarkers and highlight the clinical utility of immunotherapy to rescue normal T cell function in CLL that are likely to have relevance in other cancers.

 

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[44]

TÍTULO / TITLE:  - Endoplasmic reticulum ribosome-binding protein 1 (RRBP1) overexpression is frequently found in lung cancer patients and alleviates intracellular stress-induced apoptosis through the enhancement of GRP78.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncogene. 2013 Jan 14. doi: 10.1038/onc.2012.514.

            ●● Enlace al texto completo (gratuito o de pago) 1038/onc.2012.514

AUTORES / AUTHORS:  - Tsai HY; Yang YF; Wu AT; Yang CJ; Liu YP; Jan YH; Lee CH; Hsiao YW; Yeh CT; Shen CN; Lu PJ; Huang MS; Hsiao M

INSTITUCIÓN / INSTITUTION:  - 1] Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan [2] Genomics Research Center, Academia Sinica, Taipei, Taiwan.

RESUMEN / SUMMARY:  - Lung cancer is the leading cause of cancer deaths and is the most occurring malignancy worldwide. Unraveling the molecular mechanisms involved in lung tumorigenesis will greatly improve therapy. During early tumorigenesis, rapid proliferating tumor cells require increased activity of endoplasmic reticulum (ER) for protein synthesis, folding and secretion, thereby are subjected to ER stress. Ribosome-binding protein 1 (RRBP1) was originally identified as a ribosome-binding protein located on the rough ER and associated with unfolding protein response (UPR). In this report, we investigated the role of RRBP1 in lung cancer. RRBP1 was highly expressed in lung cancer tissue, as compared with adjacent normal tissues as assessed by immunohistochemistry (IHC) using lung cancer tissue array (n=87). Knockdown of RRBP1 by short-hairpin RNAs caused ER stress and significantly reduced cell viability and tumorigenicity. This effect was associated with a significant reduction in the expression of glucose-regulated protein 78 (GRP78). UPR regulator GRP78, an anti-apoptotic protein that is widely upregulated in cancer, has a critical role in chemotherapy resistance in some cancers. According to our results, cells with a higher level of RRBP1 were more resistant to ER stress. Ectopic expression of RRBP1 alleviated apoptosis that was induced by the ER-stress agent tunicamycin, 2-deoxy-D-glucose  (2DG) or doxorubicin via enhancing GRP78 protein expression. A strong correlation was observed between the expression of RRBP1 and GRP78 in tumor biopsies using the database GSE10072. Our results also indicated that RRBP1 may involve in the regulation of mRNA stability of UPR components including ATF6 and GRP78. Taken together, RRBP1 could alleviate ER stress and help cancer cell survive. RRBP1 is  critical for tumor cell survival, which may make it a useful target in lung cancer treatment and a candidate for the development of new targeted therapeutics.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.514.

 

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[45]

TÍTULO / TITLE:  - Increased expression of discoidin domain receptor 2 (DDR2): a novel independent prognostic marker of worse outcome in breast cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):397. doi: 10.1007/s12032-012-0397-3. Epub 2013 Jan 10.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0397-3

AUTORES / AUTHORS:  - Ren T; Zhang J; Zhang J; Liu X; Yao L

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular  Biology, the Fourth Military Medical University, Changle Western Road, Xi’an, Shaanxi, 710032, People’s Republic of China.

RESUMEN / SUMMARY:  - The discoidin domain receptors, DDR1 and DDR2, have been linked with numerous human cancers. We sought to determine expression level and distribution of DDRs in human breast cancer, and investigate prognostic determinates to determine whether levels of DDRs could predict survival. Tumor samples from 122 breast cancer patients were analyzed for relative expression of DDRs. An additional 24 matched tumor and normal tissues were tested for differential expression of DDR1  and DDR2. DDR2 was found to be significantly increased by 6-fold (P = 0.0005) and DDR1 decreased (P = 0.0001) in tumor vs. normal breast tissue. DDR1 expression was not predictive for patient survival; however, DDR2 expression was significantly associated with disease-free (HR = 0.55, 95 % CI = 0.24-0.78, P = 0.026) and overall survival (HR = 0.46, 95 % CI = 0.35-0.84, P = 0.019). Multivariate analysis revealed DDR2 is an independent favorable predictor for prognosis independent of tumor stage, histology, and patient age. The present research provided the first evidence that increased DDR2 mRNA expression in primary human breast cancer might be a powerful, independent predictor of recurrence and outcome.

 

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[46]

TÍTULO / TITLE:  - Clinical Impact of Immune Microenvironment in Stage I Lung Adenocarcinoma: Tumor  Interleukin-12 Receptor beta2 (IL-12Rbeta2), IL-7R, and Stromal FoxP3/CD3 Ratio Are Independent Predictors of Recurrence.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Feb 1;31(4):490-8. doi: 10.1200/JCO.2012.45.2052. Epub 2012 Dec 26.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.45.2052

AUTORES / AUTHORS:  - Suzuki K; Kadota K; Sima CS; Nitadori J; Rusch VW; Travis WD; Sadelain M; Adusumilli PS

INSTITUCIÓN / INSTITUTION:  - Division of Thoracic Surgery, Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; adusumip@mskcc.org.

RESUMEN / SUMMARY:  - PURPOSE Mounting evidence suggests that tumor-infiltrating immune cells have prognostic value for patients with solid organ malignancies. Our aim was to investigate the prognostic significance of the immune microenvironment in patients with stage I lung adenocarcinoma (ADC). PATIENTS AND METHODS Using tissue microarray and immunohistochemistry, we investigated eight types of tumor-infiltrating immune cells in the tumor nest and tumor-associated stroma as  well as tumor expression of five cytokines in a uniform cohort of 956 patients with stage I lung ADC (478 each in training and validation cohorts). Results Although a high density of stromal forkhead box P3 (FoxP3) -positive cells was associated with shorter recurrence-free probability (RFP; P = .043), the relative proportion of stromal FoxP3 to CD3 was a stronger predictor of recurrence (5-year RFP, 85% for high v 77% for low ratio; P = .004). High expression of tumor interleukin-12 receptor beta2 (IL-12Rbeta2) was associated with better outcome (5-year RFP, 90% for high v 80% for low expression; P = .026), whereas high expression of tumor IL-7R was associated with worse outcome (5-year RFP, 76% for  high v 86% for low expression; P = .001). In multivariate analysis, these immune  markers were independently associated with recurrence. Although IL-7R remained significant for poor overall survival, all the markers remained prognostic for recurrence in patients with stages IA and IB disease as well as for patients with tumors </= 2 cm. CONCLUSION Our investigation confirms the biologic and prognostic significance of the tumor immune microenvironment for patients with stage I lung ADC and provides support for its use to stratify clinical outcome and immunotherapeutic interventions.

 

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[47]

TÍTULO / TITLE:  - The Predictive Value of C-reactive Protein for Prognosis in Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy: A Multi-institutional Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur Urol. 2012 Dec 1. pii: S0302-2838(12)01425-X. doi: 10.1016/j.eururo.2012.11.050.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.eururo.2012.11.050

AUTORES / AUTHORS:  - Tanaka N; Kikuchi E; Shirotake S; Kanao K; Matsumoto K; Kobayashi H; Miyazaki Y; Ide H; Obata J; Hoshino K; Hayakawa N; Ito Y; Kosaka T; Kodaira K; Oyama M; Miyajima A; Momma T; Nakagawa K; Ueno M; Oya M

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Keio University School of Medicine, Tokyo, Japan; Department of Urology, Saitama City Hospital, Saitama, Japan.

RESUMEN / SUMMARY:  - BACKGROUND: Few studies have discussed the prognostic impact of serum C-reactive  protein (CRP) level in upper tract urothelial carcinoma (UTUC). OBJECTIVE: To investigate whether the perioperative level of CRP provides additional prognostic information following radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS: A total of 564 patients with UTUC from a retrospective multi-institutional cohort were included. The median follow-up was 32 mo. INTERVENTION: All patients underwent RNU without neoadjuvant chemotherapy, while  106 patients (18.8%) received adjuvant chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between perioperative CRP level and outcome were assessed using multivariate analysis. A serum CRP level >0.50mg/dl was defined as elevated. RESULTS AND LIMITATIONS: Preoperative CRP (pre-CRP) level was elevated in 136 patients (24.1%). Multivariate analysis showed that pre-CRP elevation was an independent predictor of subsequent disease recurrence (hazard ratio [HR]: 1.47 for CRP 0.51-2.00; HR: 1.89 for CRP >2.00). Five-year recurrence-free survival rates were 69.2% in patients with pre-CRP levels </=0.50mg/dl, 54.3% in patients with pre-CRP levels between 0.51 and 2.00mg/dl, and 35.4% in patients with pre-CRP levels >2.00mg/dl (p<0.001). Similar results were found in cancer-specific mortality, showing that pre-CRP elevation was an independent predictor of worse outcome (HR: 1.74 for CRP 0.51-2.00; HR: 2.31 for  CRP >2.00). In a subgroup analysis of the elevated pre-CRP group, postoperative normalisation of CRP level was an independent predictor of better outcome. This study is limited by its retrospective nature as well as its heterogeneous group of patients and variable follow-up protocols resulting from the multi-institution design. CONCLUSIONS: Serum CRP may become a possible biomarker in UTUC, suggesting that patients with an elevated pre-CRP level could be predicted to have subsequent disease recurrence and cancer-specific mortality, while postoperative normalisation of CRP level was an independent predictor for prognosis.

 

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[48]

TÍTULO / TITLE:  - Significance of folate receptor alpha and thymidylate synthase protein expression in patients with non-small-cell lung cancer treated with pemetrexed.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Thorac Oncol. 2013 Jan;8(1):19-30. doi: 10.1097/JTO.0b013e31827628ff.

            ●● Enlace al texto completo (gratuito o de pago) 1097/JTO.0b013e31827628ff

AUTORES / AUTHORS:  - Christoph DC; Asuncion BR; Hassan B; Tran C; Maltzman JD; O’Shannessy DJ; Wynes MW; Gauler TC; Wohlschlaeger J; Hoiczyk M; Schuler M; Eberhardt WE; Hirsch FR

INSTITUCIÓN / INSTITUTION:  - Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado 80045, USA.

RESUMEN / SUMMARY:  - INTRODUCTION: Folate receptor alpha (FRA) regulates cellular uptake of folates and antifolates. Information about FRA protein expression in metastatic non-small-cell lung cancer (NSCLC) is limited. We investigated FRA as a biomarker for pemetrexed-based chemotherapy and compared it with thymidylate synthase (TS), the main target of pemetrexed. METHODS: Pretreatment tumor specimens from 207 patients with advanced NSCLC were assessed for FRA and TS protein expression by immunohistochemistry using the H-score (range, 0-300) and correlated to patients’ clinicopathological data, radiographic response, progression-free survival (PFS), and overall survival (OS). RESULTS: Low total (cytoplasmic and nuclear) TS protein expression (H-score < 210) was associated with improved PFS (median: 5.6  versus 3.5 months; hazard ratio [HR] = 0.6379, p = 0.0131) and prolonged OS (median: 22.5 versus 11.5 months; HR = 0.5680,p = 0.0107). An association between lower TS levels and response to pemetrexed-based therapy was found-mean H-score 187 +/- 5, median 180 for responders versus mean H-score 201 +/- 4, median 210, for non-responders, p = 0.0244. High intracellular FRA expression (H-score >/=110) was associated with prolonged OS (28.9 versus 11.7 months, HR = 0.5316, p = 0.0040) and a trend for association with PFS (5.6 versus 4.1 months, HR = 0.7395, p = 0.0801) was noted. Membranous FRA expression was seen in 83% of patients, moreover, high membranous expression (H-score >/=20) was associated with improved PFS (5.6 versus 3.7 months, HR = 0.6445, p = 0.0306) and OS (22.1 versus 11.5 months, HR = 0.5378, p = 0.0131). CONCLUSIONS: A large number of NSCLC patients have high expression of FRA and/or a low level of TS expression. Expression levels of FRA and TS were associated with clinical benefit from pemetrexed therapy.

 

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[49]

TÍTULO / TITLE:  - Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Jan;137(2):465-70. doi: 10.1007/s10549-012-2355-3.  Epub 2012 Dec 9.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-012-2355-3

AUTORES / AUTHORS:  - Eggemann H; Ignatov A; Smith BJ; Altmann U; von Minckwitz G; Rohl FW; Jahn M; Costa SD

INSTITUCIÓN / INSTITUTION:  - University Women’s Clinic, Otto-von-Guericke University, Gerhart-Hauptmann Str. 35, 39108, Magdeburg, Germany, holm.eggemann@med.ovgu.de.

RESUMEN / SUMMARY:  - To determine the impact of adjuvant treatment with tamoxifen and aromatase inhibitors (AI) on the survival of men with breast cancer. We analyzed 257 male patients with hormone-receptor-positive breast cancer from numerous German population-based cancer registries treated with tamoxifen (N = 207) or aromatase  inhibitors (N = 50). The median follow-up was 42.2 (range 2-115) months. Median age at diagnosis was 68 (range 36-91) years. Thirty-seven (17.9 %) patients treated with tamoxifen and 16 (32.0 %) patients treated with AI died (log rank p  = 0.007). After the adjustment for the patient’s age, tumor size, node status, and tumor grading, the AI treatment was linked to a 1.5-fold increase in risk of  mortality compared to tamoxifen (HR 1.55; 95 % CI: 1.13-2.13; p = 0.007). The overall survival in male breast cancer was significantly better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor. Tamoxifen should be  considered as the treatment of choice for hormone-receptor-positive male breast cancer.

 

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[50]

TÍTULO / TITLE:  - High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFbeta pathways as fundamental Notch regulators in breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1714-9. doi: 10.1073/pnas.1214014110. Epub 2013 Jan 14.

            ●● Enlace al texto completo (gratuito o de pago) 1073/pnas.1214014110

AUTORES / AUTHORS:  - Izrailit J; Berman HK; Datti A; Wrana JL; Reedijk M

INSTITUCIÓN / INSTITUTION:  - Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, ON, Canada M5G 2M9.

RESUMEN / SUMMARY:  - Expression of the Notch ligand Jagged 1 (JAG1) and Notch activation promote poor-prognosis in breast cancer. We used high throughput screens to identify elements responsible for Notch activation in this context. Chemical kinase inhibitor and kinase-specific small interfering RNA libraries were screened in a  breast cancer cell line engineered to report Notch. Pathway analyses revealed MAPK-ERK signaling to be the predominant JAG1/Notch regulator and this was supported by gene set enrichment analyses in 51 breast cancer cell lines. In accordance with the chemical screen, kinome small interfering RNA high throughput screens identified Tribbles homolog 3 (TRB3), a known regulator of MAPK-ERK, among the most significant hits. We demonstrate that TRB3 is a master regulator of Notch through the MAPK-ERK and TGFbeta pathways. Complementary in vitro and in vivo studies underscore the importance of TRB3 for tumor growth. These data demonstrate a dominant role for TRB3 and MAPK-ERK/TGFbeta pathways as Notch regulators in breast cancer, establishing TRB3 as a potential therapeutic target.

 

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[51]

TÍTULO / TITLE:  - Rapid loss of response after withdrawal of treatment with azacitidine: a case series in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Haematol. 2013 Jan 21. doi: 10.1111/ejh.12079.

            ●● Enlace al texto completo (gratuito o de pago) 1111/ejh.12079

AUTORES / AUTHORS:  - Voso MT; Breccia M; Lunghi M; Poloni A; Niscola P; Finelli C; Bari A; Musto P; Zambello R; Fianchi L; Alimena G; Leone G

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Universita’ Cattolica S. Cuore, Rome.

RESUMEN / SUMMARY:  - In patients with myelodysplastic syndromes (MDS), the likelihood of having a sustained response to azacitidine is increased by maximizing treatment duration.  This is important as prognosis post-relapse is poor. There is also the concern that early termination of treatment may result in rapid disease progression. We reviewed outcomes in 13 patients who discontinued azacitidine (decitabine in one  patient), while still responding to the treatment. Most patients rapidly relapsed; median time to progression was 5.4 months. Reasons for treatment discontinuation included comorbidities, infections and patient choice. These findings illustrate the risk of prematurely terminating azacitidine therapy in MDS. © 2013 John Wiley & Sons A/S.

 

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[52]

TÍTULO / TITLE:  - A 12-Gene Set Predicts Survival Benefits from Adjuvant Chemotherapy in Non-Small-Cell Lung Cancer Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 28.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2321

AUTORES / AUTHORS:  - Tang H; Xiao G; Behrens C; Schiller J; Allen J; Chow CW; Suraokar M; Corvalan A; Mao JH; White M; Wistuba II; Minna JD; Xie Y

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Sciences, University of Texas Southwesten Medical Center.

RESUMEN / SUMMARY:  - PURPOSE: Prospectively identifying who will benefit from adjuvant chemotherapy (ACT) would improve clinical decisions for non-small-cell lung cancer (NSCLC) patients. In this study, we aim to develop and validate a functional gene set that predicts the clinical benefits of ACT in NSCLC. EXPERIMENTAL DESIGN: An 18-hub-gene prognosis signature was developed through a systems biology approach, and its prognostic value was evaluated in six independent cohorts. The 18-hub-gene set was then integrated with genome-wide functional (RNAi) data and genetic aberration data to derive a 12-gene predictive signature for ACT benefits in NSCLC. RESULTS: Using a cohort of 442 Stage I-III NSCLC patients who underwent surgical resection, we identified an 18-hub-gene set which robustly predicted the prognosis of patients with adenocarcinoma in all validation datasets across four  microarray platforms. The hub genes, identified through a purely data-driven approach, have significant biological implications in tumor pathogenesis, including NKX2-1, Aurora Kinase A, PRC1, CDKN3, MBIP, RRM2. The 12-gene predictive signature was successfully validated in two independent datasets (N=90 and N=176). The predicted benefit group showed significant improvement in survival after ACT (UT Lung SPORE data: hazard ratio=0.34, p=0.017; JBR.10 clinical trial data: hazard ratio=0.36, p=0.038), while the predicted non-benefit group showed no survival benefit for two datasets (hazard ratio=0.80, p=0.70; hazard ratio= 0.91, p=0.82). CONCLUSIONS: This is the first study to integrate genetic aberration, genome-wide RNAi data, and mRNA expression data to identify a functional gene set that predicts which resectable patients with non-small-cell lung cancer will have a survival benefit with ACT.

 

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[53]

TÍTULO / TITLE:  - Multicenter Validation of Cyclin D1, MCM7, TRIM29, and UBE2C as Prognostic Protein Markers in Non-Muscle-Invasive Bladder Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Pathol. 2013 Feb;182(2):339-49. doi: 10.1016/j.ajpath.2012.10.017. Epub 2012 Nov 28.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ajpath.2012.10.017

AUTORES / AUTHORS:  - Fristrup N; Birkenkamp-Demtroder K; Reinert T; Sanchez-Carbayo M; Segersten U; Malmstrom PU; Palou J; Alvarez-Mugica M; Pan CC; Ulhoi BP; Borre M; Orntoft TF; Dyrskjot L

INSTITUCIÓN / INSTITUTION:  - Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.

RESUMEN / SUMMARY:  - Transcripts from the four genes encoding cyclin D1, MCM7, TRIM29, and UBE2C have  previously been included in gene expression signatures for outcome prediction in  stage Ta/T1 urothelial carcinomas. We investigated the prognostic value of the protein expressions in Ta/T1 urothelial carcinomas patients. We used four different tissue microarrays (TMAs) with a total of 859 Ta/T1 urothelial carcinomas from Danish, Swedish, Spanish, and Taiwanese patient cohorts with long-term follow-up. Protein expression was measured by IHC, and antibody specificity was validated by Western blotting. We found the expression of cyclin  D1, MCM7, TRIM29, and UBE2C to be significantly associated with progression to muscle-invasive bladder cancer (log-rank test; P < 0.001) in the Danish training  cohort (n = 283). Multivariate Cox regression analysis identified cyclin D1 (P =  0.003), TRIM29 (P = 0.001), and UBE2C (P < 0.001) as independent prognostic markers. The prognostic value of the four proteins was validated in a joint validation cohort from Sweden, España, and Taiwan (n = 576). Computer-assisted image analysis of the prognostic markers produced results comparable to those obtained by manual scoring. Finally, a four-protein maximum-likelihood classifier was trained on the Danish training cohort and applied to the validation cohort. The four protein markers may help optimize treatment of patients with Ta/T1 bladder cancer. Additional prospective studies are needed for further validation  of their clinical relevance.

 

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[54]

TÍTULO / TITLE:  - CD30 expression defines a novel subset of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from The International DLBCL Rituximab-CHOP Consortium Program Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Blood. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1182/blood-2012-10-461848

AUTORES / AUTHORS:  - Hu S; Xu-Monette ZY; Balasubramanyam A; Manyam GC; Visco C; Tzankov A; Liu WM; Miranda RN; Zhang L; Montes-Moreno S; Dybkaer K; Chiu A; Orazi A; Zu Y; Bhagat G; Richards KL; Hsi ED; Choi WW; van Krieken JH; Huang Q; Huh J; Ai W; Ponzoni M; Ferreri AJ; Zhao X; Winter JN; Zhang M; Li L; Moller MB; Piris MA; Li Y; Go RS; Wu L; Medeiros LJ; Young KH

INSTITUCIÓN / INSTITUTION:  - Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;

RESUMEN / SUMMARY:  - CD30, originally identified as a cell-surface marker of Reed-Sternberg and Hodgkin cells of classical Hodgkin lymphoma, is also expressed by several types of non-Hodgkin lymphoma, including a subset of diffuse large B-cell lymphoma (DLBCL). However, the prognostic and biological importance of CD30 expression in  DLBCL is unknown. Here we report that CD30 expression is a favorable prognostic factor in a cohort of 903 de novo DLBCL patients. CD30 was expressed in approximately 14% of DLBCL patients. Patients with CD30(+) DLBCL had superior 5-year overall survival (CD30(+) 79% vs CD30- 59%, P=.001) and progression-free survival (P=.003). The favorable outcome of CD30 expression was maintained in both the germinal center B-cell and activated B-cell subtypes. Gene-expression profiling revealed the up-regulation of genes encoding negative regulators of NF-kB activation and lymphocyte survival, and down-regulation of those involving  B-cell receptor signaling and B-cell proliferation, as well as prominent cytokine and stromal signatures in CD30(+) DLBCL patients, suggesting a distinct molecular basis for its favorable outcome. Given the superior prognostic value, unique gene-expression signature and significant value of CD30 as a therapeutic target for Brentuximab vedotin in ongoing successful clinical trials, it would be appropriate to consider CD30(+) DLBCL as a distinct subgroup of DLBCL.

 

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[55]

TÍTULO / TITLE:  - CA 15-3 is a predictive and prognostic biomarker in patients with metastasized breast cancer undergoing Selective Internal Radiation Therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Clin Pharmacol Ther. 2013 Jan;51(1):63-66.

AUTORES / AUTHORS:  - Fahmueller YN; Nagel D; Hoffmann RT; Tatsch K; Jakobs T; Stieber P; Holdenrieder S

INSTITUCIÓN / INSTITUTION:  - Institute of Clinical Chemistry, Institute of Clinical Radiology, Clinics of Nuclear Medicine, University-Hospital Munich-Grosshadern, Munich, Institute of Radiological Diagnostics, Hospital of the Technical University Dresden, Dresden,  Department of Nuclear Medicine, Municipal Hospital Karlsruhe Inc. Karlsruhe, Department of Diagnostics and Interventional Radiology, Hospital Barmherzige Bruder Munich, Munich, and Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.

 

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[56]

TÍTULO / TITLE:  - Persistence in patients with breast cancer treated with tamoxifen or aromatase inhibitors: a retrospective database analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Jan 20.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-013-2417-1

AUTORES / AUTHORS:  - Hadji P; Ziller V; Kyvernitakis J; Bauer M; Haas G; Schmidt N; Kostev K

INSTITUCIÓN / INSTITUTION:  - Department of Gynecology, Endocrinology and Oncology, Phillips-University of Marburg, Marburg, Germany.

RESUMEN / SUMMARY:  - Compliance and persistence are often underestimated in breast cancer (BC) treatment. The aim of our study was to analyze the persistence with tamoxifen (TAM) and aromatase inhibitors (AI) in postmenopausal women with hormone-receptor-positive BC and to identify determinants of non-persistence. We  used data of the Disease Analyzer database (IMS HEALTH, Germany) including 2,067  general practices and 397 gynecological practices. Out of a dataset of 15 million patients, we identified BC patients with a first-time TAM or AI prescriptions from October 2001 to December 2010. For persistence analyses, 12,412 women on tamoxifen, 2,796 on anastrozole, 647 on exemestane, and 1,657 on letrozole met the inclusion/exclusion criteria. Within 3 years of follow-up, the discontinuation rates increased to 52.2 % for tamoxifen, 47 % for anastrozole, 55.1 % for exemestane, and 44.3 % for letrozole treated women. A minor proportion of patients switched to a different endocrine treatment; 33 % tamoxifen, 20 % anastrozole, 22.9 % exemestane, and 23 % letrozole. The multivariate hazard ratios of the cox regression models showed that patients younger than 50 were most likely to discontinue initial therapy when compared with the reference group of women over 70 (p < 0.001). In contrast, patients treated in gynecologist practice had significantly longer persistence than patients who obtained their prescriptions in general practitioner practice (p < 0.001). In addition, the presence of the co morbidities like diabetes (p < 0.001) or depression (p < 0.002) was also associated with decreased risk of treatment discontinuation. Persistence with all endocrine treatments in women with hormone-receptor-positive BC is low and needs to be significantly increased to improved outcome in clinical practice. Further research is required to understand this complex issue.

 

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[57]

TÍTULO / TITLE:  - Independent Validation of a Prognostic Genomic Signature (ColoPrint) for Patients With Stage II Colon Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Surg. 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1097/SLA.0b013e31827c1180

AUTORES / AUTHORS:  - Maak M; Simon I; Nitsche U; Roepman P; Snel M; Glas AM; Schuster T; Keller G; Zeestraten E; Goossens I; Janssen KP; Friess H; Rosenberg R

INSTITUCIÓN / INSTITUTION:  - *Department of Surgery, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany daggerAgendia NV, Amsterdam, The Netherlands Departments of double daggerEpidemiology and Statistics section signPathology, Technische Universitat Munchen, Munich, Germany paragraph signDepartment of Surgery, Leiden  University Medical Center, Leiden, The Netherlands ||Department of Surgery, Kantonsspital, Baden, Switzerland.

RESUMEN / SUMMARY:  - OBJECTIVES:: The aim of this study was to independently validate a genomic signature developed both to assess recurrence risk in stage II patients and to assist in treatment decisions. BACKGROUND:: Adjuvant therapy is recommended for high-risk patients with stage II colon cancer, but better tools to assess the patients’ prognosis accurately are still required. METHODS:: Previously, an 18-gene signature had been developed and validated on an independent cohort, using full genome microarrays. In this study, the gene signature was translated and validated as a robust diagnostic test (ColoPrint), using customized 8-pack arrays. In addition, clinical validation of the diagnostic ColoPrint assay was performed on 135 patients who underwent curative resection (R0) for colon cancer  stage II in Munich. Fresh-frozen tissue, microsatellite instability status, clinical parameters, and follow-up data for all patients were available. The diagnostic ColoPrint readout was determined blindly from the clinical data. RESULTS:: ColoPrint identified most stage II patients (73.3%) as at low risk. The 5-year distant-metastasis free survival was 94.9% for low-risk patients and 80.6% for high-risk patients. In multivariable analysis, ColoPrint was the only significant parameter to predict the development of distant metastasis with a hazard ratio of 4.28 (95% confidence interval, 1.36-13.50; P = 0.013). Clinical risk parameters from the American Society of Clinical Oncology (ASCO) recommendation did not add power to the ColoPrint classification. Technical validation of ColoPrint confirmed stability and reproducibility of the diagnostic platform. CONCLUSIONS:: ColoPrint is able to predict the development of distant metastasis of patients with stage II colon cancer and facilitates the identification of patients who may be safely managed without chemotherapy.

 

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[58]

TÍTULO / TITLE:  - Telomerase is an independent prognostic marker of overall survival in patients with colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 15. doi: 10.1038/bjc.2012.602.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2012.602

AUTORES / AUTHORS:  - Bertorelle R; Briarava M; Rampazzo E; Biasini L; Agostini M; Maretto I; Lonardi S; Friso ML; Mescoli C; Zagonel V; Nitti D; De Rossi A; Pucciarelli S

INSTITUCIÓN / INSTITUTION:  - Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto, IRCCS, Via Gattamelata 64, 35128 Padova, Italy.

RESUMEN / SUMMARY:  - Background:Colorectal cancer (CRC) is an important cause of cancer-related death. Prediction of recurrence is an important issue in the treatment of disease, particularly for stage II patients. The level of telomere-specific reverse transcriptase (hTERT), the catalytic component of the telomerase complex, increases along with CRC progression, but its prognostic value is still unclear.Methods:One hundred and thirty-seven CRC patients were studied for hTERT  expression in tumour cells by real-time PCR. hTERT level was evaluated as a prognostic factor of overall survival (OS) in all patients and of disease recurrence in a subgroup of 50 stage II patients.Results:The median hTERT level was 93.8 copies (interquartile range 48-254). Patients with high hTERT levels (above the median) showed a significantly worse survival than those with low hTERT levels (below the median; log-rank test P<0.0001; hazard ratio (HR)=3.30 (95% confidence interval (CI) 1.98-5.52); P<0.0001). The negative prognostic value of high hTERT level is independent of the pathological stage and microsatellite instability (HR=2.09 (95% CI 1.20-3.64), P=0.009). Moreover, in stage II CRC, high hTERT levels identified patients with a higher risk of disease recurrence (HR=3.06 (95% CI 1.03-9.04), P=0.043) and death (HR=3.24 (95% CI 1.37-7.71), P=0.008).Conclusion:hTERT level is an independent prognostic marker of OS in CRC patients. In addition, assessment of hTERT level could improve stratification of stage II CRC patients for the risk of disease recurrence.British Journal of Cancer advance online publication, 15 January 2013; doi:10.1038/bjc.2012.602 www.bjcancer.com.

 

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[59]

TÍTULO / TITLE:  - Role of EGFR SNPs in survival of advanced lung adenocarcinoma patients treated with Gefitinib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Gene. 2013 Jan 9. pii: S0378-1119(12)01646-0. doi: 10.1016/j.gene.2012.12.087.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.gene.2012.12.087

AUTORES / AUTHORS:  - Zhang L; Yuan X; Chen Y; Du XJ; Yu S; Yang M

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.

RESUMEN / SUMMARY:  - AIM: As a novel molecularly targeting agent for non-small-cell lung cancer (NSCLC), Gefitinib can block its tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Genetic variations in EGFR may affect its protein function or expression and lead to diverse outcomes in NSCLC patients after Gefitinib therapy. Therefore, this prospective study examined whether EGFR single nucleotide polymorphisms (SNPs) are associated with different survival time in advanced lung adenocarcinoma patients treated with Gefitinib. METHODS: One hundred and twenty-eight patients with stage IIIB or IV lung adenocarcinoma receiving Gefitinib target therapy between 2008 and 2010 were recruited in this study. Six EGFR haplotype-tagging SNPs were genotyped by the Sequenom MassArray system. Survival by different genotypes was compared using Kaplan-Meier methods.  Cox proportional hazards models were applied to estimate the effect of prognostic factors on overall survival (OS) and progression-free survival (PFS). RESULTS: After the median 16.6months of follow-up, the unfavorable EGFR rs2293347AA or GA  genotype was significantly correlated with shorter OS (AA vs. GG: 2.0 vs. 21.0months; hazard ratio (HR)=2.44, 95% confidence interval (CI)=1.06-5.56; P=0.036; GA vs. GG: 15.0 vs. 21.0months; HR=1.75, 95%CI=1.08-2.86, P=0.025) compared with the favorable rs2293347GG genotype. The prognostic significance of  EGFR rs4947492 polymorphism on OS also existed (GG carriers vs. AA carriers: median OS=24.6 vs. 14.9months, HR=0.29, 95%CI=0.10-0.83, P=0.021). No significant associations were found among other EGFR SNPs and survival. CONCLUSION: EGFR rs2293347 and rs4947492 SNPs might be potential predictive markers of OS in advanced lung adenocarcinoma patients treated with Gefitinib.

 

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[60]

TÍTULO / TITLE:  - Erratum to: Identification of clinical predictive factors of oxaliplatin-induced  chronic peripheral neuropathy in colorectal cancer patients treated with adjuvant Folfox IV.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Support Care Cancer. 2013 Jan 25.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00520-013-1724-8

AUTORES / AUTHORS:  - Vincenzi B; Frezza AM; Schiavon G; Spoto C; Silvestris N; Addeo R; Catalano V; Graziano F; Santini D; Tonini G

INSTITUCIÓN / INSTITUTION:  - Medical Oncology, Universita Campus Bio-Medico, Via Alvaro del Portillo 200, 00128, Rome, Italy.

 

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[61]

TÍTULO / TITLE:  - Identification of clinical predictive factors of oxaliplatin-induced chronic peripheral neuropathy in colorectal cancer patients treated with adjuvant Folfox  IV.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Support Care Cancer. 2012 Nov 30.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00520-012-1667-5

AUTORES / AUTHORS:  - Vincenzi B; Frezza AM; Schiavon G; Spoto C; Addeo R; Catalano V; Graziano F; Santini D; Tonini G

INSTITUCIÓN / INSTITUTION:  - Medical Oncology, Universita Campus Bio-Medico, Via Alvaro del Portillo 200, 00128, Rome, Italy.

RESUMEN / SUMMARY:  - PURPOSE: Oxaliplatin-induced neuropathy is a dose-related side effect which occurs in almost 40 % of patients treated with oxaliplatin. Aim of the present study was to identify reliable clinical factors predicting its development and duration. METHODS: One hundred sixty-nine completely resected colorectal cancer patients treated with adjuvant Folfox IV regimen were retrospectively included. The following pre-treatment clinical parameters were collected: hypocalcaemia, hypomagnesaemia, hypoalbuminaemia, anaemia, diabetes, chronic renal failure (CRF), folate deficiency, vitamin B(12) deficiency, number of cycles received and habit to alcohol consumption. Incidence, grade (NCI-CTCAE v.3) and duration of neuropathy were recorded. RESULTS: Incidence of neuropathy was found to be higher in patients with pre-treatment anaemia (p = 0.001), hypoalbuminaemia (p = 0.01) and hypomagnesaemia (p = 0.001) as well in those with habit to alcohol consumption (p = 0.003). Neuropathy durations were conversely associated with age, being longer in younger patients (p = 0.03), and again with hypoalbuminaemia (p = 0.04) and hypomagnesaemia (p = 0.002). No correlation was found with gender, hypocalcaemia, diabetes and CRF. The correlation between vitamin B(12) and folate levels and the development of neurotoxicity were not analysed because of the high number of missing data in the population. CONCLUSIONS: Age, anaemia, hypoalbuminaemia, hypomagnesaemia and alcohol consumption are reliable and easily assessable clinical factors predicting incidence and length of oxaliplatin-induced neuropathy.

 

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[62]

TÍTULO / TITLE:  - Isolated central nervous system relapse in patient with blast-crisis chronic myeloid leukemia in durable complete cytogenetic remission on dasatinib treatment: pharmacokinetics and ABL mutation analysis in cerebrospinal fluid.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Lymphoma. 2012 Dec 22.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2012.745933

AUTORES / AUTHORS:  - Zhou HS; Dai M; Wei Y; Wang Q; Xu N; Yin C; Meng F

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou , China.

 

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[63]

TÍTULO / TITLE:  - A Phase II Study of Sorafenib in Patients with Platinum-Pretreated, Advanced (Stage IIIb or IV) Non-Small Cell Lung Cancer with a KRAS Mutation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-1779

AUTORES / AUTHORS:  - Dingemans AM; Mellema WW; Groen HJ; van Wijk A; Burgers SA; Kunst PW; Thunnissen E; Heideman DA; Smit EF

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Department of Pulmonary Diseases and GROW- School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht; Departments of Pulmonology and Pathology, VU University Medical Center; Department of Thoracic Oncology, Netherlands Cancer Institute; Department of Pulmonology, Academic Medical Center, Amsterdam; and Department of Pulmonology, University Medical Center Groningen, Groningen, the Netherlands.

RESUMEN / SUMMARY:  - PURPOSE: Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non-small cell  lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib.EXPERIMENTAL DESIGN: In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity.  Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks.RESULTS: Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = +/-8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0-1.9] but not OS (HR, 1.3; 95% CI, 0.9-1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%).CONCLUSION: Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent  or combination therapy. Clin Cancer Res; 19(3); 1-9. ©2012 AACR.

 

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[64]

TÍTULO / TITLE:  - Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: Analysis of data from the EXTREME and CRYSTAL studies.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Cancer. 2012 Dec 19. pii: S0959-8049(12)00914-8. doi: 10.1016/j.ejca.2012.11.018.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2012.11.018

AUTORES / AUTHORS:  - Licitra L; Storkel S; Kerr KM; Van Cutsem E; Pirker R; Hirsch FR; Vermorken JB; von Heydebreck A; Esser R; Celik I; Ciardiello F

INSTITUCIÓN / INSTITUTION:  - Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori,  Milan, Italy.

RESUMEN / SUMMARY:  - BACKGROUND: The phase III EXTREME and CRYSTAL studies demonstrated that the addition of cetuximab to chemotherapy significantly improved survival in the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head  and neck (SCCHN) and KRAS wild-type metastatic colorectal cancer (mCRC). In advanced non-small-cell lung cancer (NSCLC), high EGFR expression was identified  as a tumour biomarker that can predict survival benefit associated with the addition of cetuximab to first-line chemotherapy. We investigated whether tumour  EGFR expression level was predictive of cetuximab benefit in EXTREME and CRYSTAL  study patients. METHODS: Prospectively collected tumour immunohistochemistry data were used to generate an EGFR immunohistochemistry score (scale 1-300) for patients in the EXTREME and CRYSTAL studies. For each study, the association between tumour immunohistochemistry score and cetuximab benefit was investigated. The EXTREME and CRYSTAL studies are registered with Clinical Trials.gov, numbers  NCT00122460 and NCT00154102, respectively. FINDINGS: Tumour EGFR immunohistochemistry data were available for 411 of 442 (93%) patients from the EXTREME study intention-to-treat (ITT) population and 664 of 666 (100%) patients  from the ITT population of the CRYSTAL study with EGFR-expressing, KRAS wild-type disease. The distribution of immunohistochemistry scores was similar between the  treatment arms of each study, but differed between studies. A clinically relevant benefit for progression-free and overall survival associated with the addition of cetuximab to chemotherapy was seen across the full score range in EXTREME study patients. Similarly, CRYSTAL study patients derived a clinical benefit across the full score range, with no meaningful association between EGFR expression level and benefit. INTERPRETATION: The addition of cetuximab to chemotherapy improved survival in the first-line treatment of recurrent/metastatic SCCHN and KRAS wild-type mCRC regardless of tumour EGFR expression level, indicating that in contrast to findings in NSCLC, EGFR expression level is not a clinically useful predictive biomarker in these settings.

 

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[65]

TÍTULO / TITLE:  - Gene mutation profiles and prognostic implications in Korean patients with T-lymphoblastic leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Hematol. 2013 Jan 25.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00277-012-1664-2

AUTORES / AUTHORS:  - Huh HJ; Lee SH; Yoo KH; Sung KW; Koo HH; Jang JH; Kim K; Kim SJ; Kim WS; Jung CW; Lee KO; Kim SH; Kim HJ

INSTITUCIÓN / INSTITUTION:  - Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, South Korea.

RESUMEN / SUMMARY:  - Genetic alterations implicated in the leukemogenesis of T cell acute lymphoblastic leukemia (T-ALL) have been identified in recent years. In this study, we investigated gene mutation profiles and prognostic implications in a series of Korean T-ALL patients. The study patients were 29 Korean patients with  T-ALL; 13 adults (45 %) and 16 children (55 %; male-to-female ratio, 25:4). Clinical, hematologic, and cytogenetic findings were reviewed. We performed mutation analyses for NOTCH1, FBXW7, PHF6, and IL7R genes and survival analyses according to the mutational status. Gene mutations were identified in 66 % of the patients in our series (19/29). Eighteen patients (62 %) had NOTCH1/FBXW7 mutations. Sixteen patients (55 %) had NOTCH1 mutations including nine novel mutations, and eight patients (28 %) had known FBXW7 mutations. Eight patients (28 %; six males and two females) had PHF6 mutations including four novel mutations. Three patients (10 %) had IL7R mutations, which were all novel in-frame insertion or deletion-insertions. The gene mutation profile combined with cytogenetics and FISH study for the p16 gene detected genetic aberrations in 90 % of patients (26/29). There was no significant difference in the frequency of gene mutations between the pediatric and adult patients with T-ALL. Survival analyses suggested a favorable prognostic implication of NOTCH1 mutations in adult T-ALL. Gene mutation studies for NOTCH1, FBXW7, PHF6, and IL7R could detect genetic alterations in a majority of Korean T-ALL patients with novel mutations.  We observed similar mutation profiles between adult and pediatric T-ALL, and a favorable prognostic implication of NOTCH1 mutations in adult T-ALL.

 

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[66]

TÍTULO / TITLE:  - Effect of HER2 on prognosis and benefit from peri-operative chemotherapy in early oesophago-gastric adenocarcinoma in the MAGIC trial.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Oncol. 2012 Dec 11.

            ●● Enlace al texto completo (gratuito o de pago) 1093/annonc/mds622

AUTORES / AUTHORS:  - Okines AF; Thompson LC; Cunningham D; Wotherspoon A; Reis-Filho JS; Langley RE; Waddell TS; Noor D; Eltahir Z; Wong R; Stenning S

INSTITUCIÓN / INSTITUTION:  - Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.

RESUMEN / SUMMARY:  - BackgroundPerioperative epirubicin, cisplatin and fluorouracil (ECF) chemotherapy improves survival in operable oesophago-gastric cancer [Adjuvant Gastric Cancer Infusional Chemotherapy (MAGIC) trial HR 0.75 (0.6-0.93)]. HER2 amplification is  reported to predict enhanced benefit from anthracyclines in breast cancer. We sought to define whether HER2 predicts benefit from ECF in oesophago-gastric cancer.Patients and methodsDiagnostic biopsies and/or resection specimens were collected from 415 of 503 MAGIC trial patients (82.5%). HER2 was evaluated by immunohistochemistry (IHC) and brightfield dual in situ hybridisation (BDISH) in  tissue microarrays. The prognostic and predictive impact of HER2 status was investigated.ResultsConcordance between HER2 over-expression (IHC3+) and amplification was 96%. Results of HER2 assessment in biopsy and resection specimens were concordant in 92.9% (145/156). HER2 positive rate (IHC3+, or IHC2+/BDISH positive) was 10.9% in the whole cohort and 10.4% in resection specimens. A further 4.0% of resections were IHC negative/BDISH positive. HER2 status was neither prognostic, nor (in pre-treatment biopsies) predicted enhanced benefit from chemotherapy [HER2 positive HR 0.74 (0.14-3.77); HER2 negative HR 0.58 (0.41-0.82), interaction P = 0.7]. However, the power of the predictive analysis was limited by the small number of HER2 positive pre-treatment biopsies.ConclusionsHER2 status is not an independent prognostic biomarker in early oesophago-gastric adenocarcinoma.

 

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[67]

TÍTULO / TITLE:  - DNA Ploidy is an Independent Predictor of Survival in Breast Invasive Ductal Carcinoma: A Long-term Multivariate Analysis of 393 Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Surg Oncol. 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1245/s10434-012-2804-6

AUTORES / AUTHORS:  - Pinto AE; Pereira T; Santos M; Branco M; Dias A; Silva GL; Ferreira MC; Andre S

INSTITUCIÓN / INSTITUTION:  - Servico de Anatomia Patologica, Instituto Portugues de Oncologia de Lisboa, EPE,  Lisbon, Portugal, aepinto@ipolisboa.min-saude.pt.

RESUMEN / SUMMARY:  - PURPOSE: To evaluate “classic” prognostic parameters, as well as DNA ploidy and S-phase fraction (SPF), in relation to disease-free (DFS) and disease-specific (DSS) survival in breast invasive ductal carcinoma (IDC) with long-term follow-up study. METHODS: The study involved 393 patients with IDC and median follow-up of  134 months (50-240). Histological grading, tumor size, axillary nodal involvement, pathological staging and hormone receptor status were considered as  established prognostic markers. Ploidy and SPF were determined prospectively by DNA flow cytometry using fresh/frozen tissue. A Cox regression model was used for statistical analysis of the prognostic variables. RESULTS: There were 105 (26.7 %) deaths and 140 (35.6 %) disease recurrences during follow-up. Two hundred thirty-one (58.8 %) tumors were aneuploid. High SPF and aneuploidy were associated with tumors with higher grade of differentiation, greater size and negative hormone receptors. Higher SPF and advanced disease stage are correlated. In univariate analysis, all the clinicopathological and cytometric features, including patients <40 years and a subgroup presenting hypertetraploid/multiploid tumors, are significantly correlated with clinical outcome, apart from SPF and estrogen receptors for DFS. In multivariate analysis, nodal involvement, DNA aneuploidy and lack of progesterone receptors (for DSS) retained statistically significant association with shorter survival. In node-negative patients, ploidy  (for DFS) and estrogen receptors (for DSS) significantly predicted survival. In both subgroups of node-positive patients and those (n = 195) with intermediate differentiation tumors (G2), aneuploidy was an indicator of worse prognosis. CONCLUSIONS: Along with nodal status and hormone receptor expression, DNA ploidy  is an independent predictor of long-term survival in IDC.

 

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[68]

TÍTULO / TITLE:  - Prognostic Significance of Carbohydrate Antigen 19-9 in Unresectable Locally Advanced Pancreatic Cancer Treated With Dose-Escalated Intensity Modulated Radiation Therapy and Concurrent Full-Dose Gemcitabine: Analysis of a Prospective Phase ½ Dose Escalation Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Radiat Oncol Biol Phys. 2012 Dec 19. pii: S0360-3016(12)03817-5. doi: 10.1016/j.ijrobp.2012.11.020.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ijrobp.2012.11.020

AUTORES / AUTHORS:  - Vainshtein JM; Schipper M; Zalupski MM; Lawrence TS; Abrams R; Francis IR; Khan G; Leslie W; Ben-Josef E

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. Electronic address: jvainsh@med.umich.edu.

RESUMEN / SUMMARY:  - PURPOSE: Although established in the postresection setting, the prognostic value  of carbohydrate antigen 19-9 (CA19-9) in unresectable locally advanced pancreatic cancer (LAPC) is less clear. We examined the prognostic utility of CA19-9 in patients with unresectable LAPC treated on a prospective trial of intensity modulated radiation therapy (IMRT) dose escalation with concurrent gemcitabine. METHODS AND MATERIALS: Forty-six patients with unresectable LAPC were treated at  the University of Michigan on a phase ½ trial of IMRT dose escalation with concurrent gemcitabine. CA19-9 was obtained at baseline and during routine follow-up. Cox models were used to assess the effect of baseline factors on freedom from local progression (FFLP), distant progression (FFDP), progression-free survival (PFS), and overall survival (OS). Stepwise forward regression was used to build multivariate predictive models for each endpoint. RESULTS: Thirty-eight patients were eligible for the present analysis. On univariate analysis, baseline CA19-9 and age predicted OS, CA19-9 at baseline and 3 months predicted PFS, gross tumor volume (GTV) and black race predicted FFLP, and CA19-9 at 3 months predicted FFDP. On stepwise multivariate regression modeling, baseline CA19-9, age, and female sex predicted OS; baseline CA19-9 and  female sex predicted both PFS and FFDP; and GTV predicted FFLP. Patients with baseline CA19-9 </=90 U/mL had improved OS (median 23.0 vs 11.1 months, HR 2.88,  P<.01) and PFS (14.4 vs 7.0 months, HR 3.61, P=.001). CA19-9 progression over 90  U/mL was prognostic for both OS (HR 3.65, P=.001) and PFS (HR 3.04, P=.001), and  it was a stronger predictor of death than either local progression (HR 1.46, P=.42) or distant progression (HR 3.31, P=.004). CONCLUSIONS: In patients with unresectable LAPC undergoing definitive chemoradiation therapy, baseline CA19-9 was independently prognostic even after established prognostic factors were controlled for, whereas CA19-9 progression strongly predicted disease progression and death. Future trials should stratify by baseline CA19-9 and incorporate CA19-9 progression as a criterion for progressive disease.

 

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[69]

TÍTULO / TITLE:  - The endoplasmic reticulum stress marker, glucose-regulated protein-78 (GRP78) in  visceral adipocytes predicts endometrial cancer progression and patient survival.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Gynecol Oncol. 2012 Nov 28. pii: S0090-8258(12)00890-6. doi: 10.1016/j.ygyno.2012.11.024.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ygyno.2012.11.024

AUTORES / AUTHORS:  - Matsuo K; Gray MJ; Yang DY; Srivastava SA; Tripathi PB; Sonoda LA; Yoo EJ; Dubeau L; Lee AS; Lin YG

INSTITUCIÓN / INSTITUTION:  - Division of Gynecologic Oncology, Department of Obstetrics/Gynecology, University of Southern California, Los Angeles, CA, USA.

RESUMEN / SUMMARY:  - OBJECTIVE: Currently, accurately identifying endometrial cancer patients at high  risk for recurrence remains poor. To ascertain if changes in the endoplasmic reticulum (ER) stress marker, glucose-regulated-protein-78 (GRP78) can serve as a prognosticator in endometrial cancer, we examined GRP78 expression in patient samples to determine its association with clinical outcome. METHODS: A retrospective cohort study was conducted in endometrial cancer patients. Archived specimens of visceral adipocytes and paired endometrial tumors were analyzed by immunohistochemistry for GRP78 and another ER stress marker, C/EBP homologous protein (CHOP). Expression of these markers was correlated with clinico-pathological information and outcomes. RESULTS: GRP78 expression in visceral adipocytes was detected in 95% of the 179 endometrial cancer patients with analyzable visceral adipocytes. Within individual samples, 24% of adipocytes (range, 0-90%, interquartile range 18%-38%) exhibited GRP78 expression. High visceral adipocyte GRP78 expression positively correlated with advanced-stage disease (p=0.007) and deep myometrial invasion (p=0.004). High visceral adipocyte GRP78 expression was significantly associated with decreased disease-free survival (DFS) in multivariate analyses (hazard ratio 2.88, 95% CI 1.37-6.04, p=0.005). CHOP expression paralleled the GRP78 expression in adipocytes (r=0.55,  p<0.001) and in the tumor (p=0.018). CONCLUSIONS: Our study demonstrates that the ER stress markers, GRP78 and CHOP, are elevated in endometrial cancer patients. Furthermore, GRP78 expression levels in visceral adipocytes from these patients were significantly correlated to disease stage and patient survival. Our results  demonstrate, for the first time, that the GRP78 levels in endometrial cancer patients may be a prognosticator and aid with clinical risk stratification and focused surveillance.

 

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[70]

TÍTULO / TITLE:  - Glutathione S-transferase M1-null genotype as risk factor for SOS in oxaliplatin-treated patients with metastatic colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 3. doi: 10.1038/bjc.2012.590.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2012.590

AUTORES / AUTHORS:  - Vreuls CP; Olde Damink SW; Koek GH; Winstanley A; Wisse E; Cloots RH; van den Broek MA; Dejong CH; Bosman FT; Driessen A

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Maastricht University Medical Centre, Maastricht, The Netherlands.

RESUMEN / SUMMARY:  - Background:Oxaliplatin is used as a neo-adjuvant therapy in hepatic colorectal carcinoma metastasis. This treatment has significant side effects, as oxaliplatin is toxic to the sinusoidal endothelial cells and can induce sinusoidal obstruction syndrome (SOS), which is related to decreased overall survival. Glutathione has an important role in the defence system, catalysed by glutathione S-transferase (GST), including two non-enzyme producing polymorphisms (GSTM1-null and GSTT1-null). We hypothesise that patients with a non-enzyme producing polymorphism have a higher risk of developing toxic injury owing to oxaliplatin.Methods:In the nontumour-bearing liver, the presence of SOS was studied histopathologically. The genotype was determined by a semi-nested PCR.Results:Thirty-two of the 55 (58%) patients showed SOS lesions, consisting of 27% mild, 22% moderate and 9% severe lesions. The GSTM1-null genotype was present in 25 of the 55 (46%). Multivariate analysis showed that the GSTM1-null genotype  significantly correlated with the presence of (moderate-severe) SOS (P=0.026).Conclusion:The GSTM1-null genotype is an independent risk factor for SOS. This finding allows us, in association with other risk factors, to conceive  a potential risk profile predicting whether the patient is at risk of developing  SOS, before starting oxaliplatin, and subsequently might result in adjustment of  treatment.British Journal of Cancer advance online publication, 3 January 2013; doi:10.1038/bjc.2012.590 www.bjcancer.com.

 

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[71]

TÍTULO / TITLE:  - Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leukemia. 2012 Nov 6. doi: 10.1038/leu.2012.312.

            ●● Enlace al texto completo (gratuito o de pago) 1038/leu.2012.312

AUTORES / AUTHORS:  - Craddock C; Quek L; Goardon N; Freeman S; Siddique S; Raghavan M; Aztberger A; Schuh A; Grimwade D; Ivey A; Virgo P; Hills R; McSkeane T; Arrazi J; Knapper S; Brookes C; Davies B; Price A; Wall K; Griffiths M; Cavenagh J; Majeti R; Weissman I; Burnett A; Vyas P

INSTITUCIÓN / INSTITUTION:  - 1] Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, UK [2]  Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham, UK.

RESUMEN / SUMMARY:  - Epigenetic therapies demonstrate significant clinical activity in acute myeloid leukemia (AML) and myelodysplasia (MDS) and constitute an important new class of  therapeutic agents. However hematological responses are not durable and disease relapse appears inevitable. Experimentally, leukemic stem/progenitor cells (LSC)  propagate disease in animal models of AML and it has been postulated that their relative chemo-resistance contributes to disease relapse. We serially measured LSC numbers in patients with high-risk AML and MDS treated with 5’-azacitidine and sodium valproate (VAL-AZA). Fifteen out of seventy-nine patients achieved a complete remission (CR) or complete remission with incomplete blood count recovery (CRi) with VAL-AZA therapy. There was no significant reduction in the size of the LSC-containing population in non-responders. While the LSC-containing population was substantially reduced in all patients achieving a CR/CRi it was never eradicated and expansion of this population antedated morphological relapse. Similar studies were performed in seven patients with newly diagnosed AML treated with induction chemotherapy. Eradication of the LSC-containing population was observed in three patients all of whom achieved a durable CR in contrast to patients with resistant disease where LSC persistence was observed. LSC quantitation provides a novel biomarker of disease response and relapse in patients with AML treated with epigenetic therapies. New drugs that target this cellular population in vivo are required.Leukemia advance online publication, 7 December 2012; doi:10.1038/leu.2012.312.

 

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[72]

TÍTULO / TITLE:  - Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B cell receptor signaling.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Blood. 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1182/blood-2012-08-452607

AUTORES / AUTHORS:  - Burger JA; Montserrat E

INSTITUCIÓN / INSTITUTION:  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;

RESUMEN / SUMMARY:  - Chronic lymphocytic leukemia (CLL) cells proliferate in pseudofollicles within the lymphatic tissues, where signals from the microenvironment and B cell receptor (BCR) signaling drive the expansion of the CLL clone. Mobilization of tissue-resident cells into the blood removes CLL cells from this nurturing milieu and sensitizes them to cytotoxic drugs. This concept recently gained momentum after establishing the clinical activity of kinase inhibitors that target BCR signaling (SYK, BTK, PI3Kdelta inhibitors). Besides anti-proliferative activity,  these drugs cause CLL cell redistribution with rapid lymph node shrinkage, along  with a transient surge in lymphocytosis, prior to inducing objective remissions.  Inactivation of critical CLL homing mechanism (chemokine receptors, adhesion molecules), thwarting tissue retention and recirculation into the tissues, appears to be the basis for this striking clinical activity. This effect of BCR-signaling inhibitors resembles re-distribution of CLL cells after glucocorticoids, described as early as in the 1940s. As such, we are witnessing a renaissance of the concept of leukemia cell redistribution in modern CLL therapy. Here, we review the molecular basis of CLL cell trafficking, homing, and redistribution, and similarities between old and new drugs affecting these processes. Also, we outline how these discoveries are changing our understanding  of CLL biology and therapy.

 

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[73]

TÍTULO / TITLE:  - Prognostic value of CA 19-9, CEA, CRP, LDH and bilirubin levels in locally advanced and metastatic pancreatic cancer: results from a multicenter, pooled analysis of patients receiving palliative chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Cancer Res Clin Oncol. 2013 Jan 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00432-012-1371-3

AUTORES / AUTHORS:  - Haas M; Heinemann V; Kullmann F; Laubender RP; Klose C; Bruns CJ; Holdenrieder S; Modest DP; Schulz C; Boeck S

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377,  Munich, Germany.

RESUMEN / SUMMARY:  - PURPOSE: CA 19-9 is the only established tumor marker in pancreatic cancer (PC);  the prognostic role of other serum markers like CEA, CRP, LDH or bilirubin has not yet been defined. METHODS: We pooled pre-treatment data on CA 19-9, CEA, CRP, LDH and bilirubin levels from two German multicenter randomized phase II trials together with prospective patient data from one high-volume German Cancer Center. Marker levels were assessed locally before the start of palliative first-line therapy for advanced PC and serially during treatment (for CA 19-9 only). Clinical and biomarker data (overall 12 variables) were correlated with the efficacy endpoints time-to-progression (TTP) and overall survival (OS) by using uni- and multivariate Cox models. RESULTS: Data from 291 patients were included in this pooled analysis; 253 patients (87 %) received treatment within prospective clinical trials. Median TTP in the study cohort was 5.1 months and median OS 9.0 months. In univariate analysis, pre-treatment CA 19-9 (HR 1.55), LDH (HR 2.04) and CEA (HR 1.89) levels were significantly associated with TTP. Regarding OS, baseline CA 19-9 (HR 1.46), LDH (HR 2.07), CRP (HR 1.69) and bilirubin (HR 1.62) were significant prognostic factors. Within multivariate analyses, pre-treatment log [CA 19-9] (as continuous variable for TTP) and log [bilirubin] as well as log [CRP] (for OS) had an independent prognostic value. A  CA 19-9 decline of >/=25 % during the first two chemotherapy cycles was predictive for TTP and OS, independent of the applied CA 19-9 assay. CONCLUSION:  Baseline CA 19-9 and CA 19-9 kinetics during first-line chemotherapy are prognostic in advanced PC. Besides that finding other serum markers like CRP, LDH and bilirubin can also provide prognostic information on TTP and OS.

 

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[74]

TÍTULO / TITLE:  - Combined Treatment With Peroxisome Proliferator-Activated Receptor (PPAR) Gamma Ligands and Gamma Radiation Induces Apoptosis by PPARgamma-Independent Up-Regulation of Reactive Oxygen Species-Induced Deoxyribonucleic Acid Damage Signals in Non-Small Cell Lung Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Radiat Oncol Biol Phys. 2013 Jan 16. pii: S0360-3016(12)03838-2. doi: 10.1016/j.ijrobp.2012.11.040.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ijrobp.2012.11.040

AUTORES / AUTHORS:  - Han EJ; Im CN; Park SH; Moon EY; Hong SH

INSTITUCIÓN / INSTITUTION:  - Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.

RESUMEN / SUMMARY:  - PURPOSE: To investigate possible radiosensitizing activities of the well-known peroxisome proliferator-activated receptor (PPAR)gamma ligand ciglitazone and novel PPARgamma ligands CAY10415 and CAY10506 in non-small cell lung cancer (NSCLC) cells. METHODS AND MATERIALS: Radiosensitivity was assessed using a clonogenic cell survival assay. To investigate the mechanism underlying PPARgamma ligand-induced radiosensitization, the subdiploid cellular DNA fraction was analyzed by flow cytometry. Activation of the caspase pathway by combined PPARgamma ligands and gamma-radiation treatment was detected by immunoblot analysis. Reactive oxygen species (ROS) were measured using 2,7-dichlorodihydrofluorescein diacetate and flow cytometry. RESULTS: The 3 PPARgamma ligands induced cell death and ROS generation in a PPARgamma-independent manner, enhanced gamma-radiation-induced apoptosis and caspase-3-mediated poly (ADP-ribose) polymerase (PARP) cleavage in vitro. The combined PPARgamma ligand/gamma-radiation treatment triggered caspase-8 activation, and this initiator caspase played an important role in the combination-induced apoptosis. Peroxisome proliferator-activated receptor-gamma ligands may enhance the gamma-radiation-induced DNA damage response, possibly by  increasing gamma-H2AX expression. Moreover, the combination treatment significantly increased ROS generation, and the ROS scavenger N-acetylcysteine inhibited the combined treatment-induced ROS generation and apoptotic cell death. CONCLUSIONS: Taken together, these results indicated that the combined treatment  of PPARgamma ligands and gamma-radiation synergistically induced DNA damage and apoptosis, which was regulated by ROS.

 

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[75]

TÍTULO / TITLE:  - A patient with retroperitoneal fibrosis treated with tamoxifen who develops pancreatic carcinoma: remarks regarding the presence of estrogen receptors-a relationship between fibrosis and neoplastic processes?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pancreas. 2013 Jan;42(1):174-5. doi: 10.1097/MPA.0b013e318255adec.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MPA.0b013e318255adec

AUTORES / AUTHORS:  - Velciov S; Gluhovschi C; Petrica L; Gluhovschi A

INSTITUCIÓN / INSTITUTION:  - Department of Nephrology County Emergency Hospital Timisoara “V. Babes” University of Medicine and Pharmacy Timisoara, Romania s_velciov@yahoo.com Department of Obstetrics and Gynecology County Emergency Hospital Timisoara “V. Babes” University of Medicine and Pharmacy Timisoara, Romania.

 

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[76]

TÍTULO / TITLE:  - Expression of PTEN and survivin in cervical cancer: promising biological markers  for early diagnosis and prognostic evaluation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Biomed Sci. 2012;69(4):143-6.

AUTORES / AUTHORS:  - Lu D; Qian J; Yin X; Xiao Q; Wang C; Zeng Y

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, Yangzhou University Medical College, Yangzhou, P R. China. ludan1968@yahoo.com.cn

RESUMEN / SUMMARY:  - This study aims to evaluate the expression of the antioncogene phosphatase and tensin (PTEN) homologue and survivin, a protein encoded by the anti-apoptotic gene baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5), in the progression of cervical neoplasia and to elucidate the relationship between PTEN  and survivin expression based on clinicopathological features in squamous cell carcinoma of the uterine cervix. A total of 20 patients with cervical ectropion and squamous metaplasia, 30 with cervical intraepithelial neoplasia, and 49 with  cervical squamous cell carcinoma were enrolled in the study. Immunohistochemical  staining was performed to detect PTEN and survivin expression in each group. Normal cervical epithelium from 10 people served as the control. Results showed that PTEN expression progressively decreased with the continuum from normal epithelium to squamous cell carcinoma (P < 0.05), whereas survivin expression progressively increased (P < 0.05). Furthermore, positive PTEN immunostaining was associated with clinical stage and tumour size (P < 0.05). The level of PTEN expression in the metastatic pelvic lymph node group was significantly lower compared with the non-metastatic pelvic lymph node group (P < 0.01). Positive PTEN immunostaining was not associated with age or degree of differentiation (P > 0.05). Positive survivin immunostaining was associated with clinical stage and tumour size (P < 0.05). Survivin-positive expression in the metastatic pelvic lymph node group was significantly higher compared with the nonmetastatic pelvic  lymph node group (P < 0.01). No obvious relationship was found between survivin expression and patient age (P > 0.05). PTEN expression negatively correlated with survivin expression in cervical intraepithelial neoplasia and cervical squamous cell carcinoma (P < 0.01). PTEN and survivin expression correlated with incidence and progression of uterine cervical cancer. Positive expression levels of PTEN and survivin provide potential evaluation indices for early diagnosis and prognosis of uterine cervical cancer, and these biomarkers are also potentially promising therapeutic targets.

 

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[77]

TÍTULO / TITLE:  - beta-Catenin-Dependent Lysosomal Targeting of Internalized Tumor Necrosis Factor-alpha Suppresses Caspase-8 Activation in Apoptosis-Resistant Colon Cancer  Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Biol Cell. 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 1091/mbc.E12-09-0662

AUTORES / AUTHORS:  - Han J; Sridevi P; Ramirez M; Ludwig KJ; Wang JY

INSTITUCIÓN / INSTITUTION:  - Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093-0820.

RESUMEN / SUMMARY:  - The Wnt/beta-catenin pathway is constitutively activated in over 90% of human colorectal cancer. Activated beta-catenin stimulates cell proliferation and survival, however, its anti-apoptotic mechanisms are not fully understood. We show here that activated beta-catenin is required to suppress caspase-8 activation but only in colon cancer cells that are resistant to tumor necrosis factor-a (TNF) induced apoptosis. We found that lysosomal delivery of internalized TNF occurred at a faster pace in apoptosis-resistant than in apoptosis-sensitive colon cancer cells. Retardation of endosomal trafficking through V-ATPase inhibition enhanced caspase-8 activation in the apoptosis-resistant but not sensitive cells. Interestingly, knockdown of beta-catenin also prolonged TNF association with the early endosome and enhanced  caspase-8 activation in the apoptosis-resistant but not sensitive colon cancer cells. In a mouse model of inflammation-associated colon tumors, we found nuclear expression of beta-catenin, resistance to TNF-induced apoptosis, and reactivation of apoptosis in vivo by cotreatment of TNF with a V-ATPase inhibitor. Together, these results suggest that activated beta-catenin can facilitate endosomal trafficking of internalized TNF to suppress caspase-8 activation in colon cancer  cells.

 

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[78]

TÍTULO / TITLE:  - Predictors of Psychopathological Outcome During Peg-Interferon and Ribavirin Therapy in Patients with Chronic HCV-Correlated Hepatitis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Interferon Cytokine Res. 2013 Jan;33(1):9-14. doi: 10.1089/jir.2012.0060. Epub  2012 Dec 31.

            ●● Enlace al texto completo (gratuito o de pago) 1089/jir.2012.0060

AUTORES / AUTHORS:  - Dell’osso B; Prati G; Palazzo MC; Rumi MG; Cavallaro F; Aghemo A; Colombo M; Altamura AC

INSTITUCIÓN / INSTITUTION:  - 1 Department of Psychiatry, Fondazione IRCSS Ca Granda Ospedale Maggiore Policlinico, Universita degli Studi di Milano , Milan, Italy .

RESUMEN / SUMMARY:  - Peg-interferon (Peg-IFN) and ribavirin (RBV) therapy is reported to induce psychiatric symptoms and syndromes in 20% of patients treated for Hepatitis C Virus (HCV) infection. Present study was aimed to quantify the phenomenon and assess the influence of psychiatric counseling over antiviral completion rate and the use of psychometric tools, in terms of prediction of psychopathological outcome. Ninety-six HCV patients were assessed, before antiviral treatment, by means of the Sheehan Disability Scale (SDS), Mood Disorder Questionnaire (MDQ), Symptom Checklist-90, and Internal State Scale (ISS). Sociodemographic and clinical variables and completion rate were collected. Binary logistic regression was performed to evaluate whether scores were predictive of psychiatric visit, development of psychiatric disorders, and need for treatment. Ninety-five patients (99%) completed antiviral treatment; 27 subjects (29%) needed psychiatric visit: among them, mood disorder was diagnosed in 15 (16%) and were pharmacologically treated. Baseline SDS and MDQ higher scores were found to be predictive of psychiatric visit [odds ratio (OR)=1.258, P<0.001 and OR=1.425, P=0.05, respectively]. Furthermore, higher MDQ score (P=0.017) and ISS hostility  scores (OR=1.048, P=0.014) at baseline predicted the subsequent development of mood episodes, while ISS activation correlated negatively (OR=0.948, P=0.009). Finally, the need for treatment was predicted by higher scores at the MDQ and ISS activation items (OR=2.467, P=0.030; OR=0.970, P=0.038). Present findings suggest that psychiatric counseling may be needed in almost 30% of HCV patients on antiviral treatment, with positive influence over the completion rate. Baseline higher scores at psychometric questionnaires-MDQ-in particular, predictors of psychopathological outcome during Peg-IFN and RBV therapy in patients with chronic HCV-correlated hepatitis reflecting individual functioning before starting antiviral therapy and positive history for mood disorders, seem to predict psychiatric visit, onset of mood episodes, and need for psychopharmacological treatment. Further investigation is warranted to confirm results.

 

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[79]

TÍTULO / TITLE:  - Prognosis of patients with primary central nervous system lymphoma after high-dose chemotherapy followed by autologous stem cell transplantation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Haematologica. 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 3324/haematol.2012.076075

AUTORES / AUTHORS:  - Schorb E; Kasenda B; Atta J; Kaun S; Morgner A; Hess G; Elter T; von Bubnoff N; Dreyling M; Ringhoffer M; Krause S; Derigs G; Klimm B; Niemann D; Fritsch K; Finke J; Illerhaus G

INSTITUCIÓN / INSTITUTION:  - Germany;

RESUMEN / SUMMARY:  - Background. High-dose chemotherapy followed by autologous stem cell transplantation has been shown to be feasible and highly effective in newly diagnosed primary central nervous system lymphoma. In this retrospective multicenter study we investigated prognosis and baseline risk factors in patients with primary central nervous system lymphoma who underwent this treatment approach. Design and Methods. We retrospectively analyzed 105 immunocompetent patients with primary central nervous system lymphoma who underwent high-dose chemotherapy followed by autologous stem cell transplantation with or without whole brain radiotherapy as first line consolidation treated at 12 German centers between 1997 and 2011. We estimated survival rates and investigated the impact of age, performance status, serum lactate dehydrogenase level, and deep brain involvement on overall and progression-free survival. Patients were additionally  categorized into three prognostic groups according to the Memorial Sloan Kettering Cancer Center prognostic model. Results. After a median follow-up of 47 months, median progression free survival and overall survival was reached after 85 and 121 months; 2 and 5-years overall survival rates were 82% and 79%, respectively. The Memorial Sloan Kettering Cancer Center prognostic model did not predict survival. Only age revealed some evidence of prognostic relevance. Overall response rate was 95%; of those patients with progressive disease before  high-dose chemotherapy, 7/20 achieved ongoing complete remission after therapy without whole brain radiation therapy. Transplantation-associated mortality was 2.8%. Conclusions. High-dose chemotherapy followed by autologous stem cell transplantation is a highly effective and safe treatment modality for selected primary central nervous system lymphoma patients. Superiority compared to standard chemotherapy still warrants further investigation.

 

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[80]

TÍTULO / TITLE:  - Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Blood. 2013 Jan 14.

            ●● Enlace al texto completo (gratuito o de pago) 1182/blood-2012-01-406272

AUTORES / AUTHORS:  - Hsieh YT; Gang EJ; Geng H; Park E; Huantes S; Chudziak D; Dauber K; Schaefer P; Scharman C; Shimada H; Shojaee S; Klemm L; Parameswaran R; Loh M; Kang ES; Koo HH; Hoffman WK; Andrade J; Crooks GM; Willman CL; Muschen M; Papayannopoulou T; Heisterkamp N; Bonig H; Kim YM

INSTITUCIÓN / INSTITUTION:  - Department of Pediatrics, Division of Hematology and Oncology, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine,  Los Angeles, CA, United States;

RESUMEN / SUMMARY:  - The bone marrow (BM) provides chemoprotection for acute lymphoblastic leukemia (ALL) cells thus contributing to the lack of efficacy of current therapies. Integrin alpha4 (alpha4) mediates adhesion of normal and malignant B-cell precursors in BM, and, according to gene expression analyses from 207 children with high-risk pre-B ALL with minimal residual disease, is particularly highly expressed in patients with the poorest outcome. Therefore, we tested whether interference with alpha4-mediated stromal adhesion might be a new ALL treatment.  For this purpose, two models of leukemia were used, one genetic (conditional alpha4 ablation of BCR-ABL1 (p210+)-induced murine leukemia) and one pharmacological (anti-functional alpha4 antibody treatment of primary pre-B ALL). Conditional deletion of alpha4 sensitized leukemia cell to Nilotinib. Adhesion of primary pre-B ALL cells was alpha4-dependent and alpha4 blockade sensitized primary ALL cells towards chemotherapy. Combination of chemotherapy with an anti-integrin alpha4 antibody, Natalizumab, prolonged survival of NOD/SCID recipients of primary ALL suggesting adjuvant integrin alpha4 inhibition as a novel strategy for pre-B ALL.

 

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[81]

TÍTULO / TITLE:  - High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Tumour Biol. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s13277-012-0638-2

AUTORES / AUTHORS:  - Wikberg ML; Edin S; Lundberg IV; Van Guelpen B; Dahlin AM; Rutegard J; Stenling R; Oberg A; Palmqvist R

INSTITUCIÓN / INSTITUTION:  - Department of Medical Biosciences, Pathology, Umea University, Building 6M, 2nd floor, Umea, SE-901 85, Sweden, maria.wikberg@medbio.umu.se.

RESUMEN / SUMMARY:  - -An active stroma is important for cancer cell invasion and metastasis. We investigated the expression of fibroblast activation protein (FAP) in relation to patient prognosis in colorectal cancer. Colorectal cancer specimens from 449 patients were immunohistochemically stained with a FAP antibody and evaluated in  the tumor center and tumor front using a semiquantitative four-level scale. FAP was expressed by fibroblasts in 85-90 % of the tumors examined. High versus no/low expression in the tumor center was associated with poor prognosis (multivariate hazard ratio, HR = 1.72; 95 % CI 1.07-2.77, p = 0.025). FAP expression in the tumor front, though more frequent than in the tumor center, was not associated with prognosis. FAP expression in the tumor center was more common in specimens with positive microsatellite instability (MSI) screening status and  in patients with high CpG island methylator phenotype (CIMP) status. However, inclusion of MSI screening status and CIMP status in the multivariate analysis strengthened the risk estimates for high FAP expression in the tumor center (HR = 1.89; 95 % CI 1.13-3.14; p = 0.014), emphasizing the role of FAP as an independent prognostic factor. Stromal FAP expression is common in colorectal cancer, and we conclude that high FAP expression in the tumor center, but not the tumor front, is an independent negative prognostic factor.

 

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[82]

TÍTULO / TITLE:  - Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):654-9. doi: 10.1073/pnas.1209310110.  Epub 2012 Dec 24.

            ●● Enlace al texto completo (gratuito o de pago) 1073/pnas.1209310110

AUTORES / AUTHORS:  - Hedlund EM; Yang X; Zhang Y; Yang Y; Shibuya M; Zhong W; Sun B; Liu Y; Hosaka K; Cao Y

INSTITUCIÓN / INSTITUTION:  - Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77  Stockholm, Sweden.

RESUMEN / SUMMARY:  - The role of placental growth factor (PlGF) in modulation of tumor angiogenesis and tumor growth remains an enigma. Furthermore, anti-PlGF therapy in tumor angiogenesis and tumor growth remains controversial in preclinical tumor models.  Here we show that in both human and mouse tumors, PlGF induced the formation of dilated and normalized vascular networks that were hypersensitive to anti-VEGF and anti-VEGFR-2 therapy, leading to dormancy of a substantial number of avascular tumors. Loss-of-function using plgf shRNA in a human choriocarcinoma significantly accelerated tumor growth rates and acquired resistance to anti-VEGF drugs, whereas gain-of-function of PlGF in a mouse tumor increased anti-VEGF sensitivity. Further, we show that VEGFR-2 and VEGFR-1 blocking antibodies displayed opposing effects on tumor angiogenesis. VEGFR-1 blockade and genetic deletion of the tyrosine kinase domain of VEGFR-1 resulted in enhanced tumor angiogenesis. These findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and tumor growth and may potentially serve as a predictive marker of anti-VEGF cancer therapy.

 

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[83]

TÍTULO / TITLE:  - Prognostic Significance of Serum Levels of Vascular Endothelial Growth Factor and Insulin-Like Growth Factor-1 in Advanced Gastric Cancer Patients Treated with FOLFOX Chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chemotherapy. 2013 Jan 4;58(6):426-434.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000345918

AUTORES / AUTHORS:  - Oh SY; Kwon HC; Kim SH; Lee S; Lee JH; Graves CA; Camphausen K; Kim HJ

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.

RESUMEN / SUMMARY:  - Background: Tumor vascular endothelial growth factor (VEGF) is a key angiogenic factor and may have an impact on tumor progression and response to chemotherapy.  The insulin-like growth factor (IGF) system is related to cell proliferation and  tumor growth. However, there is limited available data regarding the clinical and prognostic significance of VEGF or IGF-1 in advanced gastric cancer. The aim of this study was to evaluate the prognostic significance of serum VEGF and IGF-1 levels in advanced gastric cancer patients who were treated with oxaliplatin/5-fluorouracil (FOLFOX). Methods: The study population consisted of 100 advanced gastric cancer patients (median age 56 years). Patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1 plus leucovorin 20 mg/m(2) over 10 min, followed by a 5-fluorouracil (5-FU) bolus 400 mg/m(2) and 22 h of continuous infusion of 600 mg/m(2) on days 1-2. Treatment was repeated in 2-week intervals. The levels of serum VEGF and IGF-1 were measured using enzyme-linked immunoassays. Results: There was a significant correlation between  the serum level of VEGF and Lauren’s classification (p = 0.030) and previous operations (p = 0.010). IGF-1 was associated with the number of metastases (p = 0.012). The median level of serum VEGF was decreased after FOLFOX chemotherapy (p = 0.034). However, none of the measured serum markers were significantly correlated with response. In univariate analysis, overall survival (p < 0.001) was significantly shorter in patients with high serum levels of VEGF. Multivariate analysis revealed that VEGF was an independent factor for overall survival (HR 2.221; 95% CI 1.377-3.583, p = 0.001). Furthermore, IGF-1 had no significant influence on the clinical outcome. Conclusion: A high level of serum  VEGF is an independent prognostic factor in patients with advanced gastric cancer treated with chemotherapy. This may help to identify the patients who are more sensitive to the FOLFOX regimen.

 

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[84]

TÍTULO / TITLE:  - Antiproliferative effects of pomegranate extract in MCF-7 breast cancer cells are associated with reduced DNA repair gene expression and induction of double strand breaks.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Carcinog. 2013 Jan 28. doi: 10.1002/mc.21995.

            ●● Enlace al texto completo (gratuito o de pago) 1002/mc.21995

AUTORES / AUTHORS:  - Shirode AB; Kovvuru P; Chittur SV; Henning SM; Heber D; Reliene R

INSTITUCIÓN / INSTITUTION:  - Department of Environmental Health Sciences, University at Albany, State University of New York, Albany, New York; Cancer Research Center, University at Albany, Rensselaer, New York.

RESUMEN / SUMMARY:  - Pomegranate extract (PE) inhibits the proliferation of breast cancer cells and stimulates apoptosis in MCF-7 breast cancer cells. While PE is a potent antioxidant, the present studies were conducted to examine the mechanisms of action of PE beyond antioxidation by studying cellular and molecular mechanisms underlying breast tumorigenesis. PE inhibited cell growth by inducing cell cycle  arrest in G(2) /M followed by the induction of apoptosis. In contrast, antioxidants N-acetylcysteine and Trolox did not affect cell growth at doses containing equivalent antioxidant capacity as PE, suggesting that growth inhibition by PE cannot solely be attributed to its high antioxidant potential. DNA microarray analysis revealed that PE downregulated genes associated with mitosis, chromosome organization, RNA processing, DNA replication and DNA repair, and upregulated genes involved in regulation of apoptosis and cell proliferation. Both microarray and quantitative RT-PCR indicated that PE downregulated important genes involved in DNA double strand break (DSB) repair by homologous recombination (HR), such as MRE11, RAD50, NBS1, RAD51, BRCA1, BRCA2, and BRCC3. Downregulation of HR genes correlated with increased levels of their predicted microRNAs (miRNAs), miR-183 (predicted target RAD50) and miR-24 (predicted target BRCA1), suggesting that PE may regulate miRNAs involved in DNA repair processes.  Further, PE treatment increased the frequency of DSBs. These data suggest that PE downregulates HR which sensitizes cells to DSBs, growth inhibition and apoptosis. Because HR represents a novel target for cancer therapy, downregulation of HR by  PE may be exploited for sensitization of tumors to anticancer drugs. © 2013 Wiley Periodicals, Inc.

 

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[85]

TÍTULO / TITLE:  - Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 20;31(3):328-36. doi: 10.1200/JCO.2012.44.1444. Epub 2012  Dec 26.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.44.1444

AUTORES / AUTHORS:  - Erdem-Eraslan L; Gravendeel LA; de Rooi J; Eilers PH; Idbaih A; Spliet WG; den Dunnen WF; Teepen JL; Wesseling P; Sillevis Smitt PA; Kros JM; Gorlia T; van den Bent MJ; French PJ

INSTITUCIÓN / INSTITUTION:  - Department of Neurology, Be 438, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the  Netherlands; p.french@erasmusmc.nl.

RESUMEN / SUMMARY:  - PURPOSE Intrinsic glioma subtypes (IGSs) are molecularly similar tumors that can  be identified based on unsupervised gene expression analysis. Here, we have evaluated the clinical relevance of these subtypes within European Organisation for Research and Treatment of Cancer (EORTC) 26951, a randomized phase III clinical trial investigating adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study includes gene expression profiles of formalin-fixed, paraffin-embedded (FFPE) clinical trial samples. PATIENTS AND METHODS Gene expression profiling was performed in 140 samples, 47 fresh frozen samples and 93 FFPE samples, on HU133_Plus_2.0 and HuEx_1.0_st arrays, respectively. Results All previously identified six IGSs are  present in EORTC 26951. This confirms that different molecular subtypes are present within a well-defined histologic subtype. Intrinsic subtypes are highly prognostic for overall survival (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance status, and tumor location), molecular (1p/19q loss of heterozygosity [LOH], IDH1 mutation, and MGMT methylation), and histologic parameters. Combining known molecular (1p/19q LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (proportion of explained variation, 30% v 23% for each individual group of factors). Specific genetic changes (IDH1, 1p/19q LOH, and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p/19q LOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone versus 12.8 years after RT/PCV (P = .0349; hazard ratio, 2.18; 95% CI, 1.06 to 4.50). CONCLUSION Intrinsic subtypes are highly prognostic in EORTC 26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV.

 

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[86]

TÍTULO / TITLE:  - DNase is a prognostic marker in liver cancer patients receiving transarterial chemoembolization therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Clin Pharmacol Ther. 2013 Jan;51(1):80-3.

AUTORES / AUTHORS:  - Kohles N; Nagel D; Jungst D; Stieber P; Holdenrieder S

INSTITUCIÓN / INSTITUTION:  - Institute of Clinical Chemistry, University-Hospital Munich-Grosshadern, Munich,  Department of Otorhinolaryngology, Helios-Klinikum Erfurt, Erfurt, Medical Clinic II, University-Hospital Munich-Grosshadern, Munich, and Institute of Clinical Chemistry and Clinical Pharmacology, University-Hospital Bonn, Bonn, Germany.

 

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[87]

TÍTULO / TITLE:  - KRAS Mutation in Patients with Lung Cancer: A Predictor for Poor Prognosis but Not for EGFR-TKIs or Chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Surg Oncol. 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 1245/s10434-012-2754-z

AUTORES / AUTHORS:  - Guan JL; Zhong WZ; An SJ; Yang JJ; Su J; Chen ZH; Yan HH; Chen ZY; Huang ZM; Zhang XC; Nie Q; Wu YL

INSTITUCIÓN / INSTITUTION:  - Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.

RESUMEN / SUMMARY:  - BACKGROUND: The prognostic and predictive value of KRAS mutations in patients with lung cancer is controversial. Biases in disease stage, treatment regimen, small-scale patient studies, and biomarker status have led to inconsistent results in previous reports. METHODS: The KRAS and EGFR genes were examined in 1935 consecutive patients with non-small cell lung cancer. All patients were divided into KRAS mutation (KRAS group), EGFR mutation (EGFR group), and KRAS/EGFR wild type (WT group) groups. Randomly selected cases were paired with patients with the KRAS mutation, the EGFR mutation, and KRAS/EGFR wild type patients according to tumor, node, metastasis stage, time of first visit within 1 year, and pathology. Progression-free survival (PFS) and overall survival were evaluated by Kaplan-Meier and Cox models. RESULTS: The KRAS mutation rate for lung adenocarcinoma was 5.90 %. The overall survival was 14.47, 20.57, and 42.73  months for the KRAS group, WT group, and EGFR group, respectively (P < 0.001). Multivariate analysis indicated that KRAS mutation status was an independent prognostic factor (hazard ratio 2.69, 95 % confidence interval 1.91-3.80, P < 0.001). No difference was found in PFS and tumor responsiveness between patients  with a KRAS mutation and those with wild type KRAS/EGFR for chemotherapy and EGFR tyrosine kinase inhibitors (TKI). PFS did not significantly differ for chemotherapy among the three groups (P = 0.270). CONCLUSIONS: KRAS mutation is a  poor prognosis factor, but it is not an independent predictor of response to EGFR-TKI or chemotherapy in patients with lung cancer.

 

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[88]

TÍTULO / TITLE:  - Newcastle disease virus Malaysian strain AF2240 induces apoptosis in MCF-7 human  breast carcinoma cells at an early stage of the virus life cycle.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Med. 2013 Mar;31(3):525-32. doi: 10.3892/ijmm.2013.1244. Epub 2013 Jan  15.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijmm.2013.1244

AUTORES / AUTHORS:  - Ghrici M; El Zowalaty M; Omar AR; Ideris A

INSTITUCIÓN / INSTITUTION:  - Department of Veterinary Pathology and Microbiology, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor Darul Ehsan, Malaysia.

RESUMEN / SUMMARY:  - Newcastle disease virus (NDV) AF2240 Malaysian strain is a very virulent avian virus. NDV strain AF2240 was previously demonstrated to induce apoptosis in human breast carcinoma MCF-7 cells. However, at which stage of the NDV life cycle apoptosis is induced and whether NDV replication and protein synthesis are involved in apoptosis induction have yet to be determined. In the present study,  we investigated the time course of NDV strain AF2240 nucleoprotein (NP) gene expression and the early apoptotic signs in the form of activation of caspase-8 and mitochondrial transition pore opening. In addition, the induction of apoptosis by both ultraviolet-inactivated and cycloheximide-treated NDV-infected  MCF-7 cells were examined. Our findings showed that NDV strain AF2240 induced apoptosis at 1 h post-infection (pi) through activation of mitochondrial transition pore opening and at 2 h through activation of caspase-8, while the NP  gene was expressed at 6 h pi. The induced apoptosis was independent of both virus replication and protein synthesis. In conclusion, NDV strain AF2240 induces apoptosis at an early stage of its life cycle, possibly during virus binding or fusion with the cell membrane. The mitochondrial-related pathway may be the central activator in NDV strain AF2240-induced apoptosis.

 

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[89]

TÍTULO / TITLE:  - Prognostic significance of programmed cell death-1-positive cells in follicular lymphoma patients may alter in the rituximab era.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Haematol. 2013 Jan 19. doi: 10.1111/ejh.12075.

            ●● Enlace al texto completo (gratuito o de pago) 1111/ejh.12075

AUTORES / AUTHORS:  - Takahashi H; Tomita N; Sakata S; Tsuyama N; Hashimoto C; Ohshima R; Matsuura S; Ogawa K; Yamamoto W; Kameda Y; Enaka M; Inayama Y; Kasahara M; Takekawa Y; Onoda N; Motomura S; Ishigatsubo Y; Takeuchi K

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

RESUMEN / SUMMARY:  - Programmed cell death-1 (PD-1) is involved in one of the inhibitory pathways of the B7-cluster of differentiation (CD)28 family; this pathway is known to be involved in the attenuation of T cell responses and promotion of T cell tolerance. PD-1 is known to negatively regulate T cell receptor-mediated proliferation and cytokine production, lead to alternation in the tumor microenvironment. Although several studies have shown that high levels of PD-1-positive cells in follicular lymphoma (FL) patients influence their prognosis, those studies included patients treated without rituximab, and the prognostic impact of PD-1 positivity in the rituximab-era (R-era) has not yet been elucidated. We retrospectively studied 82 patients with FL uniformly treated with standard R-CHOP therapy at 6 institutions between 2001 and 2009 (median follow-up for survivors: 55 months). We also collected and examined biopsy specimens for diagnosis with respect to PD-1 positivity. The PD-1 positivity was  significantly higher in male patients and patients with high beta-2 microglobulin (B2M >/= 3.0) (p = 0.03 and 0.003, respectively). Three-year progression free survival (PFS) and overall survival (OS) were 60% and 86%, respectively. By univariate analysis, elevated LDH (p = 0.07) worsened PFS. Male gender (p = 0.03), high FLIPI score (p = 0.05), and high B2M levels (p = 0.08) worsened OS. Multivariate analysis detected no significant prognostic factors, including PD-1  positivity. However, in male subgroup, high levels of PD-1-positive cells were found to be a prognostic factor for PFS. Addition of rituximab might have altered the prognostic impact of PD-1 positive cells. © 2013 John Wiley & Sons A/S.

 

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[90]

TÍTULO / TITLE:  - The prognostic significance of p21 and Her-2 gene expression and mutation/polymorphism in patients with gastric adenocarcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):357. doi: 10.1007/s12032-012-0357-y. Epub 2012 Dec 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0357-y

AUTORES / AUTHORS:  - Ozen A; Kocak Z; Sipahi T; Oz-Puyan F; Cakina S; Saynak M; Ibis C; Karagol H

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, Medical Faculty Hospital, Trakya University, 22030, Edirne, Turkey, dralovettin@gmail.com.

RESUMEN / SUMMARY:  - Analyses of gene expression status and genetic polymorphisms are methods to identify novel histopathological prognostic factors. In patients with gastric cancer, some cell cycle regulators p53, p21, p27 and Her-2 oncogene have been proposed as prognostic factors. We aimed to investigate the expression and mutation/polymorphism of p21 and Her-2 and also relationship between that genes status and histopathological factors and prognosis in patients with gastric cancer. Forty-four patients with locally advanced gastric cancer were analyzed in this study from January 2000 to December 2008. Clinicopathological parameters, expression and mutation/polymorphism of p21 and Her-2 results were used to predict disease-free survival and overall survival. The positive expression of p21 and Her-2 was observed in 61.4 % (n = 27) and 9.1 % (n = 4) of all 44 tumors, respectively. p21 gene mutation and Her-2 gene polymorphism were detected in 20 % (n = 11) and 2.3 % (n = 1, II phenotype) of cases, respectively. The negative expression of p21 was correlated significantly with diffuse and undifferential type histologies, whole gastric involvement and positive vascular/neural invasion. The median survival rate of patients with negative expression was significantly poorer than that of patients with positive expression of p21 (17 vs. 27 months, p = 0.01, cox regression). p21 mutation was significantly higher in patients with diffuse (p = 0.03) and undifferential (p = 0.02) type histologies. There was no statistically significant association between histopathological parameters and Her-2 gene polymorphism/expression. The negative expression of p21 correlates with disease survival and may be a poor prognostic factor in patients with resected gastric cancer treated with adjuvant chemotherapy.

 

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[91]

TÍTULO / TITLE:  - Network-based approach identified cell cycle genes as predictor of overall survival in lung adenocarcinoma patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Lung Cancer. 2013 Jan 25. pii: S0169-5002(13)00005-6. doi: 10.1016/j.lungcan.2012.12.022.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.lungcan.2012.12.022

AUTORES / AUTHORS:  - Li Y; Tang H; Sun Z; Bungum AO; Edell ES; Lingle WL; Stoddard SM; Zhang M; Jen J; Yang P; Wang L

INSTITUCIÓN / INSTITUTION:  - Department of Epidemiology, College of Preventive Medicine, Third Military Medical University, Chongqing, People’s Republic of China; Department of Health Sciences Research, Mayo Clinic, College of Medicine, Rochester, MN, USA.

RESUMEN / SUMMARY:  - Lung adenocarcinoma is the most common type of primary lung cancer. The purpose of this study was to delineate gene expression patterns for survival prediction in lung adenocarcinoma. Gene expression profiles of 82 (discovery set) and 442 (validation set 1) lung adenocarcinoma tumor tissues were analyzed using a systems biology-based network approach. We also examined the expression profiles  of 78 adjacent normal lung tissues from 82 patients. We found a significant correlation of an expression module with overall survival (adjusted hazard ratio  or HR=1.71; 95% CI=1.06-2.74 in discovery set; adjusted HR=1.26; 95% CI=1.08-1.49 in validation set 1). This expression module contained genes enriched in the biological process of the cell cycle. Interestingly, the cell cycle gene module and overall survival association were also significant in normal lung tissues (adjusted HR=1.91; 95% CI, 1.32-2.75). From these survival-related modules, we further defined three hub genes (UBE2C, TPX2, and MELK) whose expression-based risk indices were more strongly associated with poor 5-year survival (HR=3.85, 95% CI=1.34-11.05 in discovery set; HR=1.72, 95% CI=1.21-2.46 in validation set 1; and HR=3.35, 95% CI=1.08-10.04 in normal lung set). The 3-gene prognostic result was further validated using 92 adenocarcinoma tumor samples (validation set 2); patients with a high-risk gene signature have a 1.52-fold increased risk  (95% CI, 1.02-2.24) of death than patients with a low-risk gene signature. These  results suggest that a network-based approach may facilitate discovery of key genes that are closely linked to survival in patients with lung adenocarcinoma.

 

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[92]

TÍTULO / TITLE:  - Is ATP7B a Predictive Marker in Patients With Ovarian Carcinoma Treated With Platinum-Taxane Combination Chemotherapy?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Gynecol Cancer. 2013 Jan;23(1):60-4. doi: 10.1097/IGC.0b013e318275afef.

            ●● Enlace al texto completo (gratuito o de pago) 1097/IGC.0b013e318275afef

AUTORES / AUTHORS:  - Katagiri H; Nakayama K; Rahman MT; Rahman M; Katagiri A; Ishibashi T; Ishikawa M; Iida K; Nakayama S; Otsuki Y; Miyazaki K

INSTITUCIÓN / INSTITUTION:  - *Department of Obstetrics and Gynecology, Shimane University School of Medicine,  Izumo, Japan; daggerDepartment of Obstetrics and Gynecology, and double daggerDepartment of Pathology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.

RESUMEN / SUMMARY:  - OBJECTIVE: This study examined the prognostic significance of copper-transporting P-type adenosine triphosphatase (ATP7B) expression in patients with ovarian carcinoma treated with platinum-taxane combination chemotherapy. METHODS: Expression of ATP7B in ovarian carcinoma was assessed by immunohistochemistry and clinical data collected by retrospective review of medical charts. RESULTS: Overexpression of ATP7B was identified in 25 (29.1%) of 86 ovarian carcinomas. The frequency of ATP7B expression in clear cell carcinomas was significantly higher than that in serous high-grade carcinomas (P < 0.05). We observed no statistically significant correlations between high ATP7B protein expression and  either disease-free survival (P = 0.722) or overall survival (P = 0.389). CONCLUSIONS: Our study is the first to demonstrate a lack of statistically significant differences between ATP7B positive and negative cases with respect to prognosis of patients with ovarian carcinoma treated with a platinum-taxane combination regimen. However, that ATP7B expression in clear cell carcinomas was  significantly higher than that in serous carcinomas may partially explain the difference in chemotherapeutic response and prognosis between patients with these 2 types of carcinomas.

 

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[93]

TÍTULO / TITLE:  - Androgen receptor phosphorylation at serine 515 by Cdk1 predicts biochemical relapse in prostate cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 15;108(1):139-48. doi: 10.1038/bjc.2012.480. Epub 2012 Dec  4.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2012.480

AUTORES / AUTHORS:  - Willder JM; Heng SJ; McCall P; Adams CE; Tannahill C; Fyffe G; Seywright M; Horgan PG; Leung HY; Underwood MA; Edwards J

INSTITUCIÓN / INSTITUTION:  - 1] Institute of Cancer, University of Glasgow, McGregor Building, Western Infirmary, Glasgow G11 6NT, UK [2] Academic Department of Surgery, School of Medicine, University of Glasgow, Walton Building, Glasgow Royal Infirmary, 84 Castle Street, Glasgow, G4 0SF, UK.

RESUMEN / SUMMARY:  - Background:Prostate cancer cell growth is dependent upon androgen receptor (AR) activation, which is regulated by specific kinases. The aim of the current study  is to establish if AR phosphorylation by Cdk1 or ERK1/2 is of prognostic significance.Methods:Scansite 2.0 was utilised to predict which AR sites are phosphorylated by Cdk1 and ERK1/2. Immunohistochemistry for these sites was then  performed on 90 hormone-naive prostate cancer specimens. The interaction between  Cdk1/ERK1/2 and AR phosphorylation was investigated in vitro using LNCaP cells.Results:Phosphorylation of AR at serine 515 (pAR(S515)) and PSA at diagnosis were independently associated with decreased time to biochemical relapse. Cdk1 and pCdk1(161), but not ERK1/2, correlated with pAR(S515). High expression of pAR(S515) in patients with a PSA at diagnosis of </=20 ng ml(-1) was associated with shorter time to biochemical relapse (P=0.019). This translated into a reduction in disease-specific survival (10-year survival, 38.1% vs 100%, P<0.001). In vitro studies demonstrated that treatment with Roscovitine  (a Cdk inhibitor) caused a reduction in pCdk1(161) expression, pAR(S515)expression and cellular proliferation.Conclusion:In prostate cancer patients with PSA at diagnosis of </=20 ng ml(-1), phosphorylation of AR at serine 515 by Cdk1 may be an independent prognostic marker.

 

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[94]

TÍTULO / TITLE:  - REG Ialpha is a biomarker for predicting response to chemotherapy with S-1 plus cisplatin in patients with unresectable stage IV gastric cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 15. doi: 10.1038/bjc.2012.572.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2012.572

AUTORES / AUTHORS:  - Sekikawa A; Fukui H; Zhang X; Maruo T; Tsumura T; Okabe Y; Wakasa T; Osaki Y; Chiba T; Tomita T; Oshima T; Watari J; Miwa H

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan.

RESUMEN / SUMMARY:  - Background:The regenerating gene Ialpha (REG Ialpha) is involved in gastric carcinogenesis as an antiapoptotic factor. Therefore, we investigated whether REG Ialpha confers resistance to chemotherapeutic drugs in gastric cancer (GC) cells  and whether REG Ialpha expression is useful for predicting the response to chemotherapy and outcome in patients with GC.Methods:A total of 70 patients with  unresectable stage IV GC received first-line chemotherapy with S-1 and cisplatin  (S-1/CDDP). The expression of REG Ialpha was evaluated immunohistochemically using biopsy samples obtained before chemotherapy, and its relationship to clinicopathological parameters was analysed statistically. The effects of REG Ialpha gene induction on resistance to 5-FU or CDDP treatment were examined by cell survival assay and flow cytometry.Results:Of the 70 patients with unresectable stage IV GC, 19 (27%) were positive for REG Ialpha expression. The expression of REG Ialpha was independently predictive of poorer progression-free  and overall survival in such patients (hazard ratio (HR) 2.46; P=0.002 and HR 1.89; P=0.037, respectively). The gene induction of REG Ialpha conferred resistance to cell death induced by 5-FU or CDDP in GC cells.Conclusion:In patients with stage IV GC, REG Ialpha, which confers resistance to chemotherapeutic drugs in GC cells, is a potential biomarker for predicting resistance to S-1/CDDP treatment.British Journal of Cancer advance online publication, 15 January 2013; doi:10.1038/bjc.2012.572 www.bjcancer.com.

 

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[95]

TÍTULO / TITLE:  - Is the immunohistochemical expression of proliferation (Ki-67) and apoptosis (Bcl-2) markers and cyclooxigenase-2 (COX-2) related to carcinogenesis in postmenopausal endometrial polyps?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Anal Quant Cytol Histol. 2012 Oct;34(5):264-72.

AUTORES / AUTHORS:  - Antunes A Jr; Andrade LA; Pinto GA; Leao R; Pinto-Neto AM; Costa-Paiva L

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, State University of Campinas-UNICAMP School of Medicine, 13083-970 Campinas, SP, Brazil.

RESUMEN / SUMMARY:  - OBJECTIVE: To evaluate the pattern of Ki-67, Bcl-2 and COX-2 expression in the glandular epithelium and stroma of malignant and benign endometrial polyps in postmenopause. STUDY DESIGN: A total of 390 postmenopausal women underwent surgical hysteroscopy; women with endometrial polyps were included. Polypoid lesions were histologically classified as benign, premalignant or malignant lesions. Ki-67, Bcl-2 and COX-2 expression were evaluated by immunohistochemistry according to percentage of stained cells, staining intensity, and final score. RESULTS: The prevalence of malignancy in endometrial polyps was 7.1% and was associated with postmenopausal bleeding. The final score showed that only mean COX-2 expression was higher in malignant polyps both in the glandular epithelium  (6.1 +/- 2.5) (p < 0.001) and stroma (2.4 +/- 3.0) (p < 0.01). There was a higher Bcl-2 expression, especially in the glandular epithelium, with no differences between benign polyps and premalignant/malignant polyps. Ki-67 expression was low in both benign polyps and premalignant/malignant polyps. CONCLUSION: Polyps in postmenopause have a high COX-2 expression that is higher in malignant polyps than in benign polyps. There was no difference in Ki-67 and Bcl-2 expression between malignant polyps and premalignant/malignant polyps.

 

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[96]

TÍTULO / TITLE:  - Prognosis in patients with non-small cell lung cancer who received erlotinib treatment and subsequent dose reduction due to skin rash.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Onkologie. 2012;35(12):747-52. doi: 10.1159/000345039. Epub 2012 Nov 20.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000345039

AUTORES / AUTHORS:  - Takashima N; Kimura T; Watanabe N; Umemura T; Katsuno S; Arakawa K; Fukatsu M; Nakamura N; Nishiyama O; Kataoka K; Kondoh Y; Taniguchi H

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacy, Tosei General Hospital, Seto, Aichi, Japan.

RESUMEN / SUMMARY:  - BACKGROUND: Severe skin rash as toxicity of erlotinib has been reported in relation to better response and survival. However, some patients require dose reduction due to skin toxicities, and their prognosis remains uncertain. We retrospectively evaluated the clinical course of non-small cell lung cancer patients receiving erlotinib at a reduced dose because of skin rash. PATIENTS AND METHODS: Among 76 patients treated with erlotinib, 55 patients who developed skin rash severer than grade 2 were divided into 2 groups: 24 patients treated with erlotinib with dose reduction because of skin rash (dose reduction group) and 31  patients without any dose reduction (non-dose reduction group). RESULTS: The median progression-free survival in the dose reduction and non-dose reduction groups was 341 and 70 days, respectively, and the median overall survival was 566 and 202 days, respectively (p < 0.001). In the dose reduction group, no smoking history, female sex, epidermal growth factor receptor gene mutation, and grade 3  skin rash were significant baseline factors. CONCLUSIONS: Patients who received erlotinib at a reduced dose following skin rash showed better survival than those without reduction. In cases of intolerable skin rash, patients may benefit from continuous treatment with a reduced dose of erlotinib.

 

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[97]

TÍTULO / TITLE:  - Application of a Proapoptotic Peptide to Intratumorally Spreading Cancer Therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2012 Dec 17.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-1979

AUTORES / AUTHORS:  - Chen R; Braun G; Luo X; Sugahara KN; Teesalu T; Ruoslahti E

INSTITUCIÓN / INSTITUTION:  - Center for Nanomedicine, Sanford-Burnham Medical Research Institute (at UCSB).

RESUMEN / SUMMARY:  - Bit1 is a pro-apoptotic mitochondrial protein associated with anoikis. Upon cell  detachment, Bit1 is released into the cytoplasm and triggers caspase-independent  cell death. Bit1 consists of 179 amino acids; the C-terminal two thirds of the molecule functions as a peptidyl-tRNA hydrolase, while the N-terminus contains a  mitochondrial localization signal. Here, we localize the cell death domain (CDD)  to the N-terminal 62 amino acids of Bit1 by transfecting cells with truncated Bit1 cDNA constructs. CDD was more potent in killing cells than the full-length Bit1 protein when equivalent amounts of cDNA were transfected. To develop Bit1 CDD into a cancer therapeutic we engineered a recombinant protein consisting of the CDD fused to iRGD, which is a tumor-specific peptide with unique tumor-penetrating and cell internalizing properties. iRGD-CDD internalized into cultured tumor cells through a neuropilin-1-activated pathway and triggered cell  death. Importantly, iRGD-CDD spread extensively within the tumor when injected intratumorally into orthotopically implanted breast tumors in mice. Repeated treatment with iRGD-CDD strongly inhibited tumor growth, resulting in an average  reduction of 77% in tumor volume and eradication of some tumors. The caspase independence of Bit1-induced cell death makes CDD a potentially attractive anti-cancer agent because tumor resistance to the main mechanisms of apoptosis is circumvented. Using iRGD to facilitate the spreading of a therapeutic agent throughout the tumor mass may be a useful adjunct to local therapy of tumors that are surgically inoperable or difficult to treat systemically.

 

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[98]

TÍTULO / TITLE:  - Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Haematologica. 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 3324/haematol.2012.076414

AUTORES / AUTHORS:  - Pollyea DA; Zehnder J; Coutre S; Gotlib J; Gallegos L; Abdel-Wahab O; Greenberg P; Zhang B; Liedtke M; Berube C; Levine R; Mitchell BS; Medeiros BC

INSTITUCIÓN / INSTITUTION:  - Denver, CO, USA;

RESUMEN / SUMMARY:  - Background There are limited treatment options for older patients with acute myeloid leukemia (AML) and prognosis remains poor, thereby warranting development of novel therapies. We evaluated the efficacy and safety of azacitidine in combination with lenalidomide as front-line therapy for older AML patients. Design and methods Patients >60 years of age with untreated AML received azacitidine 75mg/m2 for 7 days followed by escalating doses of lenalidomide daily for 21 days starting on day 8 of each cycle every 6 cycles. Patients received continued therapy until disease progression, unacceptable toxicity, or completion of 12 cycles. Results Forty-two patients (median age, 74 years) were enrolled with equal distribution according to ELN risk. Overall response rate was 40% (CR+CRi rate = 28%). The median time to CR/CRi was 12 weeks, and duration of CR/CRi was 28 weeks (range, 4- >104 weeks). Therapy-related AML and high hematopoietic cell transplantation comorbidity index were negative predictors of  response. Early death was noted in 17% of patients. Grades >/= 3 toxicities were  uncommon and most adverse events were gastrointestinal, fatigue and myelosupression. Conclusions Sequential combination of azacitidine plus lenalidomide has clinical activity in older AML patients, and further studies of  this combination are underway. This study is registered at www.clinicaltrials.gov as # NCT00890929.

 

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[99]

TÍTULO / TITLE:  - Early Viral Suppression Predicts Good Postoperative Survivals in Patients with Hepatocellular Carcinoma with a High Baseline HBV-DNA Load.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Surg Oncol. 2012 Dec 18.

            ●● Enlace al texto completo (gratuito o de pago) 1245/s10434-012-2803-7

AUTORES / AUTHORS:  - Huang G; Yang Y; Shen F; Pan ZY; Fu SY; Lau WY; Zhou WP; Wu MC

INSTITUCIÓN / INSTITUTION:  - The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital,  Second Military Medical University, Shanghai, China.

RESUMEN / SUMMARY:  - PURPOSE: To correlate early HBV-DNA suppression by antiviral treatment with posthepatectomy long-term survivals in patients with HBV-related hepatocellular carcinoma (HCC). METHODS: A retrospective study was conducted on patients with a  baseline HBV-DNA load of >2,000 IU/ml. The cumulative rates of HBV-DNA undetectability at weeks 24 and 48, as well as long-term tumor recurrence and overall survivals were determined. RESULTS: Of 1,040 patients with a high baseline HBV-DNA load, 865 patients received antiviral treatment. At a median follow-up of 42 months, 616 patients (59.2 %) had developed HCC recurrence and 482 patients (46.3 %) had died. The median time to recurrence was 25 months. In patients who received antiviral treatment, the cumulative rates of HBV-DNA undetectability (<200 IU/ml) were 54.3 and 88.1 % at weeks 24 and 48, respectively. There was no significant difference between the two groups of patients who received antiviral treatment or not for disease-free survival. On multivariate analyses, tumor size >5 cm, blood transfusion, surgical margin <1 cm, presence of satellite nodules, presence of portal vein tumor thrombus and high Ishak inflammation score were significant risk factors of HCC recurrence. Also, tumor size >5 cm, surgical margin <1 cm, presence of satellite nodules, presence of portal vein tumor thrombus and high Ishak fibrosis score were significant factors associated with poor postoperative overall survival. On the other hand, an undetectable HBV-DNA level before week 24 was a significant protective factor of disease-free survival and overall survival. CONCLUSIONS: Early HBV-DNA suppression with antiviral treatment improved prognosis of patients with HBV-related HCC.

 

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[100]

TÍTULO / TITLE:  - Biodistribution, tumor detection, and radiation dosimetry of 18F-DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Nucl Med. 2012 Dec;53(12):1883-91. doi: 10.2967/jnumed.112.104661.

            ●● Enlace al texto completo (gratuito o de pago) 2967/jnumed.112.104661

AUTORES / AUTHORS:  - Cho SY; Gage KL; Mease RC; Senthamizhchelvan S; Holt DP; Jeffrey-Kwanisai A; Endres CJ; Dannals RF; Sgouros G; Lodge M; Eisenberger MA; Rodriguez R; Carducci MA; Rojas C; Slusher BS; Kozikowski AP; Pomper MG

INSTITUCIÓN / INSTITUTION:  - Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland 21287-0014, USA.

RESUMEN / SUMMARY:  - Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein  expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-(18)F-fluorobenzyl-L-cysteine ((18)F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of (18)F-DCFBC in men with metastatic PCa. METHODS: Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of (18)F-DCFBC. Serial PET was performed until 2 h after administration. Time-activity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1. RESULTS: Most vascular organs demonstrated a slow decrease in radioactivity  concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (muGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 +/- 1.34 muSv/MBq (mean +/- SD). CONCLUSION: Although further studies are needed for validation, our findings demonstrate the potential of (18)F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for  (18)F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as (18)F-FDG.

 

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[101]

TÍTULO / TITLE:  - Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Arch Toxicol. 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00204-012-0996-y

AUTORES / AUTHORS:  - Maayah ZH; El Gendy MA; El-Kadi AO; Korashy HM

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2529, Riyadh, 11461, Kingdom of Saudi Arabia.

RESUMEN / SUMMARY:  - Sunitinib (SUN) is a new multi-targeted oral tyrosine kinase inhibitor that has both anti-angiogenic and anti-tumor activities. However, information reported in  the literature on the effects of SUN on the constitutive expression of cytochrome P450 1A1 (CYP1A1) gene in cells from mammalian species remains unclear. Therefore, the main objectives of the current work were to investigate the potentiality of SUN to induce CYP1A1 gene expression in human breast cancer MCF7  cells and to explore the molecular mechanisms involved. Our results showed that SUN induced the CYP1A1 mRNA, protein, and activity levels in a concentration-dependent manner in MCF7 cells. The increase in CYP1A1 mRNA by SUN  was completely blocked by the transcriptional inhibitor, actinomycin D; implying  that SUN increased de novo RNA synthesis. Furthermore, the ability of SUN to increase luciferase reporter gene expression suggests an aryl hydrocarbon receptor (AhR)-dependent transcriptional control and excludes the possibility of  any posttranscriptional mechanisms. In addition, blocking of AhR activation by resveratrol, a well-known AhR antagonist, prevented the SUN-induced CYP1A1 gene expression, further confirms the involvement of AhR. Interestingly, this was associated with the inability of SUN to directly bind to and induce transformation of cytosolic AhR to its DNA-binding form in vitro, suggesting that the effect of SUN does not involve direct binding to AhR. The current manuscript  provides the first evidence for the ability of SUN to induce CYP1A1 gene expression in MCF7 cells through AhR ligand-independent mechanisms.

 

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[102]

TÍTULO / TITLE:  - Systems Analysis of BCL2 Protein Family Interactions Establishes a Model to Predict Responses to Chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2013 Jan 15;73(2):519-28. doi: 10.1158/0008-5472.CAN-12-2269.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-2269

AUTORES / AUTHORS:  - Lindner AU; Concannon CG; Boukes GJ; Cannon MD; Llambi F; Ryan D; Boland K; Kehoe J; McNamara DA; Murray F; Kay EW; Hector S; Green DR; Huber HJ; Prehn JH

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Centre for Systems Medicine, Department of Physiology and  Medical Physics, Royal College of Surgeons in Ireland; Departments of Surgery, Pathology, and Gastroenterology, Beaumont Hospital, Dublin, Ireland; and Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee.

RESUMEN / SUMMARY:  - Apoptotic desensitization is a hallmark of cancer cells, but present knowledge of molecular systems controlling apoptosis has yet to provide significant prognostic insights. Here, we report findings from a systems study of the intrinsic pathway  of apoptosis by BCL2 family proteins and clinical translation of its findings into a model with applications in colorectal cancer (CRC). By determining absolute protein quantifications in CRC cells and patient tumor samples, we found that BAK and BAX were expressed more highly than their antiapoptotic inhibitors.  This counterintuitive finding suggested that sole inhibition of effector BAX and  BAK could not be sufficient for systems stability in nonstressed cells. Assuming  a model of direct effector activation by BH3-only proteins, we calculated that the amount of stress-induced BH3-only proteins required to activate mitochondrial apoptosis could predict individual death responses of CRC cells to 5-fluorouracil/oxaliplatin. Applying this model predictor to protein profiles in  tumor and matched normal tissue samples from 26 patients with CRCs, we found that differences in protein quantities were sufficient to model the increased tumor sensitivity to chemotherapy compared with normal tissue. In addition, these differences were sufficient to differentiate clinical responders from nonresponders with high confidence. Applications of our model, termed DR_MOMP, were used to assess the impact of apoptosis-sensitizing dugs in lowering the necessary dose of state-of-the-art chemotherapy in individual patients. Together, our findings offer a ready clinical tool with the potential to tailor chemotherapy to individual patients. Cancer Res; 73(2); 519-28. ©2012 AACR.

 

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[103]

TÍTULO / TITLE:  - Loss of phosphatase and tensin homolog expression is associated with recurrence and poor prognosis in patients with pancreatic ductal adenocarcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hum Pathol. 2012 Dec 19. pii: S0046-8177(12)00329-2. doi: 10.1016/j.humpath.2012.09.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.humpath.2012.09.001

AUTORES / AUTHORS:  - Foo WC; Rashid A; Wang H; Katz MH; Lee JE; Pisters PW; Wolff RA; Abbruzzese JL; Fleming JB; Wang H

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

RESUMEN / SUMMARY:  - Phosphatase and tensin homolog (PTEN) is a tumor suppressor in the AKT/mTOR pathway. Animal model studies have shown that loss of PTEN function is involved in the progression of pancreatic cancer. However, the prognostic significance of  loss of PTEN expression in pancreatic cancer is unclear. PTEN expression was evaluated by immunohistochemistry on tissue microarrays consisting of multiple cores of 133 resected stage II pancreatic ductal adenocarcinomas. A PTEN expression score was calculated as the product of the percentage of positive tumor cells and the intensity of PTEN staining. We categorized PTEN expression for each tumor as retained (PTEN score >5) or lost (PTEN score </=5). Thirty-four (25.6%) patients had tumors with loss of PTEN expression, and 99 (74.4%) had tumors with retained PTEN expression. Recurrence/Metastasis was observed in 88.2% (30/34) of patients whose tumors showed loss of PTEN compared with 68.7% (68/99)  of patients whose tumors showed retained PTEN (P = .03). Patients whose tumors showed loss of PTEN had a shorter overall survival (median, 19.9 +/- 3.6 months)  than did patients whose tumors had retained PTEN (32.7 +/- 5.0 months, P = .03).  In a multivariate analysis, loss of PTEN expression was an independent prognostic factor for poor overall survival in patients with stage II pancreatic ductal adenocarcinoma. No significant correlations between loss of PTEN expression and other clinicopathologic parameters were observed (P > .05). Assessment of PTEN expression may be used as a prognostic marker for patients with resected pancreatic ductal adenocarcinoma.

 

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[104]

TÍTULO / TITLE:  - Genome-wide single-nucleotide polymorphism array-based karyotyping in myelodysplastic syndrome and chronic myelomonocytic leukemia and its impact on treatment outcomes following decitabine treatment.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Hematol. 2012 Dec 23.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00277-012-1635-7

AUTORES / AUTHORS:  - Yi JH; Huh J; Kim HJ; Kim SH; Kim SH; Kim KH; Do YR; Mun YC; Kim H; Kim MK; Kim HJ; Kim T; Kim DD

INSTITUCIÓN / INSTITUTION:  - Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center,  Sungkyunkwan University School of Medicine, Irwon-dong 50, Gangnam-gu, Seoul, 135-710, South Korea.

RESUMEN / SUMMARY:  - Decitabine is a hypomethylating agent with proven clinical efficacy in myelodysplastic syndrome (MDS). The current study analyzed the role of single nucleotide polymorphism array (SNP-A)-based karyotyping in prediction of clinical outcome in MDS or chronic myelomonocytic leukemia (CMML) patients following decitabine therapy. A total of 61 MDS/CMML patients treated with decitabine were  evaluated with Genome-Wide Human SNP 6.0 Array using DNAs derived from marrow samples. The primary endpoint was the best response rate including complete (CR)  and partial response (PR) with overall (OS) and event-free survival (EFS) as secondary endpoints. Best response was noted in 14 patients (26.4 %) out of 53 evaluated patients including 12 CR and two PR with median follow-up of 21.6 months. A total of 81 abnormal SNP lesions were found in 25 out of 61 patients (41.0 %). The patients carrying abnormal SNP lesions showed an inferior CR/PR rate (p = 0.002) and showed a trend of worse OS (p = 0.02 in univariate, p = 0.09 in multivariate) compared to those without SNP lesions, but not were associated with inferior EFS. The presence of abnormal SNP lesions in MDS was associated with adverse outcomes following decitabine therapy. Further study is strongly warranted to establish the role of SNP-A karyotyping in MDS.

 

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[105]

TÍTULO / TITLE:  - Health Behaviors Predict Higher Interleukin-6 levels Among Patients Newly Diagnosed with Head and Neck Squamous Cell Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Epidemiol Biomarkers Prev. 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1055-9965.EPI-12-0987

AUTORES / AUTHORS:  - Duffy SA; Teknos T; Taylor JM; Fowler K; Islam M; Wolf GT; McLean SA; Ghanem TA; Terrell JE

INSTITUCIÓN / INSTITUTION:  - 1Otolaryngology & Nursing, University of Michigan.

RESUMEN / SUMMARY:  - BACKGROUND: Health behaviors have been shown to be associated with recurrence risk and survival rates in cancer patients and are also associated with Interleukin-6 levels, but few epidemiologic studies have investigated the relationship of health behaviors and Interleukin-6 among cancer populations. The  purpose of the study is to look at the relationship between five health behaviors: smoking, alcohol problems, body mass index (a marker of nutritional status), physical activity, and sleep and pretreatment Interleukin-6 levels in persons with head and neck cancer. METHODS: Patients (N=409) were recruited in otolaryngology clinic waiting rooms and invited to complete written surveys. A medical record audit was also conducted. Descriptive statistics and multivariate  analyses were conducted to determine which health behaviors were associated with  higher Interleukin-6 levels controlling for demographic and clinical variables among newly diagnosed head and neck cancer patients. RESULTS: While smoking, alcohol problems, body mass index, physical activity, and sleep were associated with Interleukin-6 levels in bivariate analysis, only smoking (current and former) and decreased sleep were independent predictors of higher Interleukin-6 levels in multivariate regression analysis. Covariates associated with higher Interleukin-6 levels were age and higher tumor stage, while comorbidities were marginally significant. CONCLUSION: Health behaviors, particularly smoking and sleep disturbances, are associated with higher Interleukin-6 levels among head and neck cancer patients. Impact: Treating health behavior problems, especially smoking and sleep disturbances, may be beneficial to decreasing Interleukin-6 levels which could have a beneficial effect on overall cancer treatment outcomes.

 

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[106]

TÍTULO / TITLE:  - Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):741-50. doi: 10.3892/or.2012.2153. Epub 2012 Nov 28.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2153

AUTORES / AUTHORS:  - Gromicho M; Magalhaes M; Torres F; Dinis J; Fernandes AR; Rendeiro P; Tavares P; Laires A; Rueff J; Sebastiao Rodrigues A

INSTITUCIÓN / INSTITUTION:  - Human Molecular Genetics Research Centre, Department of Genetics, New University  of Lisbon, Lisbon, Portugal. marta.gromicho@fcm.unl.pt

RESUMEN / SUMMARY:  - Despite the success of imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), approximately 30% of patients are resistant to therapy, mostly due to unknown causes. To profile the expression signatures of drug transporters  throughout IM therapy and correlate them with resistance, we quantified mRNA expression levels of the SLC22A12, ABCB1, ABCC1, ABCG2 and MVP genes in consecutive samples from peripheral blood or bone marrow of CML patients who were either responsive or resistant to IM. Additionally we identified and quantified BCR-ABL1 transcript variants and analyzed 1236T>C ABCB1 and 480G>C SLC22A1 polymorphisms. A relationship between the type of BCR-ABL1 transcript or ABCB1 or SLC22A1 genotype and response to treatment was not discovered. However, the studied genes had higher expression levels in follow-up compared to the diagnostic samples, demonstrating a possible induction in expression. IM-sensitive patients presented significantly higher values of SLC22A1 expression, suggesting higher drug influx. Most importantly, while responding patients demonstrated stable expression signatures in consecutive samples, there  was considerable variation in IM-resistant patients, indicating that single point sampling expression signatures are not reliable in predicting clinical outcomes or prognostic features in these patients. Studies that assessed consecutive samples from CML patients in order to evaluate the variation in expression levels of transporter genes are limited yet our study emphasizes the importance of such  approaches.

 

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[107]

TÍTULO / TITLE:  - Critical role of presenilin-dependent gamma-secretase activity in DNA damage-induced promyelocytic leukemia protein expression and apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Death Differ. 2013 Jan 11. doi: 10.1038/cdd.2012.162.

            ●● Enlace al texto completo (gratuito o de pago) 1038/cdd.2012.162

AUTORES / AUTHORS:  - Song H; Hyun Boo J; Ho Kim K; Kim C; Kim YE; Ahn JH; Sun Jeon G; Ryu H; Kang DE; Mook-Jung I

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry and Biomedical Sciences, WCU neurocytomics, College of Medicine, Seoul National University, Seoul, Korea.

RESUMEN / SUMMARY:  - Promyelocytic leukemia (PML) is a major component of macromolecular multiprotein  complexes called PML nuclear-bodies (PML-NBs). These PML-NBs recruit numerous proteins including CBP, p53 and HIPK2 in response to DNA damage, senescence and apoptosis. In this study, we investigated the effect of presenilin (PS), the main component of the gamma-secretase complex, in PML/p53 expression and downstream consequences during DNA damage-induced cell death using camptothecin (CPT). We found that the loss of PS in PS knockout (KO) MEFs (mouse embryonic fibroblasts)  results in severely blunted PML expression and attenuated cell death upon CPT exposure, a phenotype that is fully reversed by re-expression of PS1 in PS KO cells and recapitulated by gamma-secretase inhibitors in hPS1 MEFs. Interestingly, the gamma-secretase cleavage product, APP intracellular domain (AICD), together with Fe65-induced PML expression at the protein and transcriptional levels in PS KO cells. PML and p53 reciprocally positively regulated each other during CPT-induced DNA damage, both of which were dependent  on PS. Finally, elevated levels of PML-NB, PML protein and PML mRNA were detected in the brain tissues from Alzheimer’s disease (AD) patients, where gamma-secretase activity is essential for pathogenesis. Our data provide for the  first time, a critical role of the PS/AICD-PML/p53 pathway in DNA damage-induced  apoptosis, and implicate this pathway in AD pathogenesis.Cell Death and Differentiation advance online publication, 11 January 2013; doi:10.1038/cdd.2012.162.

 

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[108]

TÍTULO / TITLE:  - Low expression of nucleus accumbens-associated protein 1 predicts poor prognosis  for patients with pancreatic ductal adenocarcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pathol Int. 2012 Dec;62(12):802-10. doi: 10.1111/pin.12020.

            ●● Enlace al texto completo (gratuito o de pago) 1111/pin.12020

AUTORES / AUTHORS:  - Nishi T; Maruyama R; Urano T; Nakayama N; Kawabata Y; Yano S; Yoshida M; Nakayama K; Miyazaki K; Takenaga K; Tanaka T; Tajima Y

INSTITUCIÓN / INSTITUTION:  - Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Izumo, Japan.

RESUMEN / SUMMARY:  - Nucleus accumbens-associated protein 1 (NAC1) is overexpressed in various carcinomas including ovarian, cervical, breast, and pancreatic carcinomas. High expression of NAC1 is considered to have adverse effects on prognosis through negative regulation of growth arrest and DNA-damage-inducible 45-gamma interacting protein 1 (GADD45GIP1) in ovarian and cervical carcinomas. In the present study, the expression of NAC1 in pancreatic ductal adenocarcinoma (PDA) was measured using immunohistochemistry and computer-assisted image analysis in order to investigate its correlation with various clinicopathological parameters  and prognosis. Patients with low-NAC1 PDA had worse overall survival (P = 0.0010) and a shorter disease-free survival (P = 0.0036) than patients with high-NAC1 PDA. This was a clinical effect opposite to that reported in ovarian and cervical carcinomas. Furthermore, knockdown of NAC1 in pancreatic carcinoma cell lines did not increase expression of the GADD45GIP1 protein. These results indicate that the gene(s) regulated by NAC1 vary depending on the types of carcinoma or originating tissue, and that low expression of NAC1 predicts poor prognosis for patients with PDA.

 

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[109]

TÍTULO / TITLE:  - Neurosarcoidosis in a patient treated with tumor necrosis factor alpha inhibitors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Neurol. 2013 Jan 10.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00415-012-6726-9

AUTORES / AUTHORS:  - Mao-Draayer Y; Cash T

INSTITUCIÓN / INSTITUTION:  - Neurology Department, University of Michigan, Ann Arbor, MI, 48103, USA, maodraay@med.umich.edu.

 

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[110]

TÍTULO / TITLE:  - Plasma DNA integrity indicates response to neoadjuvant chemotherapy in patients with locally confined breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Clin Pharmacol Ther. 2013 Jan;51(1):59-62.

AUTORES / AUTHORS:  - Lehner J; Stotzer OJ; Fersching DM; Nagel D; Holdenrieder S

INSTITUCIÓN / INSTITUTION:  - Institute of Clinical Chemistry, University Hospital Munich-Grosshadern, Hematology/Oncology Outpatient Center Munich, Munich and Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.

 

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[111]

TÍTULO / TITLE:  - Perihepatic lymph node enlargement is a negative predictor for sustained responses to pegylated interferon-alpha and ribavirin therapy for Japanese patients infected with hepatitis C virus genotype 1.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hepatol Res. 2013 Jan 3. doi: 10.1111/hepr.12061.

            ●● Enlace al texto completo (gratuito o de pago) 1111/hepr.12061

AUTORES / AUTHORS:  - Hikita H; Enooku K; Satoh Y; Yoshida H; Nakagawa H; Masuzaki R; Tateishi R; Soroida Y; Sato M; Suzuki A; Gotoh H; Iwai T; Yokota H; Koike K; Yatomi Y; Ikeda H

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.

RESUMEN / SUMMARY:  - AIM: Although perihepatic lymph node enlargement (PLNE) is reportedly associated  with the negative outcome of interferon therapy for chronic hepatitis C, there were limitations in that the results were obtained in patients with various genotypes, viral loads and treatment regimens. We aimed to precisely clarify the  significance of PLNE in interferon therapy for chronic hepatitis C. METHODS: Between December 2004 and June 2005, 112 patients with hepatitis C virus (HCV) genotype 1 and HCV RNA of more than 100 KIU/mL were enrolled, who underwent pegylated interferon-alpha plus ribavirin therapy thereafter. PLNE was defined as a perihepatic lymph node of more than 1 cm in the longest axis by ultrasonography. RESULTS: The sustained virological response (SVR) rate was lower in patients with PLNE (4/22, 18.2%) than in those without (37/90, 41.1%; P = 0.045) and viral load decline was smaller in patients with PLNE than in those without (P = 0.028). The proportion of PLNE positive patients was the smallest in the SVR group (P = 0.033) among the patient groups divided by the treatment outcome. PLNE was retained as a negative predictor for SVR by multivariate logistic regression analysis (P = 0.012). Furthermore, PLNE was not significantly associated with the mutations at HCV core protein and at interferon sensitivity-determining region, or interleukin-28B polymorphism in 45 patients with HCV genotype 1, enrolled between December 2011 and March 2012. CONCLUSION: PLNE is a negative predictor for SVR in patients with HCV genotype 1 and HCV RNA  of more than 100 KIU/mL treated with pegylated interferon-alpha plus ribavirin, independent of other known predictors for SVR.

 

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[112]

TÍTULO / TITLE:  - SP600125, a JNK inhibitor, suppresses growth of JNK-inactive glioblastoma cells through cell-cycle G2/M phase arrest.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pharmazie. 2012 Nov;67(11):942-6.

AUTORES / AUTHORS:  - Li JY; Huang JY; Xing B; Ren KW; Li M; Wei D; Gu PY; Chen G; Gu B; Zhang GF; Hu WX

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing City, Nanjing, China.

RESUMEN / SUMMARY:  - SP600125 is a well studied inhibitor of c-Jun N-terminal kinase (JNK). Its direct biochemical effects on JNK-inactive tumor cells are usually ignored. In this study, we investigated the effects of SP600125 on JNK-inactive U251 human glioblastoma cells. Our results demonstrate that, 20 microM or more SP600125 can  induce significant cell growth inhibition and cell-cycle G2/M phase arrest in U251 cells. Interestingly, we also found that SP600125 can stop the duplicated chromosomes from separating into two cells and the karyokinesis progression. Our  study opened up a new perspective for further studies involved in JNK inhibitors  or anti-glioma therapy.

 

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[113]

TÍTULO / TITLE:  - Pro-adrenomedullin as a Novel Biomarker for Predicting Infections and Response to Antimicrobials in Febrile Patients With Hematologic Malignancies.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Infect Dis. 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1093/cid/cis1029

AUTORES / AUTHORS:  - Al Shuaibi M; Bahu RR; Chaftari AM; Al Wohoush I; Shomali W; Jiang Y; Debiane L; Raad S; Jabbour J; Al Akhrass F; Hachem RY; Raad I

INSTITUCIÓN / INSTITUTION:  - Department of Infectious Diseases, University of Texas MD Anderson Cancer Center, Houston.

RESUMEN / SUMMARY:  - Background. Health professionals and researchers have become increasingly interested in biomarkers that help them in diagnosis of infections with recent growing attention to procalcitonin (PCT) and pro-adrenomedullin (proADM).Methods. This study compares proADM to PCT as diagnostic and prognostic biomarkers of infection in febrile patients with hematologic malignancies (HMs). From June 2009 to December 2010, 340 febrile HM patients were evaluated for presence of sepsis,  systemic inflammatory response syndrome (SIRS), documented infections, and response to antimicrobial therapy.Results. ProADM and PCT levels were measured at onset of fever and then on days 4-7 afterward. Of the 340 patients, 103 had definite sepsis, and 159 had SIRS. Only proADM initial levels were significantly  higher in patients with localized bacterial infections than in those with no documented infection (P = .019) and in patients with definite sepsis than those with SIRS (P = .023). The initial proADM and PCT levels were significantly higher in neutropenic patients with BSIs than in those without documented infections (P  = .010 and P = . 011, respectively). Follow-up, proADM, and PCT levels decreased  significantly in response to antimicrobial therapy in patients with bacterial infections (BSIs or localized; P = .007 and P = .002, respectively).Conclusions.  ProADM and PCT have promising roles in assisting clinicians in managing febrile HM patients. However, proADM appears to have the advantage of predicting localized bacterial infection and differentiating sepsis from SIRS.

 

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[114]

TÍTULO / TITLE:  - Sense and nonsense of high-dose cytarabine for acute myeloid leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Blood. 2013 Jan 3;121(1):26-8. doi: 10.1182/blood-2012-07-444851.

            ●● Enlace al texto completo (gratuito o de pago) 1182/blood-2012-07-444851

AUTORES / AUTHORS:  - Lowenberg B

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.

RESUMEN / SUMMARY:  - High-dose cytarabine applied during remission induction or as consolidation after attainment of a complete remission has become an established element in the treatment of adults with acute myeloid leukemia. Recent evidence has challenged the need for these exceptionally high-dose levels of cytarabine. In this review,  we present a reappraisal of the usefulness of high-dose cytarabine for acute myeloid leukemia treatment.

 

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[115]

TÍTULO / TITLE:  - BTB/POZ domain-containing protein 7: Epithelial-mesenchymal transition promoter and prognostic biomarker of hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hepatology. 2013 Jan 16. doi: 10.1002/hep.26268.

            ●● Enlace al texto completo (gratuito o de pago) 1002/hep.26268

AUTORES / AUTHORS:  - Tao YM; Huang JL; Zeng S; Zhang S; Fan XG; Wang ZM; Yang HX; Yuan XH; Wang P; Wu F; Luo J; Zeng DY; Shen H

INSTITUCIÓN / INSTITUTION:  - Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, China.

RESUMEN / SUMMARY:  - Epithelial-mesenchymal transition (EMT) is a critical step in the metastasis of hepatocellular carcinoma (HCC). BTB/POZ domain-containing protein 7 (BTBD7) regulates EMT-associated proteins implicated in HCC progression. However, the role(s) of BTBD7 in HCC have not been identified. Using highly metastatic HCC HCCLM3 cells, immortalized L02 hepatocytes, metastatic HCC animal models and three independent cohorts of HCC patient specimens, we aimed to determine the involvement of BTBD7 in HCC metastasis. We show that BTBD7 mRNA and protein was highly expressed in HCC cells and tumor tissues, with such expression being associated with: enhanced cell motility, venous invasion, and poor prognosis. BTBD7 promoted HCC angiogenesis and metastasis in vitro and in vivo, but did not  influence cell proliferation or colony formation. BTBD7 enhancement of HCC invasion and EMT phenotype occurred via activation of a RhoC-Rock2-FAK signaling  pathway resulting in MMP-2/9 production and microvessel formation. Applying a predictive risk score model, Cox regression analysis revealed that high BTBD7 expression integrated with high microvessel density was a powerful independent predictive factor of HCC clinical outcome. Conclusion: The present study identifies BTBD7 as a novel candidate prognostic factor and a potential therapeutic target of HCC. (HEPATOLOGY 2013.).

 

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[116]

TÍTULO / TITLE:  - Prediction of response to chemotherapy in anaplastic glioma: how many markers does it take?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 20;31(3):297-8. doi: 10.1200/JCO.2012.46.9627. Epub 2012 Dec 26.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.46.9627

AUTORES / AUTHORS:  - de Groot JF

INSTITUCIÓN / INSTITUTION:  - The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 431,  Houston, TX 77030; jdegroot@mdanderson.org.

 

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[117]

TÍTULO / TITLE:  - The glucocorticoid receptor gene polymorphism N363S predisposes to more severe toxic side effects during pediatric acute lymphoblastic leukemia (ALL) therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Hematol. 2013 Jan 26.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12185-012-1236-1

AUTORES / AUTHORS:  - Eipel OT; Nemeth K; Torok D; Csordas K; Hegyi M; Ponyi A; Ferenczy A; Erdelyi DJ; Csoka M; Kovacs GT

INSTITUCIÓN / INSTITUTION:  - 2nd Department of Paediatrics, Semmelweis University, Faculty of Medicine, Tuzolto u.7-9, Budapest, 1094, Hungary.

RESUMEN / SUMMARY:  - The survival rates in childhood acute lymphoid leukemia (ALL) have improved dramatically; however, patients still suffer from a variety of drug-related toxicities. Individualized therapy regimens promise the least toxic therapy regimen with the best hematologic outcome. Our aim was to investigate whether increased individual glucocorticoid sensitivity due to the N363S polymorphism of  the glucocorticoid receptor increased susceptibility to steroid-related toxicities during ALL therapy. A total of 346 pediatric ALL patients were involved in the present study. N363S carrier status was investigated by allele-specific PCR. Clinical and laboratory signs of glucocorticoid-related toxicities, Day 8 prednisone response, and 5-year event-free survival were analyzed and compared retrospectively. Thirty-two of the 346 patients were heterozygous carriers (9.2 %). Hepatotoxicity (31.3 vs. 11.2 %, p = 0.004, carriers and non-carriers, respectively) and glucose metabolism abnormalities (18.8 vs. 3.8 %, p = 0.001, carriers and non-carriers, respectively) were significantly more frequent among carriers. There was no difference in the incidence of hypertension and encephalopathy/psychosis among carriers and non-carriers. Carriers were also more prone to have a combination of toxicities.  All 363S carriers were good prednisone responders (100 %) and had significantly better 5-year event-free survival rates (93.1 vs. 71.86 %, p = 0.012), whereas among non-carriers there were more poor prednisone responders (8.28 %) and worse  5-year event-free survival rates. Patients with the N363S polymorphism in the glucocorticoid receptor are more prone to steroid-related toxicity during ALL therapy and should be monitored more closely. Patients with N363S polymorphism of the glucocorticoid receptor may be appropriate candidates for inclusion in the design of individualized therapies.

 

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[118]

TÍTULO / TITLE:  - Hypertension as a predictive biomarker in bevacizumab treatment for colorectal cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):327. doi: 10.1007/s12032-012-0327-4. Epub 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0327-4

AUTORES / AUTHORS:  - Tahover E; Uziely B; Salah A; Temper M; Peretz T; Hubert A

INSTITUCIÓN / INSTITUTION:  - Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem, 91120, Israel, esthert@hadassah.org.il.

RESUMEN / SUMMARY:  - Bevacizumab treatment is associated with an increased risk of hypertension (HTN), a potential marker for effectiveness. We aimed to assess whether grades 2-3 HTN during bevacizumab treatment was associated with increased overall survival (OS)  or progression-free survival (PFS). One hundred and eighty-one patients with metastatic colorectal cancer (CRC), who were treated in our Department from January 2009-February 2011 were included. Bevacizumab was administered jointly with standard first- or second-line chemotherapy protocols. Blood pressure was measured before each treatment. HTN was graded using common toxicity criteria. There were 181 CRC patients. Grades 2-3 HTN developed in 81 patients (44.75 %) but not in 100 patients (55.25 %); no patient developed grades 4-5 HTN. Median follow-up was 15.2 months. HTN was associated with better OS in HTN-positive versus HTN-negative patients (median not reached vs. 36.8 months, p = 0.029) and  better PFS (29.9 vs. 17.2 months, p = 0.024, respectively). Bevacizumab-related HTN may represent a biomarker for clinical benefit in metastatic colorectal cancer patients.

 

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[119]

TÍTULO / TITLE:  - Impairment of Glioma Stem Cell Survival and Growth by a Novel Inhibitor for Survivin-Ran Protein Complex.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-0647

AUTORES / AUTHORS:  - Guvenc H; Pavlyukov MS; Joshi K; Kurt H; Banasavadi-Siddegowda YK; Mao P; Hong C; Yamada R; Kwon CH; Bhasin D; Chettiar S; Kitange G; Park IH; Sarkaria JN; Li C; Shakhparonov MI; Nakano I

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Department of Neurological Surgery; Division of Medicinal  Chemistry and Pharmacognosy, College of Pharmacy; James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota; Shemiakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; and Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Xi’an, Jiaotong University, Xi’an, China.

RESUMEN / SUMMARY:  - PURPOSE: Glioblastoma multiforme (GBM) is a devastating disease. Recent studies suggest that the stem cell properties of GBM contribute to the development of therapy resistance.EXPERIMENTAL DESIGN: The expression of Survivin and Ran was evaluated by immunohistochemistry with GBM tissues, and quantitative reverse transcriptase (qRT)-PCR and immunocytochemistry with patient-derived GBM sphere cultures. With a computational structure-based drug design, 11 small-molecule compounds were designed, synthesized, and evaluated as inhibitor candidates for the molecular interaction of Survivin protein. The molecular mechanism of the lead compound, LLP-3, was determined by Western blot, ELISA, in situ proximity ligation assay, and immunocytochemistry. The effects of LLP-3 treatment on GSCs were evaluated both in vitro and in vivo. Quantitative immunohistochemistry was carried out to compare Survivin expression in tissues from 44 newly diagnosed and 31 recurrent post-chemoradiation GBM patients. Lastly, the sensitivities of temozolomide-resistant GBM spheres to LLP-3 were evaluated in vitro.RESULTS: Survivin and Ran were strongly expressed in GBM tissues, particularly in the perivasculature, and also in patient-derived GSC cultures. LLP-3 treatment disrupted the Survivin-Ran protein complex in cancer cells and abolished the growth of patient-derived GBM spheres in vitro and in vivo. This inhibition was dependent on caspase activity and associated with p53 status of cells. Immunohistochemistry showed that Survivin expression is significantly increased in recurrent GBM compared with newly diagnosed tumors, and temozolomide-resistant GBM spheres exhibited high sensitivities to LLP-3 treatment.CONCLUSIONS: Disruption of the Survivin-Ran complex by LLP-3 abolishes survival and growth of  GSCs both in vitro and in vivo, indicating an attractive novel therapeutic approach for GBM. Clin Cancer Res; 19(3); 1-12. ©2012 AACR.

 

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[120]

TÍTULO / TITLE:  - Polymorphisms of the UDP-Glucuronosyl Transferase 1A Genes Are Associated with Adverse Events in Cancer Patients Receiving Irinotecan-Based Chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Tohoku J Exp Med. 2013;229(2):107-14.

AUTORES / AUTHORS:  - Inoue K; Sonobe M; Kawamura Y; Etoh T; Takagi M; Matsumura T; Kikuyama M; Kimura M; Minami S; Utsuki H; Yamazaki T; Suzuki T; Tsuji D; Hayashi H; Itoh K

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka.

RESUMEN / SUMMARY:  - A prodrug, irinotecan (CPT-11), is a semisynthetic derivative of camptothecin. It inhibits topoisomerase I and is used for treatment of lung, stomach, and colon cancers in Japan. The active form of CPT-11, SN-38, causes the adverse events such as neutropenia and diarrhea. Since SN-38 is metabolized to non-toxic SN-38-glucuronide by hepatic uridine diphosphate glucuronosyl transferase (UGT) 1A enzymes, UGT1A enzyme activities may influence adverse events of CPT-11. UGT1A enzymes consist of three isozymes (1A1, 1A7, 1A9), and their genes are characterized by polymorphisms. Here, to identify the genetic factors that affect the adverse events of CPT-11, we determined the polymorphism in three UGT 1A isozyme genes in 45 inpatients with lung, colon, or stomach cancer. The univariate and multivariate analysis of patients’ physiological and genetic factors revealed that one or more genotypes of UGT1A1*6/*28, UGT1A7*3/*3, and UGT1A9*1/*1 may enhance the adverse events. Each of the first two genotypes is expected to generate the enzyme with low catalytic activity. The UGT1A9*1 represents the wild-type allele, which however provides the lower catalytic activity, compared to the UGT1A9*22 variant that is common in this study population. Indeed, four (67%) out of six patients who carry one or more of the above-mentioned genotypes suffered from adverse events, leading to the discontinuation of chemotherapy or the decreased dose of CPT-11. By contrast, only six (15%) out of 39 patients with other genotypes suffered from adverse events. In conclusion, UGT1A1*6/*28, UGT1A7*3/*3, and UGT1A9*1/*1 should be taken into consideration as markers for preventing severe adverse events of CPT-11 administration.

 

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[121]

TÍTULO / TITLE:  - Successful azacitidine treatment with increase of regulatory T cells for relapsed acute myeloid leukemia after allogeneic stem cell transplantation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Jan 9.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2013.764420

AUTORES / AUTHORS:  - Yamamoto W; Tachibana T; Ogusa E; Matsumoto K; Maruta A; Ishigatsubo Y; Kanamori H

 

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[122]

TÍTULO / TITLE:  - Erratum to: The use of the (13)C-dextromethorphan breath test for phenotyping CYP2D6 in breast cancer patients using tamoxifen: association with CYP2D6 genotype and serum endoxifen levels.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Jan 12.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-012-2065-x

AUTORES / AUTHORS:  - Opdam FL; Dezentje VO; den Hartigh J; Modak AS; Vree R; Batman E; Smorenburg CH; Nortier JW; Gelderblom H; Guchelaar HJ

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Oncology, K-1, Leiden University Medical Center, P.O. box  9600, 2300 RC, Leiden, The Netherlands, f.l.opdam@lumc.nl.

 

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[123]

TÍTULO / TITLE:  - The use of the (13)C-dextromethorphan breath test for phenotyping CYP2D6 in breast cancer patients using tamoxifen: association with CYP2D6 genotype and serum endoxifen levels.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2012 Dec 11.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-012-2034-4

AUTORES / AUTHORS:  - Opdam FL; Dezentje VO; den Hartigh J; Modak AS; Vree R; Batman E; Smorenburg CH; Nortier JW; Gelderblom H; Guchelaar HJ

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Oncology, K-1, Leiden University Medical Center, P.O. box  9600, 2300 RC, Leiden, The Netherlands, f.l.opdam@lumc.nl.

RESUMEN / SUMMARY:  - PURPOSE: Adjuvant therapy with tamoxifen significantly reduces breast cancer recurrence and mortality in estrogen receptor positive disease. CYP2D6 is the main enzyme involved in the activation of the prodrug tamoxifen into the anti-estrogen endoxifen. Endoxifen is thought to be a main determinant for clinical efficacy in breast cancer patients using tamoxifen. As the large interindividual variation in endoxifen levels is only partly explained by CYP2D6  genotype, we explored the use of the (13)C-dextromethorphan breath test (DM-BT) for phenotyping CYP2D6 and to predict serum steady-state endoxifen levels as a marker for clinical outcome in breast cancer patients using tamoxifen. METHODS: In 65 patients with early breast cancer using tamoxifen, CYP2D6 phenotype was assessed by DM-BT. CYP2D6 genotype using Amplichip and serum steady-state levels  of endoxifen were determined. Genotype was translated into the gene activity score and into ultrarapid, extensive, heterozygous extensive, intermediate or poor metabolizer CYP2D6 predicted phenotype. RESULTS: CYP2D6 phenotype determined by the DM-BT explained variation in serum steady-state endoxifen levels for 47.5  % (R (2) = 0.475, p < 0.001). Positive and negative predictive values for a recently suggested threshold serum level of endoxifen (5.97 ng/mL) for breast cancer recurrence rate were 100 and 90 %, respectively, for both CYP2D6 phenotype by DM-BT (delta-over-baseline at t = 50 min (DOB(50)) values of 0.7-0.9) and genotype (CYP2D6 gene activity score of 1.0). CONCLUSION: DM-BT might be, along with CYP2D6 genotyping, of value in selection of individualized endocrine therapy in patients with early breast cancer, especially when concomitant use of CYP2D6 inhibiting medication alters the phenotype.

 

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[124]

TÍTULO / TITLE:  - Cystine/glutamic acid transporter is a novel marker for predicting poor survival  in patients with hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):685-9. doi: 10.3892/or.2012.2162. Epub 2012 Nov 30.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2162

AUTORES / AUTHORS:  - Kinoshita H; Okabe H; Beppu T; Chikamoto A; Hayashi H; Imai K; Mima K; Nakagawa S; Ishimoto T; Miyake K; Yokoyama N; Ishiko T; Baba H

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

RESUMEN / SUMMARY:  - Cystine/glutamic acid transporter (xCT) plays a role in tumor progression by regulating the redox status in several types of cancers. To demonstrate the importance of xCT expression for predicting the prognosis of hepatocellular carcinoma (HCC), we analyzed xCT gene expression in 130 paired HCC and non-cancerous tissues. xCT protein expression was confirmed using 7 HCC cell lines and samples from human subjects. xCT mRNA expression was detected in 34 (26%) tumor tissues. Expression of xCT was higher in HCC tissues compared to the  corresponding normal tissues according to quantitative reverse transcriptase-polymerase chain reaction findings (P<0.0001). Patients in the group presenting with xCT mRNA expression showed poorer overall and disease-free  survival than did those with an absence of xCT mRNA (P=0.0130 and 0.0416, respectively). xCT mRNA expression proved to be an independent factor for poor prognosis in a multivariate analysis of overall survival (hazard ratio, 1.68; 95% CI, 1.03-2.92). We observed xCT protein expression in both the HCC cell lines and in human tissue samples. In conclusion, the findings of the present study suggest that xCT is useful as a predictive marker for patient prognosis and that it may be a novel therapeutic target for HCC.

 

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[125]

TÍTULO / TITLE:  - Collections of simultaneously altered genes as biomarkers of cancer cell drug response.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2013 Jan 21.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-3122

AUTORES / AUTHORS:  - Masica DL; Karchin R

INSTITUCIÓN / INSTITUTION:  - Biomedical Engineering/Institute of Computational Medicine, Johns Hopkins University.

RESUMEN / SUMMARY:  - Abstract Computational analysis of cancer pharmacogenomics data has resulted in biomarkers predictive of drug response, but the majority of response is not captured by current methods. Methods typically select single biomarkers or groups of related biomarkers, but do not account for response that is strictly dependent on many simultaneous genetic alterations. This shortcoming reflects the combinatorics and multiple-testing problem associated with many-body biological interactions. We developed a novel approach, MOCA (Multivariate Organization of Combinatorial Alterations), to partially address these challenges. Extending on previous work that accounts for pairwise interactions, the approach rapidly combines many genomic alterations into biomarkers of drug response, using Boolean set operations coupled with optimization; in this framework the union, intersection, and difference Boolean set operations are proxies of molecular redundancy, synergy, and resistance, respectively. The algorithm is fast, broadly applicable to cancer genomics data, is of immediate utility for prioritizing cancer pharmacogenomics experiments, and recovers known clinical findings without bias. Furthermore, the results presented here connect many important, previously  isolated observations. Major Findings When applied to 416 pharmacogenomically characterized cancer cell lines, MOCA identifies many known and potential markers of drug response. For instance, correlation with ERBB inhibitor response drastically increased when considering EGFR (ERBB1), ERBB2, ERBB3, ERBB4, and KRAS alterations in a single feature. Similarly, a feature combining IGF1, IGF1R, and RAD51 drastically increased correlation with IGF1R inhibitor response, relative to any of these three genetic markers considered in isolation. This approach is also powerful for determining subsets of site-specific mutations, for a particular gene, that increase correlation with drug response. For example, MOCA captures the differential EGFR inhibitor response conferred by common EGFR mutations. Similarly, we find specific HDAC1 mutations cooperate with HDAC5 overexpression to potentiate cells to the HDAC inhibitor panobinostat. Additionally, considering all pairwise gene-drug interactions, MOCA recovers known and compelling correlations, including: RTK inhibitor resistance via c-MET, EGFR, ERBB2, and PDGFRB kinase switching; mutual exclusivity of TP53 mutation and response to the MDM2 inhibitor nutlin-3; greater nutilin-3 potentiation via MDM4, rather than MDM2, overexpression; MEK and RAF inhibitor response in BRAF mutated  cell lines; and, MEK inhibitor potentiating NRAS mutations.

 

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[126]

TÍTULO / TITLE:  - IgD cross-linking induces gene expression profiling changes and enhances apoptosis in chronic lymphocytic leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Res. 2013 Jan 18. pii: S0145-2126(12)00504-8. doi: 10.1016/j.leukres.2012.12.019.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.leukres.2012.12.019

AUTORES / AUTHORS:  - Tavolaro S; Peragine N; Chiaretti S; Ricciardi MR; Raponi S; Messina M; Santangelo S; Marinelli M; Di Maio V; Mauro FR; Del Giudice I; Foa R; Guarini A

INSTITUCIÓN / INSTITUTION:  - Division of Hematology, Department of Cellular Biotechnologies and Hematology, “Sapienza” University, Rome, Italy.

RESUMEN / SUMMARY:  - Gene profile and functional changes upon IgD cross-linking were evaluated in chronic lymphocytic leukemia (CLL). Microarrays highlighted responsiveness to IgD in all cases, independently of clinico-biological characteristics. Stimulated samples exhibited the down-regulation of transcripts of B-cell receptor signaling and cell-adhesion at 24h and the up-modulation of differentiation and apoptosis genes at 48h. A significant increase in apoptosis upon ligation was also documented. Furthermore, comparison between IgD and IgM stimulation displayed a differential transcriptional/functional response. In conclusion, CLL respond to IgD displaying expression changes and cell-death enhancement, indicating the apoptosis induction via-IgD as an alternative approach for CLL management.

 

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[127]

TÍTULO / TITLE:  - Aryl Hydrocarbon Receptor is a Target of 17-allylamino-17-demethoxygeldanamycin and Enhances its Anticancer Activity in Lung Adenocarcinoma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Pharmacol. 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 1124/mol.112.081646

AUTORES / AUTHORS:  - Chen PH; Chang JT; Li LA; Tsai HT; Shen MY; Lin PP

INSTITUCIÓN / INSTITUTION:  - 1 National Health Research Institutes;

RESUMEN / SUMMARY:  - We have demonstrated that aryl hydrocarbon receptor (AhR) is overexpressed in lung adenocarcinoma (AD). AhR is usually associated with heat shock protein 90 (Hsp90) in the cytoplasm. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, is currently under evaluation for its anticancer activity in clinical trials. Here, we investigated whether AhR plays a role in 17-AAG-mediated anticancer activity by functioning as a downstream target or by modulating its anticancer efficacy. AhR expression in lung AD cells was modulated by siRNA interference or overexpression. Tumor growth was determined with colony  formation in vitro or in vivo. Anticancer activity of 17-AAG was determined by measuring cell viability, cell cycle distribution and expression of cell cycle regulators. Proteins and mRNA levels were examined by immunoblotting and the real-time reverse transcription-polymerase chain reaction, respectively. In this  study, AhR overexpression positively modulated growth of lung AD cells, at least  partially, via RelA-dependent mechanisms. Although treatment with 17-AAG reduced  AhR levels and AhR-regulated gene expression in lung AD cells, AhR expression increased anticancer activity of 17-AAG. In addition, 17-AAG treatment reduced cell viability, CDK2, CDK4, cyclin E, cyclin D1 and phosphorylated Rb levels in AhR-expressing lung AD cells. NAD(P)H:quinone oxidoreductase (NQO1), which is regulated by AhR, was shown to increase anticancer activity of 17-AAG in cells. Knockdown of NQO1 expression attenuated the reduction of cell cycle regulators by 17-AAG treatment in AhR overexpressed cells. We demonstrated that AhR protein not only functions as a downstream target of 17-AAG, but also enhances anticancer activity of 17-AAG in lung AD cells.

 

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[128]

TÍTULO / TITLE:  - Sodium orthovanadate associated with pharmacological doses of ascorbate causes an increased generation of ROS in tumor cells that inhibits proliferation and triggers apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 18;430(3):883-888. doi: 10.1016/j.bbrc.2012.12.061. Epub 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.12.061

AUTORES / AUTHORS:  - Gunther TM; Kviecinski MR; Baron CC; Felipe KB; Farias MS; da Silva FO; Bucker NC; Pich CT; Ferreira EA; Filho DW; Verrax J; Calderon PB; Pedrosa RC

INSTITUCIÓN / INSTITUTION:  - Departamento de Bioquimica, Universidade Federal de Santa Catarina, Florianopolis, Brazil.

RESUMEN / SUMMARY:  - Pharmacological doses of ascorbate were evaluated for its ability to potentiate the toxicity of sodium orthovanadate (Na(3)VO(4)) in tumor cells. Cytotoxicity, inhibition of cell proliferation, generation of ROS and DNA fragmentation were assessed in T24 cells. Na(3)VO(4) was cytotoxic against T24 cells (EC(50)=5.8muM  at 24h), but in the presence of ascorbate (100muM) the EC(50) fell to 3.3muM. Na(3)VO(4) plus ascorbate caused a strong inhibition of cell proliferation (up to 20%) and increased the generation of ROS (4-fold). Na(3)VO(4) did not directly cleave plasmid DNA, at this aspect no synergism was found occurring between Na(3)VO(4) and ascorbate once the resulting action of the combination was no greater than that of both substances administered separately. Cells from Ehrlich  ascites carcinoma-bearing mice were used to determine the activity of antioxidant enzymes, the extent of the oxidative damage and the type of cell death. Na(3)VO(4) alone, or combined with ascorbate, increased catalase activity, but only Na(3)VO(4) plus ascorbate increased superoxide dismutase activity (up to 4-fold). Oxidative damage on proteins and lipids was higher due to the treatment  done with Na(3)VO(4) plus ascorbate (2-3-fold). Ascorbate potentiated apoptosis in tumor cells from mice treated with Na(3)VO(4). The results indicate that pharmacological doses of ascorbate enhance the generation of ROS induced by Na(3)VO(4) in tumor cells causing inhibition of proliferation and apoptosis. Apoptosis induced by orthovanadate and ascorbate is closer related to inhibition  on Bcl-xL and activation of Bax. Our data apparently rule out a mechanism of cell demise p53-dependent or related to Cdk2 impairment.

 

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[129]

TÍTULO / TITLE:  - Interleukin-17 enhances the production of interferon-gamma and tumour necrosis factor-alpha by bone marrow T lymphocytes from patients with lower risk myelodysplastic syndromes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Haematol. 2013 Jan 19. doi: 10.1111/ejh.12074.

            ●● Enlace al texto completo (gratuito o de pago) 1111/ejh.12074

AUTORES / AUTHORS:  - Zhang Z; Li X; Guo J; Xu F; He Q; Zhao Y; Yang Y; Gu S; Zhang Y; Wu L; Chang C

INSTITUCIÓN / INSTITUTION:  - The Sixth People’s Hospital affiliated with Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, Shanghai, China.

RESUMEN / SUMMARY:  - INTRODUCTION: Lower risk myelodysplastic syndromes (MDSs) are characterised by increased apoptosis of haematopoietic cells in the bone marrow (BM). The mechanism driving this excessive apoptosis involves multiple immune molecules, including inflammatory cytokines such as interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and interleukins (ILs). Interleukin-17(IL-17) is the hallmark cytokine produced by CD4+ Th17 cells, and IL-17 mediates activation of the adaptive T cell response, inducing an inflammatory cytokine environment. However, little is known about the role of IL-17 in MDS-associated immune dysfunction. METHODS: A total of 47 patients with myelodysplastic syndromes were enrolled in this study, and the levels of IL-17 and IL-17 receptor (IL-17R) in BM mononuclear cells (BMNCs) were detected by real-time polymerase chain reaction (RQ-PCR) and enzyme-linked immunosorbent assay (ELISA). Then, BMNCs were stimulated with recombinant human IL-17 (rhIL-17), and flow cytometry  was used to analyse the production of IFN-gamma and TNF-alpha by CD4+ and CD8+ T  lymphocytes from lower risk MDS patients. Characterisation of IL-17 expression in patients with the HLA-DR15 allele or hypocellularity was also performed. RESULTS: mRNA levels for both IL-17 and the IL-17R subunits in BMNCs and for IL-17 in the  BM and plasma were higher in patients with lower risk MDS as compared to patients with higher risk MDS and normal controls. The production of IFN-gamma and TNF-alpha by CD4+ and CD8+ T lymphocytes from lower risk MDS patients could be enhanced by recombinant human IL-17 (rhIL-17) treatment. Furthermore, increased IL-17 expression was associated with more severe anaemia in MDS patients. CONCLUSION: Elevated IL-17 levels and IL-17-induced IFN-gamma and TNF-alpha overproduction may be involved in the pathogenesis of lower risk MDS. © 2013 John Wiley & Sons A/S.

 

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[130]

TÍTULO / TITLE:  - The phosphatidylinositol-3 kinase I inhibitor BKM120 induces cell death in B-chronic lymphocytic leukemia cells in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Cancer. 2012 Dec 12. doi: 10.1002/ijc.27989.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.27989

AUTORES / AUTHORS:  - Amrein L; Shawi M; Grenier J; Aloyz R; Panasci L

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Faculty of Medicine, McGill University, Lady Davis Institute-Segal Cancer Center from the Jewish General Hospital, Montreal, Quebec, Canada.

RESUMEN / SUMMARY:  - BKM120, a pan class I PI3K inhibitor, was cytotoxic in the majority of primary B-chronic lymphocytic leukemia (CLL) lymphocytes, including samples from patients who have a high-risk for poor response to treatment (patient with del11 and del17) at clinically obtainable concentrations. The PI3Kdelta inhibitor Cal-101 is cytotoxic in B-CLL lymphocytes in vitro and is active in the treatment of CLL  in vivo. Interestingly, we demonstrated that BKM120 is 3.6 fold more toxic than Cal-101 in malignant B-CLL lymphocytes in vitro. BKM120 cytotoxicity correlated with the basal expression of proteins involved in the PI3K/Akt pathway. A protein signature of PI3K pathway proteins predicts the response to BKM120 treatment. In  the primary B-CLL lymphocytes tested in vitro, BKM120 decreased the phosphorylation status of molecular biomarkers used as indicators of PI3K pathway inhibition in vivo. Also, BKM120 induced apoptosis in primary B-CLL cells culture in the presence and absence of stromal cell support. Our findings suggest that BKM120 should be tested clinically in CLL.

 

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[131]

TÍTULO / TITLE:  - Research resource: nuclear receptors as transcriptome: discriminant and prognostic value in breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Endocrinol. 2013 Feb;27(2):350-65. doi: 10.1210/me.2012-1265. Epub 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1210/me.2012-1265

AUTORES / AUTHORS:  - Muscat GE; Eriksson NA; Byth K; Loi S; Graham D; Jindal S; Davis MJ; Clyne C; Funder JW; Simpson ER; Ragan MA; Kuczek E; Fuller PJ; Tilley WD; Leedman PJ; Clarke CL

INSTITUCIÓN / INSTITUTION:  - Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia. G.Muscat@uq.edu.au; or Christine L. Clarke, Westmead Millennium Institute, Sydney Medical School, Westmead, University of Sydney, New  South Wales, Australia. E-mail: christine.clarke@sydney.edu.au.

RESUMEN / SUMMARY:  - To identify biologically relevant groupings or clusters of nuclear receptors (NR) that are associated with breast neoplasia, with potentially diagnostic, discriminant or prognostic value, we quantitated mRNA expression levels of all 48 members of the human NR superfamily by TaqMan low-density array analysis in 116 curated breast tissue samples, including pre- and postmenopausal normal breast and both ERalpha(+) and ERalpha(-) tumor tissue. In addition, we have determined  NR levels in independent cohorts of tamoxifen-treated ERalpha(+) and ERalpha(-) tissue samples. There were differences in relative NR mRNA expression between neoplastic and normal breast, and between ER(+) and ER(-) tumors. First, there is overexpression of the NUR77 subgroup and EAR2 in neoplastic breast. Second, we identify a signature of five NR (ERalpha, EAR2, NUR77, TRalpha, and RARgamma) that classifies breast samples with more than 97% cross-validated accuracy into normal or cancer classes. Third, we find a novel negative association between five NR (TRbeta, NUR77, RORgamma, COUP-TFII, and LRH1) and histological grade. Finally, four NR (COUP-TFII, TRbeta, PPARgamma, and MR) are significant predictors of metastasis-free survival in tamoxifen-treated breast cancers, independent of ER expression. The present study highlights the discriminant and prognostic value of NR in breast cancer; identifies novel, clinically relevant, NR signatures; and highlights NR signaling pathways with potential roles in breast cancer pathophysiology and as new therapeutic targets.

 

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[132]

TÍTULO / TITLE:  - Vaccination for the prevention and treatment of breast cancer with special focus  on Her-2/neu peptide vaccines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-013-2410-8

AUTORES / AUTHORS:  - Wiedermann U; Davis AB; Zielinski CC

INSTITUCIÓN / INSTITUTION:  - Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Immunology & Infectiology, Medical University of Vienna, Kinderspitalgasse 15, 1090, Vienna, Austria, ursula.wiedermann@meduniwien.ac.at.

RESUMEN / SUMMARY:  - Immunologic interventions in a subset of breast cancer patients represent a well-established therapeutic approach reflecting individualized treatment modalities. Thus, the therapeutic administration of monoclonal antibodies targeting tumor-associated antigens (TAA), such as Her-2/neu, represents a milestone in cancer treatment. However, passive antibody administration suffers from several drawbacks, including frequency and long duration of treatment. These undesirables may be avoidable in an approach based on generating active immune responses against these same targets. Only recently has the significance of tumors in relation to their microenvironments been understood as essential for creating an effective cancer vaccine. In particular, the immune system plays an important role in suppressing or promoting tumor formation and growth. Therefore, activation of appropriate triggers (such as induction of Th1 cells, CD8+ T cells, and suppression of regulatory cells in combination with generation of antibodies  with anti-tumor activity) is a desirable goal. Current vaccination approaches have concentrated on therapeutic vaccines using certain TAA. Many cancer antigens, including breast cancer antigens, have been described and also given priority ranking for use as vaccine antigens by the US National Cancer Institute. One of the TAA antigens which has been thoroughly examined in numerous trials is  Her-2/neu. This review will discuss delivery systems for this antigen with special focus on T and B cell peptide vaccines. Attention will be given to their  advantages and limitations, as well as the use of certain adjuvants to improve anti-cancer responses.

 

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[133]

TÍTULO / TITLE:  - Molecular Pathways: Toll-like Receptors in the Tumor Microenvironment: Poor Prognosis or New Therapeutic Opportunity.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-0408

AUTORES / AUTHORS:  - Ridnour LA; Cheng RY; Switzer CH; Heinecke JL; Ambs S; Glynn SA; Young HA; Trinchieri G; Wink DA

INSTITUCIÓN / INSTITUTION:  - Radiation Biology Branch, National Cancer Institute, NIH.

RESUMEN / SUMMARY:  - Numerous reports have described toll-like receptor (TLR) expression in the tumor  microenvironment as it relates to cancer progression, as well as their involvement in inflammation. While TLRs mediate immune surveillance, clinical studies have associated TLR expression in the tumor with poor patient survival, indicating that TLR expression may affect cancer treatment and survival. This review will examine mechanisms where TLR activation up-regulates pro-tumorigenic  pathways including the induction of inducible nitric oxide synthase (NOS2) and cyclooxygenase-2 (COX2), which in turn increase TLR expression and promotes a feed forward loop leading to tumor progression and the development of more aggressive tumor phenotypes. These propagating loops involve cancer cell, stroma  and/or immune cell TLR expression. Because of abundant TLR expression in many human tumors, several TLR agonists are now in clinical and preclinical trials and some have shown enhanced efficacy when used as adjuvant with radiation, chemotherapy or cancer vaccines. These findings suggest that TLR expression influences cancer biology and therapeutic response, which may involve specific interactions within the tumor microenvironment including mediators of inflammation like nitric oxide and the arachidonic acid signaling pathways.

 

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[134]

TÍTULO / TITLE:  - DNA Index as a Strong Prognostic Factor in Patients With Adenocarcinoma of the Pancreatic Head: Results of a 5-Year Prospective Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pancreas. 2012 Dec 26.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MPA.0b013e3182773eb6

AUTORES / AUTHORS:  - Kamphues C; Al-Abadi H; Durr A; Al-Abadi N; Schricke D; Bova R; Muller V; Stenzinger A; Klauschen F; Seehofer D; Neuhaus P; Bahra M

INSTITUCIÓN / INSTITUTION:  - From the *Department of General, Visceral and Transplantation Surgery, Charite University Hospital, Berlin, Germany; daggerInstitute of Pathology, University Hospital, Heidelberg, Germany; and double daggerInstitute of Pathology, Charite University Hospital, Berlin, Germany.

RESUMEN / SUMMARY:  - OBJECTIVES: To improve the devastating prognosis of pancreatic cancer; the identification of reliable predictive factors is crucial. The aim of the present  study was to prospectively assess the prognostic value of DNA index determined by image cytometry as an predictive factor in pancreatic head cancer. METHODS: The DNA ploidy and the DNA index of 61 patients were evaluated by DNA image cytometry and were found to be correlated, as well as standard histopathologic parameters,  with patient survival. RESULTS: Through the DNA image cytometry, 15 tumors (24.6%) were identified as diploid and 46 (75.6%) as nondiploid. The median DNA index in the entire cohort was 1.9 (range, 1.0-2.5). Tumor stage, lymph node status, lymph node index, lymphatic invasion, and DNA index were identified as prognostic factors in the univariate analysis, but only DNA index (hazard ratio,  3.137; 95% confidence interval, 1.149-8.566; P = 0.026) and lymph node status (hazard ratio, 0.377; 95% confidence interval, 0.186-0.765; P = 0.007) were identified as independent predictive factors in the multivariate analysis. CONCLUSIONS: The DNA index represents an independent predictive marker in patients with pancreatic head cancer and a potential tool in designing specific treatment strategies for patients with pancreatic cancer.

 

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[135]

TÍTULO / TITLE:  - Outcome and predictors of mortality in patients requiring invasive mechanical ventilation due to acute respiratory failure while undergoing ambulatory chemotherapy for solid cancers.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Support Care Cancer. 2013 Jan 12.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00520-012-1709-z

AUTORES / AUTHORS:  - Park SY; Lim SY; Um SW; Koh WJ; Chung MP; Kim H; Kwon OJ; Park HK; Kim SJ; Im YH; Ahn MJ; Suh GY

INSTITUCIÓN / INSTITUTION:  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Chuncheon Sacred Heart Hospital, Hallym University Medical Center, Chuncheon, Gangwon-do, Republic of Korea.

RESUMEN / SUMMARY:  - PURPOSE: Acute respiratory failure that requires invasive mechanical ventilation  is a leading cause of death in critically ill cancer patients. The aim of this study was to evaluate the outcome and prognostic factors of patients requiring invasive mechanical ventilator for acute respiratory failure, within 1 month of ambulatory chemotherapy for solid cancer. METHODS: A retrospective observational  study of patients who underwent ambulatory chemotherapy at Samsung Medical Center, between January of 2007 and April of 2009, was employed for this study. RESULTS: A total of 51 patients met the inclusion criteria and were included in the study. The median age was 65 years (25-87) and the majority of the patients were male (n = 38, 74.5 %). There were 42 patients (82.3 %) with lung cancer. The most common cause of acute respiratory failure was pneumonia (n = 24, 47.1 %), followed by acute respiratory failure due to extra-pulmonary infection, drug-induced pneumonitis, alveolar hemorrhage, and cancer progression. The intensive care unit (ICU) mortality was 68.6 % and the most common cause of death in the ICU was uncorrected cause of acute respiratory failure. Before adjustment  for others factors, prechemotherapy Eastern Cooperative Oncology Group (ECOG) Performance Scale (PS) (P = 0.03), Sequential Organ Failure Assessment score (P = 0.01), and anemia (P = 0.04) were significantly associated with ICU mortality. However, when adjusted for age, sex, and Acute Physiologic and Chronic Health Evaluation II score, only poor ECOG PS (>/=2) was significantly associated with ICU mortality [OR 6.36 (95 % CI (1.02-39.5))]. CONCLUSIONS: The outcome of patients with acute respiratory failure needing invasive mechanical ventilation during ambulatory chemotherapy for solid cancer is poor. Prechemotherapy performance status is an independent predictor of mortality.

 

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[136]

TÍTULO / TITLE:  - Lapatinib-mediated COX-2 Expression Via EGFR/HuR Interaction Enhances the Aggressiveness of Triple-negative Breast Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Pharmacol. 2013 Jan 25.

            ●● Enlace al texto completo (gratuito o de pago) 1124/mol.112.082743

AUTORES / AUTHORS:  - Hsia TC; Tu CY; Chen YJ; Wei YL; Yu MC; Hsu SC; Tsai SL; Chen WS; Yeh MH; Yen CJ; Yu YL; Huang TC; Huang CY; Hung MC; Huang WC

INSTITUCIÓN / INSTITUTION:  - 1 China Medical University and Hospital;

RESUMEN / SUMMARY:  - Lapatinib, a dual EGFR/HER2 kinase inhibitor, showed clinical benefits in advanced HER2-positive breast cancer patients. Because some triple-negative breast cancers (TNBCs) frequently overexpress EGFR, the anti-tumor activity of lapatinib in such diseases was also tested. However, the results showed a worse event-free survival rate. It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells. In this study, our results demonstrated  that lapatinib facilitated axillary and lung metastases of triple-negative MDA-MB-231 breast cancer cells without affecting their viability, leading to worse survival in orthotopic xenograft mice. The lapatinib-increased motility was attributed by the elevation of EGFR through the downregulation of microRNA-7 and  by the subsequent overexpression of cyclooxygenase-2 (COX-2). Strikingly, independent of its kinase activity, the elevated EGFR at least partly stabilized  COX-2 expression by enhancing the binding of HuR to COX-2 mRNA. Our results suggest that lapatinib may increase the migration and invasion of MDA-MB-231 cells by upregulating EGFR and COX-2 through the downregulation of microRNA-7, providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib-based treatment. These findings also shed new light on the  molecular mechanism of COX-2 mRNA stabilization by EGFR in a kinase-independent manner.

 

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[137]

TÍTULO / TITLE:  - A Novel Semisynthetic Inhibitor of the FRB Domain of Mammalian Target of Rapamycin Blocks Proliferation and Triggers Apoptosis in Chemoresistant Prostate  Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Pharmacol. 2013 Feb;83(2):531-41. doi: 10.1124/mol.112.081349. Epub 2012 Dec  3.

            ●● Enlace al texto completo (gratuito o de pago) 1124/mol.112.081349

AUTORES / AUTHORS:  - Morad SA; Schmid M; Buchele B; Siehl HU; El Gafaary M; Lunov O; Syrovets T; Simmet T

INSTITUCIÓN / INSTITUTION:  - Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Helmholtzstr. 20, D-89081 Ulm, Germany. thomas.simmet@uni-ulm.de.

RESUMEN / SUMMARY:  - The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and its uncontrolled activation is a hallmark of cancer. Moreover, mTOR activation has been implicated in the resistance of cancer cells to many anticancer drugs, rendering this pathway a promising pharmacotherapeutic target. Here we explored the capability of a semisynthetic compound to intercept mTOR signaling. We synthesized and chemically characterized a novel, semisynthetic triterpenoid derivative, 3-cinnamoyl-11-keto-beta-boswellic acid (C-KbetaBA). Its pharmacodynamic effects on mTOR and several other signaling pathways were assessed in a number of prostate and breast cancer cell lines as well as in normal prostate epithelial cells. C-KbetaBA exhibits specific antiproliferative and proapoptotic effects in cancer cell lines in vitro as well as in PC-3 prostate cancer xenografts in vivo. Mechanistically, the compound significantly inhibits the cap-dependent transition machinery, decreases expression of eukaryotic translation initiation factor 4E and cyclin D1, and induces G(1) cell-cycle arrest. In contrast to conventional mTOR inhibitors, C-KbetaBA downregulates the phosphorylation of p70 ribosomal S6 kinase, the major downstream target of mTOR complex 1, without concomitant activation of mTOR complex 2/Akt and extracellular signal-regulated kinase pathways, and independently of protein phosphatase 2A, liver kinase B1/AMP-activated protein kinase/tuberous sclerosis complex, and F12-protein binding. At the molecular level, the compound binds to the FKBP12-rapamycin-binding domain of mTOR with high affinity, thereby competing with the endogenous mTOR activator phosphatidic  acid. C-KbetaBA represents a new type of proapoptotic mTOR inhibitor that, due to its special mechanistic profile, might overcome the therapeutic drawbacks of conventional mTOR inhibitors.

 

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[138]

TÍTULO / TITLE:  - Cumulative Number of Altered Biomarkers in Mammalian Target of Rapamycin Pathway  Is an Independent Predictor of Outcome in Patients With Clear Cell Renal Cell Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Urology. 2013 Jan 3. pii: S0090-4295(12)01422-7. doi: 10.1016/j.urology.2012.11.030.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.urology.2012.11.030

AUTORES / AUTHORS:  - Darwish OM; Kapur P; Youssef RF; Bagrodia A; Belsante M; Alhalabi F; Sagalowsky AI; Lotan Y; Margulis V

INSTITUCIÓN / INSTITUTION:  - Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.

RESUMEN / SUMMARY:  - OBJECTIVE: To evaluate the association of the altered expression of the mammalian target of rapamycin (mTOR) pathway components with oncologic outcomes in patients with nonmetastatic clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: Immunohistochemistry for phosphorylated-S6, phosphorylated-mTOR, mTOR, phosphorylated-AKT, hypoxia inducible factor-1alpha, Raptor, phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and phosphorylated 4E-binding protein-1 was performed on tissue microarray constructs of patients treated for nonmetastatic kidney cancer from 1997 to 2010. The relationship between individual altered marker expression and a prognostic marker score (low,  intermediate, and high, defined as </=3, 4-5, >5 altered biomarkers, respectively) and oncologic outcome was assessed. RESULTS: The study included 419 patients with nonmetastatic ccRCC, with a median follow-up period of 26 months (range 6-150). The tumors were nonorgan confined (pT3-T4) in 86 (20.5%) and high  Fuhrman nuclear grade (3-4) in 131 (31%). A low, intermediate, and high prognostic marker score was found in 214 (51%), 152 (36%), and 53 (13%) patients, respectively. Kaplan-Meier analysis demonstrated a statistically significant correlation between the risk groups and disease recurrence and cancer-specific survival. In a multivariate Cox regression analysis controlling for tumor stage and grade, a high marker score was an independent predictor of disease recurrence (hazard ratio 3.3, 95% confidence interval 1.33-8.39, P = .01), and a combination of a high and an intermediate score was an independent predictor of survival (hazard ratio 4.8, 95% confidence interval 1.27-4.78, P = .008). CONCLUSION: The  cumulative number of aberrantly expressed biomarkers correlated with aggressive tumor biology and inferior oncologic outcomes in patients with ccRCC. Our data support prospective pathway-based exploration of the mTOR signaling cascade to augment current clinicopathologic predictors of oncologic outcomes in patients with ccRCC.

 

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[139]

TÍTULO / TITLE:  - Pharmacokinetic and myocardial enzyme profiles of two administration routes of epirubicin in breast cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Arzneimittelforschung. 2012 Dec;62(12):677-81. doi: 10.1055/s-0032-1331166. Epub  2012 Nov 30.

            ●● Enlace al texto completo (gratuito o de pago) 1055/s-0032-1331166

AUTORES / AUTHORS:  - Yang RX; Ren HX; Zhuang L; Gao CL; Dong C; Luo CX; Wang XN; Feng EF; He JC

INSTITUCIÓN / INSTITUTION:  - Chemotherapy Research Center, Kunming Medical University, Kunming, China.

RESUMEN / SUMMARY:  - To evaluate the changes in myocardial enzymes and plasma epirubicin concentration following administration by micro-pump (MP) and intravenous drip (ID) in breast cancer patients.11 self-controlled breast cancer patients were recruited for a trial with epirubicin administration by MP for 48 h and by ID for 1 h during 2 cycles of treatment. Plasma concentration of epirubicin at different time points  was determined using LC-MS/MS. The levels of myocardial enzymes before and after  chemotherapy were compared. Another group of patients receiving epirubicin by ID  (n=4) or MP (n=9) were monitored for 4 months.8 patients completed the self-controlled study. The peak concentration of epirubicin in the MP group and the ID group were 21.84+/-18.85 ng/mL and 294.80+/-225.54 ng/mL, respectively. The MP group had a longer duration (54~60 h) of plasma concentration of epirubicin not less than 10 ng/mL than that of the ID group (8~14 h). There was significant difference for the alteration of myocardial enzymes before and after  chemotherapy (p<0.05) in the ID group, whereas the MP group showed no significant difference (p>0.05). The increased range of myocardial enzymes after chemotherapy in the ID group was larger than that of the MP group and the difference was significant (p<0.05). There is an increased cardiotoxicity in patients receiving  epirubicin by ID during the 4-month trial.Administration of epirubicin by MP maintained an effective drug concentration for a longer period of time than by ID. The higher peak plasma concentration observed following epirubicin administration by ID may lead to cardiac toxicity.

 

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[140]

TÍTULO / TITLE:  - Soluble receptor of advanced glycation end products (sRAGE) indicates response to chemotherapy in pancreatic cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Clin Pharmacol Ther. 2013 Jan;51(1):67-9.

AUTORES / AUTHORS:  - Wittwer C; Boeck S; Heinemann V; Haas M; Stieber P; Nagel D; Holdenrieder S

INSTITUCIÓN / INSTITUTION:  - University Hospital Munich, Institute of Clinical Chemistry, University Hospital  Munich, Department of Internal Medicine III and Comprehensive Cancer Center, Munich, and University Hospital Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, Bonn, Germany.

 

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[141]

TÍTULO / TITLE:  - Metformin-mediated downregulation of p38 mitogen-activated protein kinase-dependent excision repair cross-complementing 1 decreases DNA repair capacity and sensitizes human lung cancer cells to paclitaxel.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Feb 15;85(4):583-94. doi: 10.1016/j.bcp.2012.12.001. Epub 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2012.12.001

AUTORES / AUTHORS:  - Tseng SC; Huang YC; Chen HJ; Chiu HC; Huang YJ; Wo TY; Weng SH; Lin YW

INSTITUCIÓN / INSTITUTION:  - Molecular Oncology Laboratory, Department of Biochemical Science and Technology,  National Chiayi University, 300 Syuefu Road, Chiayi 600, Taiwan.

RESUMEN / SUMMARY:  - Metformin, an extensively used and well-tolerated drug for treating individuals with type 2 diabetes, has recently gained significant attention as an anticancer  drug. On the other hand, paclitaxel (Taxol) is a new antineoplastic drug that has shown promise in the treatment of non-small cell lung cancer (NSCLC). High expression levels of excision repair cross-complementary 1 (ERCC1) in cancers have been positively associated with the DNA repair capacity and a poor prognosis in NSCLC patients treated with platinum-containing chemotherapy. In this current  study, paclitaxel was found to increase phosphorylation of mitogen-activated protein kinase (MAPK) kinase 3/6 (MKK3/6)-p38 MAPK as well as protein and mRNA levels of ERCC1 in H1650 and H1703 cells. Moreover, paclitaxel-induced ERCC1 protein and mRNA levels significantly decreased via the downregulation of p38 activity by either a p38 MAPK inhibitor SB202190 or p38 knockdown with specific small interfering RNA (siRNA). Specific inhibition of ERCC1 with siRNA was found  to enhance the paclitaxel-induced cytotoxic effect and growth inhibition. Furthermore, metformin was able to not only decrease the paclitaxel-induced p38 MAPK-mediated ERCC1 expression, but also augment the cytotoxic effect induced by  paclitaxel. Finally, expression of constitutive activate MKK6 or HA-p38 MAPK vectors in lung cancer cells was able to abrogate ERCC1 downregulation by metformin and paclitaxel as well as cell viability and DNA repair capacity. Overall, our results suggest that inhibition of the p38 MAPK signaling by metformin coupled with paclitaxel therapy in human NSCLC cells may be a clinically useful combination, which however will require further validation.

 

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[142]

TÍTULO / TITLE:  - Antitumor Activity of Cell-Permeable RUNX3 Protein in Gastric Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 15.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2692

AUTORES / AUTHORS:  - Lim J; Duong T; Do N; Do P; Kim J; Kim H; El-Rifai W; Ruley HE; Jo D

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: ProCell R&D Institute, ProCell Therapeutics, Inc., Seoul;  Department of Biomedical Sciences, Chonnam National University Medical School, Kwangju; Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul; Interdisciplinary Program of Integrated Biotechnology, Sogang  University, Seoul, Korea; and Departments of Surgery and Cancer Biology; Department of Pathology, Microbiology & Immunology, Vanderbilt University School  of Medicine, Nashville, Tennessee.

RESUMEN / SUMMARY:  - PURPOSE: Gastric cancer is a leading cause of cancer death worldwide. Limited therapeutic options highlight the need to understand the molecular changes responsible for the disease and to develop therapies based on this understanding. The goal of this study was to develop cell-permeable (CP-) forms of the RUNT-related transcription factor 3, RUNX3-a candidate tumor suppressor implicated in gastric and other epithelial cancers-to study the therapeutic potential of RUNX3 in the treatment of gastric cancer.EXPERIMENTAL DESIGN: We developed novel macromolecule transduction domains (MTD) which were tested for the ability to promote protein uptake by mammalian cells and tissues and used to  deliver of biologically active RUNX3 into human gastric cancer cells. The therapeutic potential CP-RUNX3 was tested in the NCI-N87 human tumor xenograft animal model.RESULTS: RUNX3 fusion proteins, HM(57)R and HM(85)R, containing hydrophobic MTDs enter gastric cancer cells and suppress cell phenotypes (e.g., cell-cycle progression, wounded monolayer healing, and survival) and induce changes in biomarker expression (e.g., p21(Waf1) and VEGF) consistent with previously described effects of RUNX3 on TGF-beta signaling. CP-RUNX3 also suppressed the growth of subcutaneous human gastric tumor xenografts. The therapeutic response was comparable with studies augmenting RUNX3 gene expression in tumor cell lines; however, the protein was most active when administered locally, rather than systemically (i.e., intravenously).CONCLUSIONS: These results provide further evidence that RUNX3 can function as a tumor suppressor and suggest that practical methods to augment RUNX3 function could be useful in treating of some types of gastric cancer. Clin Cancer Res; 1-11. ©2012 AACR.

 

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[143]

TÍTULO / TITLE:  - Effects of iodonium-class flavin dehydrogenase inhibitors on growth, reactive oxygen production, cell cycle progression, NADPH oxidase 1 levels, and gene expression in human colon cancer cells and xenografts.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Free Radic Biol Med. 2013 Jan 11. pii: S0891-5849(13)00003-8. doi: 10.1016/j.freeradbiomed.2013.01.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.freeradbiomed.2013.01.002

AUTORES / AUTHORS:  - Doroshow JH; Gaur S; Markel S; Lu J; van Balgooy J; Synold TW; Xi B; Wu X; Juhasz A

INSTITUCIÓN / INSTITUTION:  - Center for Cancer Research; Division of Cancer Treatment and Diagnosis, National  Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: doroshoj@mail.nih.gov.

RESUMEN / SUMMARY:  - Iodonium-class flavoprotein dehydrogenase inhibitors have been demonstrated to possess antiproliferative potential and to inhibit reactive oxygen production in  human tumor cells, although the mechanism(s) that explains the relationship between altered cell growth and the generation of reactive oxygen species (ROS) remains an area of active investigation. Because of the ability of these compounds to inhibit the activity of flavoprotein-containing epithelial NADPH oxidases, we chose to examine the effects of several iodonium-class flavoprotein  inhibitors on human colon cancer cell lines that express high, functional levels  of a single such oxidase (NADPH oxidase 1, or Nox1). We found that diphenyleneiodonium (DPI), di-2-thienyliodonium (DTI), and iodonium diphenyl inhibited the growth of Caco2, HT-29, and LS-174T colon cancer cells at concentrations (10-250nM for DPI, 0.5-2.5muM for DTI, and 155nM to 10muM for iodonium diphenyl) substantially lower than needed for DU145 human prostate cancer cells, which do not possess functional NADPH oxidase activity. Drug treatment was associated with decreased H(2)O(2) production and diminished intracellular ROS levels, lasting up to 24h, after short-term (1-h) exposure to the iodonium analogs. Decreased tumor cell proliferation was caused, in part, by  a profound block in cell cycle progression at the G(1)/S interface in both LS-174T and HT-29 cells exposed to either DPI or DTI; and the G(1) block was produced, for LS-174T cells, by upregulation of p27 and a drug concentration-related decrease in the expression of cyclins D1, A, and E that was partially prevented by exogenous H(2)O(2). Not only did DPI and DTI decrease intracellular ROS, they both also significantly decreased the mRNA expression levels of Nox1, potentially contributing to the prolonged reduction in tumor cell reactive oxygen levels. We also found that DPI and DTI significantly decreased the growth of both HT-29 and LS-174T human tumor xenografts, at dose levels that  produced peak plasma concentrations similar to those utilized for our in vitro experiments. These findings suggest that iodonium analogs have therapeutic potential for NADPH oxidase-containing human colon cancers in vivo and that at least part of their antineoplastic mechanism of action may be related to targeting Nox1.

 

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[144]

TÍTULO / TITLE:  - Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis  in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Exp Cell Res. 2013 Jan 16. pii: S0014-4827(13)00014-1. doi: 10.1016/j.yexcr.2012.12.026.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.yexcr.2012.12.026

AUTORES / AUTHORS:  - Chen H; Landen CN; Li Y; Alvarez RD; Tollefsbol TO

INSTITUCIÓN / INSTITUTION:  - Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

RESUMEN / SUMMARY:  - The cellular development of resistance to chemotherapy contributes to the high mortality noted in patients affected by ovarian cancer. Novel compounds that specifically target cellular drug resistance in ovarian cancer are therefore highly desired. Previous epidemiological studies indicate that consumption of green tea and cruciferous vegetables is inversely associated with occurrence of ovarian cancer. Therefore revealing the effects and mechanisms of major components of green tea (epigallocatechin gallate, EGCG) and cruciferous vegetables (sulforaphane, SFN) on ovarian cancer cells will provide necessary knowledge for developing potential novel treatments for the disease. In this study, EGCG or SFN was used to treat both paclitaxel-sensitive (SKOV3-ip1) and -resistant (SKOV3TR-ip2) ovarian cancer cell lines alone or in combination. We found that SFN inhibits cell viability of both ovarian cancer cell lines time- and dose-dependently and that EGCG potentiates the inhibiting effect of SFN on ovarian cancer cells. Cell cycle analysis indicates SFN can arrest ovarian cancer cells in G2/M phase, while EGCG and SFN co-treatment can arrest cells in both G2/M and S phase. Combined EGCG and SFN treatment increases apoptosis significantly in paclitaxel-resistant SKOV3TR-ip2 cells after 6 days of treatment, while reducing the expression of hTERT, the main regulatory subunit of telomerase. Western blotting also indicates that SFN can down-regulate Bcl-2 (a gene involved in anti-apoptosis) protein levels in both cell types. Cleaved poly(ADP-ribose) polymerase (PARP) becomes up-regulated by 6 days of treatment with SFN and this is more pronounced for combination treatment indicating induction of apoptosis. Furthermore, phosphorylated H2AX is up-regulated after 6  days of treatment with SFN alone, and EGCG can potentiate this effect, suggesting that DNA damage is a potential cellular mechanism contributing to the inhibiting  effect of EGCG and SFN combination treatment. Taken together, these results indicate that EGCG and SFN combination treatment can induce apoptosis by down-regulating of hTERT and Bcl-2 and promote DNA damage response specifically in paclitaxel-resistant ovarian cancer cell lines and suggest the use of these compounds for overcoming paclitaxel resistance in ovarian cancer treatment.

 

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[145]

TÍTULO / TITLE:  - Computed Tomography RECIST Assessment of Histopathologic Response and Prediction  of Survival in Patients with Resectable Non-Small-Cell Lung Cancer after Neoadjuvant Chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Thorac Oncol. 2013 Feb;8(2):222-228.

            ●● Enlace al texto completo (gratuito o de pago) 1097/JTO.0b013e3182774108

AUTORES / AUTHORS:  - William WN Jr; Pataer A; Kalhor N; Correa AM; Rice DC; Wistuba II; Heymach J; Lee JJ; Kim ES; Munden R; Gold KA; Papadimitrakopoulou V; Swisher SG; Erasmus JJ

INSTITUCIÓN / INSTITUTION:  - *Departments of Thoracic/Head and Neck Medical Oncology, daggerThoracic and Cardiovascular Surgery, double daggerPathology, section signBiostatistics, and ||Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina; and paragraph signDepartment of Diagnostic Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

RESUMEN / SUMMARY:  - INTRODUCTION:: This study’s objectives were to determine whether tumor response measured by computed tomography (CT) and evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) correlated with overall survival (OS) in patients with non-small-cell lung cancer (NSCLC) after neoadjuvant chemotherapy and surgical resection. METHODS:: We measured primary tumor size on CT before and after neoadjuvant chemotherapy in 160 NSCLC patients who underwent surgical resection. The relationship between CT-measured response (RECIST) and histopathologic response (</= 10% viable tumor) and OS were assessed by Kaplan-Meier survival, univariable, and multivariable Cox proportional hazards regression. RESULTS:: There was a statistically significant association between CT-measured response (RECIST) and OS (p = 0.03). However, histopathologic response was a stronger predictor of OS (p = 0.002), with a more pronounced separation of the survival curves when compared with CT-measured response. In multivariable Cox regression analysis, only pathologic stage and histopathologic  response were significant predictors of OS. A 41% overall discordance rate was noted between CT RECIST response and histopathologic response. CT RECIST classified as nonresponders a subset of patients with histopathologic response (8 out of 30 points, 27%) who demonstrated prolonged survival after neoadjuvant chemotherapy. CONCLUSION:: We were unable to show that CT RECIST is a reliable predictor of OS in patients with NSCLC undergoing surgical resection after neoadjuvant chemotherapy. The failure of CT RECIST to predict long-term outcome may be because of the inability of CT imaging to consistently identify patients with histopathologic response. CT RECIST may have only a limited role as an efficacy endpoint after neoadjuvant chemotherapy in patients with resectable NSCLC.

 

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[146]

TÍTULO / TITLE:  - Association of thymidylate synthase gene 3’-untranslated region polymorphism with sensitivity of non-small cell lung cancer to pemetrexed treatment: TS gene polymorphism and pemetrexed sensitivity in NSCLC.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Biomed Sci. 2013 Jan 25;20(1):5.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1423-0127-20-5

AUTORES / AUTHORS:  - Wang X; Wang Y; Wang Y; Cheng J; Wang Y; Ha M

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Thymidylate synthase (TS) is a key enzyme responsible for DNA synthesis and repair. Altered expression of TS protein or TS gene polymorphisms has been associated with cancer progression and treatment response. This study investigated the expressions of TS and its gene SNPs in non-small cell lung cancer (NSCLC), and then its association with sensitivity to pemetrexed treatment. Immunohistochemistry and qRT-PCR were performed on 160 resected NSCLC  specimens and corresponding normal tissues to assess the expressions of TS protein and TS mRNA, and for associations with clinicopathological data. Blood samples of 106 lung adenocarcinoma patients were examined for polymorphisms of the TS gene 3’-UTR 1494del 6 bp, which was then investigated for associations with responses of the patients to pemetrexed treatment and survival. RESULTS: Expression of both TS protein and its mRNA was elevated in NSCLC tissues compared with matched normal tissues, and significantly higher in lung squamous cell carcinoma than in lung adenocarcinoma. TS expression was associated with poor tumor differentiation. Furthermore, the genotyping data showed that 56% of lung adenocarcinoma patients had the TS gene 3’-UTR 1494 bp (-6 bp/-6 bp) genotype and the rest had TS gene 3’-UTR 1494 bp (-6 bp/+6 bp). There was no TS 3’-UTR 1494 bp (+6 bp/+6 bp) genotype in any patients. Statistical analysis revealed that gender, tumor stage, and TS 3’-UTR 1494del 6 bp polymorphism were significant prognostic factors after short-term pemetrexed treatment. Log-rank analysis revealed that patients with the (-6 bp/-6 bp) genotype had significantly better progression-free and overall survival than patients with (-6 bp/+6 bp). CONCLUSIONS: This study showed that TS protein is highly expressed in NSCLC and that polymorphisms of TS 3’-UTR 1494del 6 bp are associated with sensitivity of lung adenocarcinoma patients to pemetrexed treatment. This suggests that TS gene  polymorphisms should be further evaluated as prognostic markers for personalized  therapy in lung adenocarcinoma.

 

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[147]

TÍTULO / TITLE:  - miR-9 modulates the expression of interferon-regulated genes and MHC class I molecules in human nasopharyngeal carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 4. pii: S0006-291X(12)02457-6. doi: 10.1016/j.bbrc.2012.12.097.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.12.097

AUTORES / AUTHORS:  - Gao F; Zhao ZL; Zhao WT; Fan QR; Wang SC; Li J; Zhang YQ; Shi JW; Lin XL; Yang S; Xie RY; Liu W; Zhang TT; Sun YL; Xu K; Yao KT; Xiao D

INSTITUCIÓN / INSTITUTION:  - Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.

RESUMEN / SUMMARY:  - The functions of miR-9 in some cancers are recently implicated in regulating proliferation, epithelial-mesenchymal transition (EMT), invasion and metastasis,  apoptosis, and tumor angiogenesis, etc. miR-9 is commonly down-regulated in nasopharyngeal carcinoma (NPC), but the exact roles of miR-9 dysregulation in the pathogenesis of NPC remains unclear. Therefore, we firstly used miR-9-expressing  CNE2 cells to determine the effects of miR-9 overexpression on global gene expression profile by microarray analysis. Microarray-based gene expression data  unexpectedly demonstrated a significant number of up- or down-regulated immune- and inflammation-related genes, including many well-known interferon (IFN)-induced genes (e.g., IFI44L, PSMB8, IRF5, PSMB10, IFI27, PSB9_HUMAN, IFIT2, TRAIL, IFIT1, PSB8_HUMAN, IRF1, B2M and GBP1), major histocompatibility complex (MHC) class I molecules (e.g., HLA-B, HLA-C, HLA-F and HLA-H) and interleukin (IL)-related genes (e.g., IL20RB, GALT, IL7, IL1B, IL11, IL1F8, IL1A, IL6 and IL7R), which was confirmed by qRT-PCR. Moreover, the overexpression of miR-9 with the miRNA mimics significantly up- or down-regulated the expression of above-mentioned IFN-inducible genes, MHC class I molecules and IL-related genes;  on the contrary, miR-9 inhibition by anti-miR-9 inhibitor in CNE2 and 5-8F cells  correspondingly decreased or increased the aforementioned immune- and inflammation-related genes. Taken together, these findings demonstrate, for the first time, that miR-9 can modulate the expression of IFN-induced genes and MHC class I molecules in human cancer cells, suggesting a novel role of miR-9 in linking inflammation and cancer, which remains to be fully characterized.

 

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[148]

TÍTULO / TITLE:  - Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis  and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Thorac Oncol. 2013 Jan;8(1):52-61. doi: 10.1097/JTO.0b013e3182769aa8.

            ●● Enlace al texto completo (gratuito o de pago) 1097/JTO.0b013e3182769aa8

AUTORES / AUTHORS:  - Yoshizawa A; Sumiyoshi S; Sonobe M; Kobayashi M; Fujimoto M; Kawakami F; Tsuruyama T; Travis WD; Date H; Haga H

INSTITUCIÓN / INSTITUTION:  - Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan. akyoshi@shinshu-u.ac.jp

RESUMEN / SUMMARY:  - INTRODUCTION: This study aimed to validate the utility of the new histological classification proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) for identifying the prognostic subtypes of adenocarcinomas in Japanese patients; correlations between the classification and the presence of EGFR or KRAS mutation status were also investigated. METHODS: We retrospectively reviewed 440 patients with lung adenocarcinoma, who underwent resection. The tumors were classified according to the IASLC/ATS/ERS classification. EGFR and KRAS mutations were detected using the established methods. RESULTS: Five-year disease-free survival rates were: 100% for adenocarcinoma in situ (n = 20) and minimally invasive adenocarcinoma (n = 33), 93.8% for lepidic-predominant adenocarcinoma (n = 36), 88.8% for invasive mucinous adenocarcinoma (n = 10), 66.7% for papillary-predominant adenocarcinoma (n = 179), 69.7% for acinar-predominant adenocarcinoma (n = 61), 43.3% for solid-predominant adencoarcinoma (n = 78), and 0% for micropapillary-predominant adenocarcinoma (n = 19). Multivariate analysis  revealed that the new classification was an independent predictor of disease-free survival. EGFR and KRAS mutations were detected in 90 cases (53.9%) and 21 cases  (13.3%), respectively; EGFR mutations were significantly associated with adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic- and papillary-predominant adenocarcinoma, and KRAS mutations adenocarcinomas with mucinous tumor subtypes. CONCLUSIONS: We found that the IASLC/ATS/ERS classification identified prognostic histologic subtypes of lung adenocarcinomas  among Japanese patients. Histologic subtyping and molecular testing for EGFR and  KRAS mutations can help predict patient prognosis and select those who require adjuvant chemotherapy.

 

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[149]

TÍTULO / TITLE:  - Inhibition of atypical protein kinase Ciota induces apoptosis through autophagic  degradation of beta-catenin in esophageal cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Carcinog. 2013 Jan 28. doi: 10.1002/mc.22003.

            ●● Enlace al texto completo (gratuito o de pago) 1002/mc.22003

AUTORES / AUTHORS:  - Wang BS; Yang Y; Lu HZ; Shang L; Zhang Y; Hao JJ; Shi ZZ; Wang XM; Liu YZ; Zhan QM; Jia XM; Wang MR

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

RESUMEN / SUMMARY:  - Atypical protein kinase Ciota (PKCiota) has been identified as an oncoprotein in  esophageal squamous cell carcinomas. However, the mechanisms underlying the role  of PKCiota in this disease remain unclear. In the present work, we found that inhibition of PKCiota expression by RNAi induced apoptosis via the down-regulation of beta-catenin in esophageal cancer cells. Furthermore, we found that PKCiota regulated beta-catenin in an autophagy dependent way. Since down-regulation of beta-catenin induced by knockdown of PKCiota could be rescued  by autophagy inhibition; knockdown of PKCiota activated autophagy and promoted the recruitment of beta-catenin into autophagosome. These results suggested that  PKCiota positively regulated beta-catenin through negatively regulated autophagy  and depletion of PKCiota promoted apoptosis via autophagic degradation of beta-catenin in esophageal cancer cells. These data provide new insights into PKCiota signaling in human cancer. © 2013 Wiley Periodicals, Inc.

 

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[150]

TÍTULO / TITLE:  - Validation study of a prognostic classification in patients with metastatic colorectal cancer who received irinotecan-based second-line chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Cancer Res Clin Oncol. 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00432-012-1349-1

AUTORES / AUTHORS:  - Shitara K; Yuki S; Yamazaki K; Naito Y; Fukushima H; Komatsu Y; Yasui H; Takano T; Muro K

INSTITUCIÓN / INSTITUTION:  - Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan, Kouheis0824@yahoo.co.jp.

RESUMEN / SUMMARY:  - PURPOSE: Five prognostic factors had been previously identified in patients with  metastatic colorectal cancer (MCRC) who received irinotecan-based second-line chemotherapy. Patients were classified into three prognostic groups based on significant differences in median overall survival (OS). This study is conducted  to validate this classification in an external validation cohort. METHODS: This retrospective study included 193 patients of an external validation cohort who received irinotecan-based second-line chemotherapy after first-line oxaliplatin-based chemotherapy, with or without bevacizumab at three institutions. RESULTS: Three of the five predefined factors (poorly differentiated adenocarcinoma, LDH >/=400 IU/L, progression-free survival of first-line therapy <6 months) remained highly significant in the validation cohort, although two (performance status 2 and peritoneal metastasis) were associated with borderline significance. The distribution of the three prognostic groups (low risk = no factors, intermediate risk = 1 factor, high risk = 2 or more factors) was low risk (n = 68; 35 %), intermediate risk (n = 80; 41 %), and  high risk (n = 45; 23 %). The median OS of each group were 19.8, 11.0, and 7.9 months, respectively, with significant differences between groups, as found in the previous cohort. CONCLUSION: The previous prognostic classification of patients with MCRC who received irinotecan-based second-line chemotherapy was validated in another independent cohort. Validation in prospective studies is warranted.

 

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[151]

TÍTULO / TITLE:  - Thrombocytosis and immunohistochemical expression of connexin 43 at diagnosis predict survival in advanced non-small-cell lung cancer treated with cisplatin-based chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Jan 26.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-013-2080-6

AUTORES / AUTHORS:  - Du G; Yang Y; Zhang Y; Sun T; Liu W; Wang Y; Li J; Zhang H

INSTITUCIÓN / INSTITUTION:  - Institute of Pharmacy, Pharmacy College of Henan University, Jinming street, Kaifeng, 475004, Henan, China, kfdgj@sohu.com.

RESUMEN / SUMMARY:  - PURPOSE: Patients with advanced non-small-cell lung cancer (NSCLC) have poor survival, and platinum-based chemotherapy agents are the standard first-line chemotherapy agents for advanced NSCLC. This study aimed to identify predictive factors associated with the response to chemotherapy and survival in 258 patients with advanced NSCLC treated with platinum-based chemotherapy. METHODS: Stage IIIA-IV NSCLC patients diagnosed in Kaifeng second people’s hospital (Henan, China) between March 2002 and September 2011 were retrospectively reviewed. All of the patients had received platinum-based chemotherapy, and patients were followed up to date of death or last follow-up to obtain data of response to chemotherapy and survival. Potential prognostic factors such as gender, age, tumor size, tumor type, histologic stage, anemia, calcium levels, ECOG performance status (PS), thrombocytosis, TTF-1, p63, and connexin 43 were analyzed. Response to chemotherapy, overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan-Meier method and Cox regression model. RESULTS: A univariate analysis indicated that thrombocytosis and connexin  43 were found to be significant prognostic factors (p < 0.001) and ECOG PS, Hb levels, and p63 presented a tendency toward association with survival. Kaplan-Meier survival showed that the mean OS and PFS in chemotherapy responders  with connexin 43 >/=+2 were significantly longer than in chemotherapy responders  with connexin 43 </=1+. In contrast, thrombocytosis was associated with increased mortality and resistance to chemotherapy in chemotherapy responders. In addition, all 21 patients of the 5-year OS were from chemotherapy responders with connexin  43 >/=+2 or non-thrombocytosis. CONCLUSIONS: Thrombocytosis and connexin 43 absence may be reliable surrogate markers for the prediction of chemotherapy response and prognosis for patients with advanced NSCLC, and assessment of these  factors may identify a population of patients with advanced NSCLC that is likely  to have a prolonged life expectancy.

 

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[152]

TÍTULO / TITLE:  - Risk Factors for Predicting Severe Neutropenia Induced by Amrubicin in Patients with Advanced Lung Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chemotherapy. 2013 Jan 4;58(6):419-425.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000345617

AUTORES / AUTHORS:  - Watanabe H; Ikesue H; Oshiro M; Nagata K; Mishima K; Takada A; Suetsugu K; Sueyasu M; Egashira N; Harada T; Takayama K; Nakanishi Y; Oishi R

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan.

RESUMEN / SUMMARY:  - Background: Neutropenia is one of the most frequent and dose-limiting toxicities  in amrubicin (AMR) therapy. However, the predictive factors for the development of severe neutropenia in AMR therapy remain unknown. Methods: The subjects were 61 advanced lung cancer patients treated with AMR monotherapy. All data were retrospectively collected from the electronic medical record system. A stepwise logistic regression analysis was performed to identify risk factors for grade 3-4 neutropenia. Results: Of a total 61 patients, 50 were male and 11 were female. The median dose of AMR was 35.0 mg/m(2). The incidence of grade 3-4 neutropenia during the first course was 62%. In multivariate analysis, female gender (OR = 6.68; 95% CI 1.01-134.15; p = 0.049), higher AMR doses (40 mg/m(2) or more) (OR = 5.98; 95% CI 1.77-23.74; p = 0.003), and lower hematocrit values (OR = 2.04 per 5% decrease; 95% CI 1.04-4.38; p = 0.036) were significantly associated with severe neutropenia induced by AMR. Conclusion: The present results suggest that female gender, higher doses of AMR, and lower baseline hematocrit values are predictive factors associated with severe neutropenia induced by AMR in patients  with advanced lung cancer. Patients who have these predictive factors should be monitored carefully and considered for early granulocyte colony-stimulating factor support.

 

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[153]

TÍTULO / TITLE:  - Mycobacterial Interferon-gamma Release Variations During Longterm Treatment with  Tumor Necrosis Factor Blockers: Lack of Correlation with Clinical Outcome.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Rheumatol. 2012 Dec 1.

            ●● Enlace al texto completo (gratuito o de pago) 3899/jrheum.120688

AUTORES / AUTHORS:  - Scrivo R; Sauzullo I; Mengoni F; Priori R; Coppola M; Iaiani G; Di Franco M; Vullo V; Mastroianni CM; Valesini G

INSTITUCIÓN / INSTITUTION:  - From the Dipartimento di Medicina Interna e Specialita Mediche, Reumatologia, and the Dipartimento di Sanita Pubblica e Malattie Infettive, Sapienza Universita di  Roma, Rome; UOC Malattie Infettive, Fondazione Eleonora Lorillard Spencer Cenci,  Sapienza Universita di Roma (Polo Pontino), Latina, Italy.

RESUMEN / SUMMARY:  - OBJECTIVE: To assess the performance of serial QuantiFeron-TB Gold In-Tube (QFT-GIT) tests in patients with rheumatic diseases during longterm systemic treatment with biologic therapy, evaluating conversions and reversions in relation to the clinical outcome. METHODS: We conducted a prospective study on patients awaiting biologic agents. At baseline, they had chest radiographs, QFT-GIT tests, and tuberculin skin tests (TST); QFT-GIT was repeated at 3, 6, 12, and 18 months after onset of biologic therapy. In patients with no evidence of latent tuberculosis infection (LTBI) at baseline, TST was repeated at 12 months of biologic treatment. RESULTS: Among patients (n = 102; women 65.7%; median age  47 yrs, range 20-82), 14 (13.7%) were considered as having LTBI because of a minimum of 1 abnormal screening test. The agreement between QFT-GIT and TST was 88% (kappa = 0.14). During biologic treatment, both patients with (n = 14) and those without (n = 88) evidence of LTBI at baseline showed conversions and reversions in QFT-GIT results at different timepoints. These fluctuations were not paralleled by significant clinical changes. The TST repeated at 12 months in  patients with no evidence of LTBI at baseline continued to be negative. The median baseline interferon-gamma (IFN-gamma) concentration was not significantly  different from that observed at each subsequent timepoint. CONCLUSION: Dynamic changes occur with serial IFN-gamma release assay testing in patients treated with biologic therapy that do not correlate with clinical outcome. A careful and  integrated evaluation of the patient, including clinical information, should guide the treatment decision. This study was underpowered for definite conclusions and further studies are needed to determine the significance of these findings.

 

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[154]

TÍTULO / TITLE:  - Absence of RKIP expression is an independent prognostic biomarker for gastric cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):690-6. doi: 10.3892/or.2012.2179. Epub 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2179

AUTORES / AUTHORS:  - Martinho O; Simoes K; Longatto-Filho A; Jacob CE; Zilberstein B; Bresciani C; Gama-Rodrigues J; Cecconello I; Alves V; Reis RM

INSTITUCIÓN / INSTITUTION:  - Life and Health Sciences Research Institute, Health Sciences School, University of Minho, Braga, Portugal.

RESUMEN / SUMMARY:  - Gastric cancer is a leading cause of cancer-related mortality, and the presence of lymph node metastasis an important prognostic factor. Downregulation of RKIP has been associated with tumor progression and metastasis in several types of neoplasms, being currently categorized as a metastasis suppressor gene. Our aim was to determine the expression levels of RKIP in gastric tissues and to evaluate its impact in the clinical outcome of gastric carcinoma patients. RKIP expression levels were studied by immunohistochemistry in a series of gastric tissues. Overall, we analysed 222 non-neoplastic gastric tissues, 152 primary tumors and 42 lymph node metastasis samples. We observed that RKIP was highly expressed in ~83% of non-neoplastic tissues (including normal tissue and metaplasia), was lost in ~56% of primary tumors and in ~90% of lymph node metastasis samples. Loss of RKIP expression was significantly associated with several markers of poor clinical outcome, including the presence of lymph node metastasis. Furthermore, the absence of RKIP protein constitutes an independent prognostic marker for these patients. In conclusion, RKIP expression is significantly lost during gastric carcinoma progression being almost absent in lymph node metastasis samples. Of note, we showed that the absence of RKIP expression is associated with poor outcome features of gastric cancer patients, this being also an independent prognostic marker.

 

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[155]

TÍTULO / TITLE:  - Cellular immunotherapy study of prostate cancer patients and resulting IgG responses to peptide epitopes predicted from prostate tumor-associated autoantigens.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Immunother. 2013 Jan;36(1):57-65. doi: 10.1097/CJI.0b013e3182780abc.

            ●● Enlace al texto completo (gratuito o de pago) 1097/CJI.0b013e3182780abc

AUTORES / AUTHORS:  - Hemstreet GP 3rd; Rossi GR; Pisarev VM; Enke CA; Helfner L; Hauke RJ; Tennant L; Ramsey WJ; Vahanian NN; Link CJ

INSTITUCIÓN / INSTITUTION:  - Department of Urology, University of Nebraska Medical Center, Omaha, NE, USA.

RESUMEN / SUMMARY:  - The immunogenicity of a cellular immunotherapy using genetically modified vaccines to express alpha(1,3)galactosyl epitopes (alphaGal) was evaluated in advanced prostate cancer (PC) patients. In this dose escalation phase I study, we report safety, feasibility, and immunologic data of an immunotherapy composed of  2 human PC cell lines engineered to express alphaGal epitopes (HyperAcute-Prostate, HAP, NewLink Genetics). Eight patients received up to 12 biweekly vaccinations with HAP. Enrolled patients (aged range, 53-85 y) had American Joint Committee on Cancer stage IV, any T, any N, M1, Eastern Cooperative Oncology Group PS</=2, at least 1 prior hormonal treatment and <3 prior chemotherapies, adequate bone marrow and organ function, and albumin >/=3.0 g/dL. Serum IgG antibodies to synthetic peptides overexpressed in PC were determined by enzyme-linked immunosorbent assay. Results indicate that HAP immunotherapy induced humoral immune responses to autoantigens in 2 of 8 patients. These patients developed IgG antibody to multiple epitopes overexpressed in PC after immunization. These responding patients received higher doses of the immunotherapy suggesting a dose response. Two immunogenic proteins (prostate-specific membrane antigen, hepsin) belong to the extracellular molecules family participating in malignant cell invasion. Median overall survival for patients was 25.1 months with 1 patient surviving over 70 months with stable PSA and bone metastasis before expiring of other causes. Three of 8 patients showed PSA stabilization (>100 d). In conclusion, HAP immunotherapy induces IgG responses to epitopes from autoantigens overexpressed in PC suggesting dose-dependent effect. HAP represents a viable immunotherapy approach  to induce immune responses against tumor cells and may provide clinical benefit with minimal toxicity.

 

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[156]

TÍTULO / TITLE:  - Role of ERCC5 promoter polymorphisms in response to platinum-based chemotherapy in patients with advanced non-small-cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Anticancer Drugs. 2013 Mar;24(3):300-5. doi: 10.1097/CAD.0b013e32835bd6ce.

            ●● Enlace al texto completo (gratuito o de pago) 1097/CAD.0b013e32835bd6ce

AUTORES / AUTHORS:  - He C; Duan Z; Li P; Xu Q; Yuan Y

INSTITUCIÓN / INSTITUTION:  - Tumor Etiology and Screening Department of Cancer Institute and General Surgery,  the First Affiliated Hospital of China Medical University/Key Laboratory of Cancer Control in Liaoning Province, Shenyang, China.

RESUMEN / SUMMARY:  - The ERCC5 gene plays an important role in the nucleotide excision repair pathway  that recognizes and removes platinum-DNA adducts. We aimed to examine whether ERCC5 promoter polymorphisms contribute toward intervariations in the platinum treatment response in patients with advanced non-small-cell lung cancer (NSCLC).  We evaluated the association between three tag-single nucleotide polymorphisms in the ERCC5 promoter region (rs2094258, rs751402, and rs2296147, respectively) and  the efficacy of chemotherapy in 228 advanced NSCLC patients. We found that the rs751402 AA genotype was associated with a better treatment response [AA vs. AG+GG: odds ratio (OR)=2.74, 95% confidence interval (CI) 1.04-7.26, P=0.036) in  all NSCLC patients, which was more evident in the subgroup of patients with squamous cell carcinoma (AA vs. GG: OR=6.40, 95% CI 1.15-35.50, P=0.043; AA vs. AG+GG: OR=6.12, 95% CI 1.15-32.52, P=0.019). No statistically significant association was found between rs2094258 and rs2296147 polymorphisms and treatment response. Our results suggested that the ERCC5 rs751402 AA genotype increased the chemotherapy response in advanced NSCLC, especially in patients with squamous cell carcinoma. Further and larger scale studies are still required to provide more comprehensive information on ERCC5 promoter variations in the clinical outcome of NSCLC patients treated with platinum regimens.

 

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[157]

TÍTULO / TITLE:  - AMPK inhibition enhances apoptosis in MLL-rearranged pediatric B-acute lymphoblastic leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leukemia. 2012 Nov 21. doi: 10.1038/leu.2012.338.

            ●● Enlace al texto completo (gratuito o de pago) 1038/leu.2012.338

AUTORES / AUTHORS:  - Accordi B; Galla L; Milani G; Curtarello M; Serafin V; Lissandron V; Viola G; Te Kronnie G; De Maria R; Petricoin EF 3rd; Liotta LA; Indraccolo S; Basso G

INSTITUCIÓN / INSTITUTION:  - Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy.

RESUMEN / SUMMARY:  - The serine/threonine kinase AMP-activated protein kinase (AMPK) and its downstream effectors, including endothelial nitric oxide synthase and BCL-2, are  hyperactivated in B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) cells with MLL gene rearrangements. We investigated the role of activated AMPK in supporting leukemic cell survival and evaluated AMPK as a potential drug target.  Exposure of leukemic cells to the commercial AMPK inhibitor compound C resulted in massive apoptosis only in cells with MLL gene rearrangements. These results were confirmed by targeting AMPK with specific short hairpin RNAs. Compound C-induced apoptosis was associated with mitochondrial membrane depolarization, reactive oxygen species production, cytochrome c release and caspases cleavage, indicating intrinsic apoptosis pathway activation. Treatment with low concentrations of compound C resulted in a strong antileukemic activity, together with cytochrome c release and cleavage of caspases and poly(ADP-ribose) polymerase, also in MLL-rearranged primary BCP-ALL samples. Moreover, AMPK inhibition in MLL-rearranged cell lines synergistically enhanced the antiproliferative effects of vincristine, daunorubicin, cytarabine, dexamethasone and L-asparaginase in most of the evaluated conditions. Taken together, these results indicate that the activation of the AMPK pathway directly contributes to  the survival of MLL-rearranged BCP-ALL cells and AMPK inhibitors could represent  a new therapeutic strategy for this high-risk leukemia.Leukemia advance online publication, 11 December 2012; doi:10.1038/leu.2012.338.

 

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[158]

TÍTULO / TITLE:  - A randomized phase II study of gemcitabine and carboplatin with or without cediranib as first-line therapy in advanced non-small-cell lung cancer: North Central Cancer Treatment Group Study N0528.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Thorac Oncol. 2013 Jan;8(1):79-88. doi: 10.1097/JTO.0b013e318274a85d.

            ●● Enlace al texto completo (gratuito o de pago) 1097/JTO.0b013e318274a85d

AUTORES / AUTHORS:  - Dy GK; Mandrekar SJ; Nelson GD; Meyers JP; Adjei AA; Ross HJ; Ansari RH; Lyss AP; Stella PJ; Schild SE; Molina JR; Adjei AA

INSTITUCIÓN / INSTITUTION:  - Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.

RESUMEN / SUMMARY:  - INTRODUCTION: The purpose of this study was to assess the safety and efficacy of  gemcitabine and carboplatin with (arm A) or without (arm B) daily oral cediranib  as first-line therapy for advanced non-small-cell lung cancer. METHODS: A lead-in phase to determine the tolerability of gemcitabine 1000 mg/m on days 1 and 8, and carboplatin on day 1 at area under curve 5 administered every 21 days with cediranib 45 mg once daily was followed by a 2 (A):1 (B) randomized phase II study. The primary end point was confirmed overall response rate (ORR) with 6-month progression-free survival (PFS6) rate in arm A as secondary end point. Polymorphisms in genes encoding cediranib targets and transport were correlated with treatment outcome. RESULTS: On the basis of the safety assessment, cediranib 30 mg daily was used in the phase II portion. A total of 58 and 29 evaluable patients were accrued to arms A and B. Patients in A experienced more grade 3+ nonhematologic adverse events, 71% versus 45% (p = 0.01). The ORR was 19% (A) versus 20% (B) (p = 1.0). PFS6 in A was 48% (95% confidence interval: 35%-62%), thus meeting the protocol-specified threshold of at least 40%. The median overall survival was 12.0 versus 9.9 months (p = 0.10). FGFR1 rs7012413, FGFR2 rs2912791, and VEGFR3 rs11748431 polymorphisms were significantly associated with decreased  overall survival (hazard ratio 2.78-5.01, p = 0.0002-0.0095). CONCLUSIONS: The trial did not meet its primary end point of ORR but met its secondary end point of PFS6. The combination with cediranib 30 mg daily resulted in increased toxicity. Pharmacogenetic analysis revealed an association of FGFR and VEGFR variants with survival.

 

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[159]

TÍTULO / TITLE:  - Deleted in breast cancer 1 (DBC1) deficiency results in apoptosis of breast cancer cells through impaired responses to UV-induced DNA damage.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2013 Jan 22. pii: S0304-3835(13)00058-X. doi: 10.1016/j.canlet.2013.01.026.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2013.01.026

AUTORES / AUTHORS:  - Kim W; Kim JE

INSTITUCIÓN / INSTITUTION:  - Department of PharmacologySchool of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea; Department of Biomedical Science, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.

RESUMEN / SUMMARY:  - DBC1 (deleted in breast cancer 1) participates in the regulation of cell survival and death in response to various stimuli. In particular, DBC1 promotes cell death upon DNA damage through inhibition of SIRT1 deacetylase. However, the SIRT1-independent functions of DBC1 in the regulation of DNA damage response are  less well understood. Therefore, we analyzed the DNA damage response in Hs578T breast cancer cell line in which the DBC1-SIRT1 interaction is barely detectable. DBC1-siRNA transfected cells showed a failure in the DNA damage checkpoint and the accumulation of genomic damage following UV irradiation. In addition, DBC1-deficient cells exhibited less JNK activation. Finally, the interruptions of signaling in DBC1-depeleted cells contributed to cell death in response to UV irradiation. Overall, these data suggest that DBC1 is essential for a fully efficient and effective response to UV irradiation. Therefore, DBC1 plays a critical role in maintaining genomic stability and cellular integrity following UV-induced genotoxic stress.

 

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[160]

TÍTULO / TITLE:  - PIN1 Inhibits Apoptosis in Hepatocellular Carcinoma through Modulation of the Antiapoptotic Function of Survivin.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Pathol. 2013 Jan 17. pii: S0002-9440(13)00002-3. doi: 10.1016/j.ajpath.2012.11.034.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ajpath.2012.11.034

AUTORES / AUTHORS:  - Cheng CW; Chow AK; Pang R; Fok EW; Kwong YL; Tse E

INSTITUCIÓN / INSTITUTION:  - Division of Haematology and Medical Oncology, Department of Medicine, University  of Hong Kong, Queen Mary Hospital, Hong Kong.

RESUMEN / SUMMARY:  - PIN1, a peptidyl-prolyl-isomerase, binds a specific motif comprising a phosphorylated serine or threonine preceding a proline (p-Ser/Thr-Pro) residue in proteins. Through cis-trans isomerization, it induces conformational changes and  modulates functions of many proteins that are involved in cell cycle progression, cell proliferation, and oncogenesis. PIN1 is overexpressed in hepatocellular carcinomas (HCC) and contributes to hepatocarcinogenesis. We investigated the role of PIN1 and the significance of its interaction with the inhibitor of apoptosis protein survivin in evading apoptosis in HCC cells. Using cell line and xenograft models, we determined that PIN1 overexpression inhibits apoptosis through suppression of caspase-3 and caspase-9 activity. In addition, down-regulation of survivin in PIN1-overexpressing cells attenuated the antiapoptotic effect induced by PIN1, suggesting that the inhibition of apoptosis is mediated through PIN1-survivin interaction. Coimmunoprecipitation assays showed that PIN1 interacted with survivin via the phosphorylated Thr34-Pro motif  and enhanced binding among survivin phosphorylated at Thr34, hepatitis B X-interacting protein (HBXIP), and pro-caspase-9. Taken together, these results suggest that the inhibition of apoptosis by PIN1 in HCC cells is mediated through modulation of the antiapoptotic function of survivin by increasing its binding to pro-caspase-9 via HBXIP. Such functional interaction between PIN1 and survivin may therefore play an important role in hepatocarcinogenesis and chemoresistance.

 

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[161]

TÍTULO / TITLE:  - Fulvestrant radiosensitizes human estrogen receptor-positive breast cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 10. pii: S0006-291X(13)00042-9. doi: 10.1016/j.bbrc.2013.01.006.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2013.01.006

AUTORES / AUTHORS:  - Wang J; Yang Q; Haffty BG; Li X; Moran MS

INSTITUCIÓN / INSTITUTION:  - Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road  107, Shandong Province, PR China; Department of Oncology, Affiliated Hospital of  Qingdao University Medical College, Shandong Province, PR China. Electronic address: wangstella5@163.com.

RESUMEN / SUMMARY:  - The optimal sequencing for hormonal therapy and radiation are yet to be determined. We utilized fulvestrant, which is showing promise as an alternative to other agents in the clinical setting of hormonal therapy, to assess the cellular effects of concomitant anti-estrogen therapy (fulvestrant) with radiation (F+RT). This study was conducted to assess the effects of fulvestrant alone vs. F+RT on hormone-receptor positive breast cancer to determine if any positive or negative combined effects exist. The effects of F+RT on human breast  cancer cells were assessed using MCF-7 clonogenic and tetrazolium salt colorimetric (MTT) assays. The assays were irradiated with a dose of 0, 2, 4, 6Gy +/- fulvestrant. The effects of F+RT vs. single adjuvant treatment alone on cell-cycle distribution were assessed using flow cytometry; relative expression of repair proteins (Ku70, Ku80, DNA-PKcs, Rad51) was assessed using Western Blot  analysis. Cell growth for radiation alone vs. F+RT was 0.885+/-0.013 vs. 0.622+/-0.029 @2Gy, 0.599+/-0.045 vs. 0.475+/-0.054 @4Gy, and 0.472+/-0.021 vs. 0.380+/-0.018 @6Gy RT (p=0.003). While irradiation alone induced G2/M cell cycle  arrest, the combination of F+RT induced cell redistribution in the G1 phase and produced a significant decrease in the proportion of cells in G2 phase arrest and in the S phase in breast cancer cells (p<0.01). Furthermore, levels of repair proteins DNA-PKcs and Rad51 were significantly decreased in the cells treated with F+RT compared with irradiation alone. F+RT leads to a decrease in the surviving fraction, increased cell cycle arrest, down regulating of nonhomologous repair protein DNA-PKcs and homologous recombination repair protein RAD51. Thus,  our findings suggest that F+RT increases breast cancer cell radiosensitivity compared with radiation alone. These findings have salient implications for designing clinical trials using fulvestrant and radiation therapy.

 

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[162]

TÍTULO / TITLE:  - Granocyte-colony Stimulating Factor (G-CSF) Has Significant Efficacy as Secondary Prophylaxis of Chemotherapy-induced Neutropenia in Patients with Solid Tumors: Results of a Prospective Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Anticancer Res. 2013 Jan;33(1):301-7.

AUTORES / AUTHORS:  - Freyer G; Jovenin N; Yazbek G; Villanueva C; Hussain A; Berthune A; Rotarski M; Simon H; Boulanger V; Hummelsberger M; Falandry C

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Lyon-Sud Hospital, 69495 Pierre Benite Cedex, France. gilles.freyer@chu-lyon.fr.

RESUMEN / SUMMARY:  - Aim: To carry out a prospective, multicenter and observational study describing prophylactic strategies [cycle delay, dose-reduction, (G-CSF) prescription] to prevent recurrence of neutropenic events (NE) in patients with solid tumors, and  identify potential predictive factors of NE recurrence. PATIENTS AND METHODS: Patients >/=18 years old with an NE in a previous chemotherapy cycle (cycle A) without G-CSF support, followed for four cycles (B to E) were included in the study. NE was defined as any neutropenia grade 1-4, febrile or not, which impacted on subsequent chemotherapy cycles (cycle delay, or reduction, or prophylactic G-CSF). RESULTS: Data of 548 patients were analyzed, 378 (69%) were  female, with a mean (SD) age of 61.7 (12.3) years. WHO PS: 0-1: 88.3%, incidence  of breast cancer: 40%, metastatic disease: 53.3%. Following the first NE episode, 44.5% of patients had cycle delay, 22.3% dose reduction and 466 (85%) received prophylactic G-CSF. NE recurrence rates were: 21.2% at cycle B, 18.6% at cycle C, 11.5% at cycle D and 12.9% at cycle E. G-CSF support (hazard ratio: 0.32, 0.24-0.43, p<0.001) was associated with lower NE recurrence. Pegfilgrastim seemed to offer the highest protection (hazard ratio; HR=0.23, 95% CI: 0.16-0.32; p<0.001). CONCLUSION: Secondary G-CSF prophylaxis has significant efficacy in reducing the incidence of NE and should be considered as a valuable option.

 

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[163]

TÍTULO / TITLE:  - Prospective Multicentre Evaluation of PCA3 and TMPRSS2-ERG Gene Fusions as Diagnostic and Prognostic Urinary Biomarkers for Prostate Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur Urol. 2012 Nov 15. pii: S0302-2838(12)01345-0. doi: 10.1016/j.eururo.2012.11.014.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.eururo.2012.11.014

AUTORES / AUTHORS:  - Leyten GH; Hessels D; Jannink SA; Smit FP; de Jong H; Cornel EB; de Reijke TM; Vergunst H; Kil P; Knipscheer BC; van Oort IM; Mulders PF; Hulsbergen-van de Kaa CA; Schalken JA

INSTITUCIÓN / INSTITUTION:  - Radboud University Nijmegen Medical Centre, Department of Urology, Nijmegen, The  Netherlands.

RESUMEN / SUMMARY:  - BACKGROUND: Prostate cancer antigen 3 (PCA3) and v-ets erythroblastosis virus E26 oncogene homolog (TMPRSS2-ERG) gene fusions are promising prostate cancer (PCa) specific biomarkers that can be measured in urine. OBJECTIVE: To evaluate the diagnostic and prognostic value of Progensa PCA3 and TMPRSS2-ERG gene fusions (as individual biomarkers and as a panel) for PCa in a prospective multicentre setting. DESIGN, SETTING, AND PARTICIPANTS: At six centres, post-digital rectal examination first-catch urine specimens prior to prostate biopsies were prospectively collected from 497 men. We assessed the predictive value of Progensa PCA3 and TMPRSS2-ERG (quantitative nucleic acid amplification assay to detect TMPRSS2-ERG messenger RNA [mRNA]) for PCa, Gleason score, clinical tumour  stage, and PCa significance (individually and as a marker panel). This was compared with serum prostate-specific antigen and the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculator. In a subgroup (n=61) we evaluated biomarker association with prostatectomy outcome. OUTCOME MEASUREMENTS  AND STATISTICAL ANALYSIS: Univariate and multivariate logistic regression analysis and receiver operating curves were used. RESULTS AND LIMITATIONS: Urine  samples of 443 men contained sufficient mRNA for marker analysis. PCa was diagnosed in 196 of 443 men. Both PCA3 and TMPRSS2-ERG had significant additional predictive value to the ERSPC risk calculator parameters in multivariate analysis (p<0.001 and resp. p=0.002). The area under the curve (AUC) increased from 0.799  (ERSPC risk calculator), to 0.833 (ERSPC risk calculator plus PCA3), to 0.842 (ERSPC risk calculator plus PCA3 plus TMPRSS2-ERG) to predict PCa. Sensitivity of PCA3 increased from 68% to 76% when combined with TMPRSS2-ERG. TMPRSS2-ERG added  significant predictive value to the ERSPC risk calculator to predict biopsy Gleason score (p<0.001) and clinical tumour stage (p=0.023), whereas PCA3 did not. CONCLUSIONS: TMPRSS2-ERG had independent additional predictive value to PCA3 and the ERSPC risk calculator parameters for predicting PCa. TMPRSS2-ERG had prognostic value, whereas PCA3 did not. Implementing the novel urinary biomarker  panel PCA3 and TMPRSS2-ERG into clinical practice would lead to a considerable reduction of the number of prostate biopsies.

 

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[164]

TÍTULO / TITLE:  - The Pim kinase inhibitor SGI-1776 decreases cell surface expression of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and drug transport by Pim-1-dependent and -independent mechanisms.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Feb 15;85(4):514-24. doi: 10.1016/j.bcp.2012.12.006. Epub 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2012.12.006

AUTORES / AUTHORS:  - Natarajan K; Bhullar J; Shukla S; Burcu M; Chen ZS; Ambudkar SV; Baer MR

INSTITUCIÓN / INSTITUTION:  - University of Maryland Greenebaum Cancer Center, Baltimore, MD 21201, USA.

RESUMEN / SUMMARY:  - Overexpression of the ATP-binding cassette (ABC) drug efflux proteins P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on malignant  cells is associated with inferior chemotherapy outcomes. Both, ABCB1 and ABCG2, are substrates of the serine/threonine kinase Pim-1; Pim-1 knockdown decreases their cell surface expression, but SGI-1776, the first clinically tested Pim inhibitor, was shown to reverse drug resistance by directly inhibiting ABCB1-mediated transport. We sought to characterize Pim-1-dependent and -independent effects of SGI-1776 on drug resistance. SGI-1776 at the Pim-1-inhibitory and non-cytotoxic concentration of 1muM decreased the IC(50)s of the ABCG2 and ABCB1 substrate drugs in cytotoxicity assays in resistant cells, with no effect on the IC(50) of non-substrate drug, nor in parental cells. SGI-1776 also increased apoptosis of cells overexpressing ABCG2 or ABCB1 exposed  to substrate chemotherapy drugs and decreased their colony formation in the presence of substrate, but not non-substrate, drugs, with no effect on parental cells. SGI-1776 decreased ABCB1 and ABCG2 surface expression on K562/ABCB1 and K562/ABCG2 cells, respectively, with Pim-1 overexpression, but not HL60/VCR and 8226/MR20 cells, with lower-level Pim-1 expression. Finally, SGI-1776 inhibited uptake of ABCG2 and ABCB1 substrates in a concentration-dependent manner irrespective of Pim-1 expression, inhibited ABCB1 and ABCG2 photoaffinity labeling with the transport substrate [(125)I]iodoarylazidoprazosin ([(125)I]IAAP) and stimulated ABCB1 and ABCG2 ATPase activity. Thus SGI-1776 decreases cell surface expression of ABCB1 and ABCG2 and inhibits drug transport  by Pim-1-dependent and -independent mechanisms, respectively. Decrease in ABCB1 and ABCG2 cell surface expression mediated by Pim-1 inhibition represents a novel mechanism of chemosensitization.

 

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[165]

TÍTULO / TITLE:  - Novel Mechanism of Apoptosis Resistance in Cancer Mediated by Extracellular PAR-4.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2013 Jan 15;73(2):1011-9. doi: 10.1158/0008-5472.CAN-12-3212. Epub 2012 Nov 30.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-3212

AUTORES / AUTHORS:  - Burikhanov R; Shrestha-Bhattarai T; Qiu S; Shukla N; Hebbar N; Lele SM; Horbinski C; Rangnekar VM

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Departments of Radiation Medicine, Pathology, Microbiology, Immunology, and Molecular Genetics; Graduate Center for Toxicology; L.P. Markey Cancer Center, University of Kentucky, Lexington, Kentucky; and University of Nebraska, Omaha, Nebraska.

RESUMEN / SUMMARY:  - Tumor suppressor PAR-4 acts in part by modulating sensitivity to apoptosis, but the basis for its activity is not fully understood. In this study, we describe a  novel mechanism of antiapoptosis by NF-kappaB, revealing that it can block PAR-4-mediated apoptosis by downregulating trafficking of the PAR-4 receptor GRP78 from the endoplasmic reticulum to the cell surface. Mechanistic investigations revealed that NF-kappaB mediated this antiapoptotic mechanism by upregulating expression of UACA, a proinflammatory protein in certain disease settings. In clinical specimens of cancer, a strong correlation existed between NF-kappaB activity and UACA expression, relative to normal tissues. UACA bound to intracellular PAR-4 in diverse cancer cells, where it prevented translocation of  GRP78 from the endoplasmic reticulum to the cell surface. This pathway of antiapoptosis could be inhibited by suppressing levels of NF-kappaB or UACA expression, which enhanced endoplasmic reticulum stress and restored GRP78 trafficking to the cell surface, thereby sensitizing cancer cells to apoptosis by extracellular PAR-4 or GRP78 agonistic antibody. In summary, our results identify a novel intracellular pathway of apoptosis mediated by NF-kappaB through UACA elevation, which by attenuating endoplasmic reticulum stress and GRP78 translocation to the cell surface can blunt the sensitivity of cancer cells to apoptosis. Cancer Res; 73(2); 1011-9. ©2012 AACR.

 

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[166]

TÍTULO / TITLE:  - Correction: Cyclin D2-Cyclin-Dependent Kinase 4/6 Is Required for Efficient Proliferation and Tumorigenesis following Apc Loss.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2013 Jan 1;73(1):469. doi: 10.1158/0008-5472.CAN-12-4285. Epub 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-4285

 

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[167]

TÍTULO / TITLE:  - Caspase-Independent Cell Death Is Involved in the Negative Effect of EGF Receptor Inhibitors on Cisplatin in Non-Small Cell Lung Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2621

AUTORES / AUTHORS:  - Yamaguchi H; Hsu JL; Chen CT; Wang YN; Hsu MC; Chang SS; Du Y; Ko HW; Herbst R; Hung MC

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Departments of Molecular and Cellular Oncology and Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center; Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Asia University, Taichung, Taiwan.

RESUMEN / SUMMARY:  - PURPOSE: Results of multiple clinical trials suggest that EGF receptor (EGFR) tyrosine kinase inhibitors (TKI) exhibit negative effects on platinum-based chemotherapy in patients with lung cancer with wild-type (WT) EGFR, but the underlying molecular mechanisms are still uncertain. Studies that identify the mechanism of how TKIs negatively affect patients with WT EGFR are important for future development of effective strategies to target lung cancer. Thus, we returned to in vitro study to investigate and determine a possible explanation for this phenomenon.EXPERIMENTAL DESIGN: We investigated the effects of TKIs and  cisplatin on caspase-independent cell death (CID) and the role of CID in the efficacy of each drug and the combination. Furthermore, we studied the mechanism  by which EGFR signaling pathway is involved in CID. Finally, on the basis of the  identified mechanism, we tested the combinational effects of cisplatin plus suberoylanilide hydroxamic acid (SAHA) or erastin on CID.RESULTS: We found that gefitinib inhibited cisplatin-induced CID but not caspase-dependent apoptotic cell death. In WT EGFR cells, gefitinib not only inhibited CID but also failed to induce apoptosis, therefore compromising the efficacy of cisplatin. Inhibition of EGFR-ERK/AKT by gefitinib activates FOXO3a, which in turn reduces reactive oxygen species (ROS) and ROS-mediated CID. To overcome this, we showed that SAHA and erastin, the inducers of ROS-mediated CID, strongly enhanced the effect of cisplatin in WT EGFR cells.CONCLUSION: TKI-mediated inhibition of CID plays an important role in the efficacy of chemotherapy. Moreover, FOXO3a is a key factor  in the negative effects of TKI by eliminating cisplatin-induced ROS. Clin Cancer  Res; 1-10. ©2012 AACR.

 

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[168]

TÍTULO / TITLE:  - p130Cas acts as survival factor during PMA-induced apoptosis in HL-60 promyelocytic leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Biochem Cell Biol. 2012 Dec 31;45(3):531-535. doi: 10.1016/j.biocel.2012.12.017.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biocel.2012.12.017

AUTORES / AUTHORS:  - Kumbrink J; Kirsch KH

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.

RESUMEN / SUMMARY:  - Phorbol 12-myristate 13-acetate (PMA) stimulates the differentiation of promyelocytic leukemia HL-60 cells by inducing adhesion followed by cell aggregation and, importantly, apoptosis. p130Cas (Crk-associated substrate) is an adapter molecule that controls cell growth, attachment and apoptotic programs. Notably, elevated p130Cas activity is associated with leukemias and lymphomas. Since p130Cas regulates cell adhesion, we tested the hypothesis that it participates in the differentiation of hematopoietic cells. Here we show that PMA mediates the late induction of p130Cas expression in HL-60 cells, which coincided with cell aggregation and the onset of apoptosis. Ectopic p130Cas expression led  to increased cell adhesion and earlier cell aggregation potentially contributing  to the observed increased cell viability in these transductants. p130Cas expression concurred with the induction of its own regulator the transcription factor EGR1, its coregulator NAB2, and apoptosis. NF-kappaB inhibition in PMA-treated HL-60 cells promoted the loss of cell aggregation and cell death. We  further showed a reduction of p130Cas, EGR1, and NAB2 levels in response to NF-kappaB inhibition during PMA treatment. Hence, p130Cas acts as survival factor by limiting PMA-mediated cell cluster disruption and resulting cell death in HL-60 cells.

 

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[169]

TÍTULO / TITLE:  - Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial  cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Invest New Drugs. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10637-013-9926-y

AUTORES / AUTHORS:  - Jones R; Vuky J; Elliott T; Mead G; Arranz JA; Chester J; Chowdhury S; Dudek AZ; Muller-Mattheis V; Grimm MO; Gschwend JE; Wulfing C; Albers P; Li J; Osmukhina A; Skolnik J; Hudes G

INSTITUCIÓN / INSTITUTION:  - Institute of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK, r.jones@beatson.gla.ac.uk.

RESUMEN / SUMMARY:  - Background AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (C(max)) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609). Patients and methods AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The  primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if </=2 of the first 20 evaluable patients achieved  an objective tumor response. C(max) was assessed on days 1 and 8 of cycle 1. Results None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for >/=8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade >/=3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean C(max) of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively. Conclusions AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.

 

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[170]

TÍTULO / TITLE:  - Dedifferentiation in Gastrointestinal Stromal Tumor to an Anaplastic KIT-negative Phenotype: A Diagnostic Pitfall: Morphologic and Molecular Characterization of 8  Cases Occurring Either De Novo or After Imatinib Therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Surg Pathol. 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1097/PAS.0b013e31826c1761

AUTORES / AUTHORS:  - Antonescu CR; Romeo S; Zhang L; Nafa K; Hornick JL; Nielsen GP; Mino-Kenudson M; Huang HY; Mosquera JM; Tos PA; Fletcher CD

INSTITUCIÓN / INSTITUTION:  - *Department of Pathology, Memorial Sloan-Kettering Cancer Center paragraph signWeill Medical College of Cornell University, New York, NY double daggerSurgical Pathology, Brigham & Women’s Hospital section signMassachusetts General Hospital, Boston, MA daggerTreviso General Hospital, Treviso, Italy parallelKaohsiung Chang Gung Memorial Hospital and Chang Gung University College  of Medicine, Kaohsiung, Taiwan, Republic of China.

RESUMEN / SUMMARY:  - Most gastrointestinal stromal tumors (GISTs) can be recognized by their monotonous cytologic features and overexpression of KIT oncoprotein. Altered morphology and loss of CD117 reactivity has been described previously after chronic imatinib treatment; however, this phenomenon has not been reported in imatinib-naive tumors. Eight patients with abrupt transition from a classic CD117-positive spindle cell GIST to an anaplastic CD117-negative tumor were investigated for underlying molecular mechanisms of tumor progression. Pathologic and molecular analysis was performed on each of the 2 components. Genomic DNA polymerase chain reaction for KIT, PDGFRA, BRAF, and KRAS hot spot mutations and  fluorescence in situ hybridization for detecting KIT gene copy number alterations were performed. TP53 mutational analysis was performed in 5 cases. There were 7 men and 1 woman, with an age range of 23 to 65 years. Five of the primary tumors  were located in the stomach, and 1 case each originated in the small bowel, colon, and rectum. In 3 patients, the dedifferentiated component occurred in the  setting of imatinib resistance, whereas the remaining 5 occurred de novo. The dedifferentiated component had an anaplastic appearance, including 1 angiosarcomatous phenotype, with high mitotic activity and necrosis, and showed complete loss of CD117 (8/8) and CD34 (5/8) expression and de novo expression of  either cytokeratin (4/8) or desmin (1/8). There was no difference in the KIT genotype between the 2 components. However, 2 imatinib-resistant tumors showed coexistence of KIT exon 11 and exon 13 mutations. Fluorescence in situ hybridization showed loss of 1 KIT gene in 3 cases and low-level amplification of KIT in 2 other cases in the CD117-negative component, compared with the CD117-positive area. TP53 mutation was identified in 1/5 cases tested, being present in both components. In summary, dedifferentiation in GIST may occur either de novo or after chronic imatinib exposure and can represent a diagnostic  pitfall. This phenomenon is not related to additional KIT mutations, but might be secondary to genetic instability, either represented by loss of heterozygosity or low level of KIT amplification.

 

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[171]

TÍTULO / TITLE:  - Lymphotoxin beta receptor mediates caspase-dependent tumor cell apoptosis in vitro and tumor suppression in vivo despite induction of NF-kB activation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Carcinogenesis. 2013 Jan 24.

            ●● Enlace al texto completo (gratuito o de pago) 1093/carcin/bgt014

AUTORES / AUTHORS:  - Hu X; Zimmerman M; Bardhan K; Yang D; Waller JL; Liles GB; Lee JR; Pollock R; Lev D; Ware CF; Garber E; Bailly V; Browning JL; Liu K

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA 30912.

RESUMEN / SUMMARY:  - Ligation of the lymphotoxin beta receptor (LTbetaR) has been shown to induce both tumor growth inhibition and promotion. The functions of LTbetaR in these two contrasting cellular processes require further study. We demonstrated here that mice deficient in LTbetaR ligands, LTalpha, LIGHT, or both LTbeta and LIGHT, exhibit greater susceptibility to methylcholanthrene (MCA)-induced tumor development. LTalpha, LTbeta and LIGHT were expressed in tumor-infiltrating immune cells, and LTbetaR was expressed on human colon carcinoma and soft tissue  sarcoma (STS) cells. Human LTbetaR agonist monoclonal antibody (mAb) BS-1 induced both growth inhibition and NF-B activation in human colon carcinoma, mammary carcinoma and STS cells. Interestingly, BS-1 also significantly inhibited growth  of doxorubicin-resistant and radiation-resistant human STS cells in vitro. In the molecular mechanism level, we demonstrated that BS-1 induces caspases 8 and 3 activation and cytochrome C release in tumor cells, suggesting that the LTbetaR mediates apoptosis at least partially through a caspase-dependent mechanism. Furthermore, mouse LTbetaR mAb ACH6 suppressed colon carcinoma cell metastatic potential in an experimental metastasis mouse model. Although blocking NF-kappaB  activation did not alter tumor cell growth rate and tumor cell response to LTbetaR mAb-induced growth inhibition in vitro, surprisingly, blocking NF-B activation significantly enhanced colon carcinoma cell metastatic potential in vivo, suggesting that the LTbetaR-mediated apoptosis pathway and NF-kappaB signaling pathway might cooperate to suppress tumor growth in vivo. In summary, our findings determine that LTbetaR mediates tumor cell apoptosis in colon carcinoma, mammary carcinoma and sarcoma, and that LTbetaR-activated NF-kappaB potentially functions as a tumor suppressor.

 

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[172]

TÍTULO / TITLE:  - Anti-Mullerian hormone as a marker of ovarian reserve in patients with ovarian malignancies who have undergone fertility-preserving surgery and chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Gynecol Endocrinol. 2013 Jan 10.

            ●● Enlace al texto completo (gratuito o de pago) 3109/09513590.2012.743008

AUTORES / AUTHORS:  - Iwase A; Sugita A; Hirokawa W; Goto M; Nakahara T; Bayasula; Kajiyama H; Shibata K; Nagatomo Y; Kikkawa F

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine and.

RESUMEN / SUMMARY:  - Abstract With proper and careful selection of patients, fertility-preserving surgery may be feasible in patients with ovarian malignancies. However, the loss  of follicles by oophorectomy and chemotherapy results in decreased ovarian reserve, which consecutively affects reproductive capacity. We evaluated postoperative levels of serum anti-Mullerian hormone (AMH) in women with ovarian  malignancies to assess the impact of the fertility-preserving surgery with or without the administration of chemotherapy on ovarian reserve. In 13 patients who underwent the fertility-preserving surgery with (n = 9) or without (n = 4) the administration of chemotherapy, serum AMH levels were measured and compared with  serum AMH levels measured in patients undergone cystectomy for benign ovarian tumors as a control. We found that the mean AMH level in the treatment group measured 0.9 ng/mL, which was significantly lower than that measured in the control group (4.70 +/- 3.77 ng/mL). The possibility of decreased ovarian reserve occurring in patients with ovarian malignancies following treatment with fertility-preserving surgery with or without the administration of chemotherapy should be considered for fertility planning.

 

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[173]

TÍTULO / TITLE:  - Inhibition of cholinergic signaling causes apoptosis in human bronchioalveolar carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-3190

AUTORES / AUTHORS:  - Lau JK; Brown KC; Thornhill BA; Crabtree CM; Dom AM; Witte TR; Hardman WE; McNees CA; Stover CA; Carpenter AB; Luo H; Chen YC; Shiflett BS; Dasgupta P

INSTITUCIÓN / INSTITUTION:  - Pharmacology, Physiology and Toxicology, Marshall University.

RESUMEN / SUMMARY:  - Recent case-controlled clinical studies show that bronchioalveolar carcinomas (BACs) are correlated with smoking. Nicotine, the addictive component of cigarettes, accelerates cell proliferation through nicotinic acetylcholine receptors (nAChRs). In this study, we show that human BACs produce acetylcholine  (ACh) and contain several cholinergic factors including acetylcholinesterase (AChE), choline acetyltransferase (ChAT), choline transporter 1 (CHT1, SLC5A7), vesicular acetylcholine transporter (VAChT, SLC18A3) and nACh receptors (AChRs, CHRNAs). Nicotine increased the production of ACh in human BACs and ACh acts as a growth factor for these cells. Nicotine-induced ACh production was mediated by alpha7-, alpha3beta2-, and beta3-nAChRs, ChAT and VAChT pathways. We observed that nicotine upregulated ChAT and VAChT. Therefore, we conjectured that VAChT antagonists, such as vesamicol, may suppress the growth of human BACs. Vesamicol  induced potent apoptosis of human BACs in cell culture and nude mice models. Vesamicol did not have any effect on EGF or IGF-II-induced growth of human BAC’s. siRNA-mediated attenuation of VAChT reversed the apoptotic activity of vesamicol. We also observed that vesamicol inhibited Akt phosphorylation during cell death,  and overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol. Taken together, our results suggested that disruption of nicotine-induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy.

 

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[174]

TÍTULO / TITLE:  - Effect of Leuprolide on Serum Amyloid-beta Peptide Levels and Memory in Patients  With Prostate Cancer With Biochemical Recurrence.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Urology. 2013 Jan;81(1):150-4. doi: 10.1016/j.urology.2012.08.066.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.urology.2012.08.066

AUTORES / AUTHORS:  - Tan WW; Heckman MG; Vishnu P; Crook JE; Younkin LH; Covil EG; Ferman TJ; Graff-Radford NR; Younkin SG; Smallridge RC; Wehle MJ; Buskirk SJ

INSTITUCIÓN / INSTITUTION:  - Division of Hematology, Oncology, Cancer Center, GU Oncology, Mayo Clinic, Jacksonville, FL. Electronic address: tan.winston@mayo.edu.

RESUMEN / SUMMARY:  - OBJECTIVE: To investigate whether prostate cancer patients receiving leuprolide demonstrated objective cognitive decline accompanied by a change in plasma levels of amyloid-beta. METHODS: Between November 19, 2003, and July 21, 2008, we prospectively enrolled 50 patients with biochemical recurrence of prostate cancer and measured plasma amyloid-beta peptide 40 and amyloid-beta peptide 42 levels with sandwich enzyme-linked immunosorbent assay at baseline before the first leuprolide injection and at 2, 4, and 12 months. The Mini-Mental State Examination was used to assess 49 patients at baseline and at subsequent visits,  and 24 were also assessed by the California Verbal Learning Test-Short Form. RESULTS: Patients were a median age of 71 years (range, 59-89 years). Compared with baseline levels, plasma amyloid-beta peptide 40 levels were increased at 2 months (P = .04) and 4 months (P = .02). Age was correlated with plasma amyloid-beta peptide 40 levels (P = .003) and likely accounted for this relationship. Plasma amyloid-beta peptide 42 and performance on cognitive tasks did not differ from baseline, but memory measures improved slightly after baseline, most likely due to a practice effect. CONCLUSION: Leuprolide therapy was not associated with a decline in cognition or memory function or with elevated plasma amyloid short-term. Larger studies are needed to confirm these findings.

 

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[175]

TÍTULO / TITLE:  - Can mutations of EGFR and KRAS in serum be predictive and prognostic markers in patients with advanced non-small cell lung cancer (NSCLC)?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):328. doi: 10.1007/s12032-012-0328-3. Epub 2013 Jan 10.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0328-3

AUTORES / AUTHORS:  - Kim ST; Sung JS; Jo UH; Park KH; Shin SW; Kim YH

INSTITUCIÓN / INSTITUTION:  - Division of Hematology-Oncology, Department of Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, 136-705, South Korea.

RESUMEN / SUMMARY:  - The status of epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) mutations has been used widely in management of patients with non-small cell lung cancer (NSCLC). However, it may be difficult to get tumor tissues for analyzing the status of EGFR and KRAS mutation in large proportion of patients with advanced disease. We obtained pairs of tumor and serum samples from 57 patients with advanced NSCLC, between March 2006 and January 2009. EGFR mutation status from tumor samples and KRAS mutation status from serum samples were analyzed by genomic polymerase chain reaction and direct sequence, and EGFR mutation status from serum samples was determined by the peptide nucleic acid-locked nucleic acid PCR clamp. EGFR mutations were detected in the serum samples of 11 patients and in the tumor samples of 12 patients. Fourteen patients revealed (?) KRAS mutation in the serum sample. EGFR mutation status in the serum and tumor samples was consistent in 50 (87.7 %) of the 57 pairs (correlation index 0.62, p < 0.001). Only 5 of 57 (8.7 %) patients showed mutation of both EGFR and KRAS in serum sample. Twenty-two of 57 patients (38.5 %) received EGFR-TKIs as any line therapy. The response for EGFR-TKIs was significantly associated with EGFR mutations in both tumor samples and serum samples (p < 0.05). The status of KRAS  mutation in serum was not predictive for the response of EGFR-TKI (p > 0.05). There was no significant difference in OS according to the status of EGFR mutations in both serum and tumor samples (p > 0.05) and KRAS mutations in serum  samples (p > 0.05). The status of EGFR and KRAS mutation in serum was not prognostic in patients with advanced NSCLC. However, the clinical usefulness of EGFR mutation of serum as a selection marker for EGFR-TKIs sensitivity in NSCLC might be allowed, not KRAS mutation.

 

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[176]

TÍTULO / TITLE:  - Pharmacogenetic analysis of adjuvant FOLFOX for Korean patients with colon cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Jan 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-013-2075-3

AUTORES / AUTHORS:  - Lee KH; Chang HJ; Han SW; Oh DY; Im SA; Bang YJ; Kim SY; Lee KW; Kim JH; Hong YS; Kim TW; Park YS; Kang WK; Shin SJ; Ahn JB; Kang GH; Jeong SY; Park KJ; Park JG; Kim TY

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Seoul National University Hospital, 28 Yongon-Dong, 110-744, Chongno-Gu, Seoul, Korea.

RESUMEN / SUMMARY:  - PURPOSE: Ethnic diversity of genetic polymorphism can result in individual differences in the efficacy and toxicity of cancer chemotherapy. METHODS: We analyzed 20 germline polymorphisms in 10 genes (TS, MTHFR, ERCC1, XPD, XRCC1, ABCC2, AGXT, GSTP1, GSTT1 and GSTM1) from prospectively enrolled 292 Korean patients treated with adjuvant oxaliplatin plus leucovorin plus 5-fluorouracil (FOLFOX) for colon cancer. RESULTS: In contrast to previous studies in Caucasians, neutropenia (grade 3-4, 60.5 %) was frequently observed, whereas only 16.4 % experienced grade 2 or more sensory neuropathy. Neutropenia was more frequent in MTHFR 677TT [adjusted odds ratio (OR) 2.32, 95 % confidence interval  (CI) 1.19-4.55] and ERCC1 19007TT (adjusted OR 4.58, 95 % CI 1.20-17.40) genotypes. Patients harboring XRCC1 23885GG experienced less grade 2-4 neuropathy [adjusted OR 0.52, 95 % CI 0.27-0.99]. MTHFR 677TT (p = 0.002) and XRCC1 23885GG  (p = 0.146) genotypes were also more prevalent in Koreans compared to Caucasians. TS ‘low’ genotype (adjusted HR 1.83, 95 % CI 1.003-3.34) was significantly related to shorter disease-free survival. Overall survival was not significantly  different according to the polymorphisms. CONCLUSIONS: Polymorphisms in MTHFR, XRCC1 and TS are related to toxicities and disease-free survival in patients with colon cancer. The ethnic differences in frequencies of genotypes may explain the  ethnic difference in toxicity profile following adjuvant FOLFOX chemotherapy.

 

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[177]

TÍTULO / TITLE:  - Induction of p53, p21 and apoptosis by silencing the NF90/NF45 complex in human papilloma virus-transformed cervical carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncogene. 2012 Dec 3. doi: 10.1038/onc.2012.533.

            ●● Enlace al texto completo (gratuito o de pago) 1038/onc.2012.533

AUTORES / AUTHORS:  - Shamanna RA; Hoque M; Pe’ery T; Mathews MB

INSTITUCIÓN / INSTITUTION:  - 1] Department of Biochemistry and Molecular Biology, New Jersey Medical School, UMDNJ, Newark, NJ, USA [2] Graduate School of Biomedical Sciences, UMDNJ, Newark, NJ, USA.

RESUMEN / SUMMARY:  - The heterodimeric nuclear factor (NF) 90/NF45 complex (NF90/NF45) binds nucleic acids and is a multifunctional regulator of gene expression. Here we report that  depletion of NF90/NF45 restores the expression of the p53 and p21 proteins in cervical carcinoma cells infected with high-risk human papillomaviruses (HPVs). Knockdown of either NF90 or NF45 by RNA interference led to greatly elevated levels of p53 and p21 proteins in HPV-derived HeLa and SiHa cells but not in other cancerous or normal cell lines. In HeLa cells, p21 messenger-RNA (mRNA) increased concomitantly but the level of p53 mRNA was unaffected. RNA interference directed against p53 prevented the induction of both proteins. These results indicated that the upregulation of p21 is due to p53-dependent transcription, whereas p53 is regulated post-transcriptionally. Proteasome-mediated turnover of p53 is accelerated by the HPV E6 and cellular E6AP proteins. We therefore examined the hypothesis that this pathway is regulated by NF90/NF45. Indeed, depletion of NF90 attenuated the expression of E6 RNA and inhibited transcription from the HPV early promoter, revealing a new role for NF90/NF45 in HPV gene expression. The transcription inhibition was largely independent of the reduction of P-TEFb (positive transcription elongation factor  b) levels caused by NF90 depletion. Consistent with p53 derepression, NF90/NF45-depleted HeLa cells displayed elevated poly ADP-ribose polymerase (PARP) cleavage and susceptibility to camptothecin-induced apoptosis. We conclude that high-risk strains of HPV utilize the cellular NF90/NF45 complex for viral E6 expression in infected cervical carcinoma cell lines. Interference with NF90/NF45 function could assist in controlling cervical carcinoma.Oncogene advance online publication, 3 December 2012; doi:10.1038/onc.2012.533.

 

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[178]

TÍTULO / TITLE:  - A prospective case series of women with estrogen receptor-positive breast cancer: levels of tamoxifen metabolites in controlled ovarian stimulation with high-dose  tamoxifen.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hum Reprod. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1093/humrep/des445

AUTORES / AUTHORS:  - Balkenende EM; Dahhan T; Linn SC; Jager NG; Beijnen JH; Goddijn M

INSTITUCIÓN / INSTITUTION:  - Centre for Reproductive Medicine, Department of Obstetrics and Gynecology, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, The Netherlands.

RESUMEN / SUMMARY:  - Controlled ovarian stimulation (COS) in women with estrogen receptor (ER)-positive breast cancer is potentially harmful because of the increase in serum estrogen levels. During COS for cryopreservation of oocytes or embryos, these women may receive high doses of tamoxifen (60 mg) to modulate the ER and prevent extra growth of estrogen responsive tumours during COS. However, it is unknown whether adequate serum concentrations of endoxifen, the most important metabolite of tamoxifen, can be reached. The aim of this study is to evaluate whether the tamoxifen dose used in a tamoxifen-COS combined schedule for women with ER-positive breast cancer is high enough to reach endoxifen levels that are  considered therapeutically effective to inhibit breast cancer growth. The four women with ER-positive breast cancer who underwent COS for cryopreservation of oocytes were prospectively studied at the Academic Medical Centre, Amsterdam, the Netherlands. Throughout COS, blood samples were collected and tamoxifen and endoxifen levels were determined by a validated high-performance liquid chromatography tandem mass spectrometry assay. The four women with ER-positive breast cancer underwent a total of five COS cycles, while additionally using tamoxifen 60 mg daily. The tamoxifen and endoxifen levels showed a large variability between the women, with endoxifen levels during the whole period of ovarian stimulation varying between 3.96 and 41.0 ng/ml. The average number of vitrified oocytes was 11 (5-14). Therapeutically effective endoxifen serum levels can be reached when tamoxifen is used to counteract estrogen levels during COS for fertility preservation, but not in all women. Large variations of tamoxifen and endoxifen levels between the women were observed.

 

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[179]

TÍTULO / TITLE:  - Characterization of a novel PERK kinase inhibitor with anti-tumor and anti-angiogenic activity.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-3109

AUTORES / AUTHORS:  - Atkins C; Liu Q; Minthorn EA; Zhang S; Figueroa DJ; Moss KG; Stanley TB; Sanders B; Goetz A; Gaul N; Choudhry AE; Alsaid H; Jucker BM; Axten JM; Kumar R

INSTITUCIÓN / INSTITUTION:  - Oncology R&D, GlaxoSmithKline Research & Development.

RESUMEN / SUMMARY:  - The unfolded protein response (UPR) is a signal transduction pathway that coordinates cellular adaptation to microenvironmental stresses that include hypoxia, nutrient deprivation, and change in redox status. These stress stimuli are common in many tumors and thus targeting components of the UPR signaling is an attractive therapeutic approach. We have identified a first-in-class, small molecule inhibitor of the eukaryotic initiation factor 2-alpha kinase 3 (EIF2AK3) or PERK, one of the three mediators of UPR signaling. GSK2656157 is an ATP-competitive inhibitor of PERK enzyme activity with an IC50 of 0.9 nM. It is highly selective for PERK with IC50 values >100 nM against a panel of 300 kinases. GSK2656157 inhibits PERK activity in cells with an IC50 in the range of  10-30 nM as shown by inhibition of stress-induced PERK autophosphorylation, eIF2alpha substrate phosphorylation, together with corresponding decreases in ATF4 and CHOP proteins in multiple cell lines. Oral administration of GSK2656157  to mice shows a dose- and time-dependent pharmacodynamic response in pancreas as  measured by PERK auto-phosphorylation. Twice daily dosing of GSK2656157 results in dose dependent inhibition of multiple human tumor xenografts growth in mice. Altered amino acid metabolism, decreased blood vessel density and vascular perfusion are potential mechanisms for the observed anti-tumor effect. However, despite its anti-tumor activity, given the on-target pharmacological effects of PERK inhibition on pancreatic function, development of any PERK inhibitor in human subjects would need to be cautiously pursued in cancer patients.

 

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[180]

TÍTULO / TITLE:  - Overexpression of ubiquitin-specific protease 22 predicts poor survival in patients with early-stage non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Histochem. 2012 Nov 30;56(4):e46. doi: 10.4081/ejh.2012.e46.

AUTORES / AUTHORS:  - Ning J; Zhang J; Liu W; Lang Y; Xue Y; Xu S

INSTITUCIÓN / INSTITUTION:  - The Third Affiliated Hospital of Harbin Medical University. shidong_xu@163.com.

RESUMEN / SUMMARY:  - Ubiquitin-specific protease 22 (USP22), a novel ubiquitin hydrolase, has been implicated in oncogenesis and cancer progression in various types of human cancer. However, the clinical significance of USP22 expression in non-small cell  lung cancer (NSCLC) has not been determined. In the present study, USP22 messenger RNA (mRNA) and protein levels were analyzed by quantitative real-time polymerase chain reaction (PCR) and western blot analysis in 30 cases of NSCLC and in corresponding non-tumor tissue samples. Furthermore, immunohistochemistry  was performed to detect USP22 protein expression in 86 primary tumor tissues derived from clinically annotated NSCLC cases at stage I-II. In our analysis we found that both USP22 mRNA and protein levels in NSCLC tissues were significantly higher than those in corresponding non-tumor tissues and that there was a significant correlation between the expression of USP22 mRNA and protein (P=0.000, kappa=0.732). In addition, a high-level of USP22 expression was observed in 53.3% (39 out of 86) cases and it was correlated with large tumor size (P=0.029) and lymph node metastasis (P=0.026). Patients with tumors displaying a high-level of USP22 expression showed significantly shorter survival (P=0.006, log-rank test). Importantly, multivariate analysis showed that high USP22 protein expression was an independent prognostic factor for NSCLC patients  (P=0.003). In sum, our data suggest that USP22 plays an important role in NSCLC progression at the early stage, and that overexpression of USP22 in tumor tissues could be used as a potential prognostic marker for patients with early clinical stage of NSCLC.

 

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[181]

TÍTULO / TITLE:  - Molecular subtype and response to dasatinib, a src/abl small molecule kinase inhibitor, in Hepatocellular carcinoma cell lines in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hepatology. 2013 Jan 8. doi: 10.1002/hep.26223.

            ●● Enlace al texto completo (gratuito o de pago) 1002/hep.26223

AUTORES / AUTHORS:  - Finn RS; Aleshin A; Dering J; Yang P; Ginther C; Desai A; Zhao D; Euw EV; Busuttil RW; Slamon DJ

INSTITUCIÓN / INSTITUTION:  - Department of Medicine, Division of Hematology/ Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA. Rfinn@mednet.ucla.edu.

RESUMEN / SUMMARY:  - Hepatocellular carcinoma (HCC) is the fifth most common malignancy and is the third leading cause of cancer death worldwide. Recently the multi-targeted kinase inhibitor sorafenib was shown to be the first systemic agent to improve survival  in advanced HCC. Unlike other malignancies such as breast cancer, in which molecular subtypes have been clearly defined (i.e. luminal, HER2 amplified, basal, etc) and tied to effective molecular therapeutics (hormone blockade and trastuzumab, respectively), in HCC this translational link does not exist. Molecular profiling studies of human HCC have identified unique molecular subtypes of the disease. We hypothesized that a panel of human HCC cell lines would maintain molecular characteristics of the clinical disease and could then be used as a model for novel therapeutics. 20 human HCC cell lines were collected and RNA was analyzed using the Agilent microarray platform. Profiles from the cell lines in vitro, recapitulate previously described subgroups from clinical material. Next, we evaluated whether molecular subgroup would have predictive value for response to the Src/ Abl inhibitor dasatinib. Results demonstrate that  sensitivity to dasatinib was associated with a progenitor subtype. Dasatinib was  effective at inducing cell cycle arrest and apoptosis in “progenitor-like” cell lines but not in resistant lines. These findings suggest that cell line models maintain the molecular background of HCC and that subtype may be important for selecting patients for response to novel therapies. In addition, it highlights a  potential role for Src family signaling in this progenitor subtype of HCC. (HEPATOLOGY 2013.).

 

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[182]

TÍTULO / TITLE:  - Apoptosis induction of human leukemia U937 cells by 7,8-dihydroxyflavone hydrate  through modulation of the Bcl-2 family of proteins and the MAPKs signaling pathway.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mutat Res. 2012 Dec 20. pii: S1383-5718(12)00358-0. doi: 10.1016/j.mrgentox.2012.12.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.mrgentox.2012.12.002

AUTORES / AUTHORS:  - Park HY; Kim GY; Kwon TK; Hwang HJ; Kim ND; Yoo YH; Choi YH

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacy, Busan National University, Busan 609-735, Republic of Korea.

RESUMEN / SUMMARY:  - The present study investigated possible mechanisms of apoptosis induction of U937 human leukemic cells by 7,8-dihydroxyflavone hydrate (7,8-DHF), a member of the flavonoid family and a recently identified tyrosine kinase receptor B (TrkB) agonist. 7,8-DHF treatment of U937 cells resulted in inhibition of growth and induction of apoptosis as measured by MTT assay, fluorescence microscopy, DNA fragmentation, and flow cytometry analysis. 7,8-DHF-induced apoptosis in U937 cells was correlated with the up-regulation of death receptor related protein levels and down-regulation of anti-apoptotic IAP family proteins. The increase in apoptosis was also associated with proteolytic activation of caspases, Bid cleavage, insertion of pro-apoptotic Bax into the mitochondria and release of cytochrome c from mitochondria to cytosol. Furthermore, it was found that Bcl-2 overexpression markedly protected U937 cells from 7,8-DHF-induced apoptosis by restoring activation of caspases. In addition, 7,8-DHF treatment effectively activated the mitogen-activated protein kinases (MAPK), and inhibitors of extracellular-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but not p38 MAPK, which significantly reduced 7,8-DHF-induced apoptosis. Taken together,  our results indicate that the JNK and ERK pathways, and modulation of Bcl-2 family proteins were key regulators of apoptosis in response to 7,8-DHF in U937 cells.

 

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[183]

TÍTULO / TITLE:  - Chemotherapy, targeted agents, antiemetics and growth-factors in human milk: How  should we counsel cancer patients about breastfeeding?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Treat Rev. 2012 Nov 28. pii: S0305-7372(12)00209-5. doi: 10.1016/j.ctrv.2012.10.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ctrv.2012.10.002

AUTORES / AUTHORS:  - Pistilli B; Bellettini G; Giovannetti E; Codacci-Pisanelli G; Azim HA Jr; Benedetti G; Sarno MA; Peccatori FA

INSTITUCIÓN / INSTITUTION:  - Fertility and Procreation in Oncology Unit, Department of Medicine, European Institute of Oncology, Milan, Italy; Division of Medical Oncology, Ospedale di Macerata, Macerata, Italy.

RESUMEN / SUMMARY:  - An increasing number of women are diagnosed with cancer during pregnancy and lactation. Women are usually advised to interrupt breastfeeding during systemic anticancer treatment for fear of serious adverse effects to the nursed infant. However, the issue is poorly addressed in the literature and very few studies have evaluated the safety of breastfeeding during or after cytotoxic drugs or target agents administration. In this review we will analyze the available evidence that addresses the issue of anticancer drugs, targeted agents, antiemetics and growth-factors excretion in human milk. This could serve as a unique resource that may aid physicians in the management of breastfeeding cancer patients interested in maintaining lactation during treatment.

 

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[184]

TÍTULO / TITLE:  - IL-21 gene polymorphism is associated with the prognosis of breast cancer in Chinese populations.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Feb;137(3):893-901. doi: 10.1007/s10549-012-2401-1. Epub 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-012-2401-1

AUTORES / AUTHORS:  - You Y; Deng J; Zheng J; Hu M; Li N; Wu H; Li W; Lu J; Zhou Y

INSTITUCIÓN / INSTITUTION:  - Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, 215123, China.

RESUMEN / SUMMARY:  - Interleukin (IL)-21, which is secreted by activated CD4(+) T cells and NKT cells, has been found to be able to influence the humoral and cell-mediated immune responses and have potent antitumor activity in animal models. This study was to  investigate the impact of genetic polymorphisms in IL-21 on survival of breast cancer. Four TagSNPs of IL-21 (rs12508721C>T, rs907715G>A, rs13143866G>A, rs2221903A>G) were selected and then genotyped in 891 patients with breast cancer in Eastern and Southern Chinese populations. We then examined the associations between these SNPs and overall survival. Potential function of rs12508721C>T and  association between this variation and breast cancer prognosis were further studied. Overall, 121 of the patients had died over the followed-up period of 5 years. The IL-21 rs12508721T allele predicted longer five-year survival (HR = 0.347, 95 % CI = 0.187-0.644, P < 0.0001) in the discovery cohort, the independent validation cohort (HR = 0.429, 95 % CI = 0.244-0.755, P = 0.012), and combined group (HR = 0.447, 95 % CI = 0.301-0.667, P < 0.0001). Furthermore, our  luciferase assay revealed that rs12508721T variant allele had a higher transcription activity and the RT-PCR and ELISA assay showed that rs12508721 variant genotypes (CT and TT) carriers have more IL-21 expression than CC carriers (P < 0.05). Our present study established a robust association between the functional polymorphism (rs12508721C>T) in IL-21 and prognosis of breast cancer, indicating that this polymorphism may be a potential biomarker for prognosis of breast cancer.

 

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[185]

TÍTULO / TITLE:  - Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Cancer. 2013 Jan 7. pii: S0959-8049(12)00963-X. doi: 10.1016/j.ejca.2012.12.006.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2012.12.006

AUTORES / AUTHORS:  - Fohlin H; Perez-Tenorio G; Fornander T; Skoog L; Nordenskjold B; Carstensen J; Stal O

INSTITUCIÓN / INSTITUTION:  - Regional Cancer Center, Southeast Sweden, County Council of Ostergotland, Linkoping, Sweden; Division of Oncology, Department of Clinical and Experimental  Medicine, Faculty of Health Sciences, Linkoping University, Sweden. Electronic address: helena.fohlin@lio.se.

RESUMEN / SUMMARY:  - INTRODUCTION: Akt is a signalling modulator for many cellular processes, including metabolism, cell proliferation, cell survival and cell growth. Three isoforms of Akt have been identified, but only a few studies have concerned the isoform-specific roles in the prognosis of breast cancer patients. The aim of this study was to investigate the prognostic value of v-akt murine thymoma viral  oncogene homologue 1 (Akt1) and v-akt murine thymoma viral oncogene homologue 2 (Akt2) in oestrogen receptor positive (ER+) and oestrogen receptor negative (ER-) breast cancer with long-term follow-up. MATERIAL AND METHODS: The expression of Akt in tumour tissue was analysed with immunohistochemistry in a cohort of 272 postmenopausal patients with stage II breast cancer. The median follow-up time was 19years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox’s proportional hazards model. RESULTS: The risk of distant recurrence was reduced for patients with ER+ tumours expressing Akt2 compared to patients with no Akt2 expression (HR=0.49, 95% CI 0.29-0.82, p=0.007). When adjusting for important clinical tumour characteristics and treatment, Akt2 was still an independent prognostic factor (HR=0.38, 95% CI 0.21-0.68, p=0.001) and the association remained long-term. The prognostic value  of Akt2 increased with higher oestrogen receptor levels from no effect among patients with ER- tumours to 68% risk reduction for the group with high ER-levels (P for trend=0.042). Akt1 showed no significant prognostic information. CONCLUSION: Our results indicate that Akt2 expression is associated with a lower  distant recurrence rate for patients with ER+ tumours and that this association remains long-term. The prognostic value of Akt2 increases with higher oestrogen receptor expression, motivating further mechanistic studies on the role of Akt2 in ER+ breast cancer.

 

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[186]

TÍTULO / TITLE:  - HDAC inhibition by SNDX-275 (Entinostat) restores expression of silenced leukemia-associated transcription factors Nur77 and Nor1 and of key pro-apoptotic proteins in AML.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leukemia. 2012 Dec 18. doi: 10.1038/leu.2012.366.

            ●● Enlace al texto completo (gratuito o de pago) 1038/leu.2012.366

AUTORES / AUTHORS:  - Zhou L; Ruvolo VR; McQueen T; Chen W; Samudio IJ; Conneely O; Konopleva M; Andreeff M

INSTITUCIÓN / INSTITUTION:  - Molecular Hematology and Therapy, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.

RESUMEN / SUMMARY:  - Nur77 and Nor1 are highly conserved orphan nuclear receptors. We have recently reported that nur77(-/-)nor1(-/-) mice rapidly develop acute myeloid leukemia (AML) and that Nur77 and Nor1 transcripts were universally down-regulated in human AML blasts. These findings indicate that Nur77 and Nor1 function as leukemia suppressors. We further demonstrated silencing of Nur77 and Nor1 in leukemia stem cells (LSCs). We here report that inhibition of histone deacetylase (HDAC) using the specific class I HDAC inhibitor SNDX-275, restored the expression of Nur77/Nor1 and induced expression of AP1 transcription factors c-Jun and JunB, and of death receptor TRAIL, in AML cells and in CD34+38- AML leukemic stem cells (LSC). Importantly, SNDX-275 induced extensive apoptosis in AML cells, which could be suppressed by silencing nur77 and nor1. In addition, pro-apoptotic proteins Bim and Noxa were transcriptionally up-regulated by SNDX-275 in AML cells and in LSC. Our present work is the first report of a novel mechanism of HDAC inhibitor-induced apoptosis in AML that involves restoration of the silenced nuclear receptors Nur77 and Nor1, activation of AP1 transcription factors, a death receptor and pro-apoptotic proteins.Leukemia accepted article preview online, 18 December 2012; doi:10.1038/leu.2012.366.

 

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[187]

TÍTULO / TITLE:  - Sexual outcomes of aromatase inhibitor therapy in women with breast cancer: time  for intervention.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Menopause. 2013 Feb;20(2):128-9. doi: 10.1097/gme.0b013e31828094b0.

            ●● Enlace al texto completo (gratuito o de pago) 1097/gme.0b013e31828094b0

AUTORES / AUTHORS:  - Bradford A

INSTITUCIÓN / INSTITUTION:  - Department of Gynecologic Oncology and Reproductive Medicine University of Texas  MD Anderson Cancer Center Houston, Texas.

 

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[188]

TÍTULO / TITLE:  - Preoperative elevation of carcinoembryonic antigen predicts poor tumor response and frequent distant recurrence for patients with rectal cancer who receive preoperative chemoradiotherapy and total mesorectal excision: a multi-institutional analysis in an Asian population.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Colorectal Dis. 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00384-012-1584-6

AUTORES / AUTHORS:  - Lee JH; Kim SH; Jang HS; Chung HJ; Oh ST; Lee DS; Kim JG

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, South Korea.

RESUMEN / SUMMARY:  - PURPOSE: This study was conducted to evaluate the significance of carcinoembryonic antigen (CEA) level as a predictor for tumor response to chemoradiotherapy (CRT) and a prognosticator for survival in Asian patients with  advanced rectal cancer. MATERIALS AND METHODS: We enrolled 345 patients with primary rectal cancer who had undergone preoperative CRT and total mesorectal excision. We analyzed clinicopathological factors that could be associated with pathologically complete response (ypCR) and disease-free survival (DFS). RESULTS: A cutoff level of 5 ng/mL (p = 0.002) for CEA was found to be significant for prediction of ypCR. Increased CEA level (p = 0.025) was a significant negative predictor of ypCR after CRT in patients with rectal cancer. The 5-year DFS rate was significantly higher in the CEA </=5-ng/mL group than in the CEA >5-ng/mL group (73.2 vs. 60.9 %, p = 0.002). This is mainly due to the higher chance of distant recurrence (p = 0.013), not locoregional recurrence (p = 0.732), in the CEA >5-ng/mL group. CONCLUSIONS: Elevated CEA (>5 ng/mL) is a negative predictor  of ypCR and has a negative impact on DFS in Asian rectal cancer patients who underwent preoperative CRT and surgery due to an increased chance of distant recurrences.

 

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[189]

TÍTULO / TITLE:  - Two different formulations with equivalent effect? Comparison of serum estradiol  suppression with monthly goserelin and trimonthly leuprolide in breast cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):354. doi: 10.1007/s12032-012-0354-1. Epub 2012 Dec 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0354-1

AUTORES / AUTHORS:  - Aydiner A; Kilic L; Yildiz I; Keskin S; Sen F; Kucucuk S; Karanlik H; Muslumanoglu M; Igci A

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Institute of Oncology, Istanbul University, Capa, Istanbul, Turkey, adnanaydiner@superonline.com.

RESUMEN / SUMMARY:  - Data comparing the efficacy of monthly and trimonthly formulations of LHRH agonists are lacking. The aim of this study was to compare the effects of monthly goserelin and trimonthly leuprolide on estradiol levels. A total of 79 early breast cancer patients receiving LHRH agonists for at least 6 months were enrolled in the study. Serum estradiol, FSH and LH levels were measured before drug injection and at the one-month follow-up visit. Thirty-eight patients were treated with goserelin, and 41 patients were treated with leuprolide. Patient characteristics and histopathological variables did not differ between the groups. A comparison of the mean hormone levels between the two groups revealed no significant differences in FSH or estradiol levels (p = 0.143 and p = 0.683, respectively), but the median LH level was higher in the leuprolide group (p = 0.025). Among the patients who did not receive chemotherapy, LH levels were higher in the leuprolide arm (p = 0.028). Additionally, FSH levels were significantly higher in the patients over 40 years old (p = 0.02) and in those with tumours harbouring cERB-B2 receptor (p = 0.05) in the leuprolide group. Three patients (7.9 %) in the goserelin and five patients (12.2 %) in the leuprolide group failed to achieve postmenopausal estradiol levels (p = 0.707). The effects of monthly goserelin and trimonthly leuprolide on estradiol levels did not differ significantly. Further research is required to interpret the variable effects on gonadotropins in each subgroup and the relationship between LHRH agonists and survival.

 

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[190]

TÍTULO / TITLE:  - Aberrations of MET are associated with copy number gain of EGFR and loss of PTEN  and predict poor outcome in patients with salivary gland cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Virchows Arch. 2013 Jan;462(1):65-72. doi: 10.1007/s00428-012-1358-0. Epub 2012 Dec 15.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00428-012-1358-0

AUTORES / AUTHORS:  - Ach T; Zeitler K; Schwarz-Furlan S; Baader K; Agaimy A; Rohrmeier C; Zenk J; Gosau M; Reichert TE; Brockhoff G; Ettl T

INSTITUCIÓN / INSTITUTION:  - Department of Oral and Maxillofacial Surgery, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany, tobias.ach@ukr.de.

RESUMEN / SUMMARY:  - Hepatocyte growth factor receptor (MET) is a key driver of oncogenic transformation. Copy number gain and amplification of MET positively enhance tumour growth, invasiveness and metastasis in different cancer types. In the present study, 266 carcinomas of the major and minor salivary glands were investigated for genomic MET status by fluorescence in situ hybridization and for protein expression by immunohistochemistry. Results were matched with clinicopathological parameters, long-term survival and the status of epidermal growth factor receptor (EGFR) and phosphatase and tensin homologue (PTEN). Low polysomy (n = 42), high polysomy (n = 27), amplification (n = 2) and deletion (n  = 18) were found as aberrations of genomic MET in certain subtypes. MET aberrations were associated with increased patient age (>70 years, p = 0.003), male gender (p = 0.01), increased tumour size (p = 0.002), lymph node metastases  (p < 0.001), high-grade malignancy (p < 0.001) and unfavourable overall survival  (p < 0.001). Both copy number gain (p < 0.001) and deletion (p = 0.031) of MET correlated with copy number gain of EGFR. Tumours with genomic loss of PTEN (n =  48) concurrently presented aberration of genomic MET (p < 0.001). MET gene status significantly correlated with protein status (p = 0.038). In conclusion, gain but also loss of genomic MET activity correlates with aggressive tumour growth, nodal metastasis and worse overall survival in salivary gland cancer. Moreover, aberrations of MET are associated with EGFR and PTEN signalling and might possess relevance for targeted therapies of salivary gland carcinomas in the future.

 

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[191]

TÍTULO / TITLE:  - Low NDRG1 mRNA expression predicts a poor prognosis in neuroblastoma patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pediatr Surg Int. 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00383-012-3248-6

AUTORES / AUTHORS:  - Matsushita K; Uchida K; Saigusa S; Ide S; Hashimoto K; Koike Y; Otake K; Inoue M; Tanaka K; Kusunoki M

INSTITUCIÓN / INSTITUTION:  - Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.

RESUMEN / SUMMARY:  - PURPOSE: N-myc downstream regulated gene 1 (NDRG1) markedly reduces metastasis of numerous tumors. However, NDRG1’s function in malignant tumors has not been fully determined. Therefore, we investigated the association of NDRG1 expression with clinical outcomes in neuroblastoma (NB) patients. METHODS: We obtained total RNA  from residual cancer cells using microdissection from NB patients. Furthermore, we examined the expression of NDRG1 in NB patients using immunohistochemical staining. RESULTS: Of the 48 patients observed, low NDRG1 expression was associated with poor prognostic factors such as primary tumor size and MYCN amplification. Low expression of NDRG1 was associated with a poor prognosis (p =  0.001) and multivariate analysis identified low expression of NDRG1 as an independent risk factor for predicting poor prognosis in NB patients. Furthermore, in the MYCN non-amplification group (n = 33), low expression of NDRG1 was associated with a poor prognosis (p = 0.001). Immunohistochemical analysis showed NDRG1 expression at the plasma membranes of NB cells. NDRG1 expression levels were also correlated with expression of NDRG1 mRNA. CONCLUSION: We confirmed that low NDRG1 expression is a significant and independent prognostic indicator in NB by multivariate analysis. Furthermore, NDRG1 may be a  novel prognostic marker in MYCN non-amplification NB patients.

 

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[192]

TÍTULO / TITLE:  - Honokiol synergizes chemotherapy drugs in multidrug resistant breast cancer cells via enhanced apoptosis and additional programmed necrotic death.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Feb;42(2):721-32. doi: 10.3892/ijo.2012.1739. Epub 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2012.1739

AUTORES / AUTHORS:  - Tian W; Deng Y; Li L; He H; Sun J; Xu D

INSTITUCIÓN / INSTITUTION:  - Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China.

RESUMEN / SUMMARY:  - Multidrug resistance (MDR) is a major challenge in cancer therapy. Apoptosis tolerance is one of the key mechanisms of MDR. Honokiol, a small-molecule pharmacologically active component, exhibits competent cytotoxicity in a variety  of human cancer cells through apoptosis and other forms of programmed cell death  (such as programmed necrosis). Although much work has been done on its antitumor  effects, little attention has been paid on systemic evaluation of efficacy of honokiol combined with other chemotherapeutic agents, especially in drugresistant cell lines. Here, we systematically and quantitatively assess its combinational effect with different chemotherapeutic agents using the combination index (CI) equation. We found that honokiol synergized with chemotherapeutic agents both in  sensitive and resistant, solid and non-solid (MCF-7, HL-60, MCF-7/ADR and HL-60/ADR) cell lines. Honokiol (40 microg/ml) induced necrotic cell death in MCF-7/ADR cells with characterized morphological and biochemical features. Co-incubation with honokiol and etoposide (VP-16) activated a complex death modality, which was composed of necrotic cell death and apoptosis. This dual-death pathway was shut down when pretreated with pan-caspase inhibitor (z-VAD-fmk) and cyclophilin D inhibitor (cyclosporin A). Western blot analysis results proved that honokiol also enhanced VP-16-induced apoptosis potentially via blocking nuclear factorkappaB (NF-kappaB) activation. Our data for the first  time quantitatively demonstrate that honokiol synergizes frequently-used chemotherapeutic agents via enhanced apoptosis and additional programmed necrotic death. These findings indicate a promising way to circumvent MDR and apoptosis tolerance.

 

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[193]

TÍTULO / TITLE:  - Honokiol induces caspase-independent paraptosis via reactive oxygen species production that is accompanied by apoptosis in leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 18;430(3):876-82. doi: 10.1016/j.bbrc.2012.12.063. Epub 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.12.063

AUTORES / AUTHORS:  - Wang Y; Zhu X; Yang Z; Zhao X

INSTITUCIÓN / INSTITUTION:  - West China Hospital Laboratory of Nanomedicine and Institute for Nanobiomedical Technology and Membrane Biology, Sichuan University, Chengdu 610041, Sichuan, China; First Hospital of Xi’an, Shaanxi Provincial Key Lab of Ophthalmology, Shaanxi Institute of Ophthalmology, Xi’an 710002, Shaanxi, China.

RESUMEN / SUMMARY:  - Our previous report has shown that honokiol (HNK), a constituent of Magnolia officinalis, induces a novel form of non-apoptotic programmed cell death in human leukemia NB4 and K562 cells. In this study, we further explored the relationship  between the cell death pathway and cytoplasmic vacuolization and studied the underlying mechanism of leukemia cell death mediated by honokiol. The results showed that low concentrations of honokiol activated an novel alternative cell death fitted the criteria of paraptosis, such as cytoplasmic vacuolization derived from endoplasmic reticulum swelling, lack of caspase activation, and lack of apoptotic morphology. Results further indicated that the cell death was time-  and concentration-dependent. In addition, honokiol-induced paraptosis did not involve membrane blebbing, chromatin condensation and phosphatidylserine exposure at the outer of the plasma membrane. The mechanism of the cell death may be associated, at least in part, with the increased generation of reactive oxygen species. Further analysis showed that honokiol induces cell death predominantly via paraptosis and to a certain extent via apoptosis in NB4 cells, and predominantly via apoptosis and to a certain extent via paraptosis in K562 cells. These observations suggest that cell death occurs via more than one pathway in leukemia cells and targeting paraptosis may be an alternative and promising avenue for honokiol in leukemia therapy.

 

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[194]

TÍTULO / TITLE:  - A novel antitumor activity of deguelin targeting the insulin-like growth factor (IGF) receptor pathway via up-regulation of IGF-binding protein-3 expression in breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2013 Jan 21. pii: S0304-3835(13)00051-7. doi: 10.1016/j.canlet.2013.01.022.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2013.01.022

AUTORES / AUTHORS:  - Suh YA; Kim JH; Sung MA; Boo HJ; Jeong Yun H; Lee SH; Lee HJ; Min HY; Lee HY

INSTITUCIÓN / INSTITUTION:  - Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-738, Republic of Korea.

RESUMEN / SUMMARY:  - In this study, we investigated the antitumor effects of deguelin in several human breast cancer cells in vitro and in vivo. Deguelin inhibited cell viability and the anchorage-dependent and anchorage-independent colony formation of triple-negative (MDA-MB-231 and MDA-MB-468) and triple-positive (MCF-7) breast cancer cells, and it significantly reduced the growth of MCF-7 cell xenograft tumors. The induction of apoptosis, inhibition of insulin-like growth factor-1 receptor (IGF-1R) signaling activation, and up-regulation of IGF-binding protein-3 (IGFBP-3) expression may be associated with deguelin-mediated antitumor effects. Our findings suggest a potential therapeutic use for deguelin in patients with triple-negative breast cancer and for those with breast cancers who are sensitive to endocrine- and HER2-targeted therapies.

 

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[195]

TÍTULO / TITLE:  - Importance of detecting multidrug resistance proteins in acute leukemia prognosis and therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Lab Anal. 2013 Jan;27(1):62-71. doi: 10.1002/jcla.21563. Epub 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1002/jcla.21563

AUTORES / AUTHORS:  - de Moraes AC; Maranho CK; Rauber GS; Santos-Silva MC

INSTITUCIÓN / INSTITUTION:  - Programa de Pos-graduacao em Farmacia, Universidade Federal de Santa Catarina, Campus Trindade, Florianopolis - SC, Brazil.

RESUMEN / SUMMARY:  - Multidrug resistance (MDR) is a multifactorial phenomenon and the role of these proteins in generating the MDR phenotype is controversial. With this in mind, this review compiled the current data on the role of ABCB1, ABCC1, and LRP proteins in the prognosis of hematologic neoplasms and their influence on the choice of therapy. Literature showed that the detection of these proteins, mainly ABCB1, is important in the AL prognosis. However, there is controversy regarding  the methodology used for their detection. In summary, the expression and activity profiles of ABCB1, ABCC1, and LRP, proteins capable of promoting the efflux of a  variety of chemotherapeutic agents from the cell cytoplasm represent one of the greatest causes of failure in AL treatment. J. Clin. Lab. Anal. 27:62-71, 2013. © 2012 Wiley Periodicals, Inc.

 

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[196]

TÍTULO / TITLE:  - The prognosis of gastric cancer patients with marginally elevated carcinoembryonic antigen (CEA) values after D2 radical gastrectomy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Surg Oncol. 2013 Jan 7. doi: 10.1002/jso.23300.

            ●● Enlace al texto completo (gratuito o de pago) 1002/jso.23300

AUTORES / AUTHORS:  - Chen S; Feng XY; Li YF; Zhao BW; Zhou ZW; Chen YB

INSTITUCIÓN / INSTITUTION:  - Department of Gastropancreatic Surgery, Sun Yat-Sen University Cancer Center, Guangdong, PR China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangdong, PR China.

RESUMEN / SUMMARY:  - AIM: To investigate the clinical significance of the postoperative serum carcinoembryonic antigen (CEA) levels in gastric cancer patients who underwent D2 radical gastrectomy and to identify the prognostic factors for patients with marginally elevated postoperative CEA levels. METHODS: We performed a retrospective study of 480 patients who were histologically diagnosed with gastric cancer and who underwent D2 radical surgery at the Sun Yat-sen University Cancer Center between January 2004 and December 2009. The follow-up lasted until  June 2011. Chi-squared tests and Kaplan-Meier methods were employed to compare the adverse events and prognoses. RESULTS: In this group of gastric cancer patients, the postoperative serum CEA level (P = 0.002) was an independent prognostic factor; the same was true for the histological T and N staging (P < 0.001 and P = 0.045, respectively). In the group of marginally elevated postoperative CEA level gastric cancer patients, univariate analysis demonstrated that tumor position (P = 0.042); histological grade (P = 0.002); and Boarrmann type (P = 0.003) were significant prognostic factors. Multivariate analysis showed that the tumor position (P = 0.003) and histological grade (P = 0.007) were independent prognostic factors for these patients. CONCLUSION: Our study showed that patients with normal postoperative CEA levels have a better prognosis. Furthermore, for marginally elevated postoperative CEA level gastric cancer patients, the tumor position and histological grade were two important factors for predicting the prognosis and the need for aggressive therapy. J. Surg. Oncol © 2013 Wiley Periodicals, Inc.

 

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[197]

TÍTULO / TITLE:  - The transcription factor Forkhead box P3 (FoxP3) is expressed in glioma cells and associated with increased apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Exp Cell Res. 2012 Dec 1. pii: S0014-4827(12)00475-2. doi: 10.1016/j.yexcr.2012.11.018.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.yexcr.2012.11.018

AUTORES / AUTHORS:  - Held-Feindt J; Hattermann K; Sebens S; Krautwald S; Mehdorn HM; Mentlein R

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, 24105 Kiel, Germany.

RESUMEN / SUMMARY:  - The forkhead transcription factor FoxP3 is critically involved in the development and function of regulatory T cells (Tregs) that populate tumors and are considered as powerful parts of their immune evasion. However, also tumor cells are reported to express FoxP3. Since gliomas are particularly immunosuppressive tumors, we investigated the occurrence and possible functions of FoxP3 in these malignant cells. By quantitative RT-PCR, immunohistochemistry and FACS analysis,  we detected FoxP3 in glioma cells in situ and in vitro. After exposure of glioma  cell lines to chemotherapeutics, expression of FoxP3 was significantly enhanced,  and it was dislocated from more nuclear to perinuclear localization. Overexpression of FoxP3 in glioma cell lines considerably favored apoptotic damage of nuclei, DNA fragmentation, increased cleavage of the pro-apoptotic enzyme poly(ADP-ribose) polymerase (PARP) and basal activities of effector caspases-3/7. In FoxP3-transfected cells, apoptotic stimuli like Camptothecin, Temozolomide or tumor necrosis factor-alpha synergistically enhanced caspases-3/7-activities over controls. Taking together, FoxP3 occurs in glioma cells, is induced by chemotherapeutics, and its expression is correlated with increased apoptosis of glioma cells, especially when propagated by apoptotic stimuli. Thus, FoxP3 is a novel pro-apoptotic transcription factor in gliomas that is critically involved in the action of apoptotic agents.

 

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[198]

TÍTULO / TITLE:  - Des-gamma-carboxy prothrombin identified by P-11 and P-16 antibodies reflects prognosis for patients with hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Gastroenterol Hepatol. 2012 Dec 6. doi: 10.1111/jgh.12076.

            ●● Enlace al texto completo (gratuito o de pago) 1111/jgh.12076

AUTORES / AUTHORS:  - Takeji S; Hirooka M; Koizumi Y; Tokumoto Y; Abe M; Ikeda Y; Nadano S; Hiasa Y; Onji M

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan.

RESUMEN / SUMMARY:  - BACKGROUND AND AIMS: Serum des-gamma-carboxy prothrombin (DCP) is an established  tumor marker in patients with hepatocellular carcinoma (HCC), which can be identified by using MU-3 antibody. The MU-3 antibody mainly reacts with the 9-10  glutamic acid (Glu) residues of DCP (conventional DCP). Since other variants of DCP with fewer Glu residues can be detected using P-11 and P-16 antibodies (code  name: NX-PVKA), we examined the clinical characteristics associated with NX-PVKA, and whether NX-PVKA is a useful measure in HCC patients. METHODS: Participants comprised 197 HCC patients admitted to our hospital between 2001 and 2010. NX-PVKA, conventional DCP, alpha-fetoprotein (AFP) and L3 fraction of AFP (AFP-L3) were measured prior to initiation of HCC treatment. RESULTS: Of the tumor markers assessed, NX-PVKA was the only significant predictor of prognosis (hazard ratio, 81.32; p < 0.0001). Patients with NX-PVKA level >/= 100 mAU/ml showed significantly lower survival rates (p < 0.0001). NX-PVKA level was also significantly associated with platelet count, prothrombin time, C-reactive protein, sex, maximum tumor size, number of nodules and portal venous invasion by HCC. Finally, using NX-PVKA level and other clinical parameters, we established a prognostic model to estimate patient survival time. CONCLUSIONS: NX-PVKA offers the best marker of tumor prognosis among HCC patients, and is strongly associated with tumor factors and hepatic functional reserve. NX-PVKA could be useful for clinical evaluation of tumor severity, as well as the estimated duration of survival among patients with HCC.

 

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[199]

TÍTULO / TITLE:  - PECAM-1 is involved in BCR/ABL signaling and may downregulate imatinib-induced apoptosis of Philadelphia chromosome-positive leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Feb;42(2):419-28. doi: 10.3892/ijo.2012.1729. Epub 2012 Dec 6.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2012.1729

AUTORES / AUTHORS:  - Wu N; Kurosu T; Oshikawa G; Nagao T; Miura O

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyoku, Tokyo 113-8519, Japan.

RESUMEN / SUMMARY:  - PECAM-1 (CD31) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing surface glycoprotein expressed on various hematopoietic cells as well as on endothelial cells. PECAM-1 has been shown to play roles in regulation of adhesion, migration and apoptosis. The BCR/ABL fusion tyrosine kinase is expressed in chronic myeloid leukemia and Philadelphia-positive (Ph+) acute lymphoblastic leukemia cells, and its inhibition by the clinically used tyrosine kinase inhibitors imatinib or dasatinib induces apoptosis of these cells. In the present study, we demonstrate that PECAM-1 is tyrosine phospho-rylated in its ITIM motifs in various BCR/ABL-expressing cells including  primary leukemia cells. Studies using imatinib and dasatinib as well as transient expression experiments in 293T cells revealed that PECAM-1 was phosphorylated directly by BCR/ABL, which was enhanced by the imatinib-resistant E255K and T315I mutations, or partly by the Src family tyrosine kinases, including Lyn, which were activated dependently or independently on BCR/ABL. We also demonstrate by using a substrate trapping mutant of SHP2 that tyrosine phosphorylated PECAM-1 binds SHP2 and is a major substrate for this tyrosine phosphatase in BCR/ABL-expressing cells. Overexpression of PECAM-1 in BCR/ABL-expressing cells,  including K562 human leukemia cells, enhanced cell adhesion and partially inhibited imatinib-induced apoptosis involving mitochondria depolarization and caspase-3 cleavage, at least partly, in an ITIM-independent manner. These data suggest that PECAM-1 may play a role in regulation of apoptosis as well as adhesion of BCR/ABL-expressing cells to modulate their imatinib sensitivity and would be a possible candidate for therapeutic target in Ph+ leukemias.

 

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[200]

TÍTULO / TITLE:  - Gene expression alterations in doxorubicin resistant MCF7 breast cancer cell line.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Genomics. 2012 Nov 30. pii: S0888-7543(12)00229-7. doi: 10.1016/j.ygeno.2012.11.009.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ygeno.2012.11.009

AUTORES / AUTHORS:  - Abuhammad S; Zihlif M

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacology, Faculty of Medicine, University of Jordan, Amman 11942, Jordan.

RESUMEN / SUMMARY:  - Many molecular mechanisms contribute to the development of doxorubicin resistance and different cancers can express wide and diverse arrays of drug-resistance genes. The aim of this study was to identify the changes in gene expression associated with the development of doxorubicin resistance in MCF7 breast cancer cell line. The doxorubicin resistant MCF7 cell line was developed by stepwise selection of MCF7 cells and was tested using the MTT assay. The alterations in gene expression were examined using the real-time based PCR array. The findings showed an up-regulation of many phase I/II metabolizing genes, specifically, the  CYP1A1 and the CYP1A2 that were up-regulated by 206- and 96-fold respectively. Drug efflux pump genes were also up-regulated profoundly. TOP2A was strongly down-regulated by 202-fold. Many other changes were observed in genes crucial for cell cycle, apoptosis and DNA repair. The findings of this project imply that the development of doxorubicin resistance is a multi-factorial process.

 

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[201]

TÍTULO / TITLE:  - Ki-67, mini-chromosome maintenance 2 protein (MCM2) and geminin have no independent prognostic relevance for cancer-specific survival in surgically treated squamous cell carcinoma of the penis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BJU Int. 2013 Jan 10. doi: 10.1111/j.1464-410X.2012.11735.x.

            ●● Enlace al texto completo (gratuito o de pago) 1111/j.1464-410X.2012.11735.x

AUTORES / AUTHORS:  - May M; Burger M; Otto W; Hakenberg OW; Wieland WF; May D; Hofstadter F; Gotz S; Niessl N; Fritsche HM; Birnkammer K; Gilfrich C; Peter J; Jain A; Koch S; Lebentrau S; Riedmiller H; Rossler W; Denzinger S; Brookman-May S; Gunia S

INSTITUCIÓN / INSTITUTION:  - Department of Urology, St. Elisabeth Clinic Straubing, Straubing.

RESUMEN / SUMMARY:  - WHAT’S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Only little and partly contradictory data are currently published about the prognostic role of immunohistochemically detectable proliferation-associated biomarkers in surgically treated squamous cell carcinoma of the penis (SCCP), and no data are available at present about their usefulness for refining the delineation between  different Broders’ grading categories (e.g. still G2 or just G3 SCCP?). Moreover, the accuracy of various conventional histopathological parameters for predicting  cancer-specific survival (CSS) in surgically treated SCCP has not been systematically evaluated yet. Based on the so far largest study cohort encompassing 158 consecutive patients with surgically treated PSCCs characterised by means of a central histopathological review, our data add the following to the currently available literature: (i) Ki-67, mini-chromosome maintenance 2 protein  (MCM2), and geminin indicate a more aggressive behaviour in SCPP but do not represent independent prognostic parameters in the multivariable analysis in terms of CSS, (ii) these three biomarkers are not helpful for refining the delineation between different Broders’ grading categories at the immunohistochemical level, and (iii) the conventional histopathological parameters staging, grading, nodal involvement, and lymphovascular invasion are independent prognostic parameters that together achieve a predictive accuracy of  82% for CSS. OBJECTIVE: To assess the role of cell proliferation-associated biomarkers to predict cancer-specific survival (CSS) in patients with surgically  treated squamous cell carcinoma of the penis (SCCP). PATIENTS AND METHODS: A multicentre study enrolling 158 consecutive patients with surgically treated SCCP was performed. After conducting a central histopathological review, the staining  profiles of Ki-67, mini-chromosome maintenance 2 protein (MCM2) and geminin were  evaluated for their correlation with conventional histopathological criteria and  their prognostic relevance for predicting CSS in a multivariable Cox proportional hazards regression model (median [interquartile range] follow-up 33 [6-63] months). RESULTS: Staining evaluation showed high interobserver agreement (92-96%). Ki-67 and MCM2 displayed a significant positive correlation with histological tumour grade, lymphovascular invasion (LVI) and nodal status, whereas geminin expression only correlated with tumour grade. The 5-year CSS for  the entire study cohort was 62%. Univariable analysis showed a significant prognostic impact of Ki-67 (P = 0.026), MCM2 (P = 0.007), and geminin (P = 0.036). In multivariable analysis, only pT (hazard ratio [HR] 1.67; P = 0.003) and pN stage (HR 2.62; P = 0.015) as well as tumour grade (HR 1.89; P = 0.036) and LVI (HR 2.66; P = 0.028) were identified as independent prognostic parameters for CSS. The accuracy of the Cox model for CSS prediction was 0.820 (95% confidence interval 0.741-0.898). CONCLUSIONS: At present, conventional histopathological criteria remain the most powerful predictors of CSS in surgically treated SCCP. Due to overlapping staining profiles, Ki-67, MCM2 and geminin, either singly or in various combinations, failed to immunohistochemically refine the boundaries between Broders’ grading categories.  Ki-67, MCM2 and geminin do not represent independent prognostic parameters but reflect a more aggressive behaviour in surgically treated SCCP. Further studies are needed to clarify the currently contradictory predictive role of proliferation-associated biomarkers in terms of predicting nodal involvement in SCCPs.

 

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[202]

TÍTULO / TITLE:  - Serum peptides, represented by complement 3f des-arginine, are useful for prediction of the response to pegylated interferon-alpha plus ribavirin in patients with chronic hepatitis C.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hepatol Res. 2012 Nov 5. doi: 10.1111/hepr.12018.

            ●● Enlace al texto completo (gratuito o de pago) 1111/hepr.12018

AUTORES / AUTHORS:  - Noguchi Y; Kurokawa MS; Okuse C; Matsumoto N; Nagai K; Sato T; Arito M; Suematsu N; Okamoto K; Suzuki M; Itoh F; Kato T

INSTITUCIÓN / INSTITUTION:  - Clinical Proteomics and Molecular Medicine, St Marianna University Graduate School of Medicine, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, St Marianna University School of Medicine, Japan.

RESUMEN / SUMMARY:  - AIM: Biomarkers predicting sustained virological response (SVR) to pegylated interferon-alpha plus ribavirin (PEG IFN-alpha/RBV) were investigated. METHODS: Peptides in pretreatment sera from 107 patients with hepatitis C virus (HCV) genotype 1 were comprehensively analyzed by mass spectrometry. Ion intensity of the peptides was used to generate discriminant models between the responders who  achieved SVR ® and the non-responders (NR) to PEG IFN-alpha/RBV. RESULTS: In total, 107 peptides were detected in a training set (n = 23). A discriminant model using a peptide, complement 3f des-arginine (C3f-dR), showed sensitivity of 35% and specificity of 94% for SVR prediction in a testing set (n = 68). In all the R and NR (n = 96), an area under the receiver-operator curve (AUROC) of 0.64  in the C3f-dR model was increased to 0.78 by addition of platelet (PLT) counts (C3f-dR/PLT model). Another model using the 107 peptides (AUROC, 0.77) also showed higher AUROC (0.79) by addition of hemoglobin (Hb), body mass index (BMI)  and age (107P/Hb/BMI/Age model). The sensitivity and specificity of the C3f-dR/PLT model were 59% and 88%, and those of the 107P/Hb/BMI/Age model were 70% and 92%, respectively. The C3f-dR/PLT model showed high AUROC (0.82), similar to that of interleukin-28B rs8099917 genotype analysis (0.86) in the 45 tested patients. Prediction by the combination of the C3f-dR/PLT model, the 107P/Hb/BMI/Age model and the rs8099917 genotype analysis was accurate in 44 out  of the 45 patients (AUROC, 0.95). CONCLUSION: Serum peptides, especially C3f-dR,  would be useful predictors for SVR to PEG IFN-alpha/RBV. The complements may be involved in the HCV elimination.

 

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[203]

TÍTULO / TITLE:  - Hepatitis A virus cellular receptor 1/kidney injury molecule-1 is a susceptibility gene for clear cell renal cell carcinoma and hepatitis A virus cellular receptor/kidney injury molecule-1 ectodomain shedding a predictive biomarker of tumour progression.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Cancer. 2013 Jan 23. pii: S0959-8049(12)01029-5. doi: 10.1016/j.ejca.2012.12.020.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2012.12.020

AUTORES / AUTHORS:  - Cuadros T; Trilla E; Vila MR; de Torres I; Vilardell J; Messaoud NB; Salcedo M; Sarro E; Lopez-Hellin J; Blanco A; Mir C; Ramon Y Cajal S; Itarte E; Morote J; Meseguer A

INSTITUCIÓN / INSTITUTION:  - Fisiopatologia Renal, CIBBIM, VHIR, España.

RESUMEN / SUMMARY:  - AIM OF THE STUDY: To correlate hepatitis A virus cellular receptor (HAVCR)/kidney injury molecule-1 (KIM-1) expression in clear cell renal cell carcinoma (ccRCC) tumours with patient outcome and study the consequences of HAVCR/KIM-1 ectodomain shedding. METHODS: HAVCR/KIM-1 expression in ccRCC, oncocytomes, papillary carcinomas and unaffected tissue counterparts was evaluated. Minimal change disease and pre-clamping normal and ccRCC tissue biopsies were included. Tissue microarrays from 98 ccRCC tumours were analysed. Tumour registry data and patient outcome were retrospectivelly collected. Deletions in HAVCR/KIM-1 ectodomain and  lentiviral infection of 786-O cells with HAVCR/KIM-1 mutated constructs to determine their subcellular distribution and invasive capacity were performed. RESULTS: HAVCR/KIM-1 was expressed in ccRCC, papillary tumours and in tubule cells of adjacent and distal unaffected counterparts of ccRCC tumours. The latest was not related to ischemic or tumour-related paracrine effects since pre-clamping normal biopsies were positive for HAVCR/KIM-1 and unaffected counterparts of papillary tumours were negative. HAVCR/KIM-1 analyses in patients and the invasive capacity of HAVCR/KIM-1 shedding mutants in cell lines demonstrated that: (i) relative low HAVCR/KIM-1 membrane levels correlate with activated shedding in ccRCC patients and mutant cell lines; (ii) augmented shedding directly correlates with higher invasiveness and tumour malignancy. CONCLUDING STATEMENTS: Constitutive expression of HAVCR/KIM-1 in kidney might constitute a susceptibility trait for ccRCC tumour development. Enhanced HAVCR/KIM-1 ectodomain shedding promotes invasive phenotype in vitro and more aggressive tumours in vivo.

 

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[204]

TÍTULO / TITLE:  - Sorafenib Inhibits Cell Migration and Stroma-Mediated Bortezomib Resistance by Interfering B-cell Receptor Signaling and Protein Translation in Mantle Cell Lymphoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-1935

AUTORES / AUTHORS:  - Xargay-Torrent S; Lopez-Guerra M; Montraveta A; Saborit-Villarroya I; Rosich L; Navarro A; Perez-Galan P; Roue G; Campo E; Colomer D

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliation: Hematopathology Unit, Department of Pathology, Hospital Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, España.

RESUMEN / SUMMARY:  - PURPOSE: We evaluated the antitumoral properties of the multikinase inhibitor sorafenib in mantle cell lymphoma (MCL), an aggressive B lymphoma for which current therapies have shown limited efficacy.EXPERIMENTAL DESIGN: Sensitivity to sorafenib was analyzed in MCL cell lines and primary samples in the context of BCR and microenvironment simulation. Sorafenib signaling was characterized by quantitative PCR, Western blotting, immunofluorescence, and protein immunoprecipitation. Migration analysis included flow cytometric counting, actin  polymerization assays, and siRNA-mediated knockdown of focal adhesion kinase (FAK). In vivo antitumor effect of sorafenib and bortezomib was analyzed in an MCL xenograft mouse model.RESULTS: Sorafenib rapidly dephosphorylates the BCR-associated kinases, Syk and Lyn, as well as FAK, an Src target involved in focal adhesion. In this line, sorafenib displays strong synergy with the Syk inhibitor, R406. Sorafenib also blocks Mcl-1 and cyclin D1 translation, which promotes an imbalance between pro- and antiapoptotic proteins and facilitates Bax release from cyclin D1, leading to the induction of mitochondrial apoptosis and caspase-dependent and -independent mechanisms. Moreover, sorafenib inhibits MCL cell migration and CXCL12-induced actin polymerization. FAK knockdown partially prevents this inhibitory effect, indicating that FAK is a relevant target of sorafenib. Furthermore, sorafenib enhances the antitumoral activity of bortezomib in an MCL xenograft mouse model as well as overcomes stroma-mediated bortezomib resistance in MCL cells.CONCLUSION: We show for the first time that sorafenib interferes with BCR signaling, protein translation and modulates the microenvironment prosurvival signals in MCL, suggesting that sorafenib, alone or  in combination with bortezomib, may represent a promising approach to treat patients with MCL. Clin Cancer Res; 19(3); 1-12. ©2012 AACR.

 

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[205]

TÍTULO / TITLE:  - Personalized Cancer Medicine: Molecular Diagnostics, Predictive biomarkers, and Drug Resistance.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Pharmacol Ther. 2012 Dec 7. doi: 10.1038/clpt.2012.237.

            ●● Enlace al texto completo (gratuito o de pago) 1038/clpt.2012.237

AUTORES / AUTHORS:  - Gonzalez de Castro D; Clarke PA; Al-Lazikani B; Workman P

INSTITUCIÓN / INSTITUTION:  - Molecular Diagnostics Department, The Institute of Cancer Research and the Royal  Marsden NHS Foundation Trust, London, UK.

RESUMEN / SUMMARY:  - The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by  genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine.  We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer. We envisage a future requiring the use of longitudinal genome sequencing and other omics technologies alongside combinatorial treatment to overcome cellular and molecular heterogeneity and prevent resistance caused by clonal evolution.Clinical Pharmacology & Therapeutics (2013); advance online publication 30 January 2013. doi:10.1038/clpt.2012.237.

 

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[206]

TÍTULO / TITLE:  - Clinical benefit from neoadjuvant chemotherapy in oestrogen receptor-positive invasive ductal and lobular carcinomas.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 8. doi: 10.1038/bjc.2012.557.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2012.557

AUTORES / AUTHORS:  - Delpech Y; Coutant C; Hsu L; Barranger E; Iwamoto T; Barcenas CH; Hortobagyi GN; Rouzier R; Esteva FJ; Pusztai L

INSTITUCIÓN / INSTITUTION:  - 1] Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] Department of Gynecology and Obstetrics, Lariboisiere Hospital, AP-HP, Paris, France.

RESUMEN / SUMMARY:  - Background:The aim of this study was to compare clinical and pathological outcomes after neoadjuvant chemotherapy between oestrogen receptor (ER)-positive  invasive pure lobular carcinoma (ILC) and invasive ductal carcinoma (IDC).Methods:This analysis included 1895 patients (n=177 ILC; n=1718 IDC), with  stage I-III breast cancer, who received neoadjuvant chemotherapy. Clinical and pathological response rates, the frequency of positive surgical margins and rate  of breast-conserving surgery were compared.Results:There was a trend for fewer good clinical responses in ILC compared with IDC. Tumour downstaging was significantly less frequent in ILC. Positive or close surgical resection margins  were more frequent in ILC, and breast-conserving surgery was less common (P<0.001). These outcome differences remained significant in multivariate analysis, including tumour size, nodal status, age, grade and type of chemotherapy. Invasive pure lobular carcinoma was also associated with a significantly lower pathological complete response (pCR) rate in univariate analysis, but this was no longer significant after adjusting for tumour size and  grade.Conclusion:Neoadjuvant chemotherapy results in lower rates of clinical benefit, including less downstaging, more positive margins and fewer breast-conserving surgeries in ER-positive ILC compared with ER-positive IDC. Pathological complete responses are rare in both groups, but do not significantly differ after adjusting for other variables.British Journal of Cancer advance online publication, 8 January 2013; doi:10.1038/bjc.2012.557 www.bjcancer.com.

 

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[207]

TÍTULO / TITLE:  - Anti-Mullerian hormone as a marker of ovarian reserve following chemotherapy in patients with gestational trophoblastic neoplasia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Obstet Gynecol Reprod Biol. 2012 Dec 26. pii: S0301-2115(12)00542-8. doi: 10.1016/j.ejogrb.2012.11.021.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejogrb.2012.11.021

AUTORES / AUTHORS:  - Iwase A; Sugita A; Hirokawa W; Goto M; Yamamoto E; Takikawa S; Nakahara T; Nakamura T; Kondo M; Kikkawa F

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; Department of Maternal and Perinatal Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: akiwase@med.nagoya-u.ac.jp.

RESUMEN / SUMMARY:  - OBJECTIVE: The loss of primordial follicles from gonadal damage caused by chemotherapy results in decreased ovarian reserve. To assess the impact of chemotherapy for patients with gestational trophoblastic neoplasia (GTN) on the ovarian reserve, we evaluated the post-chemotherapy serum anti-Mullerian hormone  (AMH) levels. STUDY DESIGN: In 22 patients with GTN receiving chemotherapy, serum AMH levels were measured after the administration of chemotherapy and compared with serum AMH levels measured in patients with hydatidiform mole who did not receive chemotherapy, as a control. We also analyzed differences in the serum AMH levels following the administration of different anti-cancer agents. RESULTS: The serum AMH levels measured in the GTN group after chemotherapy was administered (median 1.18, range 0.32-3.94ng/mL) significantly decreased in comparison to those measured in the control group (median 4.22, range 0.77-6.53ng/mL, P=0.002). Serum AMH levels were significantly lower in the patients who had received a regimen including etoposide than in the patients who had not received treatment with etoposide (0.71 vs. 1.30ng/mL, P=0.027). CONCLUSION: Our results suggest that chemotherapy administered to treat GTN does indeed affect the ovarian reserve, especially in patients who receive a medication regimen that includes etoposide. Measuring their serum AMH levels might therefore be helpful for counseling GTN patients regarding their ovarian reserve.

 

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[208]

TÍTULO / TITLE:  - Beclin 1 Enhances Proteasome Inhibition-Mediated Cytotoxicity of Thyroid Cancer Cells in Macroautophagy-Independent Manner.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Endocrinol Metab. 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 1210/jc.2012-2679

AUTORES / AUTHORS:  - Zhang HY; Du ZX; Meng X; Zong ZH; Wang HQ

INSTITUCIÓN / INSTITUTION:  - Department of Geriatrics (H.-Y.Z.) and Department of Endocrinology and Metabolism (Z.-X.D.), the First Affiliated Hospital, and Department of Biochemistry and Molecular Biology (X.M., Z.-H.Z., H.-Q.W.), China Medical University, Shenyang 110001, China.

RESUMEN / SUMMARY:  - Context:The ubiquitin-proteasome system and macroautophagy are two major pathways for intracellular protein degradation. Emerging lines of evidence have shown that blockade of ubiquitin-proteasome system by proteasome inhibitors activates macroautophagy.Objective:The purpose of this study was to determine the involvement of autophagy essential gene Beclin 1 in cytotoxicity of thyroid cancer cells mediated by proteasome inhibitors.Design:Autophagy was measured by acidic-trophic dye staining and EGF-LC3 distribution using fluorescence microscopy, as well as LC3-II transition using Western blot. To ascertain the effect of Beclin 1, cells were transfected with Beclin 1 plasmid or shRNA against Beclin 1. Cell viability and apoptotic cells were measured using MTT assay and flow cytometry, respectively.Results:Proteasome inhibitors decreased Beclin 1 expression. In addition, treatment with PI3K inhibitors 3-MA or wortmannin, as well as knockdown of Beclin 1 expression, was unable to affect autophagic responses mediated by proteasome inhibitors. Overexpression of Beclin 1 enhanced  proteasome inhibitor-mediated cytotoxicity of thyroid cancer cells via suppression of survivin.Conclusions:Proteasome inhibitors cause Beclin 1-independent macroautophagic responses of thyroid cancer cells in a Beclin 1-independent manner. Beclin 1 possesses autophagy-independent antitumoral effects upon exposure of thyroid cancer cells to proteasome inhibitors.

 

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[209]

TÍTULO / TITLE:  - Toll-like receptor 5 (TLR5) expression is a novel predictive marker for recurrence and survival in squamous cell carcinoma of the tongue.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 3. doi: 10.1038/bjc.2012.589.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2012.589

AUTORES / AUTHORS:  - Kauppila JH; Mattila AE; Karttunen TJ; Salo T

INSTITUCIÓN / INSTITUTION:  - 1] Department of Pathology, University of Oulu, PO Box 5000, 90014 Oulu, Finland  [2] Department of Surgery, University of Oulu, PO Box 5000, 90014 Oulu, Finland [3] Oulu University Hospital, PO Box 21, 90029 Oulu, Finland.

RESUMEN / SUMMARY:  - Background:Toll-like receptor 5 (TLR5) is an immune receptor recognising bacterial flagellin. Activation of TLR5 results in cancer invasion and cytokine release. As certain bacteria have been linked to oral cancer, we wanted to study  TLR5 expression in oral tongue squamous cell carcinoma (OTSCC).Methods:Samples from 119 patients with OTSCC were obtained, including 101 samples of adjacent normal lingual mucosa. The TLR5 histoscore (0-300) was assessed semiquantitatively by immunohistochemistry in a blinded manner.Results:Toll-like  receptor 5 was expressed in 84 normal epithelia and 118 cancer samples. Expression of TLR5 was increased in cancer when compared with normal lingual epithelium (median histoscore 15 vs 135). In cancer, higher TLR5 was associated with age of >70 years at the time of diagnosis, female gender and disease recurrence. No association between TLR5 expression and tumour grade, stage or treatment was found. In multivariate analysis, TLR5 was an independent predictor  of cancer mortality (hazard ratio (HR) 3.587, 95% confidence interval (CI) (1.632-7.882)) and disease recurrence (HR 4.455, 95% CI (2.168-9.158)).Conclusion:Toll-like receptor 5 has a previously undescribed role  in the pathophysiology of OTSCC and might represent a link between bacteria and cancer. It could be a useful marker for predicting recurrence or survival of OTSCC patients.British Journal of Cancer advance online publication, 3 January 2013; doi:10.1038/bjc.2012.589 www.bjcancer.com.

 

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[210]

TÍTULO / TITLE:  - The role of cellular FLICE-inhibitory protein (c-FLIP) in cisplatin resistance of human bladder cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Urol. 2013 Jan 9. pii: S0022-5347(13)00015-3. doi: 10.1016/j.juro.2013.01.003.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.juro.2013.01.003

AUTORES / AUTHORS:  - Lee S; Yoon CY; Byun SS; Lee E; Lee SE

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea.

RESUMEN / SUMMARY:  - PURPOSE: We investigated the mechanisms underlying cisplatin resistance in human  bladder cancer cells to provide novel molecular targets for the treatment of cisplatin-resistant bladder cancer. MATERIALS AND METHODS: Differential gene expression between cisplatin-sensitive (T24) and -resistant (T24R2) human bladder cancer cell lines was analyzed and validated by microarray and Western blot analysis. Changes in cisplatin sensitivity by cellular FLICE-inhibitory protein (c-FLIP) knockdown and related mechanisms in T24R2 cells were assessed by Cell Counting Kit-8 (CCK-8) assay and Western blotting. The siRNA oligonucleotides that specifically target c-FLIP were prepared and siRNA transfection was performed. RESULTS: Microarray analysis demonstrated that the expression of 1,086 and 322 genes show more than 2-fold and 4-fold changes, respectively between T24R2 and T24 cell lines. Especially genes involved c-FLIP-related death receptor apoptosis pathway (caspase 2, caspase 9, NF-kB, BID, c-FLIP, XIAP, cIAP1 and cIAP2) showed differential expression between two cell lines. Western blot analysis demonstrated complete cisplatin-mediated suppression of c-FLIP expression in T24 cells, whereas no changes in c-FLIP expression were observed in T24R2 cells following treatment with cisplatin in the same dose range. Suppression of c-FLIP expression in T24R2 cells by siRNA transfection rendered these cells significantly more sensitive to cisplatin treatment than untransfected T24R2 cells (p < 0.05). CONCLUSIONS: These studies demonstrated that c-FLIP plays an important role in the cisplatin-resistance of human bladder  cancer cells and that c-FLIP modulation may, at least partially, reverse cisplatin resistance in bladder cancer cells.

 

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[211]

TÍTULO / TITLE:  - BMS-936564/MDX-1338: A Fully Human Anti-CXCR4 Antibody Induces Apoptosis In Vitro and Shows Antitumor Activity In Vivo in Hematologic Malignancies.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 15;19(2):357-66. doi: 10.1158/1078-0432.CCR-12-2333. Epub 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2333

AUTORES / AUTHORS:  - Kuhne MR; Mulvey T; Belanger B; Chen S; Pan C; Chong C; Cao F; Niekro W; Kempe T; Henning KA; Cohen LJ; Korman AJ; Cardarelli PM

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Department of Cell Biology and Physiology, BDC, Bristol-Myers Squibb; Departments of Hybridoma and Discovery Research, BDC, Redwood City, California; and Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Lawrenceville, New Jersey.

RESUMEN / SUMMARY:  - PURPOSE: CXCR4 has been identified as a prognostic marker for acute myeloid leukemia (AML) and other malignancies. We describe the development and characterization of a fully human antibody to CXCR4 and its application for therapy of AML, non-Hodgkin lymphoma (NHL), chronic lymphoid leukemia (CLL), and  multiple myeloma. EXPERIMENTAL DESIGN: Human transgenic mice were immunized with  CXCR4-expressing cells, and antibodies reactive with CXCR4 were analyzed for apoptosis induction and ability to interfere with CXCL12-induced migration and calcium flux. In vivo efficacy was determined in multiple AML, NHL, and multiple  myeloma xenograft tumors in severe combined immunodeficient mice. RESULTS: BMS-936564/MDX-1338 is a fully human IgG(4) monoclonal antibody that specifically recognizes human CXCR4. In vitro studies show that MDX-1338 binds to CXCR4-expressing cells with low nanomolar affinity, blocks CXCL12 binding to CXCR4-expressing cells, and inhibits CXCL12-induced migration and calcium flux with low nanomolar EC(50) values. When given as monotherapy, MDX-1338 exhibits antitumor activity in established tumors including AML, NHL, and multiple myeloma xenograft models. In addition, we show that MDX-1338 induced apoptosis on a panel of cell lines and propose that antibody-induced apoptosis is one of the mechanisms of tumor growth inhibition. CONCLUSIONS: BMS-936564/MDX-1338 is a potent CXCR4 antagonist which is efficacious as monotherapy in tumor-bearing mice and is currently in phase I for the treatment of relapsed/refractory AML, NHL, CLL, and multiple myeloma. Clin Cancer Res; 19(2); 357-66. ©2012 AACR.

 

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[212]

TÍTULO / TITLE:  - Suppressibility of Thyroglobulin as a Useful Parameter for Prognosis of Patients  With Thyroid Carcinoma: A New Basis to Understand Molecular Mechanisms in Dedifferentiation?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Nucl Med. 2013 Jan 25.

            ●● Enlace al texto completo (gratuito o de pago) 1097/RLU.0b013e3182814aec

AUTORES / AUTHORS:  - Caobelli F; Pizzocaro C; Guerra UP

INSTITUCIÓN / INSTITUTION:  - Department of Nuclear Medicine Department Fondazione Poliambulanza Brescia, Italy federico.caobelli@gmail.com.

 

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[213]

TÍTULO / TITLE:  - Down-regulation of human leukocyte antigen class I (HLA-I) is associated with poor prognosis in patients with clear cell renal cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Acta Histochem. 2012 Dec 12. pii: S0065-1281(12)00166-3. doi: 10.1016/j.acthis.2012.11.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.acthis.2012.11.002

AUTORES / AUTHORS:  - Yuan J; Liu S; Yu Q; Lin Y; Bi Y; Wang Y; An R

INSTITUCIÓN / INSTITUTION:  - Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People’s Republic of China.

RESUMEN / SUMMARY:  - Human leukocyte antigen class I (HLA-I) molecules are transmembrane glycoproteins that have been reported to be down-regulated in multiple types of human malignancies, including clear cell renal cell carcinoma (CCRCC). However, only one study has investigated its prognostic value in CCRCC. In the present study, HLA-I protein expression was analyzed in 120 archived, paraffin-embedded CCRCC samples and 10 adjacent normal tissues using immunohistochemistry. The correlation between HLA-I expression and clinicopathological factors was evaluated by the chi(2) test. Patients’ overall survival was analyzed by the Kaplan-Meier method. HLA-I down-regulation was observed in 38.3% (46/120) of renal tumor samples, but only in 10% (1/10) of adjacent normal tissues. Statistical analysis showed a significant correlation of HLA-I expression with TNM stage, lymph node metastasis, and Fuhrman grade. Patients with tumors displaying down-regulation of HLA-I showed significantly shorter overall survival (P=0.021, log-rank test). More importantly, multivariate analysis indicated that  down-regulation of HLA-I was an independent prognostic factor for CCRCC patients  (P=0.033). Overall, our data suggest that HLA-I down-regulation is associated with tumor progression and a poor prognosis in CCRCC patients, and emphasize the  importance of HLA-I in natural and therapeutic immune surveillance of patients with CCRCC.

 

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[214]

TÍTULO / TITLE:  - Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-alpha-independent mechanism.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Jan;137(2):359-71. doi: 10.1007/s10549-012-2352-6.  Epub 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-012-2352-6

AUTORES / AUTHORS:  - Allensworth JL; Sauer SJ; Lyerly HK; Morse MA; Devi GR

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Duke University Medical Center, Durham, NC, 27710, USA.

RESUMEN / SUMMARY:  - X-linked inhibitor of apoptosis protein (XIAP), the most potent mammalian caspase inhibitor, has been associated with acquired therapeutic resistance in inflammatory breast cancer (IBC), an aggressive subset of breast cancer with an extremely poor survival rate. The second mitochondria-derived activator of caspases (Smac) protein is a potent antagonist of IAP proteins and the basis for  the development of Smac mimetic drugs. Here, we report for the first time that bivalent Smac mimetic Birinapant induces cell death as a single agent in TRAIL-insensitive SUM190 (ErbB2-overexpressing) cells and significantly increases potency of TRAIL-induced apoptosis in TRAIL-sensitive SUM149 (triple-negative, EGFR-activated) cells, two patient tumor-derived IBC models. Birinapant has high  binding affinity (nM range) for cIAP1/2 and XIAP. Using isogenic SUM149- and SUM190-derived cells with differential XIAP expression (SUM149 wtXIAP, SUM190 shXIAP) and another bivalent Smac mimetic (GT13402) with high cIAP1/2 but low XIAP binding affinity (K (d) > 1 muM), we show that XIAP inhibition is necessary  for increasing TRAIL potency. In contrast, single agent efficacy of Birinapant is due to pan-IAP antagonism. Birinapant caused rapid cIAP1 degradation, caspase activation, PARP cleavage, and NF-kappaB activation. A modest increase in TNF-alpha production was seen in SUM190 cells following Birinapant treatment, but no increase occurred in SUM149 cells. Exogenous TNF-alpha addition did not increase Birinapant efficacy. Neutralizing antibodies against TNF-alpha or TNFR1  knockdown did not reverse cell death. However, pan-caspase inhibitor Q-VD-OPh reversed Birinapant-mediated cell death. In addition, Birinapant in combination or as a single agent decreased colony formation and anchorage-independent growth  potential of IBC cells. By demonstrating that Birinapant primes cancer cells for  death in an IAP-dependent manner, these findings support the development of Smac  mimetics for IBC treatment.

 

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[215]

TÍTULO / TITLE:  - Anisomycin treatment enhances TRAIL-mediated apoptosis in renal carcinoma cells through the down-regulation of Bcl-2, c-FLIP(L) and Mcl-1.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochimie. 2012 Dec 20. pii: S0300-9084(12)00478-6. doi: 10.1016/j.biochi.2012.12.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biochi.2012.12.002

AUTORES / AUTHORS:  - Seo BR; Min KJ; Kim S; Park JW; Park WK; Lee TJ; Kwon TK

INSTITUCIÓN / INSTITUTION:  - Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.

RESUMEN / SUMMARY:  - Anisomycin is known to inhibit protein synthesis and induce ribotoxic stress. In  this study, we investigated whether anisomycin treatment could modulate TRAIL-mediated apoptosis in human renal carcinoma Caki cells. We found that anisomycin treatment (10-15 nM) alone had no effect on the level of apoptosis, but a combination treatment of anisomycin and TRAIL significantly increased the level of apoptosis in human renal carcinoma (Caki, ACHN and A498), human glioma (U251MG), and human breast carcinoma (MDA-MB-361 and MCF7) cells. Anisomycin treatment led to the down-regulation of Bcl-2 expression at the transcriptional level, and the over-expression of Bcl-2 inhibited the apoptosis induced by the combination treatment of anisomycin and TRAIL. Furthermore, anisomycin treatment  resulted in the down-regulation of c-FLIP(L) and Mcl-1 at the post-transcriptional level, and the over-expression of c-FLIP(L) and Mcl-1 blocked the induction of apoptosis caused by the combination treatment of anisomycin with TRAIL. In contrast, anisomycin treatment had no effect on the levels of TRAIL-mediated apoptosis in mouse kidney cells (TMCK-1) or normal human skin fibroblasts (HSF). Cumulatively, our study demonstrates that anisomycin treatment enhances TRAIL-mediated apoptosis through the down-regulation of Bcl-2, c-FLIP(L) and Mcl-1 at the transcriptional or post-transcriptional level.

 

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[216]

TÍTULO / TITLE:  - Gene expression profiles in esophageal adenocarcinoma predict survival after resection.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Thorac Cardiovasc Surg. 2013 Feb;145(2):505-13. doi: 10.1016/j.jtcvs.2012.10.031.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jtcvs.2012.10.031

AUTORES / AUTHORS:  - Pennathur A; Xi L; Litle VR; Gooding WE; Krasinskas A; Landreneau RJ; Godfrey TE; Luketich JD

INSTITUCIÓN / INSTITUTION:  - Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa.

RESUMEN / SUMMARY:  - OBJECTIVE: The incidence of esophageal adenocarcinoma is rapidly increasing in the western population. Despite aggressive treatment, survival after esophagectomy is suboptimal. The main objective of the present study was to evaluate the gene expression profiles in esophageal adenocarcinoma and determine  their association with survival after resection. METHODS: We conducted a prospective National Institutes of Health/National Cancer Institute funded study  to evaluate the prognostic significance of gene expression in patients with esophageal adenocarcinoma undergoing esophagectomy. Gene expression in tumor tissue was analyzed using high-throughput oligonucleotide arrays. The association of gene expression and overall survival was analyzed using the tail-strength statistic and Cox regression analysis. Gene signatures were constructed with semisupervised methods using principal components. A cross-validated risk score was devised by conducting 10-fold cross-validation, 100 times. RESULTS: We evaluated the gene expression in 64 patients with esophageal adenocarcinoma who underwent esophagectomy. The median overall survival was 27 months (95% confidence interval 22 to not reached). After filtering, 10,214 probe sets were used for survival analysis. The tail-strength statistic for these probe sets (0.318) indicated a significant association with overall survival. Patients were  classified into high- and low-risk groups, according to the gene signature. High-risk patients had a predicted median survival of 19 months, but the median was not reached for the low-risk group (P < .05). On multivariate analysis, the gene signature was independently associated with survival (hazard ratio, 2.22; P  = .04). CONCLUSIONS: Global gene expression levels were significantly associated  with overall survival after esophagectomy. Furthermore, individual genes could be successfully combined into a strongly predictive, internally cross-validated gene signature. If validated further, these results could help direct additional clinical trials of neoadjuvant and adjuvant therapies for esophageal adenocarcinoma.

 

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[217]

TÍTULO / TITLE:  - Maintenance therapy with dasatinib after allogeneic hematopoietic stem cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Hematol. 2013 Jan 11.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00277-012-1670-4

AUTORES / AUTHORS:  - Teng CL; Yu JT; Chen HC; Hwang WL

INSTITUCIÓN / INSTITUTION:  - Division of Hematology/Oncology, Department of Medicine, Taichung Veterans General Hospital, 160, Section 3, Chungkang Road, Taichung, 407, Taiwan.

 

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[218]

TÍTULO / TITLE:  - Prognostic Significance of Quantitative Carcinoembryonic Antigen and Cytokeratin  20 mRNA Detection in Peritoneal Washes of Gastric Cancer Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hepatogastroenterology. 2013 Jan 16;60(127). doi: 10.5754/hge121058.

            ●● Enlace al texto completo (gratuito o de pago) 5754/hge121058

AUTORES / AUTHORS:  - Lee SR; Kim HO; Shin JH

RESUMEN / SUMMARY:  - Background/Aims: Peritoneal carcinomatosis is the most common recurrence type in  gastric cancer. Disseminated tumor cells derived from serosal invasion may be indicators of early peritoneal seeding and subsequent peritoneal dissemination. Reverse-transcriptase polymerase chain reaction (RT-PCR) techniques have been introduced to aid in detection of disseminated tumor cells in peritoneal washes,  however, use of a single molecular marker lacks adequate sensitivity. We sought to improve both sensitivity and specificity in detecting disseminated tumor cells in peritoneal washes by using two markers; carcinoembryonic antigen (CEA) and cytokeratin 20 mRNA (CK20 mRNA). Methodology: Between July 2007 and June 2010, peritoneal washing samples were collected from 131 patients who underwent surgery for histologically proven gastric cancer. CEA and CK20 mRNA levels were quantified using a Light Cycler. Results: Analysis using of the two markers had higher sensitivity (93.9%) and specificity (87.7%) than single marker detection (p<0.01, p<0.001 respectively). These analyses also correlated with various clinicopathological factors, and aided in predicting survival and peritoneal recurrence. Conclusions: Two-marker analysis has a significant correlation of survival or peritoneal recurrence in gastric cancer, and this analysis may be more useful as a prognostic predictor of peritoneal recurrence compared with RT-PCR mediated detection of CEA or CK20 alone.

 

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[219]

TÍTULO / TITLE:  - Serum lactic dehydrogenase strongly predicts survival in metastatic nasopharyngeal carcinoma treated with palliative chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Cancer. 2012 Dec 21. pii: S0959-8049(12)00928-8. doi: 10.1016/j.ejca.2012.11.032.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2012.11.032

AUTORES / AUTHORS:  - Jin Y; Ye X; Shao L; Lin BC; He CX; Zhang BB; Zhang YP

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Zhejiang Cancer Hospital, China.

RESUMEN / SUMMARY:  - BACKGROUND AND OBJECTIVE: The survival outcomes of patients with metastatic nasopharyngeal carcinoma (NPC) differ significantly between individuals. This study aimed to evaluate whether serum lactic dehydrogenase (S-LDH) level had a clinical value in predicting clinical response and survival outcome for patients  with metastatic NPC. METHODS: S-LDH level was measured at baseline and then before every cycle of treatment in 689 NPC patients with distant metastases. Correlations of pre-treatment and post-treatment S-LDH levels to response of treatment and survival were analysed retrospectively. RESULTS: Patients with elevated values of pre-treatment S-LDH (>245IU/L) had significantly worse survival than those with normal values of pre-treatment S-LDH (245IU/L) (P<0.001). Patients with elevated values of post-treatment S-LDH had worse survival compared with those with normal values of post-treatment S-LDH (P<0.001). Patients with normal values of pre-treatment and post-treatment S-LDH  showed the highest response rate and the most favourable prognosis. CONCLUSION: S-LDH appears to be a significant independent prognostic index in patients with disseminated NPC that should be considered in the comparison of the results achieved with different therapies and in planning new randomised clinical therapeutic trials.

 

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[220]

TÍTULO / TITLE:  - RPF101, a new capsaicin-like analogue, disrupts the microtubule network accompanied by arrest in the G2/M phase, inducing apoptosis and mitotic catastrophe in the MCF-7 breast cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Toxicol Appl Pharmacol. 2013 Feb 1;266(3):385-98. doi: 10.1016/j.taap.2012.11.029. Epub 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.taap.2012.11.029

AUTORES / AUTHORS:  - de-Sa-Junior PL; Pasqualoto KF; Ferreira AK; Tavares MT; Damiao MC; de Azevedo RA; Camara DA; Pereira A; de Souza DM; Parise Filho R

INSTITUCIÓN / INSTITUTION:  - Laboratory of Genetics, Butantan Institute, Vital Brasil Avenue 1500, Postal Code: 05503-900, Sao Paulo, Brazil.

RESUMEN / SUMMARY:  - Breast cancer is the world’s leading cause of death among women. This situation imposes an urgent development of more selective and less toxic agents. The use of natural molecular fingerprints as sources for new bioactive chemical entities has proven to be a quite promising and efficient method. Capsaicin, which is the primary pungent compound in red peppers, was reported to selectively inhibit the  growth of a variety tumor cell lines. Here, we report for the first time a novel  synthetic capsaicin-like analogue, RPF101, which presents a high antitumor activity on MCF-7 cell line, inducing arrest of the cell cycle at the G2/M phase  through a disruption of the microtubule network. Furthermore, it causes cellular  morphologic changes characteristic of apoptosis and a decrease of Deltapsim. Molecular modeling studies corroborated the biological findings and suggested that RPF101, besides being a more reactive molecule towards its target, may also  present a better pharmacokinetic profile than capsaicin. All these findings support the fact that RPF101 is a promising anticancer agent.

 

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[221]

TÍTULO / TITLE:  - Plant cyclopeptide RA-V kills human breast cancer cells by inducing mitochondria-mediated apoptosis through blocking PDK1-AKT interaction.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Toxicol Appl Pharmacol. 2013 Feb 15;267(1):95-103. doi: 10.1016/j.taap.2012.12.010. Epub 2012 Dec 26.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.taap.2012.12.010

AUTORES / AUTHORS:  - Fang XY; Chen W; Fan JT; Song R; Wang L; Gu YH; Zeng GZ; Shen Y; Wu XF; Tan NH; Xu Q; Sun Y

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing, China.

RESUMEN / SUMMARY:  - In the present paper, we examined the effects of a natural cyclopeptide RA-V on human breast cancer cells and the underlying mechanisms. RA-V significantly inhibited the growth of human breast cancer MCF-7, MDA-MB-231 cells and murine breast cancer 4T1 cells. In addition, RA-V triggered mitochondrial apoptotic pathway which was indicated by the loss of mitochondrial membrane potential, the  release of cytochrome c, and the activation of caspase cascade. Further study showed that RA-V dramatically inhibited phosphorylation of AKT and 3-phosphoinositide dependent protein kinase 1 (PDK1) in MCF-7 cells. Moreover, RA-V disrupted the interaction between PDK1 and AKT in MCF-7 cells. Furthermore,  RA-V-induced apoptosis could be enhanced by phosphatidylinositol 3-kinase inhibitor or attenuated by over-expression of AKT in all the three kinds of breast cancer cells. Taken together, this study shows that RA-V, which can induce mitochondria-mediated apoptosis, exerts strong anti-tumor activity against human  breast cancer. The underlying anti-cancer mechanism of RA-V is related to the blockage of the interaction between PDK1 and AKT.

 

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[222]

TÍTULO / TITLE:  - Mechanisms of cisplatin-induced cell death in malignant mesothelioma cells: Role  of inhibitor of apoptosis proteins (IAPs) and caspases.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Feb;42(2):444-52. doi: 10.3892/ijo.2012.1715. Epub 2012 Nov 28.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2012.1715

AUTORES / AUTHORS:  - Cregan IL; Dharmarajan AM; Fox SA

INSTITUCIÓN / INSTITUTION:  - School of Anatomy and Human Biology, The University of Western Australia, Crawley, WA, Australia.

RESUMEN / SUMMARY:  - Malignant mesothelioma (MM) is an aggressive and highly chemoresistant tumour. Although cisplatin is used in frontline therapy of this disease treatment remains palliative at best. The biochemical pathways activated by cisplatin and the mechanisms of resistance in mesothelioma cells are poorly understood. Overexpression of inhibitor of apoptosis proteins (IAPs) has been described in clinical mesothelioma tumours and proposed as therapeutic targets. In this study, we examined cisplatin-induced cell death pathways and IAPs in three mesothelioma-derived cell lines. Cisplatin induced cell death in mesothelioma cell lines was characterised by biochemical mechanisms classically associated with apoptosis including: mitochondrial depolarisation, phosphatidylserine translocation and caspase activation. Surprisingly mRNA expression of IAPs in mesothelioma was not upregulated relative to primary mesothelial cells except for survivin which was higher in the most resistant cell line. In contrast, protein expression of both XIAP and survivin was upregulated in all mesothelioma cells, consistent with post-translational regulation. Knockdown of either XIAP or survivin by RNAi did not affect the sensitivity to cisplatin in any of the cell lines. Survivin RNAi did, however, inhibit proliferation in the highest expressing cell line, ONE58. The pan-caspase inhibitor z-VAD and the more selective caspase 3/7 inhibitor z-DEVD had no effect upon the sensitivity of any  of the cell lines to cisplatin indicating that caspase-independent pathways predominate. The findings of the present study provide insights into cisplatin-induced mechanisms in mesothelioma cells and show that alternative pathways are operating which may provide new options for targeting this extremely resistant tumour.

 

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[223]

TÍTULO / TITLE:  - Re-emergence of interferon-alpha in the treatment of chronic myeloid leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leukemia. 2012 Nov 7. doi: 10.1038/leu.2012.313.

            ●● Enlace al texto completo (gratuito o de pago) 1038/leu.2012.313

AUTORES / AUTHORS:  - Talpaz M; Hehlmann R; Quintas-Cardama A; Mercer J; Cortes J

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Division of Hematology Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.

RESUMEN / SUMMARY:  - Treatment for chronic myeloid leukemia (CML) has evolved from chemotherapy (busulfan, hydroxyurea) to interferon-alpha (IFNalpha), and finally to tyrosine kinase inhibitors such as imatinib. Although imatinib has profoundly improved outcomes for patients with CML, it has limitations. Most significantly, imatinib  cannot eradicate CML primitive progenitors, which likely accounts for the high relapse rate when imatinib is discontinued. IFNalpha, unlike imatinib, preferentially targets CML stem cells. Early studies with IFNalpha in CML demonstrated its ability to induce cytogenetic remission. Moreover, a small percentage of patients treated with IFNalpha were able to sustain durable remissions after discontinuing therapy and were probably cured. The mechanisms by which IFNalpha exerts its antitumor activity in CML are not well understood; however, activation of leukemia-specific immunity may have a role. Some clinical  studies have demonstrated that the combination of imatinib and IFNalpha is superior to either therapy alone, perhaps because of their different mechanisms of action. Nonetheless, the side effects of IFNalpha often impede its administration, especially in combination therapy. Here, we review the role of IFNalpha in CML treatment and the recent developments that have renewed interest  in this once standard therapy for patients with CML.Leukemia advance online publication, 14 December 2012; doi:10.1038/leu.2012.313.

 

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[224]

TÍTULO / TITLE:  - A novel antitubulin agent, DPQZ, induces cell apoptosis in human oral cancer cells through Ras/Raf inhibition and MAP kinases activation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Arch Toxicol. 2012 Dec 5.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00204-012-0991-3

AUTORES / AUTHORS:  - Hour MJ; Lee KT; Wu YC; Wu CY; You BJ; Chen TL; Lee HZ

INSTITUCIÓN / INSTITUTION:  - School of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung, 40402, Taiwan.

RESUMEN / SUMMARY:  - 6-(N,N-Dimethylamino)-2-(naphthalene-1-yl)-4-quinazolinone (DPQZ)-induced apoptosis was accompanied by the characteristics of DNA fragmentation and phosphatidylserine externalization in human oral cancer HSC-3 cells. The IC(50) (half maximal inhibitory concentration) value of DPQZ is about 0.25 muM at 24 h.  The interference in the dynamics of tubulin and cell division of DPQZ, like vinblastine (0.01 muM), has been proven in this study. Treatment of HSC-3 cells with DPQZ resulted in many of mitotic cells with multipolar spindles. Up-regulation of MAP kinases, such as ERK, JNK, and p38, mediated by DPQZ appears to be involved in DPQZ-induced apoptosis in HSC-3 cells. It is worthy of note that the expression of Ras and c-Raf that lie upstream of ERK were inhibited by DPQZ. In addition, the DPQZ-induced cell death was attenuated by JNK inhibitor SP600125 (3 or 10 muM), not by the ERK or p38 inhibitors. JNK inhibitor abolished the DPQZ-induced increase in the phosphorylation of Bcl-2 and the protein levels  of proform caspase-3, caspase-8, and caspase-9, indicating that JNK is an upstream activator of Bcl-2 and caspase family members and plays a key role in DPQZ-induced HSC-3 cell apoptosis. We also attempted to develop an anticancer drug that is designed to kill rapidly dividing cancer cells while causing less damage to normal cells. The DPQZ-induced cytotoxicity against human gingival fibroblasts was less than that against HSC-3 cells. Our work provides a new strategy and mechanism for developing anticancer drug and may contribute to clinical anticancer drug discovery and application.

 

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[225]

TÍTULO / TITLE:  - Radiographic assessment and therapeutic decisions at RECIST progression in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Lung Cancer. 2012 Dec 14. pii: S0169-5002(12)00628-9. doi: 10.1016/j.lungcan.2012.11.007.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.lungcan.2012.11.007

AUTORES / AUTHORS:  - Nishino M; Cardarella S; Dahlberg SE; Jackman DM; Ramaiya NH; Hatabu H; Rabin MS; Janne PA; Johnson BE

INSTITUCIÓN / INSTITUTION:  - Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave. Boston MA, 02215, USA; Department of Radiology, Brigham and Women’s Hospital, 75 Francis St. Boston MA, 02215, USA. Electronic address: Mizuki_Nishino@DFCI.HARVARD.EDU.

RESUMEN / SUMMARY:  - PURPOSE: Advanced NSCLC harboring epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs) typically progresses after initial response due to acquired resistance. TKIs are often continued beyond progressive disease by RECIST. We investigated the practice of continuing EGFR-TKIs after RECIST-PD via CT findings. METHODS: Among 101 advanced NSCLC patients with sensitizing EGFR mutations treated with first-line EGFR-TKIs, 70 patients had baseline and at least one follow-up CT for retrospective radiographic assessments using RECIST1.1; 56 patients had experienced PD by the data closure date of June 2011. RESULTS: Among 56 patients experiencing PD, 82% were female, median age was 63 years, 50% were never-smokers, 57% had distant metastasis, 57% had exon 19 deletion, and 89% were treated with erlotinib. 49 patients (88%) continued TKI therapy beyond retrospectively assessed PD. 31/32 (97%) patients who progressed by an increase in their target lesions continued TKI. 13/16 (81%) patients who progressed by appearance of a new lesion remained on TKI. 5/6 (83%) patients with both increase of target lesions and new lesion at PD continued TKI. Two patients with PD in non-target lesions discontinued therapy at PD. In 49 continuing patients, the median time from retrospectively assessed RECIST-PD to termination of TKI was 10.1 months. CONCLUSIONS: 88% of EFGR-mutant  NSCLC patients who progressed on first-line TKI continued therapy beyond RECIST-PD, which is not the single determining factor for terminating TKI in EGFR-mutant NSCLC patients. Additional radiographically defined progression criteria are needed for this population.

 

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[226]

TÍTULO / TITLE:  - MiR-214 reduces cell survival and enhances cisplatin-induced cytotoxicity via down-regulation of Bcl2l2 in cervical cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - FEBS Lett. 2013 Jan 18. pii: S0014-5793(13)00047-1. doi: 10.1016/j.febslet.2013.01.016.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.febslet.2013.01.016

AUTORES / AUTHORS:  - Wang F; Liu M; Li X; Tang H

INSTITUCIÓN / INSTITUTION:  - Tianjin Life Science Research Center and Basic Medical School, Tianjin Medical University, Tianjin 300070, China.

RESUMEN / SUMMARY:  - MiR-214 has been shown to inhibit cell growth, migration and invasion. Here we demonstrate that ectopic expression of miR-214 reduces cell survival, induces apoptosis and enhances sensitivity to cisplatin through directly inhibiting Bcl2l2 expression in cervical cancer HeLa and C-33A cells. Further analysis reveals that apoptosis induced by miR-214 is correlated with increased expression of Bax, caspase-9, caspase-8 and caspase-3. Moreover, we show that miR-214 is regulated by DNA methylation and histone deacetylation. Taken together, these data suggest that miR-214 might be a candidate target for the development of novel therapeutic strategies to treat cervical cancer.

 

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[227]

TÍTULO / TITLE:  - Overexpression of lysine specific demethylase 1 predicts worse prognosis in primary hepatocellular carcinoma patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Gastroenterol. 2012 Dec 7;18(45):6651-6. doi: 10.3748/wjg.v18.i45.6651.

            ●● Enlace al texto completo (gratuito o de pago) 3748/wjg.v18.i45.6651

AUTORES / AUTHORS:  - Zhao ZK; Yu HF; Wang DR; Dong P; Chen L; Wu WG; Ding WJ; Liu YB

INSTITUCIÓN / INSTITUTION:  - Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200092, China.

RESUMEN / SUMMARY:  - AIM: To investigate the clinicopathological features and prognostic value of lysine specific demethylase 1 (LSD1) in hepatocellular carcinoma (HCC). METHODS:  We examined LSD1 expression in 60 paired liver cancer tissues and adjacent noncancerous tissues by quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting. In addition, we analyzed LSD1 expression in 198 HCC samples by immunohistochemistry. The relationship between LSD1 expression, clinicopathological features and patient survival was investigated. RESULTS: Immunohistochemistry, Western blotting, and qRT-PCR consistently confirmed LSD1 overexpression in HCC tissues compared to adjacent non-neoplastic tissues (P < 0.01). Additionally, immunostaining showed more LSD1-positive cells in the higher tumor stage (T3-4) and tumor grade (G3) than in the lower tumor stage (T1-2, P <  0.001) and tumor grade (G1-2, P < 0.001), respectively. Moreover, HCC patients with high LSD1 expression had significantly lower 5-year overall survival rates (P < 0.001) and lower 5-year disease-free survival rates (P < 0.001), respectively. A Cox proportional hazards model further demonstrated that LSD1 over-expression was an independent predictor of poor prognosis for both 5-year disease-free survival [hazards ratio (HR) = 1.426, 95%CI: 0.672-2.146, P < 0.001] and 5-year overall survival (HR = 2.456, 95%CI: 1.234-3.932, P < 0.001) in HCC. CONCLUSION: Our data suggest for the first time that the overexpression of LSD1 protein in HCC tissues indicates tumor progression and predicts poor prognosis.

 

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[228]

TÍTULO / TITLE:  - Gedunin Inactivates the Co-chaperone p23 Causing Cancer Cell Death by Apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Biol Chem. 2013 Jan 25.

            ●● Enlace al texto completo (gratuito o de pago) 1074/jbc.M112.427328

AUTORES / AUTHORS:  - Patwardhan CA; Fauq A; Peterson LB; Miller C; Blagg BS; Chadli A

INSTITUCIÓN / INSTITUTION:  - Georgia Health Sciences University, United States;

RESUMEN / SUMMARY:  - Pharmacological inhibition of Hsp90 is an exciting option for cancer therapy. The clinical efficacy of Hsp90 inhibitors is, however, less than expected. Binding of the co-chaperone p23 to Hsp90, and induced overexpression of anti-apoptotic proteins, Hsp70 and Hsp27, are thought to contribute to this outcome. Herein, we  report that the natural product, gedunin, may provide a new alternative to inactivate the Hsp90 machine. We show that gedunin directly binds to p23 and inactivates it, without overexpression of Hsp27 and relatively modest induction of Hsp70. Using molecular docking and mutational analysis, we mapped the gedunin-binding site on p23. Functional analysis shows that gedunin inhibits p23  chaperoning activity, blocks its cellular interaction with Hsp90 and interferes with p23-mediated gene regulation. Cell treatment with gedunin leads to cancer cell death by apoptosis through inactivation of p23 and activation of caspase 7,  which cleaves p23 at the C-terminus. These results provide important insight into the molecular mechanism of action of this promising lead compound.

 

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[229]

TÍTULO / TITLE:  - Transforming Growth Factor-beta directly induces PUMA during the rapid induction  of apoptosis in Myc-driven B-cell lymphomas.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Biol Chem. 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 1074/jbc.M112.410274

AUTORES / AUTHORS:  - Spender LC; Carter MJ; O’Brien DI; Clark LJ; Yu J; Michalak EM; Happo L; Cragg MS; Inman GJ

INSTITUCIÓN / INSTITUTION:  - University of Dundee, United Kingdom;

RESUMEN / SUMMARY:  - c-MYC transformed human Burkitts Lymphoma (BL) cells are highly sensitive to Transforming Growth Factor-beta (TGF-beta-induced apoptosis. Previously we demonstrated that TGF-beta-mediated cell death in BL cells is regulated via the mitochondrial intrinsic apoptosis pathway which is dependent on the activation of BAX and/or BAK. TGF-beta directly induces transcription of the BH3-only protein BIK and represses expression of the pro-survival factor BCL-XL, but has no effect on the direct BAX/BAK activators BIM or BID (tBID). Here we show that TGF-beta induces the BH3-only activator PUMA to aid induction of the intrinsic cell death  pathway. TGF-beta also induced PUMA in normal germinal centre CD77 positive centroblasts isolated from human tonsil tissue. PUMA was a direct TGF-beta target gene in B cells and we identify a putative SMAD binding region (SBR) within the human PUMA promoter that recruits Smad3 and Smad4 in cells in response to TGF-beta signalling. Consitutive activity of the isolated SBR in luciferase reporter assays was dependent on SMAD consensus sequences and was partially dependent on endogenous TGF-betasignalling and Smad4. Knockdown of PUMA in BL cells using lentiviral shRNA resulted in slower kinetics of the TGF-beta-mediated apoptotic response. Analysis of Emu-Myc cell lines demonstrated that c-myc driven murine lymphomas are also sensitive to TGF-beta-mediated apoptosis. Moreover Puma-/- Emu-Myc lines demonstrated significantly delayed kinetics of the apoptotic response when compared with wild type lymphomas. TGF-beta therefore induces a polygenic response in Myc-driven lymphomas involving transcription of PUMA, which is necessary for the rapid induction of cell death.

 

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[230]

TÍTULO / TITLE:  - The depletion of Interleukin-8 causes cell cycle arrest and increases the efficacy of docetaxel in breast cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 12. pii: S0006-291X(13)00058-2. doi: 10.1016/j.bbrc.2013.01.022.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2013.01.022

AUTORES / AUTHORS:  - Shao N; Chen LH; Ye RY; Lin Y; Wang SM

INSTITUCIÓN / INSTITUTION:  - Breast Disease Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China.

RESUMEN / SUMMARY:  - IL-8 is a multi-functional pro-inflammatory chemokine, which is highly expressed  in cancers, such as ER-negative breast cancer. The present study demonstrates the pervasive role of IL-8 in the malignant progression of ER-negative breast cancer. IL-8 siRNA inhibited proliferation and delayed the G1 to S cell cycle progression in MDA-MB-231 and BT549 cells. IL-8 silencing resulted in the upregulation of the CDK inhibitor p27, the downregulation of cyclin D1, and the reduction of phosphorylated-Akt and NF-kappaB activities. IL-8 depletion also increased the chemosensitivity to docetaxel. These results indicate a role for IL-8 in promoting tumor cell survival and resistance to docetaxel and highlight the potential therapeutic significance of IL-8 depletion in ER-negative breast cancer patients.

 

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[231]

TÍTULO / TITLE:  - Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncogene. 2013 Jan 28. doi: 10.1038/onc.2012.636.

            ●● Enlace al texto completo (gratuito o de pago) 1038/onc.2012.636

AUTORES / AUTHORS:  - Kong W; He L; Richards EJ; Challa S; Xu CX; Permuth-Wey J; Lancaster JM; Coppola D; Sellers TA; Djeu JY; Cheng JQ

INSTITUCIÓN / INSTITUTION:  - Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

RESUMEN / SUMMARY:  - MicroRNA-155 (miR-155) is frequently upregulated in various types of human cancer; however, its role in cancer angiogenesis remains unknown. Here, we demonstrate the role of miR-155 in angiogenesis through targeting von Hippel-Lindau (VHL) tumour suppressor in breast cancer. Ectopic expression of miR-155 induced whereas knockdown of miR-155 inhibited human umbilical vein endothelial cell network formation, proliferation, invasion and migration. Furthermore, mammary fat pad xenotransplantation of ectopically expressed miR-155 resulted in extensive angiogenesis, proliferation, tumour necrosis and recruitment of pro-inflammatory cells such as tumour-associated macrophages. Expression of VHL abrogated these miR-155 effects. Moreover, miR-155 expression inversely correlates with VHL expression level and is associated with late-stage, lymph node metastasis and poor prognosis, as well as triple-negative tumour in breast cancer. These findings indicate that miR-155 has a pivotal role in tumour  angiogenesis by downregulation of VHL, and provide a basis for miR-155-expressing tumours to embody an aggressive malignant phenotype, and therefore miR-155 is an  important therapeutic target in breast cancer.Oncogene advance online publication, 28 January 2013; doi:10.1038/onc.2012.636.

 

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[232]

TÍTULO / TITLE:  - Kallikrein-related peptidase 4 (KLK4) mRNA predicts short-term relapse in colorectal adenocarcinoma patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2013 Mar 1;330(1):106-12. doi: 10.1016/j.canlet.2012.11.036. Epub 2012 Nov 29.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2012.11.036

AUTORES / AUTHORS:  - Kontos CK; Chantzis D; Papadopoulos IN; Scorilas A

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry and Molecular Biology, University of Athens, Athens, Greece.

RESUMEN / SUMMARY:  - The members of the kallikrein-related peptidase (KLK) family are aberrantly expressed in cancer, including colorectal adenocarcinoma. KLK4 is an endogenous activator of protease-activated receptor 1 (PAR1) in HT-29 colorectal adenocarcinoma cells, inducing PAR1 signaling and subsequent ERK1/2 activation. The aim of this study was to analyze KLK4 mRNA expression in colorectal adenocarcinoma and to examine its prognostic value as a novel molecular tissue biomarker in this malignancy. Therefore, total RNA was isolated from primary tumors of 81 colorectal adenocarcinoma patients, cDNA was prepared, and KLK4 mRNA expression analysis was performed using quantitative real-time PCR. KLK4 mRNA was significantly associated with the Dukes stage, tumor invasion, size, and histological grade. Survival analysis demonstrated that KLK4 mRNA expression constitutes an unfavorable prognostic biomarker in colorectal adenocarcinoma, predicting poor disease-free survival (DFS), independently of the nodal status and tumor size. Furthermore, KLK4 mRNA predicts short-term relapse of lymph node-negative patients or those with tumors of early Dukes stage. In conclusion,  KLK4 mRNA expression can be regarded as a novel potential tissue biomarker in colorectal adenocarcinoma.

 

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[233]

TÍTULO / TITLE:  - Observation Versus Adjuvant Radiation or Chemotherapy in the Management of Stage  I Seminoma: Clinical Outcomes and Prognostic Factors for Relapse in a Large US Cohort.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Clin Oncol. 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1097/COC.0b013e318277d839

AUTORES / AUTHORS:  - Soper MS; Hastings JR; Cosmatos HA; Slezak JM; Wang R; Lodin K

INSTITUCIÓN / INSTITUTION:  - *Department of Radiation Oncology, Kaiser Permanente Los Angeles Medical Center,  Los Angeles daggerDepartment of Research and Evaluation, Southern California Permanente Medical Group, Pasadena, CA.

RESUMEN / SUMMARY:  - PURPOSE:: The management of stage I seminoma has evolved over the past 20 years.  Contemporary management options after orchiectomy include adjuvant radiation, adjuvant chemotherapy, and observation. This analysis defines the experience at Kaiser Permanente Southern California from 1990 to 2010. We examined outcomes for stage I seminoma patients and reviewed prognostic factors for recurrence in those managed with observation. MATERIALS AND METHODS:: This is a retrospective study of 502 stage I seminoma patients who underwent orchiectomy from 1990 to 2010. Outcomes examined were relapse-free survival (RFS), overall survival (OS), and cause-specific survival (CSS). Risk factors for recurrence evaluated were age, preoperative hCG elevation, preoperative LDH elevation, tumor size, lymphovascular invasion, rete testis invasion, epididymis invasion, and invasion  through the tunica albuginea. RESULTS:: Among radiation patients, 5-year RFS was  97.2%, OS was 98.0%, and CSS was 99.3%. Among chemotherapy patients, 2-year RFS was 98.3% and OS and CSS were 100%. Among observation patients, 5-year RFS was 89.2%, OS was 98.8%, and CSS was 100%. There was no difference in OS or CSS among the groups. RFS was significantly lower for observation patients. Among observation patients, univariate analysis identified tumor size, lymphovascular invasion, and rete testis invasion as risk factors for relapse. No factors were significant on multivariate analysis. CONCLUSIONS:: Our data show that adjuvant radiation and chemotherapy yield similar outcomes in the management of stage I seminoma. Observation results in a lower RFS, but patients who relapse can be salvaged; OS and CSS are not affected.

 

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[234]

TÍTULO / TITLE:  - Differential regulation of apoptosis-associated genes by estrogen receptor alpha  in human neuroblastoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Restor Neurol Neurosci. 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 3233/RNN-120272

AUTORES / AUTHORS:  - Brendel A; Felzen V; Morawe T; Manthey D; Behl C

INSTITUCIÓN / INSTITUTION:  - Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

RESUMEN / SUMMARY:  - Purpose: The neuroendocrinology of female sex hormones is of great interest for a variety of neuropsychiatric disorders. In fact, estrogens and estrogen receptors  (ERs) exert neuromodulatory and neuroprotective functions. Here we investigated potential targets of the ER subtype alpha that may mediate neuroprotection and focused on direct modulators and downstream executors of apoptosis. Methods: We employed subclones of human neuroblastoma cells (SK-N-MC) stably transfected with one of the ER subtypes, ERalpha or ERbeta. Differences between the cell lines regarding the mRNA expression levels were examined by qPCR, changes on protein levels were examined by Western Blot and immunocytochemistry. Differences concerning apoptosis induction were analysed by cell survival assays which included primary rat neurons. Results: In this report we show a potent protection against apoptosis-stimuli in ERalpha expressing cells compared to controls lacking ERalpha. In fact, almost a complete silencing of Caspase 3 expression in  SK-ERalpha cells compared to SK-01 control transfected cells was observed. In addition, prosurvival bcl2, bag1 and bag3 expression was highly up-regulated in the presence of ERalpha. Conclusion: Taken together, we identified Caspase 3, BAG1 and BAG3 as key targets of ERalpha in neuronal cells that may play a role in ERalpha-mediated neuroprotection.

 

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[235]

TÍTULO / TITLE:  - Activation of AMP-activated Protein Kinase and Phosphorylation of Glycogen Synthase Kinase3 beta Mediate Ursolic Acid Induced Apoptosis in HepG2 Liver Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Phytother Res. 2013 Jan 16. doi: 10.1002/ptr.4925.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ptr.4925

AUTORES / AUTHORS:  - Son HS; Kwon HY; Sohn EJ; Lee JH; Woo HJ; Yun M; Kim SH; Kim YC

INSTITUCIÓN / INSTITUTION:  - College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Korea.

RESUMEN / SUMMARY:  - Despite the antitumour effect of ursolic acid observed in several cancers, the underlying mechanism remains unclear. Thus, in the present study, the roles of AMP-activated protein kinase (AMPK) and glycogen synthase kinase 3 beta (GSK3beta) were examined in ursolic acid induced apoptosis in HepG2 hepatocellular carcinoma cells. Ursolic acid significantly exerted cytotoxicity,  increased the sub-G1 population and the number of ethidium homodimer and terminal deoxynucleotidyl transferase(TdT) mediated dUTP nick end labeling positive cells  in HepG2 cells. Also, ursolic acid enhanced the cleavages of poly-ADP-ribose polymerase (PARP) and caspase3, attenuated the expression of astrocyte elevated gene (AEG1) and survivin in HepG2 cells. Interestingly, ursolic acid increased the phosphorylation of AMPK and coenzyme A carboxylase and also enhanced phosphorylation of GSK3beta at inactive form serine 9, whereas ursolic acid attenuated the phosphorylation of AKT and mTOR in HepG2 cells. Conversely, AMPK inhibitor compound C or GSK3beta inhibitor SB216763 blocked the cleavages of PARP and caspase 3 induced by ursolic acid in HepG2 cells. Furthermore, proteosomal inhibitor MG132 suppressed AMPK activation, GSK3beta phosphorylation, cleaved PARP and deceased AEG-1 induced by ursolic acid in HepG2 cells. Overall, our findings suggest that ursolic acid induced apoptosis in HepG2 cells via AMPK activation and GSK3beta phosphorylation as a potent chemopreventive agent. Copyright © 2013 John Wiley & Sons, Ltd.

 

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[236]

TÍTULO / TITLE:  - Soluble FAS in the prediction of benefit from cetuximab and irinotecan for patients with advanced colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):428. doi: 10.1007/s12032-012-0428-0. Epub 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0428-0

AUTORES / AUTHORS:  - Codony-Servat J; Garcia-Albeniz X; Pericay C; Alonso V; Escudero P; Fernandez-Martos C; Gallego R; Martinez-Cardus A; Martinez-Balibrea E; Maurel J

INSTITUCIÓN / INSTITUTION:  - Medical Oncology Department, Hospital Clinic Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Catalonia, España, jordicodonyservat@yahoo.es.

RESUMEN / SUMMARY:  - The FAS/FASL system, comprising membrane-bound (mFAS and mFASL) and soluble forms (sFAS and sFASL), has been related to apoptosis driven by chemotherapy administration. In vitro experiments show chemotherapy upregulating membrane-bound forms, leading to an increase of receptor availability (at 24-72 h) and favoring apoptosis. The regulatory effect of chemotherapy on sFAS in patients has never been explored prospectively in advanced colorectal cancer (ACRC). We performed a pharmacodynamic study to address sFAS/sFASL variation. A prospective phase II translational multicenter study was designed to evaluate progression-free rate (PFR) in patients with ACRC treated with irinotecan and cetuximab in third-line therapy. The effect of sFAS was studied in vitro in colorectal cancer cell lines. Our results showed that statistically significant changes were observed in sFAS at 24-72 h compared to baseline levels in the pharmacodynamic study. Of the 93 patients enrolled in the prospective study in third-line therapy with cetuximab-irinotecan, 85 were evaluated for sFAS/sFASL changes at 48 h. There was no difference in PFR at 4 months between patients with sFAS and sFASL changes. In vitro analysis showed that although LoVo cell lines were sensitive to oxaliplatin and fluorouracil due to modulation of sFAS and FAS, HT29 lines were not. In summary, chemotherapy regulates FAS soluble fractions in  vitro and in vivo, but does not predict PFR in ACRC patients undergoing third-line therapy with the combination of cetuximab and irinotecan.

 

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[237]

TÍTULO / TITLE:  - Triptolide induced DNA damage in A375.S2 human malignant melanoma cells is mediated via reduction of DNA repair genes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):613-8. doi: 10.3892/or.2012.2170. Epub 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2170

AUTORES / AUTHORS:  - Chueh FS; Chen YL; Hsu SC; Yang JS; Hsueh SC; Ji BC; Lu HF; Chung JG

INSTITUCIÓN / INSTITUTION:  - Departments of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan, ROC.

RESUMEN / SUMMARY:  - Numerous studies have demonstrated that triptolide induces cell cycle arrest and  apoptosis in human cancer cell lines. However, triptolide-induced DNA damage and  inhibition of DNA repair gene expression in human skin cancer cells has not previously been reported. We sought the effects of triptolide on DNA damage and associated gene expression in A375.S2 human malignant melanoma cells in vitro. Comet assay, DAPI staining and DNA gel electrophoresis were used for examining DNA damage and results indicated that triptolide induced a longer DNA migration smear based on single cell electrophoresis and DNA condensation and damage occurred based on the examination of DAPI straining and DNA gel electrophoresis.  The real-time PCR technique was used to examine DNA damage and repair gene expression (mRNA) and results indicated that triptolide led to a decrease in the  ataxia telangiectasia mutated (ATM), ataxia-telangiectasia and Rad3-related (ATR), breast cancer 1, early onset (BRCA-1), p53, DNA-dependent serine/threonine protein kinase (DNA-PK) and O6-methylguanine-DNA methyltransferase (MGMT) mRNA expression. Thus, these observations indicated that triptolide induced DNA damage and inhibited DNA damage and repair-associated gene expression (mRNA) that may be factors for triptolide-mediated inhibition of cell growth in vitro in A375.S2 cells.

 

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[238]

TÍTULO / TITLE:  - HIF-2alpha inhibits hepatocellular carcinoma growth through the TFDP3/E2F1-dependent apoptotic pathway.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hepatology. 2012 Dec 5. doi: 10.1002/hep.26188.

            ●● Enlace al texto completo (gratuito o de pago) 1002/hep.26188

AUTORES / AUTHORS:  - Sun HX; Xu Y; Yang XR; Wang WM; Bai H; Shi RY; Nayar SK; Devbhandari RP; He YZ; Zhu QF; Sun YF; Hu B; Khan M; Anders RA; Fan J

INSTITUCIÓN / INSTITUTION:  - Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai 200032, P.  R. China; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Division of Gastrointestinal and Liver Pathology,  Baltimore, MD 21205, USA.

RESUMEN / SUMMARY:  - Hypoxia inducible factors (HIFs) are activated in many tumors and show either promoter or suppressor activity depending on the tumor cell biology and background. However, the role of HIF member HIF-2alpha remains unclear in hepatocellular carcinoma (HCC). Here, HIF-2alpha expression was measured in HCC and paired peritumoral tissues by qRT-PCR, western blot analysis, and immunofluorescence assays, and the clinical significance was explored in 246 HCC  patients. In cell culture, HIF-2alpha levels were over-expressed or knocked-down  by use of expression or short hairpin RNA recombinant plasmid respectively. Cells were analyzed by immunoblot, chromatin immunoprecipitation coupled with microarray, co-immunoprecipitation, and histochemical staining. In vivo tumor growth was analyzed in nude mice. We found that the average expression of HIF-2alpha was relatively low in HCC tissues, and the decreased level was associated with lower overall survival (p=0.006). High HIF-2alpha expression in HCC cells induced higher levels of apoptosis and expression of pro-apoptotic proteins, and it inhibited cell and tumor growth. Furthermore, HIF-2alpha inhibited expression of the novel target gene transcription factor dimerization partner 3 (TFDP3). TFDP3 protein was found to bind with E2F transcription factor  1 (E2F1) and inhibit its transcriptional activity through both p53-dependent and  -independent pathways. Re-introduction of TFDP3 expression reversed HIF-2alpha-induced apoptosis. Conclusions: Data gathered from cell lines, tumorigenicity studies, and primary HCC samples demonstrate a negative role of HIF-2alpha in tumors, which is mediated by the TFDP3/E2F1 pathway. Our study provides evidence supporting a possible tumor suppressor role for HIF-2alpha and  has uncovered a mechanism that links HIF-2alpha to a fundamental biological regulator, E2F1. (HEPATOLOGY 2012.).

 

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[239]

TÍTULO / TITLE:  - Predictors for Locoregional Recurrence for Clinical Stage III-N2 Non-small Cell Lung Cancer with Nodal Downstaging After Induction Chemotherapy and Surgery.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Surg Oncol. 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1245/s10434-012-2800-x

AUTORES / AUTHORS:  - Amini A; Lou F; Correa AM; Baldassarre R; Rimner A; Huang J; Roth JA; Swisher SG; Vaporciyan AA; Lin SH

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

RESUMEN / SUMMARY:  - PURPOSE: Pathologic downstaging following chemotherapy for stage III-N2 NSCLC is  a well-known positive prognostic indicator. However, the predictive factors for locoregional recurrence (LRR) in these patients are largely unknown. METHODS: Between 1998 and 2008, 153 patients with clinically or pathologically staged III-N2 NSCLC from two cancer centers in the United States were treated with induction chemotherapy and surgery. All had pathologic N0-1 disease, and none received postoperative radiotherapy. LRR were defined as recurrence at the surgical site, lymph nodes (levels 1-14 including supraclavicular), or both. RESULTS: Median follow-up was 39.3 months. Pretreatment N2 status was confirmed pathologically (18.2 %) or by PET/CT (81.8 %). Overall, the 5-year LRR rate was 30.8 % (n = 38), with LRR being the first site of failure in 51 % (22/+99877943). Five-year overall survival for patients with LRR compared with those without was  21 versus 60.1 % (p < 0.001). Using multivariate analysis, significant predictors for LRR were pN1 disease at time of surgery (p < 0.001, HR 3.43, 95 % CI 1.80-6.56) and a trend for squamous histology (p = 0.072, HR 1.93, 95 % CI 0.94-3.98). Five-year LRR rate for pN1 versus pN0 disease was 62 versus 20 %. Neither single versus multistation N2 disease (p = 0.291) nor initial staging technique (p = 0.306) were predictors for LRR. N1 status also was predictive for  higher distant recurrence (p = 0.021, HR 1.91, 95 % CI 1.1-3.3) but only trended  for poorer survival (p = 0.123, HR 1.48, 95 % CI 0.9-2.44). CONCLUSIONS: LRR remains high in resected stage III-N2 NSCLC patients after induction chemotherapy and nodal downstaging, particularly in patients with persistent N1 disease.

 

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[240]

TÍTULO / TITLE:  - FoxP3 inhibits proliferation and induces apoptosis of gastric cancer cells by activating the apoptotic signaling pathway.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 11;430(2):804-9. doi: 10.1016/j.bbrc.2012.11.065. Epub 2012 Nov 29.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.11.065

AUTORES / AUTHORS:  - Ma GF; Chen SY; Sun ZR; Miao Q; Liu YM; Zeng XQ; Luo TC; Ma LL; Lian JJ; Song DL

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China.

RESUMEN / SUMMARY:  - Forkhead Box Protein 3 (FoxP3) was identified as a key transcription factor to the occurring and function of the regulatory T cells (Tregs). However, limited evidence indicated its function in tumor cells. To elucidate the precise roles and underlying molecular mechanism of FoxP3 in gastric cancer (GC), we examined the expression of FoxP3 and the consequences of interfering with FoxP3 gene in human GC cell lines, AGS and MKN45, by multiple cellular and molecular approaches, such as immunofluorescence, gene transfection, CCK-8 assay, clone formation assay, TUNEL assay, Flow cytometry, immunoassay and quantities polymerase chain reaction (PCR). As a result, FoxP3 was expressed both in nucleus and cytoplasm of GC cells. Up-regulation of FoxP3 inhibited cell proliferation and promoted cell apoptosis. Overexpression of FoxP3 increased the protein and mRNA levels of proapoptotic molecules, such as poly ADP-ribose polymerase1 (PARP), caspase-3 and caspase-9, and repressed the expression of antiapoptotic molecules, such as cellular inhibitor of apoptosis-1 (c-IAP1) and the long isoform of B cell leukemia/lymphoma-2 (Bcl-2). Furthermore, silencing of FoxP3 by siRNA in GC cells reduced the expression of proapoptotic genes, such as PARP, caspase-3 and caspase-9. Collectively, our findings identify the novel roles of FoxP3 in inhibiting proliferation and inducing apoptosis in GC cells by regulating apoptotic signaling, which could be a promising therapeutic approach for gastric cancer.

 

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[241]

TÍTULO / TITLE:  - The presence of mutations in epidermal growth factor receptor gene is not a prognostic factor for long-term outcome after surgical resection of non-small-cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Thorac Oncol. 2013 Feb;8(2):171-8. doi: 10.1097/JTO.0b013e318277a3bb.

            ●● Enlace al texto completo (gratuito o de pago) 1097/JTO.0b013e318277a3bb

AUTORES / AUTHORS:  - Kim YT; Seong YW; Jung YJ; Jeon YK; Park IK; Kang CH; Kim JH

INSTITUCIÓN / INSTITUTION:  - *Department of Thoracic and Cardiovascular Surgery, Clinical Research Institute,  Seoul National University Hospital, Seoul, Korea; daggerGenomic Medicine Institute, Medical Research Center and Cancer Research Institute, double daggerDepartment of Pathology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

RESUMEN / SUMMARY:  - BACKGROUND: : The presence of mutation in EGFR gene is known as a predictive marker for the response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. However, whether or not these EGFR mutations are prognostic factors for non-small-cell lung cancer (NSCLC) is debatable. METHODS: : We retrospectively collected a series of samples from patients whose EGFR mutation status had been tested, and analyzed their survival. The pathologic cell types of 863 patients (520 men, 343 women) were squamous cell carcinoma in 227, adenocarcinoma in 636 patients. RESULTS: : EGFR mutations were detected in 354 patients and it was frequently observed in adenocarcinoma in younger, early-stage, female never-smokers. In univariate analysis of younger, early-stage, never-smoker women, bronchioloalveolar carcinoma pattern and the presence of EGFR mutation showed better long-term survival. However, in multivariate analysis, age, pathologic stage, and smoking status remained significant prognostic factors, whereas EGFR mutation was not. For recurrence, pathologic stage was the only independent prognostic factor. After recurrence, smoking status was the only significant risk factor that affected postrecurrence  survival. However, when EGFR TKIs were used in EGFR-mutated patients, survival was longer than for those treated with conventional chemotherapy. CONCLUSIONS: :  Although the EGFR mutation is a predictive marker for EGFR TKI response, it is not a prognostic factor in NSCLC. The clinical observation that patients with EGFR mutation seem to survive longer may be because EGFR mutation is more frequently associated with other good prognostic factors. Once there is a recurrence, administration of EGFR TKI for patients with EGFR mutation may increase survival.

 

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[242]

TÍTULO / TITLE:  - Leucine-rich repeat-containing G protein-coupled receptor 5 expression in ductular reactions after chemotherapy for metastatic colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hepatol Res. 2013 Jan;43(1):84-90. doi: 10.1111/j.1872-034X.2012.01048.x.

            ●● Enlace al texto completo (gratuito o de pago) 1111/j.1872-034X.2012.01048.x

AUTORES / AUTHORS:  - Saigusa S; Tanaka K; Toiyama Y; Matsushita K; Kawamura M; Okugawa Y; Uchida K; Inoue Y; Mohri Y; Kusunoki M

INSTITUCIÓN / INSTITUTION:  - Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie. Japan.

RESUMEN / SUMMARY:  - Aim: Oval cells with ductular reactions (DR) in damaged liver are referred to as  “intermediate hepatobiliary cells”. In a preliminary study, we had found expression of the leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) known as a potential marker for stem cells in the small intestine and colon in DR in liver damaged by chemotherapy for metastatic colorectal cancer (CRC). The aim of this study was to confirm LGR expression in DR in damaged liver after chemotherapy. Methods: A total of 68 liver specimens obtained after surgical resection were stained with monoclonal antibodies for cytokeratin (CK)7, neural cell adhesion molecule (NCAM; a bile ductular and liver progenitor cell marker), CD133 (a candidate stem cell marker of hepatocellular carcinoma as well  as CRC) and LGR5. Additionally, these mRNA levels were investigated according to  the location in damaged liver after chemotherapy using microdissected specimens.  Results: We observed that LGR5 was expressed in DR with CD133, CK7 and NCAM expression. By contrast, LGR5, CD133 and NCAM were not expressed in mature bile ducts with CK7. In transcriptional analysis, LGR5 mRNA levels in fibrotic tissue  including DR were higher compared with that in adjacent normal liver without significant difference. Conclusion: These findings suggest that LGR5 may be involved in maintaining DR in damaged liver.

 

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[243]

TÍTULO / TITLE:  - MR Imaging for the Prediction of Breast Cancer Response to Neoadjuvant Chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Radiology. 2013 Jan;266(1):367. doi: 10.1148/radiol.12121371.

            ●● Enlace al texto completo (gratuito o de pago) 1148/radiol.12121371

AUTORES / AUTHORS:  - Hall FM; Hylton N

INSTITUCIÓN / INSTITUTION:  - Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215.

 

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[244]

TÍTULO / TITLE:  - Antiproliferative and apoptotic effects of the oxidative dimerization product of  methyl caffeate on human breast cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Bioorg Med Chem Lett. 2013 Jan 15;23(2):574-8. doi: 10.1016/j.bmcl.2012.11.009. Epub 2012 Nov 22.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bmcl.2012.11.009

AUTORES / AUTHORS:  - Bailly F; Toillon RA; Tomavo O; Jouy N; Hondermarck H; Cotelle P

INSTITUCIÓN / INSTITUTION:  - Universite Lille 1, EA4478, F-59650 Villeneuve d’Ascq, France.

RESUMEN / SUMMARY:  - Caffeic acid derivatives are increasingly regarded as potential oncoprotective that could inhibit both the initiation and progression of cancer. Here we have synthesized seven 1-arylnaphthalene lignans and related compounds and tested their impact on breast cancer cell growth in tissue culture. The product of the oxidative dimerization of methyl caffeate, 1-phenylnaphthalene lignan, was found  to induce a strong decrease in breast cancer cell number (IC(50) approximately 1muM) and was selected for further investigation. Flow cytometry analysis revealed a decrease in cell proliferation and an increase in apoptosis in both MCF-7 and MDA-MB-231 breast cancer cell lines that are representative of the two  main categories of breast tumors. The 3,4-dihydroxyphenyl group probably induced  the biological activity, as the control compounds lacking it had no effect on breast cancer cells. Together, our data indicate that the oxidative dimerization  product of methyl caffeate can inhibit breast cancer cell growth at a concentration adequate for pharmacological use.

 

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[245]

TÍTULO / TITLE:  - Impact of preoperative serum interleukin-2 receptor alpha levels on survival and  its correlation with clinicopathological parameters in colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Colorectal Dis. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00384-012-1638-9

AUTORES / AUTHORS:  - Liu X; Zhang Y; Zhang J; Zhu Z; Ha M; Liu C

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Liaoning University of Traditional Chinese Medicine, No.79 Chongshan Road, Huanggu District, Shenyang, 110032, People’s Republic of China.

 

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[246]

TÍTULO / TITLE:  - Combined Treatment with Erlotinib and a Transforming Growth Factor-beta Type I Receptor Inhibitor Effectively Suppresses the Enhanced Motility of Erlotinib-Resistant Non-Small-Cell Lung Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Thorac Oncol. 2013 Jan 17.

            ●● Enlace al texto completo (gratuito o de pago) 1097/JTO.0b013e318279e942

AUTORES / AUTHORS:  - Serizawa M; Takahashi T; Yamamoto N; Koh Y

INSTITUCIÓN / INSTITUTION:  - *Drug Discovery and Development Division, and daggerDivision of Thoracic Oncology, Shizuoka Cancer Center Hospital, Shizuoka, Japan.

RESUMEN / SUMMARY:  - INTRODUCTION:: Despite an initial dramatic response to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, the majority of non-small cell lung cancer (NSCLC) patients with EGFR-activating  mutations develop acquired resistance. Therefore, there is an urgent need to elucidate the unknown mechanisms and biological behaviors of EGFR TKI-resistant lung tumors. We investigated the motility of EGFR TKI-resistant cells, as these characteristics are relevant to cancer metastasis. METHODS:: Erlotinib-resistant  PC-9ER cells were generated from PC-9 NSCLC cells, which harbor an EGFR-activating mutation, and used in this study. We investigated the involvement of the transforming growth factor beta (TGF-beta) pathway in cell motility, and tested the effects of erlotinib and TGF-beta type I receptor (RI) inhibition on cell motility. RESULTS:: PC-9ER cells displayed enhanced motility resulting from  autocrine activation of the TGF-beta pathway. Increased TGF-beta2 secretion resulting from TGF-beta2 up-regulation at the transcriptional level was suggested to be responsible for the phosphorylation of Smad2 and the subsequently elevated  transcriptional regulatory activity in PC-9ER cells. The motility of PC-9ER cells was suppressed by treatment with either the TGF-betaRI inhibitor LY364947 or erlotinib, and greater suppression was observed when used in combination. LY364947 or erlotinib exerted no growth-inhibitory effects, suggesting that motility and growth are driven by different signaling pathways in PC-9ER cells. CONCLUSIONS:: Our results imply that blockade of the TGF-beta signaling pathway combined with continuous EGFR TKI treatment will be beneficial in preventing metastasis in patients with EGFR TKI-resistant NSCLC without the EGFR T790M resistance mutation.

 

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[247]

TÍTULO / TITLE:  - Inhibition of the Wnt-beta-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 3. pii: S0006-291X(12)02478-3. doi: 10.1016/j.bbrc.2012.12.118.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.12.118

AUTORES / AUTHORS:  - Ma Y; Ren Y; Han EQ; Li H; Chen D; Jacobs JJ; Gitelis S; O’Keefe RJ; Konttinen YT; Yin G; Li TF

INSTITUCIÓN / INSTITUTION:  - Department of Orthopaedics, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China.

RESUMEN / SUMMARY:  - Osteosarcoma (OS) is one of the most common malignant bone tumors in early adolescence. Multi-drug chemotherapy has greatly increased the five year survival rate from 20% to 70%. However, the rate has been staggering for 30years and the prognosis is particularly poor for patients with recurrence and metastasis. Our study aimed to investigate the role of Wnt-beta-catenin, Notch and Hedgehog pathway in OS development because all these pathways are involved in skeletal development, tumorigenesis and chemoresistance. Our results showed that the major components in Wnt-beta-catenin pathway, e.g. Wnt3a, beta-catenin and Lef1, were consistently upregulated in human osteosarcoma cell line Saos2 cells compared to  human fetal osteoblasts (hFOB), whereas the changes in the expression levels of Notch and Hh signaling molecules were not consistent. Knocking down beta-catenin  increased the Saos2 sensitivity to methotrexate (MTX) induced cell death. Consistently, the expression level of beta-catenin protein correlated with the invasiveness of OS, as evidenced by more intensive beta-catenin immunoreactivity  in higher grade OS samples. Chemical inhibition of the Wnt-beta-catenin signaling enhanced MTX mediated death of Saos2 cells. A synergistic effect with MTX was observed when both inhibitors for Wnt-beta-catenin and Notch pathways were simultaneously used, while the addition of the Hh inhibitor did not further improve the efficacy. Our findings provide some novel insight to OS pathogenesis  and lay a foundation for future application of Wnt-beta-catenin and Notch inhibitors together with the currently used chemotherapeutic drugs to improve the outcome of OS treatment.

 

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[248]

TÍTULO / TITLE:  - Effect of tumor suppressor PTEN gene on apoptosis and cell cycle of human airway  smooth muscle cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Cell Biochem. 2013 Mar;375(1-2):1-9. doi: 10.1007/s11010-012-1484-7. Epub 2012 Dec 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11010-012-1484-7

AUTORES / AUTHORS:  - Luo L; Gong YQ; Qi X; Lai W; Lan H; Luo Y

INSTITUCIÓN / INSTITUTION:  - Department of Medical Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhong Shan Er Road, Guangzhou, People’s Republic of China.

RESUMEN / SUMMARY:  - It is well established that hyperplasia and decreased apoptosis of airway smooth  muscle cells (ASMCs) play an important role in the asthmatic airway remodeling. Tumor suppressor PTEN gene with phosphatase activity plays an important regulatory role in embryonic development, cell proliferation, and apoptosis, cell cycle regulation, migration (invasion) of the cytoskeleton. We hypotheses that PTEN gene could affect the growth and viability of ASMCs through the regulation of PI3K/Akt, MAPK, and cell cycle-related gene expression. We constructed a recombinant adenovirus to transfect ASMCs. Cells were divided into the overexpression of PTEN gene group (Ad-PTEN-GFP), negative control group (Ad-GFP), and blank control group (DMEM). The cell apoptosis of ASMCs were evaluated by Hoechst-33342 staining and PE-7AAD double-labeled flow cytometry. The cell cycle  distribution was observed by flow cytometry with PI staining. The expression of PTEN, p-Akt, total-Akt, p-ERK1/2, total-ERK1/2, cleaved-Caspases-3, Caspases-9, p21, and Cyclin D1 were tested by the Western blotting. Our study revealed that overexpression of PTEN gene did not induce apoptosis of human ASMCs cultured in vitro. However, overexpression of PTEN inhibited proliferation of human ASMCs cultured in vitro and was associated with downregulation of Akt phosphorylation levels, while did not affect ERK1/2 phosphorylation levels. Moreover, overexpression of PTEN could induce ASMCs arrested in the G0/G1 phase through the downregulation of Cyclin D1 and upregulation of p21 expressions.

 

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[249]

TÍTULO / TITLE:  - Fucoidan induces changes in the epithelial to mesenchymal transition and decreases metastasis by enhancing ubiquitin-dependent TGFbeta receptor degradation in breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Carcinogenesis. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1093/carcin/bgs396

AUTORES / AUTHORS:  - Hsu HY; Lin TY; Hwang PA; Tseng LM; Chen RH; Tsao SM; Hsu J

INSTITUCIÓN / INSTITUTION:  - Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.

RESUMEN / SUMMARY:  - Fucoidan, a polysaccharide extracted from brown seaweeds, reduces tumor cell proliferation. Fucoidan inhibits the growth of breast cancer cells such as 4T1 and MDA-MB-231 and decreases their cell colony formation. Moreover, fucoidan reduces metastatic lung nodules in 4T1 xenograft female Balb/c mice. The molecular network of transforming growth factor beta (TGFbeta) receptors (TGFRs)  plays an important role in the regulation of the epithelial to mesenchymal transition (EMT) in cancer cells. Using 4T1 and MDA-MB-231 cells, we found that fucoidan effectively reverses TGFR-induced EMT morphological changes, upregulates epithelial markers, downregulates mesenchymal markers and decreases the expression of transcriptional repressors Snail, Slug and Twist. Moreover, fucoidan inhibits migration and invasion during the EMT, suggesting the involvement of TGFR-mediated signaling in breast cancer cells. Fucoidan decreases TGFRI and TGFRII proteins and affects downstream signaling molecules, including Smad2/3 phosphorylation and Smad4 expression. In order to elucidate how fucoidan  decreases TGFRI and TGFRII proteins in MDA-MB-231 cells, we investigated ubiquitination activity downregulation of TGFRs. It was found that fucoidan enhances proteasome-mediated degradation/ubiquitination of TGFR. This study is the first to identify a novel mechanism for fucoidan antitumor activity, namely regulation of the EMT via modulation of TGFR/Smad-dependent signaling, which leads to an inhibition of breast cancer cell growth in vitro and in vivo. Our current findings indicate that fucoidan is a potential therapeutic agent for breast cancer and acts via an ubiquitin-dependent degradation pathway that affects the TGFR/Smad/Snail, Slug, Twist and EMT axes.

 

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[250]

TÍTULO / TITLE:  - Expression of alphavbeta6 integrin and collagen fibre in oral squamous cell carcinoma: association with clinical outcomes and prognostic implications.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Oral Pathol Med. 2013 Jan 18. doi: 10.1111/jop.12044.

            ●● Enlace al texto completo (gratuito o de pago) 1111/jop.12044

AUTORES / AUTHORS:  - Li HX; Zheng JH; Fan HX; Li HP; Gao ZX; Chen D

INSTITUCIÓN / INSTITUTION:  - Department of Anatomy, Basic Medical Science College, Harbin Medical University,  Harbin, China.

RESUMEN / SUMMARY:  - BACKGROUND: This study aims to investigate the expression and significance of the alphavbeta6 integrin, collagen fibres and matrix metalloproteinases (MMP)-3 in oral squamous cell carcinoma (OSCC) and to analyse the possible regulatory relationships between alphavbeta6, collagen fibres and MMP-3. MATERIALS AND METHODS: A series of 80 patients (mean age 56.4 years) diagnosed with OSCC were enrolled. Associations between alphavbeta6, MMP-3, collagen fibre expression levels and clinicopathological parameters were evaluated using the Fisher exact test. Survival analysis was performed with Kaplan-Meier curves. Spearman rank correlation was used to analyse interactions between alphavbeta6, MMP-3 and collagen fibres. RESULTS: alphavbeta6 and MMP-3 were strongly expressed in human  OSCC, especially at the peripheral borders of invasive tumour islands, and collagen fibres were generally disrupted and degraded in the same areas. The expression intensity of alphavbeta6 was associated with the differentiation state of cells. beta6 mRNA was expressed in almost all cancer cells. In carcinomas, alphavbeta6 and MMP-3 expression were correlated with the distribution of collagen fibres. CONCLUSIONS: Tumour cells highly expressing alphavbeta6 have a strong capability for invasion and migration, due to concomitant protease production and the destruction and remodelling of collagen fibres. Increased alphavbeta6 integrin and MMP-3 expression and collagen fibre changes in human OSCCs are related to unfavourable clinical prognostic factors and decreased survival.

 

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[251]

TÍTULO / TITLE:  - Inhibition of lymphangiogenic factor VEGF-C expression and production by the histone deacetylase inhibitor suberoylanilide hydroxamic acid in breast cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar;29(3):1238-44. doi: 10.3892/or.2012.2188. Epub 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2188

AUTORES / AUTHORS:  - Cheng HT; Hung WC

INSTITUCIÓN / INSTITUTION:  - Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, R.O.C.

RESUMEN / SUMMARY:  - Suberoylanilide hydroxamic acid (SAHA), a potent histone deacetylase (HDAC) inhibitor, has been shown to exert anticancer effects in various types of human cancer and is now used in the clinic for cancer treatment. In addition to cytostatic and cytotoxic activities, SAHA also represses angiogenesis to inhibit  tumor growth. However, the effect of SAHA on tumor lymphangiogenesis, a step in which cancer cells produce pro-lymphangiogenic factors such as vascular endothelial growth factor-C (VEGF-C) to stimulate proliferation and migration of  lymphatic endothelial cells, remains largely unclear. In this study, we investigated the expression of VEGF-C in breast cancer cell lines and found that  VEGF-C was highly expressed in MDA-MB-231, MCF-7, MDA-MB-453 and BT-474 cells. SAHA inhibited VEGF-C expression in a dose-dependent manner in these cell lines.  The secretion of VEGF-C into conditioned medium was also suppressed. We cloned human VEGF-C gene promoter and demonstrated that SAHA directly repressed promoter activity in MDA-MB-231 cells. Promoter deletion assay suggested that SAHA repressed VEGF-C via the -185/+38 region which contained several transcription factor binding sites. Notably, we found that SAHA reduced Sp1, but not Sp3 and NF-kappaB protein levels. Treatment with Sp1 inhibitor mithramycin A also inhibited VEGF-C expression in breast cancer cells. In addition, enforced expression of Sp1 partially rescued the inhibition of VEGF-C by SAHA. Collectively, our results suggest that SAHA inhibits VEGF-C expression in breast  cancer cells via transcriptional repression and this drug may exert anti-lymphangiogenic activity in cancer treatment.

 

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[252]

TÍTULO / TITLE:  - 5’benzylglycinyl-amiloride kills proliferating and non-proliferating malignant glioma cells through caspase-independent necroptosis mediated by apoptosis-inducing factor.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Pharmacol Exp Ther. 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 1124/jpet.112.200519

AUTORES / AUTHORS:  - Pasupuleti N; Leon L; Carraway KL; Gorin FA

INSTITUCIÓN / INSTITUTION:  - University of California, Davis.

RESUMEN / SUMMARY:  - 5’benzylglycinyl-amiloride (UCD38B) and glycinyl-amiloride (UCD74A) are cell permeant and cell impermeant derivatives of Amiloride, respectively, and used here to identify the cellular mechanisms of action underlying their anti-glioma effects. UCD38B comparably kills proliferating and non-proliferating gliomas cells when cell cycle progression is arrested either by cyclin D1 siRNA or by acidosis. Cell impermeant UCD74A inhibits plasmalemal urokinase plasminogen activator (uPA) and the type 1 sodium-proton exchanger (NHE1) with potencies analogous to UCD38B, but is cytostatic. In contrast, UCD38B targets intracellular uPA causing mis-trafficking of uPA into perinuclear mitochondria, reducing the mitochondrial membrane potential (MMP), and followed by the release of apoptotic  inducible factor (AIF). AIF nuclear translocation is followed by a caspase-independent necroptotic cell death. Reduction in AIF expression by siRNA  reduces the anti-glioma cytotoxic effects of UCD38B, while not activating the caspase pathway. Ultrastructural changes shortly following treatment with UCD38B  demonstrate dilation of endoplasmic reticulum (ER), mitochondrial swelling followed by nuclear condensation within hours consistent with a necroptotic cell  death differing from apoptosis and from autophagy. These drug mechanism of action studies demonstrated that UCD38B induces a cell cycle independent, caspase-independent necroptotic glioma cell death that is mediated by AIF and independent of PARP and H2AX activation.

 

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[253]

TÍTULO / TITLE:  - Crosstalk between Lysine-specific Demethylase 1 (LSD1) and Histone Deacetylases Mediates Antineoplastic Efficacy of HDAC inhibitors in Human Breast Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Carcinogenesis. 2013 Jan 25.

            ●● Enlace al texto completo (gratuito o de pago) 1093/carcin/bgt033

AUTORES / AUTHORS:  - Vasilatos SN; Katz TA; Oesterreich S; Wan Y; Davidson NE; Huang Y

INSTITUCIÓN / INSTITUTION:  - University of Pittsburgh Cancer Institute; Pittsburgh, PA, USA.

RESUMEN / SUMMARY:  - Our previous studies demonstrated that lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) closely interact in controlling growth of breast cancer cells. However the underlying mechanisms are largely unknown. Here we showed that knockdown of LSD1 expression (LSD1-KD) by RNAi decreased mRNA levels  of HDAC isozymes in triple-negative breast cancer (TNBC) cells. siRNA-mediated depletion of HDAC5 expression induced the most significant accumulation of H3K4me2, a specific substrate of LSD1. Combined treatment with LSD1 inhibitor, Pargyline, and HDAC inhibitor, SAHA (vorinostat), led to superior growth inhibition and apoptotic death in TNBC cells, but exhibited additive or antagonistic effect on growth inhibition in non-TNBC counterparts or non-tumorigenic breast cells. Additionally, LSD1-KD enhanced SAHA-induced reexpression of a subset of aberrantly silenced genes such as NR4A1, PCDH1, RGS16, BIK, and E-cadherin whose reexpression may be tumor-suppressive. Genome-wide microarray study in MDA-MB-231 cells identified a group of tumor suppressor genes whose expression was induced by SAHA and significantly enhanced  by LSD1-KD. We also showed that concurrent depletion of RGS16 by siRNA reduced overall cytotoxicity of SAHA and blocked the reexpression of E-cadherin, CDKN1C and ING1 in LSD1 deficient MDA-MB-231 cells. Furthermore, co-treatment with RGS16 siRNA reversed the down-regulation of NF-kB expression induced by combined inhibition of LSD1 and HDACs, suggesting a crucial role of RGS16 in controlling key pathways of cell death in response to combination therapy. Taken together, these results provide novel mechanistic insight into the breast cancer subtype-dependent role of LSD1 in mediating HDAC activity and therapeutic efficacy of HDAC inhibitor.

 

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[254]

TÍTULO / TITLE:  - Photodynamic Therapy in Combination with Talaporfin Sodium Induces Mitochondrial  Apoptotic Cell Death Accompanied with Necrosis in Glioma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biol Pharm Bull. 2012 Nov 29.

AUTORES / AUTHORS:  - Miki Y; Akimoto J; Yokoyama S; Homma T; Tsutsumi M; Haraoka J; Hirano K; Beppu M

INSTITUCIÓN / INSTITUTION:  - School of Pharmacy, Tokyo University of Pharmacy and Life Sciences.

RESUMEN / SUMMARY:  - Photodynamic therapy (PDT) induces selective cell death of neoplastic tissue and  connecting vasculature by combining photosensitizers with light. Here we clarified the types of cell death induced by PDT in combination with the photosensitizer talaporfin sodium (mono-L-aspartyl chlorine e6, NPe6) in order to evaluate the potential of this therapy as a treatment for glioma. PDT with NPe6 (NPe6-PDT) induces dose-dependent cell death in human glioblastoma T98G cells. Specifically, cell death modalities were observed in NPe6-PDT treated T98G cells, including signs of apoptosis (activation of caspase-3, expression of phosphatidylserine, and DNA fragmentation) and necrosis (stainability of propidium iodide). In addition, high doses of NPe6-PDT decreased the proportion of apoptotic cell death, while increasing necrosis. Closer examination of apoptotic characteristics revealed release of cytochrome-c from mitochondria as well as activation of both caspse-9 and caspase-3 in cells treated with low doses of NPe6-PDT. Z-LEHD-fmk, a caspase-9 specific inhibitor, and Z-DQMD-fmk, a caspase-3 specific inhibitor, showed dose-dependent prevention of cell death in NPe6-PDT treated cells, indicating that mitochondrial apoptotic pathway was a factor in the observed cell death. Further, the cell morphology was observed after PDT. Time- and NPe6-dose dependent necrotic features were increased in NPe6-PDT treated cells. These results suggest that NPe6-PDT could be an effective treatment for glioma if used in mild doses to avoid the increased necrosis that may induce undesirable obstacles.

 

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[255]

TÍTULO / TITLE:  - Proteasome inhibitor MG132 induces NAG-1/GDF15 expression through the p38 MAPK pathway in glioblastoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 25;430(4):1277-82. doi: 10.1016/j.bbrc.2012.11.137. Epub 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.11.137

AUTORES / AUTHORS:  - Shimizu S; Kadowaki M; Yoshioka H; Kambe A; Watanabe T; Kinyamu HK; Eling TE

INSTITUCIÓN / INSTITUTION:  - Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States; Division of Neurosurgery, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Tottori 683-8503, Japan.

RESUMEN / SUMMARY:  - The expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) is regulated by the p53 and Egr-1 tumor suppressor pathways. Many anti-cancer drugs  and chemicals induce NAG-1 expression, but the mechanisms are not fully understood. Transgenic mice expressing human NAG-1 are resistant to intestinal and prostate cancer, suggesting that NAG-1 is a tumor suppressor. Proteasome inhibitors exhibit anti-glioblastoma activities in preclinical studies. Here, we  show that the proteasome inhibitors MG132 and bortezomib induced NAG-1 expression and secretion in glioblastoma cells. MG132 increased NAG-1 expression through transcriptional and post-transcriptional mechanisms. At the transcriptional level, the induction of NAG-1 required the -133 to +41bp region of the promoter.  At post-transcriptional levels, MG132 stabilized NAG-1 mRNA by increasing the half-life from 1.5h to >8h. Because of the dramatic increase in mRNA stability, this is likely the major contributor to MG132-mediated NAG-1 induction. Further probing into the mechanism revealed that MG132 increased phosphorylation of the p38 MAPK pathway. Consequently, inhibiting p38 phosphorylation blocked activation of the NAG-1 promoter and decreased mRNA stability, indicating that p38 MAPK activation mediates both MG132-dependent promoter activation and mRNA stabilization of NAG-1. We propose that the induction of NAG-1 by p38 MAPK is a potential contributor to the anti-glioblastoma activity of proteasome inhibitors.

 

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[256]

TÍTULO / TITLE:  - Histone Deacetylase (HDAC) Inhibitors with a Novel Connecting Unit Linker Region  Reveal a Selectivity Profile for HDAC4 and HDAC5 with Improved Activity against Chemoresistant Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Med Chem. 2013 Jan 24;56(2):427-36. doi: 10.1021/jm301254q. Epub 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 1021/jm301254q

AUTORES / AUTHORS:  - Marek L; Hamacher A; Hansen FK; Kuna K; Gohlke H; Kassack MU; Kurz T

INSTITUCIÓN / INSTITUTION:  - Institut fur Pharmazeutische und Medizinische Chemie, Heinrich Heine Universitat  , Universitatsstrasse 1, 40225 Dusseldorf, Germany.

RESUMEN / SUMMARY:  - The synthesis and biological evaluation of new potent hydroxamate-based HDAC inhibitors with a novel alkoxyamide connecting unit linker region are described.  Biological evaluation includes MTT and cellular HDAC assays on sensitive and chemoresistant cancer cell lines as well as HDAC profiling of selected compounds. Compound 19i (LMK235) (N-((6-(hydroxyamino)-6-oxohexyl)oxy)-3,5-dimethylbenzamide) showed similar effects compared to vorinostat on inhibition of cellular HDACs in a pan-HDAC assay but enhanced cytotoxic effects against the human cancer cell lines A2780, Cal27, Kyse510, and MDA-MB231. Subsequent HDAC profiling yielded a novel HDAC isoform selectivity profile of 19i in comparison to vorinostat or trichostatin A  (TSA). 19i shows nanomolar inhibition of HDAC4 and HDAC5, whereas vorinostat and  TSA inhibit HDAC4 and HDAC5 in the higher micromolar range.

 

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[257]

TÍTULO / TITLE:  - An ent-Kaurane Diterpenoid from Croton tonkinensis Induces Apoptosis by Regulating AMP-Activated Protein Kinase in SK-HEP1 Human Hepatocellular Carcinoma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biol Pharm Bull. 2013;36(1):158-64.

AUTORES / AUTHORS:  - Sul YH; Lee MS; Cha EY; Thuong PT; Khoi NM; Song IS

INSTITUCIÓN / INSTITUTION:  - Surgical Oncology Research Lab., Chungnam National University Hospital.

RESUMEN / SUMMARY:  - Hepatocellular carcinoma (HCC) is the most common type of liver cancer with high  mortality worldwide. Traditional chemotherapy for HCC is not widely accepted by clinical practitioners because of its toxic side effects. Thus, there is a need to identify chemotherapeutic drugs against HCC. AMP-activated protein kinase (AMPK) is a biologic sensor for cellular energy status that acts a tumor suppressor and a potential cancer therapeutic target. The traditional Vietnamese  medicinal plant Croton tonkinensis shows cytotoxicity in various cancer cells; however, its anticancer mechanism remains unclear. In this study, we determined whether the ent-kaurane diterpenoid ent-18-acetoxy-7beta-hydroxy kaur-15-oxo-16-ene (CrT1) isolated from this plant plays a role as a chemotherapeutic drug targeting AMPK. CrT1 blocked proliferation in dose- and time-dependent manners in human hepatocellular carcinoma SK-HEP1 cells. CrT1 induced sub-G(1) arrest and caspase-dependent apoptosis. CrT1 activated caspase-3, -7, -8, -9, and poly(ADP-ribose) polymerase, and its effect was inhibited by z-VAD-fmk suppressing caspase-3 cleavage. CrT1 induced increases in  p53 and Bax levels but decreased Bcl(2) levels. In addition, CrT1 resulted in increased translocation of cytochrome c into the cytoplasm. We showed that CrT1-activated AMPK activation was followed by modulating the mammalian target of rapamycin/p70S6K pathway and was inactivated by treating cells with compound C. Treatment with CrT1 and aminoimidazole carboxamide ribonucleotide (AICAR) synergistically activated AMPK. CrT1-induced AMPK activation regulated cell viability and apoptosis. These results suggest that CrT1 is a novel AMPK activator and that AMPK activation in SK-HEP1 cells is responsible for CrT1-induced anticancer activity including apoptosis.

 

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[258]

TÍTULO / TITLE:  - Melatonin potentiates the antiproliferative and pro-apoptotic effects of ursolic  acid in colon cancer cells by modulating multiple signaling pathways.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Pineal Res. 2012 Dec 8. doi: 10.1111/jpi.12035.

            ●● Enlace al texto completo (gratuito o de pago) 1111/jpi.12035

AUTORES / AUTHORS:  - Wang J; Guo W; Chen W; Yu W; Tian Y; Fu L; Shi D; Tong B; Xiao X; Huang W; Deng W

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.

RESUMEN / SUMMARY:  - Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, is largely distributed in medical herbs and edible plants. Melatonin is an indoleamine compound produced in the pineal gland and also a plant-derived product. Both UA and melatonin have been shown to inhibit cancer cell growth in numerous studies,  but they have never been combined altogether as an anticolon cancer treatment. In this study, we investigated whether the association between UA and melatonin leads to an enhanced antiproliferative and pro-apoptotic activities in colon cancer SW480 and LoVo cells. We found that combined treatment with UA and melatonin significantly enhanced inhibition of cell viability and migration, promoted changes in cell morphology and spreading, and increased induction of apoptosis, thereby potentiating the effects of UA alone in colon cancer cells. Moreover, we found that the enhanced effects of UA and melatonin combination are  mediated through simultaneous modulation of cytochrome c/caspase, MMP9/COX-2, and p300/NF-kappaB signaling pathways. Combined treatment with UA and melatonin triggered the release of cytochrome c from the mitochondrial intermembrane space  into the cytosol, induced cleavage of caspase and PARP proteins, enhanced inhibition of MMP9 and COX-2 expression, promoted p300 and NF-kappaB translocation from cell nuclei to cytoplasm, and abrogated NF-kappaB binding and  p300 recruitment to COX-2 promoter in colon cancer cells. These results, therefore, demonstrated that melatonin potentiated the antiproliferative and pro-apoptotic effects of UA in colon cancer cells by modulating multiple signaling pathways and suggest that such a combinational treatment might potentially become an effective way in colon cancer therapy.

 

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[259]

TÍTULO / TITLE:  - The novel PI3K-mTOR inhibitor, BEZ235, circumvents erlotinib- resistance of EGFR  mutant lung cancer cells triggered by HGF.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Cancer. 2013 Jan 15. doi: 10.1002/ijc.28034.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.28034

AUTORES / AUTHORS:  - Sano T; Takeuchi S; Nakagawa T; Ishikawa D; Nanjo S; Yamada T; Nakamura T; Matsumoto K; Yano S

INSTITUCIÓN / INSTITUTION:  - Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

RESUMEN / SUMMARY:  - Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, is a critical problem in the management of patients with EGFR mutant lung cancer. Several mechanisms have  been reported involved in this acquired resistance, including hepatocyte growth factor (HGF) activation of an alternative pathway. PI3K and mTOR are downstream molecules of receptor tyrosine kinases, such as EGFR and Met, and are thought to  be ideal targets for controlling various tumor types. We assessed whether BEZ235, a dual inhibitor of PI3K and mTOR, could overcome the EGFR-TKI resistance induced by HGF in an EGFR mutant lung cancer model. Exogenous and endogenous HGF triggered resistance to erlotinib in the PC-9 and HCC827, EGFR mutant lung cancer cell lines. BEZ235 alone inhibited the viability of PC-9 and HCC827 cells in vitro, irrespective of the presence or absence of HGF. Using a xenograft model of SCID mice with HGF-gene transfected PC-9 cells (PC-9/HGF), we found that BEZ235 inhibited tumor growth, whereas erlotinib did not. BEZ235 monotherapy also inhibited the phosphorylation of Akt and p70S6K/S6RP, downstream molecules of PI3K and mTOR, respectively, as well as suppressing tumor-cell proliferation and  angiogenesis of PC-9/HGF tumors. These results suggest that BEZ235, even as monotherapy, may be useful in managing HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer. © 2013 Wiley Periodicals, Inc.

 

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[260]

TÍTULO / TITLE:  - Genomic Mapping and Survival Prediction in Glioblastoma: Molecular Subclassification Strengthened by Hemodynamic Imaging Biomarkers.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Radiology. 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1148/radiol.12120846

AUTORES / AUTHORS:  - Jain R; Poisson L; Narang J; Gutman D; Scarpace L; Hwang SN; Holder C; Wintermark M; Colen RR; Kirby J; Freymann J; Brat DJ; Jaffe C; Mikkelsen T

INSTITUCIÓN / INSTITUTION:  - Division of Neuroradiology, Department of Radiology, Department of Neurosurgery,  and Department of Public Health Sciences, Henry Ford Health System, 2799 W Grand  Blvd, Detroit, MI 48202; Departments of Pathology and Laboratory Medicine and Department of Radiology, Emory University School of Medicine, Atlanta, Ga Department of Radiology, University of Virginia, Charlottesville, Va; Department  of Radiology, Brigham and Women’s Hospital, Boston, Mass; Clinical Research Directorate, CMRP, SAIC-Frederick, Inc, NCI-Frederick, Frederick, Md.

RESUMEN / SUMMARY:  - Purpose:To correlate tumor blood volume, measured by using dynamic susceptibility contrast material-enhanced T2*-weighted magnetic resonance (MR) perfusion studies, with patient survival and determine its association with molecular subclasses of glioblastoma (GBM).Materials and Methods:This HIPAA-compliant retrospective study was approved by institutional review board. Fifty patients underwent dynamic susceptibility contrast-enhanced T2*-weighted MR perfusion studies and had gene expression data available from the Cancer Genome Atlas. Relative cerebral blood volume (rCBV) (maximum rCBV [rCBV(max)] and mean rCBV [rCBV(mean)]) of the contrast-enhanced lesion as well as rCBV of the nonenhanced  lesion (rCBV(NEL)) were measured. Patients were subclassified according to the Verhaak and Phillips classification schemas, which are based on similarity to defined genomic expression signature. We correlated rCBV measures with the molecular subclasses as well as with patient overall survival by using Cox regression analysis.Results:No statistically significant differences were noted for rCBV(max), rCBV(mean) of contrast-enhanced lesion or rCBV(NEL) between the four Verhaak classes or the three Phillips classes. However, increased rCBV measures are associated with poor overall survival in GBM. The rCBV(max) (P = .0131) is the strongest predictor of overall survival regardless of potential confounders or molecular classification. Interestingly, including the Verhaak molecular GBM classification in the survival model clarifies the association of rCBV(mean) with patient overall survival (hazard ratio: 1.46, P = .0212) compared with rCBV(mean) alone (hazard ratio: 1.25, P = .1918). Phillips subclasses are not predictive of overall survival nor do they affect the predictive ability of rCBV measures on overall survival.Conclusion:The rCBV(max) measurements could be  used to predict patient overall survival independent of the molecular subclasses  of GBM; however, Verhaak classifiers provided additional information, suggesting  that molecular markers could be used in combination with hemodynamic imaging biomarkers in the future.© RSNA, 2012.

 

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[261]

TÍTULO / TITLE:  - Inhibition of T-type calcium channels disrupts Akt signaling and promotes apoptosis in glioblastoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Jan 1. pii: S0006-2952(12)00825-8. doi: 10.1016/j.bcp.2012.12.017.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2012.12.017

AUTORES / AUTHORS:  - Valerie NC; Dziegielewska B; Hosing AS; Augustin E; Gray LS; Brautigan DL; Larner JM; Dziegielewski J

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, University of Virginia, Charlottesville, VA, United States.

RESUMEN / SUMMARY:  - Glioblastoma multiforme (GBM) are brain tumors that are exceptionally resistant to both radio- and chemotherapy regimens and novel approaches to treatment are needed. T-type calcium channels are one type of low voltage-gated channel (LVCC)  involved in embryonic cell proliferation and differentiation; however they are often over-expressed in tumors, including GBM. In this study, we found that inhibition of T-type Ca(2+) channels in GBM cells significantly reduced their survival and resistance to therapy. Moreover, either T-type selective antagonists, such as mibefradil, or siRNA-mediated knockdown of the T-type channel alpha subunits not only reduced cell viability and clonogenic potential,  but also induced apoptosis. In response to channel blockade or ablation, we observed reduced phosphorylation of Akt and Rictor, suggesting inhibition of the  mTORC2/Akt pathway. This was followed by reduction in phosphorylation of anti-apoptotic Bad and caspases activation. The apoptotic response was specific for T-type Ca(2+) channels, as inhibition of L-type Ca(2+) channels did not induce similar effects. Our results implicate T-type Ca(2+) channels as distinct  entities for survival signaling in GBM cells and suggest that they are a novel molecular target for tumor therapy.

 

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[262]

TÍTULO / TITLE:  - alphaB-Crystallin complexes with 14-3-3zeta to induce epithelial-mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hepatology. 2013 Jan 12. doi: 10.1002/hep.26255.

            ●● Enlace al texto completo (gratuito o de pago) 1002/hep.26255

AUTORES / AUTHORS:  - Huang XY; Ke AW; Shi GM; Zhang X; Zhang C; Shi YH; Wang XY; Ding ZB; Xiao YS; Yan J; Qiu SJ; Fan J; Zhou J

INSTITUCIÓN / INSTITUTION:  - Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China.

RESUMEN / SUMMARY:  - The overall survival of patients with hepatocellular carcinoma (HCC) remains poor, and the molecular pathogenesis remains incompletely defined in HCC. Here, we report that increased expression of alphaB-Crystallin in human HCC predicts poor survival and disease recurrence after surgery. Multivariate analysis identifies alphaB-Crystallin expression as an independent predictor for postoperative recurrence and overall survival. We unveil that elevated expression of alphaB-Crystallin promotes HCC progression in vivo and in vitro. We demonstrate that alphaB-Crystallin overexpression fosters HCC progression by inducing epithelial-mesenchymal transition (EMT) in HCC cells through activation  of the ERK cascade, which can counteract the effect of sorafenib. alphaB-Crystallin complexes with and elevates 14-3-3zeta protein, leading to up-regulation of ERK1/2 activity. Moreover, overexpression of alphaB-Crystallin in HCC cells induces EMT progression through an ERK1/2/Fra-1/slug signaling pathway. Clinically, our data reveal that overexpression of both alphaB-Crystallin and 14-3-3zeta correlates with the HCC poorest survival outcomes, and sorafenib response is impaired in patients with alphaB-Crystallin overexpression. Conclusions: These data suggest that the alphaB-Crystallin-14-3-3zeta complex acts synergistically to promote HCC progression by constitutively activating ERK signaling. This study reveals alphaB-Crystallin as a potential therapeutic target for HCC and a biomarker for predicting sorafenib treatment response. (HEPATOLOGY 2013.).

 

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[263]

TÍTULO / TITLE:  - Hepatitis B virus X gene differentially modulates cell cycle progression and apoptotic protein expression in hepatocyte versus hepatoma cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Viral Hepat. 2013 Jan;20(1):50-8. doi: 10.1111/j.1365-2893.2012.01625.x. Epub 2012 May 24.

            ●● Enlace al texto completo (gratuito o de pago) 1111/j.1365-2893.2012.01625.x

AUTORES / AUTHORS:  - Yang CH; Cho M

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry, School of Medicine, Jeju National University, Jeju, Korea.

RESUMEN / SUMMARY:  - The hepatitis B virus (HBV) X gene, which encodes the hepatitis B virus x protein (HBx), is essential for viral infection and genome replication, virus-associated  liver disease, and development of hepatocellular carcinoma. However, the exact role(s) of HBx remain controversial. In this study, we focus on studying the role of HBx in the regulation of cell cycle and apoptosis in normal liver and hepatoma cell lines. We established the Huh7-X and Chang-X cell lines that constitutively  express HBx. There were differences between the two cell lines in terms of cell cycle regulation and expression of p27 and transforming growth factor-beta. Expression of HBx proteins dramatically increases expression of Bcl-2 and reduces levels of cleaved PARP protein in Chang-X cells, and it inhibits apoptosis under  unfavourable conditions, such as serum starvation, in both cell lines. Our findings provide clues about the intracellular roles of HBx and demonstrate that  expression of this protein is important for multiple cellular processes, that is, cell cycle progression and apoptosis, in hepatoma cells and normal liver cell lines.

 

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[264]

TÍTULO / TITLE:  - All-trans retinoic acid and arsenic trioxide resistance of acute promyelocytic leukemia with the variant STAT5B-RARA fusion gene.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leukemia. 2012 Dec 28. doi: 10.1038/leu.2012.371.

            ●● Enlace al texto completo (gratuito o de pago) 1038/leu.2012.371

AUTORES / AUTHORS:  - Strehl S; Konig M; Boztug H; Cooper BW; Suzukawa K; Zhang SJ; Chen HY; Attarbaschi A; Dworzak MN

INSTITUCIÓN / INSTITUTION:  - CCRI, Children’s Cancer Research Institute, St. Anna Kinderkrebsforschung e.V, Vienna, Austria.

 

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[265]

TÍTULO / TITLE:  - Aberrant expression of GATA binding protein 6 correlates with poor prognosis and  promotes metastasis in cholangiocarcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Cancer. 2013 Jan 10. pii: S0959-8049(12)00985-9. doi: 10.1016/j.ejca.2012.12.015.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2012.12.015

AUTORES / AUTHORS:  - Tian F; Li D; Chen J; Liu W; Cai L; Li J; Jiang P; Liu Z; Zhao X; Guo F; Li X; Wang S

INSTITUCIÓN / INSTITUTION:  - Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.

RESUMEN / SUMMARY:  - AIM: GATA6, a zinc-finger transcription factor, functions as a tumour promoter or suppresser according to different tumour origins. We investigated the clinical significance of GATA6 and its role in invasion and metastasis in cholangiocarcinoma (CCA). METHODS: Expression of GATA6 in 87 cancerous, 24 paracancerous, 32 lymph-node metastatic and 8 liver metastatic samples from 87 CCA patients undergoing surgical resection was detected by immunohistochemistry.  Impact of GATA6 on invasion, metastasis and 67kDa laminin receptor expression (67LR) was evaluated in CCA cells by shRNA lentivirus or expressed-plasmid transfection. RESULTS: Aberrant expression of GATA6 in CCAs was significantly associated with lymph-node metastasis. GATA6 expression was higher in lymph-node  and liver metastatic tissues compared with primary cancerous tissues. Kaplan-Meier analysis showed GATA6 expression correlated with poor overall survival and early recurrence in CCAs. Cox analysis suggested GATA6 was an independent prognostic marker for overall survival and recurrence-free survival.  CCA cell invasion and migration were decreased by GATA6 knockdown and enhanced by GATA6 overexpression in vitro. Knockdown of GATA6 reduced CCA cell metastasis by  xenotransplantation into nude mice. 67LR, which is overexpressed in CCAs and promotes invasion and metastasis through several pathways, positively correlated  with GATA6 expression in 87 CCAs. Both mRNA and protein levels of 67LR were regulated by GATA6 in CCA cells. Moreover, ChIP analysis showed GATA6 bound to 67LR gene promoter in CCA cells. CONCLUSION: Aberrant expression of GATA6 correlates with poor prognosis and promotes invasion and metastasis in CCA.

 

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[266]

TÍTULO / TITLE:  - 5’-OH-5-nitro-Indirubin oxime (AGM130), an Indirubin derivative, induces apoptosis of Imatinib-resistant chronic myeloid leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Res. 2013 Jan 18. pii: S0145-2126(12)00502-4. doi: 10.1016/j.leukres.2012.12.017.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.leukres.2012.12.017

AUTORES / AUTHORS:  - Kim WS; Lee MJ; Kim DH; Lee JE; Kim JI; Kim YC; Song MR; Park SG

INSTITUCIÓN / INSTITUTION:  - School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea; BioImaging and Immune Synapse Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.

RESUMEN / SUMMARY:  - Imatinib is a highly effective drug for the treatment of chronic myeloid leukemia (CML) that targets the BCR-ABL kinase. However, a number of patients have CML that is resistant to Imatinib treatment. In this report, we developed AGM130 as a potential therapeutic drug for Imatinib-resistant CML treatment. The AGM130 compound is derived from Indirubin, which is an ingredient of Danggui Longhui Wan and known as a cyclin-dependent kinase (CDK) inhibitor. The water solubility of AGM130 is more enhanced than that of the original form of Indirubin, which has very poor water solubility. Our data showed that the AGM130 compound efficiently  decreased the viability of CML-derived K562 cells. Moreover, this compound also efficiently decreased the viability of Imatinib-resistant K562 cells in in vitro  and in vivo systems. In addition, like Indirubin, AGM130 also inhibited phosphorylation of retinoblastoma protein (Rb), which is a major substrate of CDK. Conclusively, our data suggest that AGM130 is a strong candidate for treating Imatinib-resistant CML.

 

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[267]

TÍTULO / TITLE:  - Induction of apoptosis by a potent caffeic acid derivative, caffeic acid undecyl  ester, is mediated by mitochondrial damage in NALM-6 human B cell leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):425-9. doi: 10.3892/or.2012.2163. Epub 2012 Dec 3.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2163

AUTORES / AUTHORS:  - Tomizawa A; Kanno S; Osanai Y; Goto A; Sato C; Yomogida S; Ishikawa M

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, Sendai, Japan.

RESUMEN / SUMMARY:  - Caffeic acid esters have various biological activities, and we previously reported that undecyl caffeate (caffeic acid undecyl ester, CAUE), a new caffeic  acid derivative, has strong pharmacological activity. The present study investigated the cytotoxicity of both CAUE and its parent compound, caffeic acid  phenethyl ester (CAPE), and characterized the mechanisms by which they induce apoptosis in the human B cell leukemia cell line NALM-6. Treatment with CAUE reduced cell survival in NALM-6 cells but had no significant effect on the survival of normal lymphocytes. When assessing the 50% inhibitory concentration (IC(50)) for cytotoxicity, CAUE had 10-fold higher activity than CAPE in NALM-6 cells. CAUE treatment resulted in induction of apoptotic features in NALM-6 cells, including cleaved poly (ADP-ribose) polymerase and activated caspase-3. A  caspase inhibitor completely blocked CAUE-induced apoptosis. CAUE treatment resulted in a concentration- and time-dependent decrease in both mitochondrial membrane potential and downregulation of Bcl-2 expression. Moreover, CAUE-induced apoptosis was enhanced in the Bcl-2 knockdown condition induced by small interfering RNA. These data suggest that CAUE-induced apoptosis was mediated via  an apoptotic intrinsic pathway including mitochondrial damage and was caspase-dependent. These data also suggest that CAUE is a powerful anti-leukemic  agent that acts via induction of apoptosis by mitochondrial damage and selective  action in leukemia cells.

 

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[268]

TÍTULO / TITLE:  - Resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus: Role of type I interferon signaling.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Virology. 2013 Feb 5;436(1):221-34. doi: 10.1016/j.virol.2012.11.014. Epub 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.virol.2012.11.014

AUTORES / AUTHORS:  - Moerdyk-Schauwecker M; Shah NR; Murphy AM; Hastie E; Mukherjee P; Grdzelishvili VZ

INSTITUCIÓN / INSTITUTION:  - Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.

RESUMEN / SUMMARY:  - Oncolytic virus (OV) therapy takes advantage of common cancer characteristics, such as defective type I interferon (IFN) signaling, to preferentially infect and kill cancer cells with viruses. Our recent study (Murphy et al., 2012. J. Virol.  86, 3073-87) found human pancreatic ductal adenocarcinoma (PDA) cells were highly heterogeneous in their permissiveness to vesicular stomatitis virus (VSV) and suggested at least some resistant cell lines retained functional type I IFN responses. Here we examine cellular responses to infection by the oncolytic VSV recombinant VSV-DeltaM51-GFP by analyzing a panel of 11 human PDA cell lines for  expression of 33 genes associated with type I IFN pathways. Although all cell lines sensed infection by VSV-DeltaM51-GFP and most activated IFN-alpha and beta  expression, only resistant cell lines displayed constitutive high-level expression of the IFN-stimulated antiviral genes MxA and OAS. Inhibition of JAK/STAT signaling decreased levels of MxA and OAS and increased VSV infection, replication and oncolysis, further implicating IFN responses in resistance. Unlike VSV, vaccinia and herpes simplex virus infectivity and killing of PDA cells was independent of the type I IFN signaling profile, possibly because these two viruses are better equipped to evade type I IFN responses. Our study demonstrates heterogeneity in the type I IFN signaling status of PDA cells and suggests MxA and OAS as potential biomarkers for PDA resistance to VSV and other  OVs sensitive to type I IFN responses.

 

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[269]

TÍTULO / TITLE:  - Thioredoxin-Mimetic Peptides (TXM) Reverse Auranofin Induced Apoptosis and Restore Insulin Secretion in Insulinoma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Jan 14. pii: S0006-2952(13)00020-8. doi: 10.1016/j.bcp.2013.01.003.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2013.01.003

AUTORES / AUTHORS:  - Cohen-Kutner M; Khomsky L; Trus M; Aisner Y; Niv MY; Benhar M; Atlas D

INSTITUCIÓN / INSTITUTION:  - Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, 919104, Israel.

RESUMEN / SUMMARY:  - The thioredoxin reductase/thioredoxin system (TrxR/Trx1) plays a major role in protecting cells from oxidative stress. Disruption of the TrxR-Trx1 system keeps  Trx1 in the oxidized state leading to cell death through activation of the ASK1-Trx1 apoptotic pathway. The potential mechanism and ability of tri- and tetra oligopeptides derived from the canonical -CxxC- motif of the Trx1-active site to mimic and enhance Trx1 cellular activity, was examined. The Trx mimetics  peptides (TXM) protected insulinoma INS832/13 cells from oxidative stress induced by selectively inhibiting TrxR with auranofin (AuF). TXM reversed the AuF-effects preventing apoptosis, and increasing cell-viability. The TXM peptides were effective in inhibiting AuF-induced MAPK, JNK and p38(MAPK) phosphorylation, in correlation with preventing caspase-3 cleavage and thereby PARP-1 dissociation. The ability to form a disulfide-bridge-like conformation was estimated from molecular dynamics simulations. The TXM peptides restored insulin secretion and displayed Trx1 denitrosylase activity. Their potency was 10 to 100 fold higher than redox reagents like NAC, AD4, or ascorbic acid. Unable to reverse ERK1/2 phosphorylation, TXM-CB3 (NAc-Cys-Pro-Cys amide) appeared to function in part, through inhibiting ASK1-Trx dissociation. These highly effective anti-apoptotic effects of Trx1 mimetic peptides exhibited in INS832/13 cells could become valuable in treating adverse oxidative-stress related disorders such as diabetes.

 

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[270]

TÍTULO / TITLE:  - TNF receptor-associated factor 6 regulates proliferation, apoptosis, and invasion of glioma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Cell Biochem. 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11010-013-1573-2

AUTORES / AUTHORS:  - Peng Z; Shuangzhu Y; Yongjie J; Xinjun Z; Ying L

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, The First Affiliated Hospital of Xinxiang Medical University, NO.88, Jian-kang Road, Xinxiang, 453100, Henan, China, zhangpeng_hn@163.com.

RESUMEN / SUMMARY:  - Tumor necrosis factor receptor-associated factor 6 (TRAF6), which plays an important role in inflammation and immune response, is an essential adaptor protein for the NF-kappaB (nuclear factor kappaB) signaling pathway. Recent studies have shown that TRAF6 played an important role in tumorigenesis and invasion by suppressing NF-kappaB activation. However, up to now, the biologic role of TRAF6 in glioma has still remained unknown. To address the expression of  TRAF6 in glioma cells, four glioma cell lines (U251, U-87MG, LN-18, and U373) and a non-cancerous human glial cell line SVG p12 were used to explore the protein expression of TRAF6 by Western blot. Our results indicated that TRAF6 expression  was upregulated in human glioma cell lines, especially in metastatic cell lines.  To investigate the role of TRAF6 in cell proliferation, apoptosis, invasion, and  migration of glioma, we generated human glioma U-87MG cell lines in which TRAF6 was either overexpressed or depleted. Subsequently, the effects of TRAF6 on cell  viability, cell cycle distribution, apoptosis, invasion, and migration in U-87MG  cells were determined with 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium  bromide (MTT) assay, flow cytometry analysis, transwell invasion assay, and wound-healing assay. The results showed that knockdown of TRAF6 could decrease cell viability, suppress cell proliferation, invasion and migration, and promote  cell apoptosis, whereas overexpression of TRAF6 displayed the opposite effects. In addition, the effects of TRAF6 on the expression of phosphor-NF-kappaB (p-p65), cyclin D1, caspase 3, and MMP-9 were also probed. Knockdown of TRAF6 could lower the expression of p-p65, cyclin D1, and MMP-9, and raise the expression of caspase 3. All these results suggested that TRAF6 might be involved in the potentiation of growth, proliferation, invasion, and migration of U-87MG cell, as well as inhibition of apoptosis of U-87MG cell by abrogating activation  of NF-kappaB.

 

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[271]

TÍTULO / TITLE:  - Wogonin induced cytotoxicity in human hepatocellular carcinoma cells by activation of unfolded protein response and inactivation of AKT.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hepatol Res. 2012 Dec 4. doi: 10.1111/hepr.12036.

            ●● Enlace al texto completo (gratuito o de pago) 1111/hepr.12036

AUTORES / AUTHORS:  - Xu M; Lu N; Zhang H; Dai Q; Wei L; Li Z; You Q; Guo Q

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University.

RESUMEN / SUMMARY:  - AIM: To investigate the potential anticancer effects of the natural flavonoid wogonin on human hepatocellular carcinoma (HCC) cells and tumor xenografts and the contribution of the unfolded protein response (UPR) and AKT pathways to the cytotoxicity of wogonin. METHODS: The HCC cell lines HepG2, SMMC-7721 and Hep3B were treated with wogonin. 3-(4 5-Dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide assays were used to evaluate the cell viability. Flow cytometry assays were used to identify the cell death types and measure the concentrations of intracellular H(2) O(2) and Ca(2+) . Western blotting assays were used to detect  the protein expression levels of members in the UPR and AKT pathways. Relative quantitative real-time polymerase chain reaction assays were used to analysis the mRNA expression levels of chop and trb3. Furthermore, the male BALB/c nude mice with SMMC-7721 xenografts were treated with wogonin. The tumor volume, tumor weight and bodyweight were monitored during the tumorigenicity assays. RESULTS: Wogonin significantly inhibited the viability of HCC cells by inducing apoptosis  and necrosis. This cytotoxicity was at least partially attributed to the activation of the UPR pathway and consequent inactivation of AKT signaling, which resulted from the production of intracellular H(2) O(2) and causal release of endoplasmic reticulum Ca(2+) . Moreover, wogonin evidently repressed the growth of xenografts but slightly influenced the bodyweight of mice. CONCLUSION: Wogonin is a prospect for improving the systemic chemotherapy strategy on HCC by concurrently rectifying the aberrant UPR and AKT signaling pathways, which are crucial to the biology of HCC.

 

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[272]

TÍTULO / TITLE:  - TCEA3 binds to TGF-beta receptor I and induces Smad-independent, JNK-dependent apoptosis in ovarian cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Signal. 2013 Jan 25. pii: S0898-6568(13)00027-2. doi: 10.1016/j.cellsig.2013.01.016.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.cellsig.2013.01.016

AUTORES / AUTHORS:  - Cha Y; Kim DK; Hyun J; Kim SJ; Park KS

INSTITUCIÓN / INSTITUTION:  - Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea.

RESUMEN / SUMMARY:  - TFIIS is a transcription elongation factor conserved in frog, mouse and human. Recently, knockdown of TCEA1, the most well-characterized isoform of TFIIS, by RNA silencing was reported to inhibit cancer cell proliferation and induce apoptosis in breast, lung and pancreatic cancer cell lines through activation of  p53 [1]. However, the functions of other TFIIS isoforms are poorly defined. The present study shows that TCEA3, an isoform of TFIIS, can trigger ovarian cancer-specific cell death by activating the JNK signaling pathway. TCEA3 expression is low in ovarian cancer cell lines compared to noncancerous ovarian epithelial cells. Suppression of TCEA3 in noncancerous ovarian epithelial cells promotes cell growth whereas ectopic expression of TCEA3 in ovarian cancer cell lines induces the caspase-dependent mitochondrial cell death pathway. Molecular and chemical inhibition assays show that the interaction of TCEA3 with TGFbeta receptor I induces cell death in ovarian cancer cell through Smad-independent activation of the JNK pathway. These results reveal that TCEA3 induces a novel apoptotic mechanism in OEC, which provides TCEA3 as a novel target to develop therapeutics of ovarian cancer.

 

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[273]

TÍTULO / TITLE:  - Humanised antihuman IL-6R antibody with interferon inhibits renal cell carcinoma  cell growth in vitro and in vivo through suppressed SOCS3 expression.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Cancer. 2012 Dec 26. pii: S0959-8049(12)00957-4. doi: 10.1016/j.ejca.2012.11.038.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2012.11.038

AUTORES / AUTHORS:  - Oguro T; Ishibashi K; Sugino T; Hashimoto K; Tomita S; Takahashi N; Yanagida T; Haga N; Aikawa K; Suzutani T; Yamaguchi O; Kojima Y

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Fukushima Medical University, Fukushima, Japan.

RESUMEN / SUMMARY:  - Interleukin-6 (IL-6), one of the proinflammatory cytokines, is considered to be one of the factors associated with poor prognosis of patients with renal cell carcinoma (RCC). Suppressor of cytokine signalling-3 (SOCS3) is rapidly up-regulated by IL-6 and a negative regulator of cytokine signalling. SOCS3 not only suppresses cytokine-mediated JAK/STAT signalling, but also sustains MAPK pathways. In our study, among the RCC cell lines, IL-6 mRNA expression was the highest in the 786-O cells, which also showed the highest level of SOCS3 mRNA expression under the condition of interferon stimulation. In contrast, ACHN cells had the lowest expression of both IL-6 and SOCS3 mRNA under the same condition. Our study is undertaken to evaluate the effect of humanised antihuman IL-6 receptor (IL-6R) antibody, which completely neutralises IL-6 activity, in RCC cell proliferation and its effect on signalling pathways. IL-6R antibody, tocilizumab, significantly suppressed cell proliferation in 786-O cells with interferon stimulation. Western blot analysis revealed that the tocilizumab enhanced the interferon-induced phosphorylation of STAT1 and inhibited SOCS3 expression and the phosphorylation of both STAT3 and ERK. In contrast, the IL-6 inhibited STAT1 phosphorylation, enhanced STAT3 phosphorylation and accelerated cell proliferation in ACHN cells. The in vivo effects of combination therapy with tocilizumab and interferon showed significant suppression of 786-O tumour growth  in a xenograft model. Morphological observation of the tumours revealed the apoptosis, invasion of inflammatory cells and fibrosis. These findings suggest that combination therapy using an antihuman IL-6R antibody with interferon may represent a novel therapeutic approach for the treatment of RCC.

 

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[274]

TÍTULO / TITLE:  - Tetra-O-methyl nordihydroguaiaretic acid, an inhibitor of Sp1-mediated survivin transcription, induces apoptosis and acts synergistically with chemo-radiotherapy in glioblastoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Invest New Drugs. 2013 Jan 9.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10637-012-9917-4

AUTORES / AUTHORS:  - Castro-Gamero AM; Borges KS; Moreno DA; Suazo VK; Fujinami MM; de Paula Gomes Queiroz R; de Oliveira HF; Carlotti CG Jr; Scrideli CA; Tone LG

INSTITUCIÓN / INSTITUTION:  - Department of Genetics, Faculty of Medicine of Ribeirao Preto, University of Sao  Paulo (USP), Ribeirao Preto, Brazil, amcgen@gmail.com.

RESUMEN / SUMMARY:  - Glioblastoma (GBM), one of the most malignant human neoplasias, responds poorly to current treatment modalities, with temozolomide (TMZ) being the drug most frequently used for its treatment. Tetra-O-methyl Nordihydroguaiaretic Acid (M4N) is a global transcriptional repressor of genes dependent on the Sp1 transcription factor, such as Survivin and Cdk1. In the present study we evaluated the gene expression of Survivin, its spliced variants and Cdk1 in GBM samples and cell lines. Moreover, we investigated the effects of M4N combined or not with TMZ and/or radiation on GBM primary cultures and cell lines. qRT-PCR assays were performed to determine the Survivin-spliced variants and Cdk1 gene mRNA expression in GBM tumor samples and cell lines. Cell proliferation was measured by XTT assay and cell cycle and apoptosis were determined by flow cytometry. Drug combination analyses using different schedules of administration (simultaneous and sequential) were performed on GBM cell lines and primary cultures based on the Chou-Talalay method. For clonogenic survival, doses of 2, 4, and 6 Gy of gamma radiation. were used. All Survivin-spliced variants and the Cdk1 gene were  expressed in GBM samples (n = 16) and cell lines (n = 6), except the Survivin-2B  variant that was only expressed in GBM cell lines. M4N treatment down regulated the expression of Cdk1, Survivin and the Survivin-DeltaEx3 variant, while the Survivin-2B variant was up-regulated. M4N decreased the cell proliferation separately and synergistically with TMZ, and enhanced the effects of radiation, mainly when associated with TMZ. M4N also induced apoptotic cell death, decreased the mitotic index and arrested the cell cycle mainly in the G2/M phase. Our results suggest a potential clinical application of M4N in combination with TMZ and radiation for GB treatment.

 

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[275]

TÍTULO / TITLE:  - Combined Loss of E-cadherin and Aberrant beta-Catenin Protein Expression Correlates With a Poor Prognosis for Small Intestinal Adenocarcinomas.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Clin Pathol. 2013 Feb;139(2):167-76. doi: 10.1309/AJCPS54RTFCTHGWX.

            ●● Enlace al texto completo (gratuito o de pago) 1309/AJCPS54RTFCTHGWX

AUTORES / AUTHORS:  - Lee HJ; Lee OJ; Jang KT; Bae YK; Chung JY; Eom DW; Kim JM; Yu E; Hong SM

INSTITUCIÓN / INSTITUTION:  - Dept of Pathology, Asan Medical Center, University of Ulsan College of Medicine,  388-1, Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea; smhong28@gmail.com.

RESUMEN / SUMMARY:  - Small intestinal adenocarcinomas (SIACs) are rare, and their molecular pathogenesis is largely unknown. To define the roles of E-cadherin and beta-catenin, we performed immunohistochemistry for E-cadherin and beta-catenin in 194 surgically resected SIACs with tissue microarrays and compared the data with clinicopathologic factors, including survival rates of patients with SIAC. Loss of E-cadherin expression and aberrant beta-catenin expression were observed  in 41.8% (81/194 cases) and 40.7% (79/194 cases) of SIACs, respectively. Combined loss of E-cadherin and aberrant beta-catenin expression was observed in 24.2% (47/194 cases) of SIACs, and this feature was most frequently observed in mucinous adenocarcinomas and signet ring cell carcinomas (P < .001), poorly differentiated and undifferentiated carcinomas (P < .001), and tumors with advanced pT classification (P = .03). Survival times for patients with SIAC with  both loss of E-cadherin and aberrant beta-catenin expression (median, 13.9 months) were significantly shorter than those for patients without aberrant expression of both proteins (49.9 months), as determined by univariate (P < .001) and multivariate (P = .01) analyses. In conclusion, loss of E-cadherin and aberrant beta-catenin expression correlate with poorly differentiated tumors, advanced T classification, and decreased patient survival time; therefore, it could be a prognostic factor in patients with SIAC.

 

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[276]

TÍTULO / TITLE:  - Epidermal growth factor receptor inhibitors for treatment of orbital squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Arch Ophthalmol. 2012 Dec 1;130(12):1608-11. doi: 10.1001/archophthalmol.2012.2515.

            ●● Enlace al texto completo (gratuito o de pago) 1001/archophthalmol.2012.2515

AUTORES / AUTHORS:  - El-Sawy T; Sabichi AL; Myers JN; Kies MS; William WN; Glisson BS; Lippman S; Esmaeli B

 

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[277]

TÍTULO / TITLE:  - LAPTM4B gene polymorphism and endometrial carcinoma risk and prognosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biomarkers. 2013 Jan 11.

            ●● Enlace al texto completo (gratuito o de pago) 3109/1354750X.2012.752526

AUTORES / AUTHORS:  - Meng F; Li H; Zhou R; Luo C; Hu Y; Lou G

INSTITUCIÓN / INSTITUTION:  - Department of Gynaecology.

RESUMEN / SUMMARY:  - Abstract A novel gene called LAPTM4B (lysosome-associated protein transmembrane 4 beta) plays several crucial roles in carcinogenesis. In this case-control study,  we investigated the relationship between LAPTM4B gene polymorphism and susceptibility to endometrial carcinoma (EC). In an adjusted multivariate logistic regression analyses, subjects with the LAPTM4B*1/2 and *2/2 genotypes respectively exhibited 1.572-fold (95% confidence interval (CI) = 1.041-2.375) and 2.335-fold (95% CI = 1.365-3.995) increases in the risk of developing EC relative to those carrying LAPTM4B*1/1. Patients with LAPTM4B *2 had both significantly shorter overall survival (OS) and shorter disease-free survival (DFS) (both p < 0.001). Multivariate analysis showed that LAPTM4B genotype is an  independent prognostic factor for OS and DFS (both p < 0.001). These results suggest that LAPTM4B polymorphisms might play an important role in the aetiology  of EC.

 

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[278]

TÍTULO / TITLE:  - Effects of steroidal aromatase inhibitors on sensitive and resistant breast cancer cells: Aromatase inhibition and autophagy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Steroid Biochem Mol Biol. 2013 Jan 11. pii: S0960-0760(13)00003-4. doi: 10.1016/j.jsbmb.2012.12.017.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jsbmb.2012.12.017

AUTORES / AUTHORS:  - Amaral C; Varela C; Azevedo M; da Silva ET; Roleira F; Chen S; Correia-da-Silva G; Teixeira N

INSTITUCIÓN / INSTITUTION:  - Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, no 228, 4050-313 Porto, Portugal; Institute for Molecular and Cell Biology (IBMC), University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal.

RESUMEN / SUMMARY:  - Several therapeutic approaches are used in estrogen receptor positive (ER(+)) breast cancers, being one of them the use of aromatase inhibitors (AIs). Although AIs demonstrate higher efficacy than tamoxifen, they can also exhibit de novo or  acquired resistance after prolonged treatment. Recently, we have described the synthesis and biochemical evaluation of four steroidal AIs, 3beta-hydroxyandrost-4-en-17-one (1), androst-4-en-17-one (12), 4alpha,5alpha-epoxyandrostan-17-one (13a) and 5alpha-androst-2-en-17-one (16), obtained from modifications in the A-ring of the aromatase substrate, androstenedione. In this study, it was investigated the biological effects of these AIs in different breast cancer cell lines, an ER(+) aromatase-overexpressing human breast cancer cell line (MCF-7aro cells), an estrogen-receptor negative (ER(-)) human breast cancer cell line (SK-BR-3 cells), and a late stage of acquired resistance cell line (LTEDaro cells). The effects of an autophagic inhibitor (3-methyladenine) plus AIs 1, 12, 13a or exemestane in LTEDaro cells were also studied to understand the involvement of autophagy in AI  acquired resistance. Our results showed that these steroids inhibit aromatase of  MCF-7aro cells and decrease cell viability in a dose- and time-dependent manner.  The new AI 1 is the most potent inhibitor, although the AI 12 demonstrates to be  the most effective in decreasing cell viability. Besides, and in advantage over exemestane, AIs 12 and 13a also reduced LTEDaro cells viability. The use of the autophagic inhibitor allowed AIs to diminish viability of LTEDaro cells, presenting a similar behavior to the sensitive cells. Thus, inhibition of autophagy may sensitize hormone-resistant cancer cells to anti-estrogen therapies.

 

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[279]

TÍTULO / TITLE:  - Berberine represses DAXX gene transcription and induces cancer cell apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Lab Invest. 2013 Jan 7. doi: 10.1038/labinvest.2012.172.

            ●● Enlace al texto completo (gratuito o de pago) 1038/labinvest.2012.172

AUTORES / AUTHORS:  - Li J; Gu L; Zhang H; Liu T; Tian D; Zhou M; Zhou S

INSTITUCIÓN / INSTITUTION:  - Institute of Pathology, Tongji hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

RESUMEN / SUMMARY:  - Death-domain-associated protein (DAXX) is a multifunctional protein that regulates a wide range of cellular signaling pathways for both cell survival and  apoptosis. Regulation of DAXX gene expression remains largely obscure. We recently reported that berberine (BBR), a natural product derived from a plant used in Chinese herbal medicine, downregulates DAXX expression at the transcriptional level. Here, we further investigate the mechanisms underlying the transcriptional suppression of DAXX by BBR. By analyzing and mapping the putative DAXX gene promoter, we identified the core promoter region (from -161 to -1), which contains consensus sequences for the transcriptional factors Sp1 and Ets1.  We confirmed that Sp1 and Ets1 bound to the core promoter region of DAXX and stimulated DAXX transcriptional activity. In contrast, BBR bound to the DAXX core promoter region and suppressed its transcriptional activity. Following studies demonstrated a possible mechanism that BBR inhibited the DAXX promoter activity through blocking or disrupting the association of Sp1 or Ets1 and their consensus sequences in the promoter. Downregulation of DAXX by BBR resulted in inhibition of MDM2 and subsequently, activation of p53, leading to cancer cell death. Our results reveal a novel possible mechanism: by competitively binding to the Sp1 and Ets1 consensus sequences, BBR inhibits the transcription of DAXX, thus inducing cancer cell apoptosis through a p53-dependent pathway.Laboratory Investigation advance online publication, 7 January 2013; doi:10.1038/labinvest.2012.172.

 

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[280]

TÍTULO / TITLE:  - Multi-level disruption of the extrinsic apoptotic pathway mediates resistance of  leukemia cells to TNF-related apoptosis-inducing ligand (TRAIL).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Neoplasma. 2013;60(2):223-31.

AUTORES / AUTHORS:  - Leahomschi S; Molinsky J; Klanova M; Andera L; Peterka M; Gasova Z; Klener P Sr; Trneny M; Necas E; Simonova T; Zivny J; Klener P Jr

RESUMEN / SUMMARY:  - Disruption of apoptotic pathways belongs to commonly reported molecular mechanisms that underlie cancer drug resistance. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL, Apo2L) is acytokine of the TNF family with selective anti-tumor activity and minimal toxicity toward healthy tissues. Primary leukemia cells are, however, largely intrinsically resistant to  TRAIL-induced apoptosis. In this study we analyzed molecular differences between  TRAIL-resistant K562 cell line and TRAIL-sensitive K562 clones. We demonstrate that TRAIL-sensitive K562 cells differ from the TRAIL-resistant cell line by cell surface downregulation of TRAIL decoy receptor 1, upregulation of both TRAIL death receptors, enhanced assembly and improved functioning of the death-inducing signaling complex, and increased cytoplasmic protein expression of CASP8 and key  proapoptotic BCL2 members BID, BIM, BAD and BAK. The molecular basis of the intrinsic leukemia cell TRAIL resistance thus appears aconsequence of the multi-level disruption of the extrinsic apoptotic pathway. The results of this study also suggest that the leukemia TRAIL-resistance is functional, leaving apossibility of overcoming the resistance by preexposure of the leukemia cells to potent TRAIL sensitizers, e.g. BH3-mimetics. Keywords: leukemia, drug-resistance, TRAIL, apoptosis, BCL2 family.

 

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[281]

TÍTULO / TITLE:  - Interference of a novel indolylmaleimide with microtubules induces mitotic arrest and apoptosis in human progenitor and cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Pharmacol. 2012 Dec 26. pii: S0006-2952(12)00799-X. doi: 10.1016/j.bcp.2012.12.013.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2012.12.013

AUTORES / AUTHORS:  - Eisenloffel C; Schmole AC; Pews-Davtyan A; Brennfuhrer A; Kuznetsov SA; Hubner R; Frech S; Schult C; Junghanss C; Beller M; Rolfs A; Frech MJ

INSTITUCIÓN / INSTITUTION:  - Albrecht-Kossel-Institute for Neuroregeneration (AKos), Center for Mental Health, University of Rostock, Gehlsheimer Str. 20, D-18147 Rostock, Germany. Electronic  address: christian.eisenloeffel@uni-rostock.de.

RESUMEN / SUMMARY:  - Indolylmaleimides display a broad spectrum of biological activity and offer great opportunity to influence several aspects of cell fate, as proliferation and differentiation. In this study we describe the effect of PDA-66, a newly synthesised indolylmaleimide, showing a strong dose dependent anti-proliferative  effect on immortalised human progenitor and cancer cells. We demonstrated a highly depolymerizing effect on in vitro tubulin assembly and conclude that PDA-66 acts as microtubule destabilising agent. In addition we found that PDA-66  induces mitotic arrest of cells in the G(2)/M phase of the cell cycle. Subsequently cells undergo apoptosis, indicating the major mechanism of the anti-proliferative effect. To prove a potential anti-cancer activity of PDA-66 we examined the effect of PDA-66 on human SH-SY5Y neuroblastoma and A-459 lung cancer cells, showing a significant reduction in cancer cell proliferation in a dose dependent manner. Thus PDA-66 is a new anti-mitotic compound with an indole-core with the potential to be used for cancer therapy.

 

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[282]

TÍTULO / TITLE:  - Saxifragifolin D induces the interplay between apoptosis and autophagy in breast  cancer cells through ROS-dependent endoplasmic reticulum stress.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Jan 21. pii: S0006-2952(13)00046-4. doi: 10.1016/j.bcp.2013.01.009.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2013.01.009

AUTORES / AUTHORS:  - Shi JM; Bai LL; Zhang DM; Yiu A; Yin ZQ; Han WL; Liu JS; Li Y; Fu DY; Ye WC

INSTITUCIÓN / INSTITUTION:  - College of Pharmacy, Jinan University, Guangzhou 510632, China.

RESUMEN / SUMMARY:  - Breast cancer is the leading cause of cancer death among females, and novel chemotherapeutic drugs for treating breast cancer are needed urgently. Saxifragifolin D (SD) was isolated by our group from Androsace umbellata which is commonly used to treat solid tumor. In this study, we evaluated its growth inhibitory effect on breast cancer cells and explored the underlying molecular mechanisms. Our results showed that SD inhibited the growth of both MCF-7 and MDA-MB-231 cells significantly. Mechanistic studies demonstrated that SD induced  apoptosis through mitochondrial apoptotic pathway. Evidence of SD-induced autophagy included the occurrence of autophagic vacuoles, up-regulation of LC3-II, Beclin1 and Vps34. Inhibition of autophagy by bafilomycin A1 or Beclin1 siRNA pretreatment decreased the ratio of apoptosis, indicating that autophagy induction contributes to apoptosis and is required for the latter. SD was also found to induce endoplasmic reticulum stress, accompanied by ROS production, increase of intracellular calcium and up-regulation of Bip, IRE1alpha and XBP-1s. Inhibition of endoplasmic reticulum stress by N-acetyl-L-cysteine, tauroursodeoxycholic acid or IRE1alpha siRNA pretreatment could suppress both apoptosis and autophagy. Besides, increases in CHOP, calnexin, calpain, p-JNK and p-Bcl-2 were followed by subsequent dissociation of Beclin1 from Bcl-2, further suggesting endoplasmic reticulum stress to be the common signaling pathway shared by SD-induced apoptosis and autophagy. In conclusion, SD inhibits breast cancer cell growth and induces interplay between apoptosis and autophagy through ROS-mediated endoplasmic reticulum stress. It will provide molecular bases for developing SD into a drug candidate for the treatment of breast cancer.

 

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[283]

TÍTULO / TITLE:  - Bcl-2 family proteins and cytoskeleton changes involved in DM-1 cytotoxic effect  on melanoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Tumour Biol. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s13277-013-0666-6

AUTORES / AUTHORS:  - Faiao-Flores F; Suarez JA; Soto-Cerrato V; Espona-Fiedler M; Perez-Tomas R; Maria DA

INSTITUCIÓN / INSTITUTION:  - Laboratory of Biochemistry and Biophysics, Butantan Institute, 1500 Vital Brasil  Avenue, Sao Paulo, 05503-900, Brazil, feflor@uol.com.br.

RESUMEN / SUMMARY:  - Melanoma is one of the most aggressive types of skin cancer and its incidence rate is still increasing. All existing treatments are minimally effective. Consequently, new therapeutic agents for melanoma treatment should be developed.  The DM-1 compound is a curcumin analog that possesses several curcumin characteristics, such as antiproliferative, antitumor, and anti-metastatic properties. The aim of this study was to evaluate the different signaling pathways involved in the cytotoxic effect of DM-1 on melanoma cells. The apoptotic process and cytoskeletal changes were evaluated by immunoblotting and immunofluorescence, respectively, in melanoma cells. After DM-1 treatment, SK-MEL-5 melanoma cells showed actin filament disorganization with spicule formation throughout the cytoskeleton and significant reduction of focal adhesion as well as they were present only at cell extremities, conferring a poor connection between the cell and the substrate. Besides this, there was significant filopodium retraction and loss of typical cytoskeleton scaffold. These modifications contributed to cell detachment followed by cell death. Furthermore, DM-1-induced apoptosis was triggered by multiple Bcl-2 proteins involved in both the extrinsic and the intrinsic apoptotic pathways. SK-MEL-5 cells showed a death mechanism mainly by Bcl-2/Bax ratio decrease, whereas A375 cells presented apoptosis induction by Mcl-1 and Bcl-xL downregulation. In SK-MEL-5 and A375 melanoma cells, there was a significant increase in the active  form of caspase 9, and the inactive form of the effector caspase 3 was decreased  in both cell lines. Expression of cleaved poly ADP ribose polymerase was increased after DM-1 treatment in these melanoma cell lines, demonstrating that the apoptotic process occurred. Altogether, these data elucidate the cellular and molecular mechanisms involved in the cytotoxicity induced by the antitumor agent  DM-1 in melanoma cells.

 

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[284]

TÍTULO / TITLE:  - Bmi1 gene silencing inhibits the proliferation and invasiveness of human hepatocellular carcinoma cells and increases their sensitivity to 5-fluorouracil.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar;29(3):967-74. doi: 10.3892/or.2012.2189. Epub 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2189

AUTORES / AUTHORS:  - Zhang R; Xu LB; Yue XJ; Yu XH; Wang J; Liu C

INSTITUCIÓN / INSTITUTION:  - Department of Hepato-Pancreato-Biliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong Province, P.R. China.

RESUMEN / SUMMARY:  - The Bmi1 gene has been reported to play important roles in cancer initiation and  progression. The aim of this study was to investigate the effects of RNA interference (RNAi)-mediated silencing of Bmi1 gene expression on the proliferation and invasiveness of hepatocellular carcinoma (HCC) cells and on the efficacy of chemotherapy in HCC patients. The Bmi1 gene was silenced by Bmi1-siRNA (small interfering RNA) in the human HCC cell lines HepG2 and Bel-7402, and the gene expression levels were assayed by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. The proliferation and migration of Bmi1-silenced tumor cells and their sensitivity to 5-FU treatment were determined by Cell Counting Kit-8 (CCK-8), transwell assays and 4’,6-diamidino-2-phenylindole (DAPI) staining and flow cytometry, respectively. Bmi1-siRNA inhibited the Bmi1 expression at both the mRNA and protein levels in HCC cells. Proliferation and migration of HCC cells treated with Bmi1-siRNA was significantly lower compared to that of the control cells. Moreover, Bmi1 gene silencing increased the percentage of apoptotic cells  treated by 5-FU and decreased the IC50 values of 5-FU to a greater extent. Downregulation of the Bmi1 gene by RNAi can inhibit the proliferation and invasivesness of HCC cells and increase their sensitivity to 5-FU treatment.

 

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[285]

TÍTULO / TITLE:  - Enhancement of adriamycin cytotoxicity by sodium butyrate involves hTERT downmodulation-mediated apoptosis in human uterine cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Carcinog. 2013 Jan 28. doi: 10.1002/mc.21998.

            ●● Enlace al texto completo (gratuito o de pago) 1002/mc.21998

AUTORES / AUTHORS:  - Yu M; Kong H; Zhao Y; Sun X; Zheng Z; Yang C; Zhu Y

INSTITUCIÓN / INSTITUTION:  - Key Laboratory of Transgenetic Animal Research, Liaoning Province, Department of  Laboratory Animal, China Medical University, Shenyang, China.

RESUMEN / SUMMARY:  - Activation of telomerase is a key element in oncogenesis and resistance to apoptosis for many cancers. Some histone deacetylase inhibitors (HDACi) or chemotheraputic agents have been reported to downregulate the expression of human telomerase reverse transcriptase (hTERT). However, whether hTERT is involved in cell death of uterine cancer cells induced by combination of HDACi with chemotheraputic regents remain unknown. The present study shows that combining sodium butyrate (NaBu) and adriamycin (ADR) inhibits proliferation of uterine cancer cell lines in a concentration and time-dependent manner. Growth inhibition was accompanied by caspase-dependent apoptosis with reduced telomerase activity and decreased hTERT mRNA expression. Ectopic wild type (WT)-hTERT suppressed the  apoptosis induced by NaBu/ADR treatment, while knockdown of hTERT sensitized uterine cancer cells to ADR. Moreover, the addition of NaBu significantly enhanced ADR cytotoxicity for the primary uterine cancer cells with high hTERT expression. These data indicate that downregulation of hTERT is an important part of the mechanism by which NaBu enhances ADR-induced apoptosis, and suggests that  combining NaBu and ADR may be effective in treating uterine tumor with high telomerase activity. © 2013 Wiley Periodicals, Inc.

 

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[286]

TÍTULO / TITLE:  - Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Jan;137(2):397-406. doi: 10.1007/s10549-012-2376-y. Epub 2012 Dec 15.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-012-2376-y

AUTORES / AUTHORS:  - Bostner J; Karlsson E; Pandiyan MJ; Westman H; Skoog L; Fornander T; Nordenskjold B; Stal O

INSTITUCIÓN / INSTITUTION:  - Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University & County Council of Ostergotland, SE-581 85, Linkoping, Sweden, josefine.bostner@liu.se.

RESUMEN / SUMMARY:  - The frequent alterations of the PI3K/Akt/mTOR-growth signaling pathway are proposed mechanisms for resistance to endocrine therapy in breast cancer, partly  through regulation of estrogen receptor alpha (ER) activity. Reliable biomarkers  for treatment prediction are required for improved individualized treatment. We performed a retrospective immunohistochemical analysis of primary tumors from 912 postmenopausal patients with node-negative breast cancer, randomized to either tamoxifen or no adjuvant treatment. Phosphorylated (p) Akt-serine (s) 473, p-mTOR-s2448, and ER phosphorylations-s167 and -s305 were evaluated as potential  biomarkers of prognosis and tamoxifen treatment efficacy. High expression of p-mTOR indicated a reduced response to tamoxifen, most pronounced in the ER+/progesterone receptor (PgR) + subgroup (tamoxifen vs. no tamoxifen: hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.31-2.38; P = 0.78), whereas low p-mTOR expression predicted tamoxifen benefit (HR, 0.29; 95 % CI, 0.18-0.49;  P = 0.000002). In addition, nuclear p-Akt-s473 as well as p-ER at -s167 and/or -s305 showed interaction with tamoxifen efficacy with borderline statistical significance. A combination score of positive pathway markers including p-Akt, p-mTOR, and p-ER showed significant association with tamoxifen benefit (test for  interaction; P = 0.029). Cross-talk between growth signaling pathways and ER-signaling has been proposed to affect tamoxifen response in hormone receptor-positive breast cancer. The results support this hypothesis, as an overactive pathway was significantly associated with reduced response to tamoxifen. A clinical pre-treatment test for cross-talk markers would be a step toward individualized adjuvant endocrine treatment with or without the addition of PI3K/Akt/mTOR pathway inhibitors.

 

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[287]

TÍTULO / TITLE:  - Neutropenia-associated outcomes in adults with acute myeloid leukemia receiving cytarabine consolidation chemotherapy with or without granulocyte colony-stimulating factor.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pharmacotherapy. 2012 Dec;32(12):1070-7. doi: 10.1002/phar.1150.

            ●● Enlace al texto completo (gratuito o de pago) 1002/phar.1150

AUTORES / AUTHORS:  - Bradley AM; Deal AM; Buie LW; van Deventer H

INSTITUCIÓN / INSTITUTION:  - Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Augusta, GA 30912, USA. abradley@georgiahealth.edu

RESUMEN / SUMMARY:  - STUDY OBJECTIVE: To determine whether granulocyte colony-stimulating factor (G-CSF) prophylaxis after consolidation with high- or intermediate-dose cytarabine (H/IDAC) for treatment of acute myeloid leukemia (AML) reduces the frequency of neutropenia-associated complications. DESIGN: Retrospective medical  record review. SETTING: Academic medical center. PATIENTS: Seventy-eight patients aged 18 years or older in whom H/IDAC consolidation chemotherapy was initiated for consolidation of AML between November 2004 and November 2010. MEASUREMENTS AND MAIN RESULTS: Patient demographic data, information on the hospitalization for consolidation, data on G-CSF use after H/IDAC chemotherapy, and details on any readmissions were collected. Patients were deemed to have received G-CSF prophylaxis if there was documentation of the intent for use of either filgrastim or pegfilgrastim. Outcome data also were collected, including dates of relapse or second induction treatment course, and death or last follow-up visit. We compared data based on patient receipt of G-CSF (G-CSF vs no G-CSF) after each chemotherapy cycle. We assessed differences in the duration of hospitalization, fever, intravenous antibiotic use, and neutropenia, as well as rate of documented infections, time to disease recurrence, and overall survival. Compared with no G-CSF, use of G-CSF after cycle 1 of H/IDAC significantly reduced the rate of hospitalization for febrile neutropenia (p=0.039); however, no significant differences were noted for subsequent cycles. No significant differences were seen in duration of hospitalization, rate of documented infections, or time to treatment failure between groups. Overall survival was longer for patients who received G-CSF during their first cycle (p=0.018) and for those who received G-CSF during any of their cycles (p=0.04). CONCLUSION: Use of G-CSF prophylaxis after cycle 1 of H/IDAC consolidation for AML appears to reduce the frequency of  hospitalization for febrile neutropenia and to increase overall survival compared with no G-CSF use. Prospective, controlled studies are needed to support our findings.

 

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[288]

TÍTULO / TITLE:  - Zoledronic acid significantly enhances radiationinduced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Feb;42(2):525-34. doi: 10.3892/ijo.2012.1735. Epub 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2012.1735

AUTORES / AUTHORS:  - Koto K; Murata H; Kimura S; Sawai Y; Horie N; Matsui T; Ryu K; Ashihara E; Maekawa T; Kubo T; Fushiki S

INSTITUCIÓN / INSTITUTION:  - Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan.

RESUMEN / SUMMARY:  - Zoledronic acid (ZOL), a third-generation bisphosphonate, inhibits bone resorption, as well as exhibiting direct antitumor activity. To date, however, the combined effects of ZOL and ionizing radiation (IR) have not been assessed in patients with soft tissue sarcoma. We have, therefore, assessed the combined effects of ZOL and IR in fibrosarcoma cells. HT1080 fibrosarcoma cells were treated with ZOL and/or IR, together or sequentially and the antitumor effects were assessed. We found that ZOL significantly enhanced IR-induced apoptosis, especially when cells were treated with ZOL followed by IR. We, therefore, assessed the detailed mechanism of sequential treatment with ZOL and IR. Cells in G2 and M phases, the most radiosensitive phases of the cell cycle, were not increased by low concentrations of ZOL. However, the levels of expression of Akt, ERK1/2 and NF-kappaB proteins, all of which are related to radioadaptive resistance, were increased within a short time after irradiation with 3 Gy, and this expression was inhibited by a low concentration of ZOL, which blocked the prenylation of small GTPases. This sequential treatment also increased the generation of reactive oxygen species (ROS). These results suggest that the combination of ZOL with IR may be beneficial in treating patients with soft tissue sarcoma.

 

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[289]

TÍTULO / TITLE:  - Nanosecond electric pulses induce DNA breaks in cisplatin-sensitive and -resistant human ovarian cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 11;430(2):695-9. doi: 10.1016/j.bbrc.2012.11.089. Epub 2012 Dec 2.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.11.089

AUTORES / AUTHORS:  - Linghu L; Tan Y; Lou Y; Hu L; Yang H; Yu T

INSTITUCIÓN / INSTITUTION:  - Laboratory of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.

RESUMEN / SUMMARY:  - Human ovarian cancer cells COC1 and COC1/DDP (cisplatin-resistant subline) were exposed to 6kV/cm nanosecond electric pulses (nsEP) with a pulse length of 8, 16  or 24ns. The potential in a subcellular unit was calculated using a multilayer dielectric spherical model, and area under the voltage-time curves (AUC) integrated with a lower limit of 0.2V. Cell viability was determined, and double-stand and total DNA breaks detected with the neutral and alkaline comet assays. nsEP evoked a higher voltage and AUC in nucleoplasm, and the levels in COC1 cells was just above those in COC1/DDP cells. Comets only appeared in the alkaline assay demonstrating single-stand DNA break. Fewer DNA break (16.51% vs.  35.13% at 24ns, p=0.0150) and more survival (22.42% vs. 13.19% at 24ns, p=0.0015) occurred in COC1/DDP cells despite an equal electric energy and almost equal cell sizes. 24-ns EP led to higher rates of cell-death and comet. The comet rate correlated with cell-death fraction in either cell line (r=0.5701, p=0.0135; r=0.5110, p=0.0302). There was no a correlation between the tail length, tail moment or Olive tail moment and cell-death rate. The data showed that response of chemosensitive cells differed from that of chemoresistant cells and DNA damage contributed to percent of cell death.

 

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[290]

TÍTULO / TITLE:  - Associations between single-nucleotide polymorphisms of the VEGF gene and long-term prognosis of oral squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Oral Pathol Med. 2012 Dec 10. doi: 10.1111/jop.12026.

            ●● Enlace al texto completo (gratuito o de pago) 1111/jop.12026

AUTORES / AUTHORS:  - Kammerer PW; Koch FP; Schiegnitz E; Kumar VV; Berres M; Toyoshima T; Al-Nawas B; Brieger J

INSTITUCIÓN / INSTITUTION:  - Harvard Medical School, Boston, MA, USA; Department of Oral, Maxillofacial and Plastic Surgery, University Medical Centre, Mainz, Germany; M.R. Ambedkar Dental  College and Hospital, Bangalore, India.

RESUMEN / SUMMARY:  - INTRODUCTION: Functional polymorphisms (SNPs) of the vascular endothelial growth  factor (VEGF) are associated with the incidence of oral squamous cell carcinoma (OSCC). An impact of VEGF-SNPs on prognosis of OSCC patients seems possible. Therefore, correlations between prognostic parameters of OSCC patients and five VEGF-SNPs were determined. MATERIALS AND METHODS: In a retrospective long-term study, in 113 OSCC patients that underwent curative resections, five VEGF-SNPs (-1154 G/A, +405 G/C, +936 C/T, -2578 C/A, and -460 C/T) were analyzed. Associations between SNPs and prognosis (incidence of local recurrent disease, second cancer, metastases, death, total disease-free survival) were examined. RESULTS: After a mean follow-up time of 57.6 months, 32 patients had local recurrences; 15 patients had second cancer, 15 patients metastases, and 23 patients died. The mean disease-free survival was 43.1 months. A significant increased incidence of OSCC in smokers with the VEGF -2578 A/C and -460 C/T SNP was seen (each P < 0.0001). In univariate analysis, patients with advanced OSCCs  (T > 2 or N > 0) together with the -1154 A/A allele had a significant worse survival and a worse disease-free survival (both P < 0.04). The same was seen for the +405 G/G SNP (both P = 0.002). In multivariate analysis, only the negative influence of the +405 G/G SNP on survival in advanced OSCCs (T > 2) could be confirmed (P = 0.002). DISCUSSION: Possible reciprocal interactions between smoking and VEGF-SNP function were observed. Multivariate analysis confirmed the  VEGF +405 G/G genotype to be associated with poor survival in advanced OSCCs; a further use of this haplotype as biomarker has to be discussed.

 

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[291]

TÍTULO / TITLE:  - Synergistic apoptotic effect of celecoxib and luteolin on breast cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):819-25. doi: 10.3892/or.2012.2158. Epub 2012 Nov 29.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2158

AUTORES / AUTHORS:  - Jeon YW; Suh YJ

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, The Catholic University of Korea St. Vincent’s Hospital, Suwon, Republic of Korea.

RESUMEN / SUMMARY:  - Breast cancer is heterogeneous and often hormone-dependent. There are many breast cancer treatment options, including endocrine therapy, chemotherapy, radiotherapy and targeted therapy. Unfortunately, not all patients respond to first-line treatments, and others will eventually relapse despite an initial response. Therapeutic options for these patients are limited. In the past decade, several studies have demonstrated the antitumor effect of celecoxib and luteolin in breast cancer as single treatment. The effect of combination treatment of celecoxib and luteolin in human breast cancer cells has not been well characterized. The present study examined the synergistic effect of celecoxib and luteolin on the human breast cancer cell lines MCF-7 and MDA-MB-231. We analyzed  cell proliferation, cell death, apoptosis and changes in protein expression by performing cell survival assays, apoptosis assays and western blotting. The combination treatment significantly decreased cancer cell viability, and it had a greater efficiency in killing tumor cells after 72 h of treatment, compared to treatment with either agent alone or the control in a concentration- and time-dependent manner (P=0.01). The combination treatment demonstrated a greater  than additive increase in breast cancer cell apoptosis (P=0.01). Decreased levels of Akt phosphorylation (pAkt) were noted after celecoxib and luteolin combination treatment. The combination of celecoxib and luteolin provided superior inhibition of breast cancer cell growth than either celecoxib or luteolin treatment alone. These results suggest that celecoxib and luteolin combination may be a new possible treatment option for breast cancer.

 

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[292]

TÍTULO / TITLE:  - Harmol induces autophagy and subsequent apoptosis in U251MG human glioma cells through the downregulation of survivin.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Jan 18. doi: 10.3892/or.2013.2242.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2242

AUTORES / AUTHORS:  - Abe A; Kokuba H

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan.

RESUMEN / SUMMARY:  - The beta-carboline alkaloids are plant substances that exhibit a wide spectrum of neuropharmacological, psychopharma-cological and antitumor effects. In the present study, we found that harmol, a beta-carboline alkaloid, induced autophagy and suppression of survivin expression, and subsequently induced apoptotic cell death in U251MG human glioma cells. Autophagy was induced within 12 h by treatment with harmol. When treated for over 36 h, however, apoptotic cell death  was induced. Harmol treatment also reduced survivin protein expression. Small interfering RNA (siRNA)-mediated knockdown of survivin enhanced the harmol-induced apoptosis. Knockdown of survivin by siRNA also induced autophagy.  Therefore, harmol-induced apoptosis is a result of the reduction in survivin protein expression. Treatment with 3-methyladenine (3-MA) in the presence of harmol did not affect the expression of survivin and diminished harmol-induced cell death. Treatment with chloroquine in the presence of harmol did not suppress the reduction of survivin expression and increased harmol-induced cell death. From these results, harmol-induced reduction of survivin expression was closely related to autophagy. It is assumed that when isolation membrane formation is inhibited by treatment with 3-MA, reduction of survivin protein expression and apoptotic cell death were not induced. However, when isolation membrane formation is started and an autophagosome is formed, survivin expression is suppressed and  apoptosis is executed. Harmol treatment reduced phosphorylation of Akt, mammalian target of rapamycin (mTOR) and its downstream targets p70-ribosomal protein S6 kinase and 4E-binding protein 1, resulting in induction of autophagy. Conversely, activation of the Akt/mTOR pathway inhibited harmol-induced autophagy and cell death. These findings indicate that harmol-induced autophagy involves the Akt/mTOR pathway. Taken together, autophagy induced by harmol represented a pro-apoptotic mechanism, and harmol suppressed the expression of survivin and subsequently induced apoptosis.

 

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[293]

TÍTULO / TITLE:  - Ligation of CM1 enhances apoptosis of lung cancer cells through different mechanisms in conformity with EGFR mutation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Feb;42(2):469-77. doi: 10.3892/ijo.2012.1731. Epub 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2012.1731

AUTORES / AUTHORS:  - Lee HK; Park GB; Kim YS; Song H; Broaddus VC; Hur DY

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Inje University Busan Paik Hospital, Busan 614-735, Republic of Korea.

RESUMEN / SUMMARY:  - Although remarkable developments in lung cancer treatments have been made, lung cancer remains the leading cause of cancer mortality worldwide. Epidermal growth  factor receptor (EGFR) is occasionally mutated in non-small cell lung cancer and  heterogeneity in treatment response results from different EGFR mutations. In the present study, we found that centrocyte/centroblast marker 1 (CM1), previously reported as a possible apoptosis inducer of B lymphoma cells, is expressed on both A549 with wildtype EGFR and HCC827 with mutant EGFR lung cancer cells. Ligation of CM1 with anti-CM1 mAb enhanced apoptosis in both lung cancer cell lines through generation of reactive oxygen species (ROS) and disruption of mitochondrial membrane potential, however, the signaling mechanisms differed from each other. Further studies to investigate the signaling mechanisms identified that ligation of CM1induced apoptosis in A549 cell involved FasL expression, caspase-8, ERK1/2 and Akt kinase, whereas apoptosis of HCC827 cells was induced through caspase-9, JNK and c-jundependent pathways. Taken together, we suggest that CM1 could be developed as a therapeutic target of lung cancer regardless of  EGFR mutation status.

 

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[294]

TÍTULO / TITLE:  - Mycophenolic acid regulates spleen tyrosine kinase to repress tumour necrosis factor-alpha-induced monocyte chemotatic protein-1 production in cultured human aortic endothelial cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Biol Int. 2013 Jan;37(1):19-28. doi: 10.1002/cbin.10003. Epub 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cbin.10003

AUTORES / AUTHORS:  - Koo TY; Kim YJ; Yang WS; Park JS; Han NJ; Lee JM; Park SK

INSTITUCIÓN / INSTITUTION:  - Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea.

RESUMEN / SUMMARY:  - Atherosclerosis develops from cascades of inflammatory processes. Spleen tyrosine kinase (Syk) and monocyte chemotatic protein-1 (MCP-1) play important roles in the pathogenesis of atherosclerosis. Mycophenolic acid (MPA) has an anti-inflammatory effect. We have investigated whether MPA regulates Syk to repress tumour necrosis factor-alpha (TNF-alpha)-induced MCP-1 production in cultured human aortic endothelial cells. Expression of MCP-1 mRNA and its protein were measured by real time RT-PCR and ELISA, respectively. Reactive oxygen species (ROS) production were measured using 2’7’-dichlorofluorescein diacetate.  Activation of AP-1 and NF-kappaB were assessed by electrophoretic mobility shift  assay. Tyrosine phosphorylation of Syk was examined by Western blot analysis. TNF-alpha increased MCP-1 at both mRNA and protein levels. TNF-alpha-induced MCP-1 mRNA expression was inhibited by N-acetylcysteine (NAC), Syk inhibitor, Syk-siRNA and MPA. TNF-alpha-induced MCP-1 protein production was also inhibited  by Syk inhibitor and MPA. TNF-alpha increased DNA binding activity of AP-1 and NF-kappaB, whereas both AP-1 and NF-kappaB decoy oligodeoxynucleotides downregulated TNF-alpha-induced MCP-1 mRNA expression. TNF-alpha increased ROS generation, which was inhibited by NAC and MPA, but not by Syk inhibitor. TNF-alpha increased tyrosine phosphorylation of Syk, which was attenuated by NAC  and MPA. MPA and Syk inhibitor attenuated TNF-alpha-induced DNA binding activity  of NF-kappaB and AP-1. TNF-alpha induced MCP-1 expression via activation of AP-1  and NF-kappaB. AP-1 and NF-kappaB were mediated through ROS, followed by Syk. MPA exerts anti-inflammatory effect by inhibiting MCP-1 expression via suppression of ROS and Syk.

 

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[295]

TÍTULO / TITLE:  - Alterations in brain structure and function in breast cancer survivors: effect of post-chemotherapy interval and relation to oxidative DNA damage.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Jan;137(2):493-502. doi: 10.1007/s10549-012-2385-x. Epub 2012 Dec 22.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-012-2385-x

AUTORES / AUTHORS:  - Conroy SK; McDonald BC; Smith DJ; Moser LR; West JD; Kamendulis LM; Klaunig JE; Champion VL; Unverzagt FW; Saykin AJ

INSTITUCIÓN / INSTITUTION:  - Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine Indianapolis, 355 W. 16th St., GH Suite 4100, Indianapolis, IN, 46202, USA.

RESUMEN / SUMMARY:  - Neuroimaging studies have begun to uncover the neural substrates of cancer and treatment-related cognitive dysfunction, but the time course of these changes in  the years following chemotherapy is unclear. This study analyzed multimodality 3T MRI scans to examine the structural and functional effects of chemotherapy and post-chemotherapy interval (PCI) in a cohort of breast cancer survivors (BCS; n = 24; PCI mean 6, range 3-10 y) relative to age- and education-matched healthy controls (HC; n = 23). Assessments included voxel-based morphometry for gray matter density (GMD) and fMRI for activation profile during a 3-back working memory task. The relationships between brain regions associated with PCI and neuropsychological performance, self-reported cognition, and oxidative and direct DNA damage as measured in peripheral lymphocytes were assessed in secondary analyses. PCI was positively associated with GMD and activation on fMRI in the right anterior frontal region (Brodmann Areas 9 and 10) independent of participant age. GMD in this region was also positively correlated with global neuropsychological function. Memory dysfunction, cognitive complaints, and oxidative DNA damages were increased in BCS compared with HC. Imaging results indicated lower fMRI activation in several regions in the BCS group. BCS also had lower GMD than HC in several regions, and in these regions, GMD was inversely related to oxidative DNA damage and learning and memory neuropsychological domain scores. This is the first study to show structural and functional effects of PCI  and to relate oxidative DNA damage to brain alterations in BCS. The relationship  between neuroimaging and cognitive function indicates the potential clinical relevance of these findings. The relationship with oxidative DNA damage provides  a mechanistic clue warranting further investigation.

 

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[296]

TÍTULO / TITLE:  - Vimentin DNA methylation predicts survival in breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Jan;137(2):383-96. doi: 10.1007/s10549-012-2353-5.  Epub 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-012-2353-5

AUTORES / AUTHORS:  - Ulirsch J; Fan C; Knafl G; Wu MJ; Coleman B; Perou CM; Swift-Scanlan T

INSTITUCIÓN / INSTITUTION:  - The University of North Carolina at Chapel Hill School of Nursing, Lab 013, Carrington Hall, CB #7460, Chapel Hill, NC, 27599-7460, USA.

RESUMEN / SUMMARY:  - The Vimentin gene plays a pivotal role in epithelial-to-mesenchymal transition and is known to be overexpressed in the prognostically poor basal-like breast cancer subtype. Recent studies have reported Vimentin DNA methylation in association with poor clinical outcomes in other solid tumors, but not in breast  cancer. We therefore quantified Vimentin DNA methylation using MALDI-TOF mass spectrometry in breast tumors and matched normal pairs in association with gene expression and survival in a hospital-based study of breast cancer patients. Gene expression data via qRT-PCR in cell lines and oligomicroarray data from breast tissues were correlated with percent methylation in the Vimentin promoter. A threshold of 20 percent average methylation compared with matched normal pairs was set for bivariate and multivariate tests of association between methylation and tumor subtype, tumor histopathology, and survival. Vimentin was differentially methylated in luminal breast cancer cell lines, and in luminal A,  luminal B, and HER2-enriched breast tumor subtypes, but was rare in basal-like cell lines and tumors. Increased methylation was strongly correlated with decreased mRNA expression in cell lines, and had a moderate inverse correlation in breast tumors. Vimentin methylation predicted poor overall survival independent of race, subtype, stage, nodal status, or metastatic disease and holds promise as a new prognostic biomarker for breast cancer patients.

 

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[297]

TÍTULO / TITLE:  - A polysaccharide fraction of adlay seed (Coixlachryma-jobi L.) induces apoptosis  in human non-small cell lung cancer A549 cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 11;430(2):846-51. doi: 10.1016/j.bbrc.2012.11.058. Epub 2012 Nov 27.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.11.058

AUTORES / AUTHORS:  - Lu X; Liu W; Wu J; Li M; Wang J; Wu J; Luo C

INSTITUCIÓN / INSTITUTION:  - Key Laboratory of Food Nutrition and Safety, Ministry of Education, School of Food Engineering and Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.

RESUMEN / SUMMARY:  - Different seed extracts from Coix lachryma-jobi (adlay seed) have been used for the treatment of various cancers in China, and clinical data support the use of these extracts for cancer therapy; however, their underlying molecular mechanisms have not been well defined. A polysaccharide fraction, designated as CP-1, was extracted from the C.lachryma-jobi L. var. using the ethanol subsiding method. CP-1 induced apoptosis in A549 cells in a dose-dependent manner, as determined by MTT assay. Apoptotic bodies were observed in the cells by scanning electronic microscopy. Apoptosis and DNA accumulation during S-phase of the cell cycle were  determined by annexin V-FITC and PI staining, respectively, and measured by flow  cytometry. CP-1 also extended the comet tail length on single cell gel electrophoresis, and disrupted the mitochondrial membrane potential. Further analysis by western blotting showed that the expression of caspase-3 and caspase-9 proteins was increased. Taken together, our results demonstrate that CP-1 is capable of inhibiting A549 cell proliferation and inducing apoptosis via  a mechanism primarily involving the activation of the intrinsic mitochondrial pathway. The assay data suggest that in addition to its nutritional properties, CP-1 is a very promising candidate polysaccharide for the development of anti-cancer medicines.

 

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[298]

TÍTULO / TITLE:  - The antiproliferative activity of 3-deoxyanthocyanins extracted from red sorghum  (Sorghum bicolor) bran through P(53)-dependent and Bcl-2 gene expression in breast cancer cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Life Sci. 2013 Jan 16. pii: S0024-3205(13)00011-8. doi: 10.1016/j.lfs.2013.01.006.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.lfs.2013.01.006

AUTORES / AUTHORS:  - Suganyadevi P; Saravanakumar KM; Mohandas S

INSTITUCIÓN / INSTITUTION:  - P.G. Department of Biotechnology, Dr. Mahalingam Centre for Research and Development, NGM College, Pollachi 642001, India. Electronic address: suganyabiotech@yahoo.co.in.

RESUMEN / SUMMARY:  - AIMS: The aim of this study was to investigate the anti proliferative activity of 3-deoxyanthocyanin extracted from red sorghum bran on human breast cancer cell line MCF 7. The confirmatory tests were carried out in vitro through the expression studies of p(53) and (bcl) 2 genes in MCF 7 cells. METHOD: The 3-deoxyanthocyanins were isolated from red sorghum bran and cytotoxic studies were performed in MCF 7 cell line by MTT assay. The mRNA expression levels of p(53) and (bcl) 2 genes were performed using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in MCF 7 cells. KEY FINDINGS: On cytotoxic studies, the present data indicates sorghum anthocyanins,  which showed 84.09% of inhibition in the proliferation of MCF 7 cells, and the CTC(50) value was 300mug/ml. The sorghum 3-deoxyanthocyanins induced apoptosis in MCF 7 was mediated by stimulation of the p(53) gene and down regulation of the (bcl) 2 gene. SIGNIFICANCE: The significance of our work was the anthocyanin isolated from red sorghum bran inhibits the proliferation of human breast cancer  cell line.

 

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[299]

TÍTULO / TITLE:  - HDAC inhibitor DWP0016 activates p53 transcription and acetylation to inhibit cell growth in U251 glioblastoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Cell Biochem. 2013 Jan 7. doi: 10.1002/jcb.24491.

            ●● Enlace al texto completo (gratuito o de pago) 1002/jcb.24491

AUTORES / AUTHORS:  - Jin H; Liang L; Liu LF; Deng WP; Liu JW

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China.

RESUMEN / SUMMARY:  - Here we report a hydroacid named DWP0016, which exhibited HDAC inhibition and induced p53 acetylation in U251 glioblastoma cells. DWP0016 effectively inhibited the cell growth of U251 cells and other 4 carcinoma cell lines but did not affect the normal cells. Cell cycle distribution analysis showed DWP0016 arrested at G(1) phase cell cycle dose-dependently in U251 cells. DWP0016 induced caspase-dependent and independent apoptosis in U251 cells, which was identified by flow cytometry analysis, caspases activity analysis, western blotting assay and caspases inhibition. Mechanisms research suggested that DWP0016 activated transcription and acetylation of tumor suppressor p53. DWP0016 regulated p300, CBP and PCAF to facilitate p53 acetylation at lys382 in U251 cells. In addition,  activation of p53 by DWP0016 promoted PUMA to catalyze mitochondrial pathway. Besides, siRNA assay indicated p53 was the key gene to induce growth inhibition,  cell cycle arrest and apoptosis in DWP0016 treated U251 cells. Conclusively, our  results show DWP0016 is a potent HDAC inhibitor and the anti-tumor activity is consistent with its intended p53 activation mechanisms. These findings indicate the promising antitumor potential of DWP0016 for further glioblastoma treatment applications. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.

 

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[300]

TÍTULO / TITLE:  - The Bruton tyrosine kinase (BTK) inhibitor PCI-32765 synergistically increases proteasome inhibitor activity in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Haematol. 2013 Jan 30. doi: 10.1111/bjh.12206.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bjh.12206

AUTORES / AUTHORS:  - Dasmahapatra G; Patel H; Dent P; Fisher RI; Friedberg J; Grant S

INSTITUCIÓN / INSTITUTION:  - Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA.

RESUMEN / SUMMARY:  - Interactions between the Bruton tyrosine kinase (BTK) inhibitor PCI-32765 and the proteasome inhibitor (bortezomib) were examined in diffuse large-B cell lymphoma  (DLBCL) and mantle cell lymphoma (MCL) cells, including those highly resistant to bortezomib. Co-administration of PCI-32765/bortezomib synergistically increased mitochondrial injury and apoptosis in germinal centre- or activated B-cell-like-DLBCL cells and in MCL cells. These events were accompanied by marked AKT and nuclear factor (NF)-kappaB (NFKB1) inactivation, down-regulation of Mcl-1 (MCL1), Bcl-xL (BCL2L1), and XIAP, and enhanced DNA damage (e.g., gammaH2A.X formation) and endoplasmic reticulum (ER) stress. Similar interactions were observed in highly bortezomib-resistant DLBCL and MCL cells, and in primary DLBCL cells. In contrast, PCI-32765/bortezomib regimens displayed minimal toxicity toward normal CD34(+) bone marrow cells. Transfection of DLBCL cells with a constitutively active AKT construct attenuated AKT inactivation and significantly diminished cell death, whereas expression of an NF-kappaB “super-repressor” (IkappaBalpha(ser34/36) ) increased both PCI-32765 and bortezomib lethality. Moreover, cells in which the ER stress response was disabled by a dominant-negative eIF2alpha construct were resistant to this regimen. Finally, combined exposure to PCI-32765 and bortezomib resulted in more pronounced and sustained reactive oxygen species (ROS) generation, and ROS scavengers significantly diminished lethality. Given promising early clinical results for PCI-32765 in DLBCL and MCL, a strategy combining BTK/proteasome inhibitor warrants attention in these malignancies.

 

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[301]

TÍTULO / TITLE:  - Expression of Genes of Glutathione Transferase Isoforms GSTP1-1, GSTA4-4, and GSTK1-1 in Tumor Cells during the Formation of Drug Resistance to Cisplatin.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Bull Exp Biol Med. 2012 Oct;154(1):64-7.

AUTORES / AUTHORS:  - Kalinina EV; Berozov TT; Shtil AA; Chernov NN; Glasunova VA; Novichkova MD; Nurmuradov NK

INSTITUCIÓN / INSTITUTION:  - People’s Friendship University of Russia; N. N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences, Moscow, Russia. kevsan@orc.ru.

RESUMEN / SUMMARY:  - We studied the expression of genes encoding glutathione-S-transferase isoforms GSTP1-1, GSTA4-4, and GSTK1-1 during the development of the resistance of human erythroleukemia (K562), mammary adenocarcinoma (MCF-7) and ovary adenocarcinoma (SKOV-3) cells to cisplatin (CDDP). It was found that drug resistance development in all three strains of tumor cells is associated with significant increase in hGSTP1 and hGSTA4 gene expression, whereas increased hGSTK1 gene expression was detected only in resistant K562/CDDP and MCF-7/CDDP cells.

 

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[302]

TÍTULO / TITLE:  - Dual Response of Human Leukemia U937 Cells to Hypertonic Shrinkage: Initial Regulatory Volume Increase (RVI) and Delayed Apoptotic Volume Decrease (AVD).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Physiol Biochem. 2012 Sep 20;30(4):964-973.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000341473

AUTORES / AUTHORS:  - Yurinskaya VE; Moshkov AV; Wibberley AV; Lang F; Model MA; Vereninov AA

INSTITUCIÓN / INSTITUTION:  - Laboratory of Cell Physiology, Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia.

RESUMEN / SUMMARY:  - Background/Aims: Osmotic cell shrinkage is a powerful trigger of suicidal cell death or apoptosis, which is paralleled and enforced by apoptotic volume decrease (AVD). Cells counteract cell shrinkage by volume regulatory increase (RVI). The present study explored the response of human U937 cells to hypertonic solution thus elucidating the relationship between RVI and AVD. Methods: Cell water, concentration of monovalent ions and the appearance of apoptotic markers were followed for 0.5-4 h after the cells were transferred to a hypertonic medium. Intracellular water, K+, Na+, and Cl- content, ouabain-sensitive and -resistant Rb+ influxes were determined by measurement of the cell buoyant density in Percoll density gradient, flame emission analysis and 36Cl- assay, respectively.  Fluorescent microscopy of live cells stained by acridine orange and ethidium bromide was used to verify apoptosis. Results: After 2-4 h incubation in hypertonic media the cell population was split into light (L) and heavy (H) fractions. According to microscopy and analysis of monovalent ions the majority of cells in the L population were healthy, while the H fractions were enriched with apoptotic cells. The density of L cells was decreasing with time, while the  density of H cells was increasing, thus reflecting the opposite effects of RVI and AVD. At the same time, some of the cells were shifting from L to H fractions, indicating that apoptosis was gradually extending to cells that were previously displaying normal RVI. Conclusion: The findings suggest that apoptosis can develop in cells capable of RVI.

 

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[303]

TÍTULO / TITLE:  - Curcumin resistance induced by hypoxia in HepG2 cells is mediated by multidrug-resistance-associated proteins.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Anticancer Res. 2012 Dec;32(12):5337-42.

AUTORES / AUTHORS:  - Sakulterdkiat T; Srisomsap C; Udomsangpetch R; Svasti J; Lirdprapamongkol K

INSTITUCIÓN / INSTITUTION:  - Laboratory of Biochemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Talat Bang Khen, Laksi, Bangkok 10210, Thailand.

RESUMEN / SUMMARY:  - BACKGROUND: Tumor hypoxia, a common pathophysiological feature of solid tumors, contributes to drug resistance and treatment failure. Here, we demonstrate that hypoxia in HepG2 cells induces resistance towards cytotoxicity of curcumin, a promising anticancer agent. MATERIALS AND METHODS: The number of surviving cells  after exposure to chemotherapeutic drugs under normoxia (ambient O(2)) and hypoxia (1% O(2)) was determined by crystal violet staining. The expression levels of drug transporter genes were analyzed by quantitative real-time reverse  transcription-polymerase chain reaction. RESULTS: Increased resistance to curcumin, as well as to etoposide and doxorubicin, was observed in HepG2 cells under hypoxia. Gene expression analysis revealed that hypoxia increased the expression of ATP-binding cassette (ABC) drug transporter genes, sub-family C including ABCC1, ABCC2, and ABCC3, by more than two-fold. While expression of ABC drug transporter genes sub-family B member 1 and sub-family G member 2 (ABCB2/P-gp and ABCG2, respectively) did not change significantly. Both inhibitors of ABCC1/ABCC2 and depletion of intracellular glutathione levels were  able to reverse hypoxia-induced curcumin resistance. CONCLUSION: ABCC1 and ABCC2  play an important role in hypoxia-induced curcumin resistance in human hepatocellular carcinoma.

 

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[304]

TÍTULO / TITLE:  - Sulindac sulfide inhibits sarcoendoplasmic reticulum Ca(2+) ATPase, induces endoplasmic reticulum stress response, and exerts toxicity in glioma cells: Relevant similarities to and important differences from celecoxib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Neurosci Res. 2013 Mar;91(3):393-406. doi: 10.1002/jnr.23169. Epub 2012 Dec 30.

            ●● Enlace al texto completo (gratuito o de pago) 1002/jnr.23169

AUTORES / AUTHORS:  - White MC; Johnson GG; Zhang W; Hobrath JV; Piazza GA; Grimaldi M

INSTITUCIÓN / INSTITUTION:  - Laboratory of Neuropharmacology, Medicinal Chemistry Department, Drug Discovery Division, Southern Research Institute, Birmingham, Alabama.

RESUMEN / SUMMARY:  - Malignant gliomas have low survival expectations regardless of current treatments. Nonsteroidal anti-inflammatory drugs (NSAIDs) prevent cell transformation and slow cancer cell growth by mechanisms independent of cyclooxygenase (COX) inhibition. Certain NSAIDs trigger the endoplasmic reticulum stress response (ERSR), as revealed by upregulation of molecular chaperones such  as GRP78 and C/EBP homologous protein (CHOP). Although celecoxib (CELE) inhibits  the sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA), an effect known to induce ERSR, sulindac sulfide (SS) has not been reported to affect SERCA. Here, we investigated these two drugs for their effects on Ca(2+) homeostasis, ERSR, and glioma cell survival. Our findings indicate that SS is a reversible inhibitor of  SERCA and that both SS and CELE bind SERCA at its cyclopiazonic acid binding site. Furthermore, CELE releases additional Ca(2+) from the mitochondria. In glioma cells, both NSAIDS upregulate GRP78 and activate ER-associated caspase-4 and caspase-3. Although only CELE upregulates the expression of CHOP, it appears  that CHOP induction could be associated with mitochondrial poisoning. In addition, CHOP induction appears to be uncorrelated with the gliotoxicity of these NSAIDS in our experiments. Our data suggest that activation of ERSR is primarily responsible for the gliotoxic effect of these NSAIDS. Because SS has good brain bioavailability, has lower COX-2 inhibition, and has no mitochondrial  effects, it represents a more appealing molecular candidate than CELE to achieve  gliotoxicity via activation of ERSR. © 2012 Wiley Periodicals, Inc.

 

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[305]

TÍTULO / TITLE:  - p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Toxicol Appl Pharmacol. 2013 Feb 15;267(1):113-24. doi: 10.1016/j.taap.2012.12.016. Epub 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.taap.2012.12.016

AUTORES / AUTHORS:  - Huang SW; Wu CY; Wang YT; Kao JK; Lin CC; Chang CC; Mu SW; Chen YY; Chiu HW; Chang CH; Liang SM; Chen YJ; Huang JL; Shieh JJ

INSTITUCIÓN / INSTITUTION:  - Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.

RESUMEN / SUMMARY:  - Compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), has been reported to cause apoptotic cell death in myeloma, breast cancer cells and glioma cells. In this study, we have demonstrated that compound C not only induced autophagy in all tested skin cancer cell lines but also caused more apoptosis in p53 wildtype skin cancer cells than  in p53-mutant skin cancer cells. Compound C can induce upregulation, phosphorylation and nuclear translocalization of the p53 protein and upregulate expression of p53 target genes in wildtype p53-expressing skin basal cell carcinoma (BCC) cells. The changes of p53 status were dependent on DNA damage which was caused by compound C induced reactive oxygen species (ROS) generation and associated with activated ataxia-telangiectasia mutated (ATM) protein. Using  the wildtype p53-expressing BCC cells versus stable p53-knockdown BCC sublines, we present evidence that p53-knockdown cancer cells were much less sensitive to compound C treatment with significant G2/M cell cycle arrest and attenuated the compound C-induced apoptosis but not autophagy. The compound C induced G2/M arrest in p53-knockdown BCC cells was associated with the sustained inactive Tyr15 phosphor-Cdc2 expression. Overall, our results established that compound C-induced apoptosis in skin cancer cells was dependent on the cell’s p53 status.

 

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[306]

TÍTULO / TITLE:  - Complete remission after a single cycle of azacitidine in a case of relapsed acute myeloid leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Wien Klin Wochenschr. 2013 Jan 5.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00508-012-0319-6

AUTORES / AUTHORS:  - Valentiny C; Mitrovic M; Pleyer L; Steurer M; Willenbacher W; Stauder R

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine V (Hematology and Oncology), Innsbruck Medical University, Innsbruck, Austria.

RESUMEN / SUMMARY:  - A 75-year-old female patient presented with late relapse of acute myeloid leukemia (AML). She received a single cycle of azacitidine before refusing further treatment. Around 6 weeks after this single azacitidine cycle, complete remission-according to international working group criteria-was observed with continuous improvement in peripheral blood counts to normal values, transfusion-independence, normal blast count (< 5 %) with normal morphology and flow cytometry, as well as a normal bone marrow karyotype and no dysplastic stigmata suggestive of a coexisting myelodysplastic syndrome. The patient also showed a pronounced improvement in performance status. Seven months later a second relapse occurred, followed by one additional azacitidine cycle that showed only a transient and a minor increase in thrombocytes and granulocytes, corresponding to an international working group nonresponse. As azacitidine treatment was interrupted after a single cycle, this case gives insight into the  kinetics of response. The lack of response to azacitidine in AML after the second relapse suggests that azacitidine administration should be maintained after response.

 

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[307]

TÍTULO / TITLE:  - The combination of an oxygen-dependent degradation domain-regulated adenovirus expressing the chemokine RANTES/CCL5 and NK-92 cells exerts enhanced antitumor activity in hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar;29(3):895-902. doi: 10.3892/or.2012.2217. Epub 2012 Dec 28.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2217

AUTORES / AUTHORS:  - Li J; Liu H; Li L; Wu H; Wang C; Yan Z; Wang Y; Su C; Jin H; Zhou F; Wu M; Qian Q

INSTITUCIÓN / INSTITUTION:  - Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgical Hospital and Institute, The Second Military Medical University, Shanghai 200438, P.R. China.

RESUMEN / SUMMARY:  - Oncolytic adenoviruses are modified based on adenovirus serotype 5 (Ad5), which belongs to subgroup C and depends on Coxsackie-adenovirus receptor (CAR) to recognize target cells. However, expression of CAR is generally low or lost in certain tumors including hepatocellular carcinoma (HCC). By contrast, CD46 is highly expressed in various types of malignant tumor cells. Therefore, we constructed an adenovirus vector expressing the human RANTES/CCL5 gene regulated  by oxygen-dependent degradation domain (ODD) and analyzed its antitumor effects in vitro and in vivo. The human RANTES/CCL5 gene was fused with ODD by PCR and the recombinant oncolytic adenovirus containing RANTES-ODD, SG511-CCL5-ODD, was constructed by the Gateway system, which infected cells by binding CD46. Viral replication experiments were performed to evaluate the selective replication ability of SG511-CCL5-ODD. RANTES expression was determined by ELISA. The chemotactic test was used to analyze the ability of the expressed RANTES to recruit NK92 cells. The antitumor effects of SG511-CCL5-ODD were examined in HCC  xenografts in nude mice. A chimeric oncolytic adenovirus, SG511-CCL5-ODD, was constructed successfully. Cells infected with the recombinant virus were able to  express RANTES selectively in different environments controlled by ODD and the expressed RANTES was able to recruit NK92 cells by its chemotactic effect in vitro and improve the anticancer immune response in HCC xenografts in nude mice.  The chimeric adenovirus SG511-CCL5-ODD highly expressed the RANTES-ODD fusion gene in the hypoxia of HCC under the control of the ODD and effectively attracted NK92 cells and a high number of immunocytes. These factors had complementary advantages and, in combination, exerted enhanced antitumor efficacy.

 

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[308]

TÍTULO / TITLE:  - Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Exp Cell Res. 2012 Dec 27. pii: S0014-4827(12)00495-8. doi: 10.1016/j.yexcr.2012.12.018.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.yexcr.2012.12.018

AUTORES / AUTHORS:  - Takeda H; Takigawa N; Ohashi K; Minami D; Kataoka I; Ichihara E; Ochi N; Tanimoto M; Kiura K

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Oncology, and Respiratory Medicine, Okayama University  Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

RESUMEN / SUMMARY:  - The effectiveness of vandetanib, an agent that targets RET, VEGFR and EGFR signaling, against EGFR-mutant lung cancer cells with PTEN loss was investigated. Two EGFR mutant non-small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild type) and NCI-H1650 (PTEN null), were used. We transfected an intact PTEN gene into H1650 cells and knocked down PTEN expression in PC-9 cells using shRNA. The  effectiveness of gefitinib and vandetanib was assessed using a xenograft model. While PC-9 cells were more resistant to vandetanib than gefitinib, H1650 cells were more sensitive to vandetanib than gefitinib. Both gefitinib and vandetanib suppressed the activation of EGFR and MAPK in H1650 cells, although phosphorylated AKT levels were not affected. In an H1650 cell xenograft model, vandetanib was also more effective than gefitinib. Although PTEN-transfected H1650 cells did not show restoration of sensitivity to gefitinib in vitro, the xenograft tumors responded to gefitinib and vandetanib. Knockdown of PTEN in PC-9 cells caused resistance to gefitinib. In conclusion, vandetanib might be effective in NSCLC with EGFR mutations that lack PTEN expression. The contribution of PTEN absence to vandetanib activity in NSCLC cells harboring EGFR mutations should be further examined.

 

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[309]

TÍTULO / TITLE:  - NPACT: Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Nucleic Acids Res. 2013 Jan 1;41(D1):D1124-9. doi: 10.1093/nar/gks1047. Epub 2012 Nov 29.

            ●● Enlace al texto completo (gratuito o de pago) 1093/nar/gks1047

AUTORES / AUTHORS:  - Mangal M; Sagar P; Singh H; Raghava GP; Agarwal SM

INSTITUCIÓN / INSTITUTION:  - Bioinformatics Division, Institute of Cytology and Preventive Oncology, I-7 Sector-39, Noida-201301 and Bioinformatics Centre, Institute of Microbial Technology, Sector 39A, Chandigarh 160036, India.

RESUMEN / SUMMARY:  - Plant-derived molecules have been highly valued by biomedical researchers and pharmaceutical companies for developing drugs, as they are thought to be optimized during evolution. Therefore, we have collected and compiled a central resource Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database (NPACT, http://crdd.osdd.net/raghava/npact/) that gathers the information related to experimentally validated plant-derived natural compounds exhibiting anti-cancerous activity (in vitro and in vivo), to complement the other databases. It currently contains 1574 compound entries, and each record provides information on their structure, manually curated published data on in vitro and in vivo experiments along with reference for users referral, inhibitory values (IC(50)/ED(50)/EC(50)/GI(50)), properties (physical, elemental and topological), cancer types, cell lines, protein targets, commercial suppliers and drug likeness of compounds. NPACT can easily be browsed or queried using various  options, and an online similarity tool has also been made available. Further, to  facilitate retrieval of existing data, each record is hyperlinked to similar databases like SuperNatural, Herbal Ingredients’ Targets, Comparative Toxicogenomics Database, PubChem and NCI-60 GI(50) data.

 

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[310]

TÍTULO / TITLE:  - Sonic hedgehog antagonists induce cell death in acute myeloid leukemia cells with the presence of lipopolysaccharides, tumor necrosis factor-alpha, or interferons.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Invest New Drugs. 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10637-012-9908-5

AUTORES / AUTHORS:  - Lu FL; Yu CC; Chiu HH; Liu HE; Chen SY; Lin S; Goh TY; Hsu HC; Chien CH; Wu HC; Chen MS; Schuyler SC; Hsieh WS; Wu MH; Lu J

INSTITUCIÓN / INSTITUTION:  - Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.

RESUMEN / SUMMARY:  - Due to the development of drug resistance, the outcome for the majority of patients with acute myeloid leukemia (acute myelogenous leukemia; AML) remains poor. To prevent drug resistance and increase the therapeutic efficacy of treating AML, the development of new combinatory drug therapies is necessary. Sonic hedgehog (Shh) is expressed in AML biopsies and is essential for the drug resistance of cancer stem cells of AML. AML patients are frequently infected by bacteria and exposed to lipopolysaccharide (LPS). LPS itself, its derivatives, and its downstream effectors, such as tumor necrosis factor-alpha (TNF-alpha) and interferons (IFNs), have been shown to provoke anti-tumor effects. The application of a Shh inhibitor against AML cells in the presence of LPS/TNF-alpha/IFNs has not been investigated. We found that the Shh inhibitor cyclopamine in combination with LPS treatment synergistically induced massive cell apoptosis in THP-1 and U937 cells. The cytotoxic effects of this combined drug treatment were confirmed in 5 additional AML cell lines, in primary AML cells, and in an AML mouse model. Replacing cyclopamine with another Shh inhibitor, Sant-1, had the same effect. LPS could be substituted by TNF-alpha or  IFNs to induce AML cell death in combination with cyclopamine. Our results suggest a potential strategy for the development of new therapies employing Shh antagonists in the presence of LPS/TNF-alpha/IFNs for the treatment of AML patients.

 

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[311]

TÍTULO / TITLE:  - Pharmacokinetics and dose escalation of the heat shock protein inhibitor 17-allyamino-17-demethoxygeldanamycin in combination with bortezomib in relapsed  or refractory acute myeloid leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Jan 24.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2012.760733

AUTORES / AUTHORS:  - Walker AR; Klisovic R; Johnston JS; Jiang Y; Geyer S; Kefauver C; Binkley P; Byrd JC; Grever MR; Garzon R; Phelps MA; Marcucci G; Blum KA; Blum W

INSTITUCIÓN / INSTITUTION:  - Division of Hematology, Department of Internal Medicine.

RESUMEN / SUMMARY:  - This phase I study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of the heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) in combination with bortezomib, and to provide pharmacokinetic data in relapsed or refractory acute myeloid leukemia (AML). Eleven patients were enrolled. The MTD was 17-AAG 150 mg/m(2) and bortezomib 0.7 mg/m(2). Hepatic toxicity and cardiac toxicity were dose limiting. Co-administration on day 4 led to a decrease in clearance (p = 0.005) and increase in AUC (p = 0.032) of 17-amino-17-demethoxygeldanamycin (17-AG), not observed when 17-AAG was administered alone. Pharmacokinetic parameters of patients who developed toxicities and those who did not were not different. The combination of 17-AAG and bortezomib led to toxicity without measurable response in patients with relapsed or refractory AML. Pharmacokinetic  data provide insight for studies of related agents in AML. Next-generation HSP90  inhibitors are appealing for further development in this area.

 

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[312]

TÍTULO / TITLE:  - Apoptosis Imaging Probe Predicts Early Chemotherapy Response in Preclinical Models: A Comparative Study with 18F-FDG PET.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Nucl Med. 2013 Jan;54(1):104-10. doi: 10.2967/jnumed.112.109397.

            ●● Enlace al texto completo (gratuito o de pago) 2967/jnumed.112.109397

AUTORES / AUTHORS:  - Song S; Xiong C; Lu W; Ku G; Huang G; Li C

INSTITUCIÓN / INSTITUTION:  - Department of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China.

RESUMEN / SUMMARY:  - Previously, we reported a small-molecular-weight peptide, single amino acid chelae((99m)Tc)-conjugated phosphatidylserine-binding peptide (SAAC((99m)Tc)-PSBP-6), with high binding affinity to phosphatidylserine on the surface of apoptotic cells. The purpose of this study was to determine the effectiveness of SAAC((99m)Tc)-PSBP-6 in detecting apoptosis induced by chemotherapy. METHODS: B16/F10 melanoma and 38C13 lymphoma tumor models were used in this study. For each type of tumor model, mice were divided into a group treated for imaging (treated group [TG]) and a control group that was not treated (nontreated group [N-TG]). In the TG, mice bearing murine B16/F10 melanoma received a single dose of intravenous polymeric paclitaxel (equivalent dose, 80 mg/kg), and mice bearing 38C13 xenografts received intraperitoneal cyclophosphamide (100 mg/kg). Mice in the N-TG were given the same volume of saline. gamma-imaging 4 h after intravenous injection of SAAC((99m)Tc)-PSBP-6 and small-animal PET 1 h after intravenous injection of (18)F-FDG were performed before chemotherapy and at 1 d after chemotherapy. On day 1, immediately after the apoptosis imaging sessions, 3 mice each in the TGs and N-TGs were killed, and tumor tissues were excised for hematoxylin and eosin histology, autoradiography,  and immunohistochemical staining using anti-active caspase 3 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). The tumor volumes in the remaining mice (n = 5/group) were measured every other day for 7 d. RESULTS: In both tumor models, the uptake of SAAC((99m)Tc)-PSBP-6 increased significantly on day 1 after treatment, whereas (18)F-FDG uptake decreased significantly during the same time. The mean tumor uptake values for SAAC((99m)Tc)-PSBP-6 increased 142.4% +/- 36.9% and 112% +/- 42.9% in 38C13 and B16/F10 tumors, respectively (both P < 0.05, pretreatment vs. day 1 after treatment). The mean tumor uptake value for (18)F-FDG decreased 67.36% +/- 17.52% and 62.82% +/- 4.53% in 38C13 and B16/F10 tumors, respectively. The uptake of SAAC((99m)Tc)-PSBP-6 negatively correlated with (18)F-FDG (r = -0.79, P < 0.05).  Treated tumors had smaller volumes than untreated controls, treated tumors had significantly higher numbers of apoptotic cells, and tumor uptake of SAAC((99m)Tc)-PSBP-6 correlated with the number of TUNEL-positive cells. CONCLUSION: SAAC((99m)Tc)-PSBP-6 gamma-imaging is useful for the early assessment of treatment-induced apoptosis and, thus, may be used as a substitute for (18)F-FDG PET for assessing early treatment response.

 

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[313]

TÍTULO / TITLE:  - Detectable Prostate-Specific Antigen Nadir During Androgen-Deprivation Therapy Predicts Adverse Prostate Cancer-Specific Outcomes: Results from the SEARCH Database.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur Urol. 2012 Dec 6. pii: S0302-2838(12)01437-6. doi: 10.1016/j.eururo.2012.11.052.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.eururo.2012.11.052

AUTORES / AUTHORS:  - Keto CJ; Aronson WJ; Terris MK; Presti JC; Kane CJ; Amling CL; Freedland SJ

INSTITUCIÓN / INSTITUTION:  - Duke University School of Medicine, Durham, NC, USA; Veterans Affairs Medical Center, Durham, NC, USA.

RESUMEN / SUMMARY:  - BACKGROUND: A prostate-specific antigen (PSA) level <0.2 ng/ml 8 mo after starting on androgen-deprivation therapy (ADT) is correlated with better outcomes. However, not all men reach a nadir PSA level within 8 mo. Whether the lowest PSA on ADT-specifically, <0.2 ng/ml-can be used for risk stratification is untested. OBJECTIVE: We examined the predictive value of small but detectable PSA nadir values on prostate cancer (PCa)-specific outcomes in men treated with early ADT after radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective review of men treated with ADT after RP before metastases from the SEARCH database. We identified 402 men treated with ADT for elevated PSA following RP, of whom 294 men had complete data. Median follow-up after PSA nadir was 49 mo. All men had a PSA nadir <4 ng/ml; 223 men (76%) had an undetectable nadir. INTERVENTION: ADT for an elevated PSA following RP with no radiographic evidence of metastatic disease. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA nadir on ADT was defined as the lowest PSA value during ADT. Proportional hazards models and the C index were used to test the association and predictive accuracy, respectively, between PSA nadir and PCa-specific outcomes. RESULTS AND LIMITATIONS: Men with a PSA nadir between 0.01 and 0.2 ng/ml had a greater risk of progression to castration-resistant PCa (CRPC) (hazard ratio [HR]: 5.14; p<0.001), metastases (HR: 3.98; p=0.006), and PCa-specific mortality  (PCSM) (HR: 5.33; p=0.003) than men with an undetectable nadir. When data were restricted to men followed with ultrasensitive PSA values (sensitivity of 0.01 ng/ml), the C index of PSA nadir alone for predicting CRPC, metastases, and PCSM  was 0.88, 0.91, and 0.96, respectively. CONCLUSIONS: A PSA nadir on ADT, even at  a very low level, strongly predicts progression to CRPC, metastases, and PCSM. Men with a detectable PSA nadir during ADT should be considered for clinical trials.

 

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[314]

TÍTULO / TITLE:  - Gliotoxin is a potent NOTCH2 transactivation inhibitor and efficiently induces apoptosis in chronic lymphocytic leukaemia (CLL) cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Haematol. 2012 Dec 24. doi: 10.1111/bjh.12183.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bjh.12183

AUTORES / AUTHORS:  - Hubmann R; Hilgarth M; Schnabl S; Ponath E; Reiter M; Demirtas D; Sieghart W; Valent P; Zielinski C; Jager U; Shehata M

INSTITUCIÓN / INSTITUTION:  - Clinic of Internal Medicine I, Division of Haematology and Haemostaseology, Comprehensive Cancer Centre Vienna, Drug and Target Screening Unit DTSU, Medical  University of Vienna, Vienna, Austria.

RESUMEN / SUMMARY:  - Chronic lymphocytic leukaemia (CLL) cells express constitutively activated NOTCH2 in a protein kinase C (PKC)- dependent manner. The transcriptional activity of NOTCH2 correlates not only with the expression of its target gene FCER2 (CD23) but is also functionally linked with CLL cell viability. In the majority of CLL cases, DNA-bound NOTCH2 complexes are less sensitive to the gamma-secretase inhibitor (GSI) DAPT. Therefore, we searched for compounds that interfere with NOTCH2 signalling at the transcription factor level. Using electrophoretic mobility shift assays (EMSA), we identified the Aspergillum-derived secondary metabolite gliotoxin as a potent NOTCH2 transactivation inhibitor. Gliotoxin completely blocked the formation of DNA-bound NOTCH2 complexes in CLL cells independent of their sensitivity to DAPT. The inhibition of NOTCH2 signalling by  gliotoxin was associated with down regulation of CD23 (FCER) expression and induction of apoptosis. Short time exposure of CLL cells indicated that the early apoptotic effect of gliotoxin is independent of proteasome regulated nuclear factor kappaB activity, and is associated with up regulation of NOTCH3 and NR4A1  expression. Gliotoxin could overcome the supportive effect of primary bone marrow stromal cells in an ex vivo CLL microenvironment model. In conclusion, we identified gliotoxin as a potent NOTCH2 inhibitor with a promising therapeutic potential in CLL.

 

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[315]

TÍTULO / TITLE:  - Bevacizumab reduces tumor targeting of anti-epidermal growth factor and anti-insulin-like growth factor 1 receptor antibodies.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Cancer. 2013 Jan 21. doi: 10.1002/ijc.28046.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.28046

AUTORES / AUTHORS:  - Heskamp S; Boerman OC; Molkenboer-Kuenen JD; Oyen WJ; van der Graaf WT; van Laarhoven HW

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. s.heskamp@nucmed.umcn.nl.

RESUMEN / SUMMARY:  - Bevacizumab (anti-VEGF) and cetuximab (anti-EGFR) are approved antibodies for treatment of cancer. However, in advanced colorectal cancer, the combination fails to improve survival. As the reason for the lack of activity is unknown, this study aims to determine the effect of bevacizumab on targeting of anti-EGFR  and IGF-1R antibodies in tumors with SPECT/CT imaging. Mice with subcutaneous EGFR and IGF-1R-expressing SUM149 xenografts received a single dose of bevacizumab (10 mg/kg) or saline. After four days, mice were injected with radiolabeled cetuximab or R1507, an anti-IGF-1R antibody. A control group received a radiolabeled irrelevant IgG (hLL2). Three days later, SPECT/CT images  were acquired and mice were dissected to determine the concentration of antibodies in the tissues. Tumors were analyzed immunohistochemically to determine vascular density (CD34), VEGF, EGFR and IGF-1R expression. SPECT/CT imaging revealed that bevacizumab treatment significantly reduced tumor targeting of radiolabeled cetuximab by 40% from 33.1 +/- 1.1 %ID/g to 19.8 +/- 5.7 %ID/g (p = 0.009) for untreated and bevacizumab treated tumors, respectively. A similar effect was found for (111) In-R1507: tumor targeting of R1507 decreased by 35%. No significant differences in tumor uptake were observed in mice that received an irrelevant IgG. Uptake in normal organs was not altered by bevacizumab. Immunohistochemical analysis showed that vascular density decreased with 43%, while EGFR and IGF-1R expression was unaltered. In conclusion, bevacizumab treatment significantly reduces tumor targeting of anti-EGFR and anti-IGF-1R antibodies. This emphasizes the importance of timing and sequencing of bevacizumab in combination with other antibodies.

 

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[316]

TÍTULO / TITLE:  - 2-Hydroxypropyl-beta-cyclodextrin-modified SLN of paclitaxel for overcoming p-glycoprotein function in multidrug-resistant breast cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Pharm Pharmacol. 2013 Jan;65(1):72-8. doi: 10.1111/j.2042-7158.2012.01578.x. Epub 2012 Aug 13.

            ●● Enlace al texto completo (gratuito o de pago) 1111/j.2042-7158.2012.01578.x

AUTORES / AUTHORS:  - Baek JS; Cho CW

INSTITUCIÓN / INSTITUTION:  - College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Yuseong-gu, Daejeon, South Korea.

RESUMEN / SUMMARY:  - OBJECTIVES: This study aimed to evaluate the potential of solid lipid nanoparticles (SLNs) of paclitaxel (PTX) modified with a 2-hydroxypropyl-beta-cyclodextrin system to enhance cellular accumulation of PTX  into p-glycoprotein (p-gp)-expressing cells. METHODS: The PTX-loaded-SLNs consisted of lipid (stearic acid) and surfactants (lecithin and poloxamer 188) and were then modified with 2-hydroxypropyl-beta-cyclodextrin by a sonication method. KEY FINDINGS: In terms of cytotoxicity, PTX-loaded SLNs modified with 2-hydroxypropyl-beta-cyclodextrin showed higher cytotoxicity than other formulations. In particular, the cellular uptake of PTX from PTX-loaded SLNs modified with 2-hydroxypropyl-beta-cyclodextrin was about 5.8- and 1.5-fold higher than that from PTX solution and unmodified PTX-loaded SLNs in MCF-7/ADR cells, respectively. After a 4-h incubation, clear fluorescence images inside cells were observed over time. When PTX-loaded SLNs modified with 2-hydroxypropyl-beta-cyclodextrin were incubated with MCF-7/ADR cells for 4 h, cellular uptake of PTX increased 1.7-fold versus that of PTX in the presence of verapamil. CONCLUSIONS: These results suggest that optimized SLNs modified with 2-hydroxypropyl-beta-cyclodextrin may have potential as an oral drug delivery system for PTX.

 

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[317]

TÍTULO / TITLE:  - An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Jan 25.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-013-2078-0

AUTORES / AUTHORS:  - De P; Dey N; Terakedis B; Bergsagel PL; Li ZH; Mahadevan D; Garlich JR; Trudel S; Makale MT; Durden DL

INSTITUCIÓN / INSTITUTION:  - Department of Hematology/Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.

RESUMEN / SUMMARY:  - PURPOSE: Multiple reports point to an important role for the phosphoinositide-3 kinase (PI3K) and AKT signaling pathways in tumor survival and chemoresistance in multiple myeloma (MM). The goals of our study were: (1) to generate the preclinical results necessary to justify a Phase I clinical trial of SF1126 in hematopoietic malignancies including MM and (2) to begin combining pan-PI3K inhibitors with other agents to augment antitumor activity of this class of agent in preparation for combination therapy in Phase I/II trials. METHODS: We determined the in vitro activity of SF1126 with 16 human MM cell lines. In vivo tumor growth suppression was determined with human myeloma (MM.1R) xenografts in  athymic mice. In addition, we provide evidence that SF1126 has pharmacodynamic activity in the treatment of patients with MM. RESULTS: SF1126 was cytotoxic to all tested MM lines, and potency was augmented by the addition of bortezomib. SF1126 affected MM.1R cell line signaling in vitro, inhibiting phospho-AKT, phospho-ERK, and the hypoxic stabilization of HIF1alpha. Tumor growth was 94 % inhibited, with a marked decrease in both cellular proliferation (PCNA immunostaining) and angiogenesis (tumor microvessel density via CD31 immunostaining). Our clinical results demonstrate pharmacodynamic knockdown of p-AKT in primary patient-derived MM tumor cells in vivo. CONCLUSIONS: Our results establish three important points: (1) SF1126, a pan-PI3K inhibitor has potent antitumor activity against MM in vitro and in vivo, (2) SF1126 displays augmented antimyeloma activity when combined with proteasome inhibitor, bortezomib/Velcade(®), and (3) SF1126 blocks the IGF-1-induced activation of AKT in primary MM tumor cells isolated from SF1126-treated patients The results support the ongoing early Phase I clinical trial in MM and suggest a future Phase I trial in combination with bortezomib in hematopoietic malignancies.

 

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[318]

TÍTULO / TITLE:  - Crocin Triggers the Apoptosis Through Increasing the Bax/Bcl-2 Ratio and Caspase  Activation in Human Gastric Adenocarcinoma, AGS, Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - DNA Cell Biol. 2013 Feb;32(2):50-7. doi: 10.1089/dna.2012.1866.

            ●● Enlace al texto completo (gratuito o de pago) 1089/dna.2012.1866

AUTORES / AUTHORS:  - Hoshyar R; Bathaie SZ; Sadeghizadeh M

INSTITUCIÓN / INSTITUTION:  - 1 Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University , Tehran, Iran .

RESUMEN / SUMMARY:  - We previously showed the anticancer property of crocin, a carotenoid isolated and purified from saffron against chemical-induced gastric and breast cancer in rats. In this study, the mechanism of crocin action was investigated in the gastric adenocarcinoma (AGS) cells in comparison with human normal fibroblast skin cells  (HFSF-PI3). Crocin revealed a dose- and time-dependent cytotoxic effect against an AGS cell line, as determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Crocin-induced apoptosis was evidenced by flow cytometry and measuring caspase activity. The increased sub-G1 population and activated caspases in the treated AGS cells confirmed its anticancer effect. Expression of both Bax and Bcl-2 was determined using a semiquantitative reverse transcriptase-polymerase chain reaction and Western blot in these cells before and after treatment with crocin.  Apoptosis was significantly stimulated as indicated by increasing the Bax/Bcl-2 ratio after crocin treatment. All of the above-mentioned parameters remained normal in HFSF-PI3 treated with crocin. These data are providing insight into the molecular mechanisms underlying the crocin-induced apoptosis in the AGS cells, rendering it as the potential anticancer agent.

 

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[319]

TÍTULO / TITLE:  - Serum microRNA expression profile: miR-1246 as a novel diagnostic and prognostic  biomarker for oesophageal squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 29. doi: 10.1038/bjc.2013.8.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2013.8

AUTORES / AUTHORS:  - Takeshita N; Hoshino I; Mori M; Akutsu Y; Hanari N; Yoneyama Y; Ikeda N; Isozaki Y; Maruyama T; Akanuma N; Komatsu A; Jitsukawa M; Matsubara H

INSTITUCIÓN / INSTITUTION:  - Department of Frontier Surgery, Chiba University Graduate School of Medicine, Inohana 1-8-1, Chuo-ku, Chiba 260 8670, Japan.

RESUMEN / SUMMARY:  - Background:Recent studies have demonstrated that microRNAs (miRNAs) are stably detectable in blood and can serve as useful biomarkers for cancer.Methods:We performed an miRNA array using serum samples obtained from oesophageal squamous cell carcinoma (ESCC) patients or healthy controls. MiR-1246 was the most markedly elevated in ESCC patients. Therefore, miR-1246 was selected as a candidate for further analysis. The serum miR-1246 level in 46 healthy controls and 101 ESCC patients was evaluated and compared among various clinicopathological characteristics. MiR-1246 expressions in tissue, exosomal, and cellular samples were also examined.Results:Serum miR-1246 alone yielded an receiver-operating characteristic curve area of 0.754, with 71.3% sensitivity and 73.9% specificity for distinguishing ESCC patients from healthy controls. Serum miR-1246 was significantly correlated with the TNM stage and showed to be the strongest independent risk factor for poor survival (HR, 4.032; P=0.017). Unlike  the tendency shown in previous reports, miR-1246 was not upregulated in ESCC tissue samples. Furthermore, exosomal miR-1246 did not reflect the abundance in the cell of origin.Conclusion:These data support our contention that serum miR-1246 has strong potential as a novel diagnostic and prognostic biomarker in ESCC, and its releasing mechanism is selective and independent of tissue miRNA abundance.British Journal of Cancer advance online publication, 29 January 2013;  doi:10.1038/bjc.2013.8 www.bjcancer.com.

 

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[320]

TÍTULO / TITLE:  - Sequential combination of azacitidine and lenalidomide in del(5q) higher-risk myelodysplastic syndromes or acute myeloid leukemia: a phase I study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leukemia. 2013 Jan 28. doi: 10.1038/leu.2013.26.

            ●● Enlace al texto completo (gratuito o de pago) 1038/leu.2013.26

AUTORES / AUTHORS:  - Platzbecker U; Braulke F; Kundgen A; Gotze K; Bug G; Schonefeldt C; Shirneshan K; Rollig C; Bornhauser M; Naumann R; Neesen J; Giagounidis A; Hofmann WK; Ehninger G; Germing U; Haase D; Wermke M

INSTITUCIÓN / INSTITUTION:  - Medical Clinic and Polyclinic I, University Hospital, Technical University Dresden, Dresden, Germany.

 

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[321]

TÍTULO / TITLE:  - Detection of miR-34a Promoter Methylation in Combination with Elevated Expression of c-Met and beta-Catenin Predicts Distant Metastasis of Colon Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-1703

AUTORES / AUTHORS:  - Siemens H; Neumann J; Jackstadt R; Mansmann U; Horst D; Kirchner T; Hermeking H

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Experimental and Molecular Pathology, Institute of Pathology, Institute of Pathology, and Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-Universitat Munchen, Munich, Germany; and German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.

RESUMEN / SUMMARY:  - PURPOSE: Here, we determined whether epigenetic inactivation of miR-34a and miR-34b/c genes may serve as a prognostic marker for distant metastases in colon  cancer.EXPERIMENTAL DESIGN: Using a case-control study design of 94 primary colon cancer samples with and without liver metastases, we determined CpG methylation frequencies of miR-34a and miR-34b/c promoters, expression of miR-34a, and its targets c-Met, Snail, and beta-catenin and their prognostic value.RESULTS: miR-34a methylation was detected in 45.1% (n = 42 of 93) of the samples and strongly associated with metastases to the liver (P = 0.003) and lymph nodes (P = 0.006). miR-34b/c methylation was detected in 91.9% of the samples (n = 79/86). A significant inverse correlation between miR-34a methylation and expression of mature miR-34a (P = 0.018) was detected. Decreased miR-34a expression was associated with upregulation of c-Met, Snail, and beta-catenin protein levels (P  = 0.031, 0.132, and 0.004), which were associated with distant metastases (P = 0.001, 0.017, and 0.005). In a confounder-adjusted multivariate regression model  miR-34a methylation, high c-Met and beta-catenin levels provided the most significant prognostic information about metastases to the liver (P = 0.014, 0.031, and 0.058) and matched pairs showed a higher prevalence of these risk factors in the samples with distant spread (P = 0.029). Finally, we obtained statistical evidence indicating that the simultaneous detection of these three markers has the highest prognostic value.CONCLUSIONS: Silencing of miR-34a and upregulation of c-Met, Snail, and beta-catenin expression is associated with liver metastases of colon cancer. Detection of miR-34a silencing in resected primary colon cancer may be of prognostic value, especially in combination with detection of c-Met and beta-catenin expression. Clin Cancer Res; 19(3); 1-11. ©2012 AACR.

 

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[322]

TÍTULO / TITLE:  - Xiao Jin Wan, a traditional Chinese herbal formula, inhibits proliferation via arresting cell cycle progression at the G2/M phase and promoting apoptosis via activating the mitochondrialdependent pathway in U-2OS human osteosarcoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Mar;42(3):1070-80. doi: 10.3892/ijo.2013.1795. Epub 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2013.1795

AUTORES / AUTHORS:  - Wu G; Chu J; Huang Z; Ye J; Chen P; Zheng C; Li X; Liu X; Wu M

INSTITUCIÓN / INSTITUTION:  - Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, P.R. China.

RESUMEN / SUMMARY:  - Xiao Jin Wan (XJW) is a well-known traditional Chinese folk-medicine, which is commonly used for the treatment of various types of diseases including cancers. However, the mechanism of the anticancer activity of XJW against U-2OS human osteosarcoma cells, have not yet been reported. In the present study, we investigated the cellular effects of the XJW on the U-2OS human osteosarcoma cell line. Our results showed that XJW induced cell morphological changes, reduced cell viability in a dose- and time-dependent manner and arrested in the G2/M phase of the cell cycle suggesting that XJW inhibited the proliferation of U-2OS  cells. Hoechst 33258 staining and Annexin V/propidium iodide double staining exhibited the typical nuclear features of apoptosis and increased the proportion  of apoptotic Annexin V-positive cells in a dose-dependent manner, respectively. In addition, XJW treatment caused loss of plasma membrane asymmetry, collapse of  mitochondrial membrane potential, activation of caspase-9 and caspase-3, and increase of the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2. Taken together, the results indicate that the U-2OS cell growth inhibitory activity of  XJW was due to cell cycle arrested and mitochondrial-mediated apoptosis, which may partly explain the anticancer activity of Xiao Jin Wan.

 

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[323]

TÍTULO / TITLE:  - A 13-gene signature prognostic of HPV-negative oral cavity cancer: discovery and  external validation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 14.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2647

AUTORES / AUTHORS:  - Lohavanichbutr P; Mendez E; Holsinger C; Rue TC; Zhang Y; Houck J; Upton M; Futran N; Schwartz SM; Wang P; Chen C

INSTITUCIÓN / INSTITUTION:  - Program in Epidemiology, Fred Hutchinson Cancer Research Center.

RESUMEN / SUMMARY:  - PURPOSE: To identify a prognostic gene signature for HPV-negative OSCC patients.  EXPERIMENTAL DESIGN: Two gene expression datasets were used; a training dataset from the Fred Hutchinson Cancer Research Center (FHCRC) (n=97), and a validation  dataset from the MD Anderson Cancer Center (MDACC) (n=71). We applied L1/L2-penalized Cox regression models to the FHCRC data on the 131-gene signature previously identified to be prognostic in OSCC patients to identify a prognostic  model specific for high-risk HPV-negative OSCC patients. The models were tested with the MDACC dataset using a receiver operating characteristic analysis. RESULTS: A 13-gene model was identified as the best predictor of HPV-negative OSCC-specific survival in the training dataset. The risk score for each patient in the validation dataset was calculated from this model and dichotomized at the  median. The estimated 2-year mortality (+/- SE) of patients with high risk scores was 47.1 (+/-9.24)% compared with 6.35 (+/- 4.42)% for patients with low risk scores. ROC analyses showed that the areas under the curve for the age, gender, and treatment modality-adjusted models with risk score (0.78, 95%CI: 0.74-0.86) and risk score plus tumor stage (0.79, 95%CI: 0.75-0.87) were substantially higher than for the model with tumor stage (0.54, 95%CI: 0.48-0.62). CONCLUSIONS: We identified and validated a 13-gene signature that is considerably better than  tumor stage in predicting survival of HPV-negative OSCC patients. Further evaluation of this gene signature as a prognostic marker in other populations of  patients with HPV-negative OSCC is warranted.

 

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[324]

TÍTULO / TITLE:  - Interleukin-6 induces vascular endothelial growth factor expression and promotes  angiogenesis through apoptosis signal-regulating kinase 1 in human osteosarcoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Feb 15;85(4):531-40. doi: 10.1016/j.bcp.2012.11.021. Epub 2012 Dec 5.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2012.11.021

AUTORES / AUTHORS:  - Tzeng HE; Tsai CH; Chang ZL; Su CM; Wang SW; Hwang WL; Tang CH

INSTITUCIÓN / INSTITUTION:  - Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, ROC; Division of Hematology/Oncology, Taichung Veterans General Hospital, Taichung, Taiwan, ROC.

RESUMEN / SUMMARY:  - Osteosarcoma is characterized by a high malignant and metastatic potential. Angiogenesis is essential for the caner metastasis. Interleukin-6 (IL-6) is a multifunctional cytokine that is associated with the disease status and outcomes  of cancers. However, the relationship between IL-6 and vascular endothelial growth factor (VEGF) expression in human osteosarcoma is mostly unknown. Here we  found that the IL-6 and VEGF expression was correlated with tumor stage and significantly higher than that in normal bone. Incubation of osteosarcoma cells with IL-6 increased VEGF mRNA and protein expression. Pretreatment of cells with  IL-6R antibody reduced IL-6-mediated VEGF production. The apoptosis signal-regulating kinase 1 (ASK1)/p38/AP-1 pathway was activated after IL-6 treatment, and IL-6-induced VEGF expression was abolished by the specific inhibitor and siRNA of ASK1, p38, and AP-1 cascades. Importantly, knockdown IL-6  reduced VEGF expression and abolished osteosarcoma conditional medium-mediated angiogenesis. Taken together, these results indicate that IL-6 occurs through ASK1 and p38, which in turn activates AP-1, resulting in the activations of VEGF  expression and contributing the angiogenesis of human osteosarcoma cells.

 

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[325]

TÍTULO / TITLE:  - Knockdown of RLIP76 expression by RNA interference inhibits invasion, induces cell cycle arrest, and increases chemosensitivity to the anticancer drug temozolomide in glioma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Neurooncol. 2013 Jan 6.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1045-2

AUTORES / AUTHORS:  - Wang Q; Qian J; Wang J; Luo C; Chen J; Hu G; Lu Y

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai, 200003, People’s Republic of China.

RESUMEN / SUMMARY:  - RLIP76, a GTPase-activating protein, is a central regulator in multiple pathways  that respond to redox states and control cell growth, motility, division, and apoptosis in many malignant cancer cells. In this study, human glioblastoma cell  lines U87 and U251 were stably transfected with a lentivirus vector expressing a  short hairpin RNA (shRNA) targeting RLIP76. shRNA knockdown of RLIP76 induced cell cycle arrest in U87 and U251 cells and inhibited their invasiveness. Quantitative Western blot analysis revealed that cells stably underexpressing RLIP76 showed lower expression of cyclin D1 and decreased expression and activity of matrix metalloproteinase 2 compared to cells stably transfected with a control vector. Furthermore, RLIP76 expression levels were correlated with IC(50) values  for the antitumor drug temozolomide (TMZ). Compared with TMZ alone (17.19 +/- 1.78 and 22.18 +/- 1.99 mug/mL in U87 and U251 cells, respectively) or combined shGFP and TMZ (18.04 +/- 1.07 and 23.040 +/- 1.77 mug/mL in U87 and U251 cells, respectively), combined shRNA and TMZ therapy resulted in a significant decrease  in IC(50) value (7.61 +/- 2.99 and 6.91 +/- 2.59 mug/mL in U87 and U251 cells, respectively). Combined RLIP76 knockdown and TMZ treatment inhibited cell proliferation in vitro more effectively than either treatment alone. Furthermore, RLIP76 downregulation enhanced chemosensitivity to TMZ without affecting protein  expression of MDR1 and MRP1. The results indicate that inhibition of RLIP76 expression may be an effective means for overcoming RLIP76-associated chemoresistance in human malignant glioma cells and may represent a potential gene-targeting approach for glioma treatment.

 

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[326]

TÍTULO / TITLE:  - Prediction of Bacteremia in Children with Febrile Episodes During Chemotherapy for Acute Lymphoblastic Leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pediatr Hematol Oncol. 2013 Jan 2.

            ●● Enlace al texto completo (gratuito o de pago) 3109/08880018.2012.748111

AUTORES / AUTHORS:  - Lucking V; Rosthoj S

INSTITUCIÓN / INSTITUTION:  - Department of Pediatrics, Aarhus University Hospital , Aalborg , Denmark.

RESUMEN / SUMMARY:  - The purpose was to identify risk factors for bacteremia in febrile episodes occurring during chemotherapy for acute lymphoblastic leukemia (ALL) in children, and to develop a risk score permitting risk-adapted antibiotic therapy. We reviewed a total of 172 febrile episodes occurring during chemotherapy in 31 children and adolescents with ALL. Temperature, hematological parameters, culture findings, and antibiotic therapy were recorded. Bacteremias were classified as transmucosal or CVC-dependent. Blood cultures were positive with mucosal pathogens in 15 cases (9%) and with skin/environmental bacteria in 34 (20%). CVC-dependent infections occurred throughout the treatment phases, while transmucosal primarily during induction therapy. Transmucosal bacteremia was associated with induction therapy, leukocyte count </=0.5 x 10(9)/L, neutrophil count </=0.1 x 10(9)/L, monocyte count </=0.01 x 10(9)/L, and platelet count </=50 x 10(9)/L. Based on logistic conversion of the odds ratios for the five factors, a weight of 2 was assigned to induction therapy and leukocyte count </=0.5 x 10(9)/L, and a weight of 1 to the remaining three parameters. The weights were included in a simple additive score ranging from 0 to 7, which defined groups with 4%, 6%, 24%, and 40% risk of transmucosal bacteremia. CVC-dependent bacteremia was not associated with markers of poor bone marrow function. In conclusion, transmucosal bacteremia in children with ALL is related  to infiltration or suppression of the bone marrow. A score reflecting the condition of the marrow can define low-risk and high-risk groups and may prove clinically useful.

 

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[327]

TÍTULO / TITLE:  - Total alkaloids of Rubus aleaefolius Poir inhibit hepatocellular carcinoma growth in vivo and in vitro via activation of mitochondrial-dependent apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Mar;42(3):971-8. doi: 10.3892/ijo.2013.1779. Epub 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2013.1779

AUTORES / AUTHORS:  - Zhao J; Chen X; Lin W; Wu G; Zhuang Q; Zhong X; Hong Z; Peng J

INSTITUCIÓN / INSTITUTION:  - Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China.

RESUMEN / SUMMARY:  - The aim of this study was to evaluate the therapeutic efficacy of Rubus aleaefolius Poir total alkaloids (TARAP) against hepatocellular carcinoma growth  in vivo and in vitro, and to investigate the possible molecular mechanisms mediating its biological activity. Nude mice were implanted with HepG2 human hepatocellular carcinoma cells and fed with vehicle (physiological saline) or 3 g/kg/d dose of TARAP, 5 days per week, for 21 days. The in vivo efficacy of TARAP against tumor growth was investigated by evaluating its effect on tumor volume and tumor weight in mice with HCC xenografts and its adverse effect was determined by measuring the body weight gain. The in vitro effect of TARAP on the viability of HepG2 cells was determined by MTT assay. HepG2 cell morphology was observed via phase-contrast microscopy. Apoptosis in tumor tissues or in HepG2 cells was analyzed by TUNEL assay or FACS analysis with Annexin V/PI, respectively. The loss of mitochondrial membrane potential in HepG2 cells was determined via JC-1 staining followed by FACS analysis. Activation of caspase-9 and -3 in HepG2 cells was examined by a colorimetric assay. The mRNA and protein  expression of Bcl-2 and Bax in tumor tissues were measured by RT-PCR and immunohistochemistry. TARAP reduced tumor volume and tumor weight, but had no effect on the body weight gain in HCC mice. TARAP decreased the viability of HepG2 cells and induced cell morphological changes in vitro in a dose- and timedependent manner. In addition, TARAP induced apoptosis both in tumor tissues  and in HepG2 cells. Moreover, TARAP treatment resulted in the collapse of mitochondrial membrane potential in HepG2 cells, as well as the activation of caspase-9 and -3. Furthermore, administration of TARAP increased the pro-apoptotic Bax/Bcl-2 ratio in HCC mouse tumors, at both transcriptional and translational levels. TARAP inhibits hepatocellular carcinoma growth both in vivo and in vitro probably through the activation of mitochondrialdependent apoptosis, which may, in part, explain its anticancer activity. These results suggest that total alkaloids in Rubus aleaefolius Poir may be a potential novel therapeutic agent for the treatment of hepatocellular carcinoma and other cancers.

 

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[328]

TÍTULO / TITLE:  - Tat-SmacN7 induces radiosensitization in cancer cells through the activation of caspases and induction of apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Mar;42(3):985-92. doi: 10.3892/ijo.2013.1785. Epub 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2013.1785

AUTORES / AUTHORS:  - Chen F; Xu C; Du L; Wang Y; Cao J; Fu Y; Guo Y; Liu Q; Fan F

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Hazard Evaluation, Institute of Radiation Medicine of Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, P.R. China.

RESUMEN / SUMMARY:  - A major concern in cancer therapy is resistance of tumors such as human non-small cell lung cancer and esophageal cancer to radiotherapy. Intrinsic radioresistance of these cancer cells limits therapeutic ef fi ciency. Here, we determined in two cancer cell lines the potential radiosensitizing activity of Tat-SmacN7, a small  molecule compound, which mimics the activity of Smac, a mitochondrial protein released during apoptosis. We found that Tat-SmacN7 can enter the cells and promote RNA expression and the activity of caspase-3, -8 and -9 and sensitized the cancer cells to radiation with a sensitization enhancement ratio (SER) of 1.5-1.6. Tat-SmacN7 radiosensitization was mediated by both extrinsic and intrinsic apoptosis pathways through activation of caspases. Consistently, blockage of caspase activation, through treatment with a caspase inhibitor, z-VAD-fmk, inhibited apoptosis and abrogated Tat-SmacN7 radiosensitization. Our study demonstrates that Tat-SmacN7 also has radiosensitization effects in vivo, so it could be further developed as a novel class of radiosensitizers for the treatment of radioresistant human non-small cell lung cancer and esophageal cancer.

 

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[329]

TÍTULO / TITLE:  - Apoptosis induction of human prostate carcinoma cells by cordycepin through reactive oxygen speciesmediated mitochondrial death pathway.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Mar;42(3):1036-44. doi: 10.3892/ijo.2013.1762. Epub 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2013.1762

AUTORES / AUTHORS:  - Lee HH; Park C; Jeong JW; Kim MJ; Seo MJ; Kang BW; Park JU; Kim GY; Choi BT; Choi YH; Jeong YK

INSTITUCIÓN / INSTITUTION:  - Department of Biotechnology, Dong-A University, Busan 604-714, Republic of Korea.

RESUMEN / SUMMARY:  - Cordycepin is the main functional component of Cordyceps militaris, which has been widely used in oriental traditional medicine. This compound has been shown to possess many pharmacological properties, such as enhancing the body’s immune function, and anti-inflammatory, anti-aging and anticancer effects. In the present study, we investigated the apoptotic effects of cordycepin in human prostate carcinoma cells. We found that treatment with cordycepin significantly inhibited cell growth by inducing apoptosis in PC-3 cells. Apoptosis induction of PC-3 cells by cordycepin showed correlation with proteolytic activation of caspase-3 and -9, but not caspase-8, and concomitant degradation of poly (ADP-ribose) polymerases, collapse of the mitochondrial membrane potential (MMP). In addition, cordycepin treatment resulted in an increase of the Bax/Bcl-2 (or Bcl-xL) ratio, downregulation of inhibitor of apoptosis protein (IAP) family members, Bax conformational changes, and release of cytochrome c from the mitochondria to the cytosol. The cordycepin-induced apoptosis was also associated with the generation of intracellular reactive oxygen species (ROS). However, the  quenching of ROS generation with antioxidant N-acetyl-L-cysteine conferred significant protection against cordycepin-elicited ROS generation, disruption of  the MMP, modulation of Bcl-2 and IAP family proteins, caspase-3 and -9 activation and apoptosis. This indicates that the cellular ROS generation plays a pivotal role in the initiation of cordycepin-triggered apoptotic death. Collectively, our findings suggest that cordycepin is a potent inducer of apoptosis of prostate cancer cells via a mitochondrial-mediated intrinsic pathway and that this agent may be of value in the development of a potential therapeutic candidate for both  the prevention and treatment of cancer.

 

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[330]

TÍTULO / TITLE:  - Anacardic acid induces mitochondrial-mediated apoptosis in the A549 human lung adenocarcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Mar;42(3):1045-51. doi: 10.3892/ijo.2013.1763. Epub 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2013.1763

AUTORES / AUTHORS:  - Seong YA; Shin PG; Kim GD

INSTITUCIÓN / INSTITUTION:  - Department of Microbiology, College of Natural Sciences, Pukyong National University, Busan 608-737, Republic of Korea.

RESUMEN / SUMMARY:  - Anacardic acid (AA) is a constituent of the cashew nut shell and is known as an inhibitor of nuclear factor-kappaB (NF-kappaB). We investigated the cytotoxicity  of AA on cancer cells and more experiments to reveal the cell death mechanism focused on A549 lung adenocarcinoma cells for our interest in lung cancer. To examine the molecular mechanism of cell death in AA treated A549 cells, we performed experiments such as transmission electron microscopy (TEM), western blot analysis, fluorescence-activated cell sorting (FACS), genomic DNA extraction and staining with 4’,6-diamidino-2-phenylindole (DAPI). For the first time we revealed that AA induces caspaseindependent apoptosis with no inhibition of cytotoxicity by pan-caspase inhibitor, Z-VAD-fmk, in A549 cells. Our results showed the possibility of mitochondrial-mediated apoptosis through the activation of apoptosis-inducing factor (AIF) and an intrinsic pathway executioner such as cytochrome c. This study will be helpful in revealing the cell death mechanisms and in developing potential drugs for lung cancer using AA.

 

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[331]

TÍTULO / TITLE:  - Real-life experience with pegylated interferon and conventional interferon in adjuvant melanoma therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Immunother. 2013 Jan;36(1):52-6. doi: 10.1097/CJI.0b013e31827809c7.

            ●● Enlace al texto completo (gratuito o de pago) 1097/CJI.0b013e31827809c7

AUTORES / AUTHORS:  - Rozati S; Naef L; Levesque MP; French LE; Dummer R

INSTITUCIÓN / INSTITUTION:  - Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

RESUMEN / SUMMARY:  - Interferon (IFN) is the most studied and the only approved adjuvant therapy for melanoma. There are 2 formulations of IFN, conventional IFN and pegylated IFN (peg-IFN), which have been investigated in multiple randomized clinical trials. We have compared the feasibility and tolerability of low-dose conventional IFN and peg-IFN in real life, outside the controlled settings of clinical trials. In  this study, we analyzed 99 patients with resected melanoma, who were treated with either conventional IFN (n=48) or with peg-IFN (n=51), retrospectively. The median treatment duration in conventional IFN group was 13.3 versus 16.5 months in peg-IFN (P=0.52). Moreover, patients with peg-IFN tended to have dose reduction or treatment discontinuation due to adverse events (AE) significantly more often. In addition, neutropenia occurred significantly more often in peg-IFN group versus IFN group (n=2; 5% conventional vs. n=16; 36.4% peg-IFN, P=0.00). More than 90% of these patients developed only grade 2 neutropenia and there were no reported infections. We conclude that the 100 microg flat dose peg-IFN, which  is commonly referred to as “low-dose,” actually represents a higher dose of IFN,  which consequently results in more frequent dose reductions and discontinuation of treatment. The use of peg-IFN is certainly more convenient for the patient in  terms of application, thus close monitoring, early medical interventions, and dose adjustments to avoid treatment discontinuation are crucial for compliance.

 

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[332]

TÍTULO / TITLE:  - T-cell immunoglobulin- and mucin-domain-containing molecule 3 gene polymorphisms  and prognosis of non-small-cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Tumour Biol. 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s13277-012-0610-1

AUTORES / AUTHORS:  - Bai J; Li X; Tong D; Shi W; Song H; Li Q

INSTITUCIÓN / INSTITUTION:  - Internal Medicine Division of the Emergency Center, Shanghai East Hospital, Tongji University, 150 Jimo Road, Shanghai, 200120, China.

RESUMEN / SUMMARY:  - Lung cancer is the leading cause of death worldwide. Non-small-cell lung cancer (NSCLC) accounts for most of these cases. T-cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3) has been established as a negative regulatory molecule and plays a critical role in immune tolerance. Studies have shown that polymorphisms in TIM-3 gene can be associated with various diseases. The aim of this study was to investigate whether polymorphisms in the TIM-3 gene  were associated with susceptibility to NSCLC. Three polymorphisms in TIM-3 gene (-1516G/T, -574G/T, and +4259T/G) were identified by polymerase chain reaction-restriction fragment length polymorphism in 432 NSCLC patients and 466 healthy controls. Results showed that frequencies of TIM-3 +4259TG genotype for cases and controls were 10.9 and 4.1 %, respectively; subjects carrying the +4259TG genotype had a 2.81-fold increased risk of NSCLC compared to the wild-type genotype (P < 0.0001). The TIM-3 -1516G/T and -574G/T polymorphisms did not show any correlation with NSCLC. In addition, when analyzing the survival time of NSCLC patients with TIM-3 +4259T/G polymorphism, cases with +4259TG genotype had significantly shorter survival time compared to the wild-type patients (15.2 months vs. 26.7 months, P = 0.007). These results suggested polymorphism in TIM-3 gene is associated with increased susceptibility to NSCLC and could be used as prognostic factor for this malignancy.

 

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[333]

TÍTULO / TITLE:  - 14-3-3zeta as a predictor of early time to recurrence and distant metastasis in hormone receptor-positive and -negative breast cancers.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Feb;137(3):689-96. doi: 10.1007/s10549-012-2390-0.  Epub 2012 Dec 28.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-012-2390-0

AUTORES / AUTHORS:  - Bergamaschi A; Frasor J; Borgen K; Stanculescu A; Johnson P; Rowland K; Wiley EL; Katzenellenbogen BS

INSTITUCIÓN / INSTITUTION:  - Department of Molecular and Integrative Physiology, University of Illinois and College of Medicine at Urbana-Champaign, Urbana, IL, 61801, USA.

RESUMEN / SUMMARY:  - The 14-3-3zeta gene, on 8q22, is often amplified in breast cancer and encodes a survival factor that interacts with and stabilizes many key signaling proteins. We examined the relationship between the expression of 14-3-3zeta, estrogen receptor alpha (ERalpha), and other parameters ( tumor size, grade, nodal status, progesterone receptor, HER2, EGFR, and p53) in matched primary and recurrence tumor tissue and how these factors impact time to recurrence, properties of the recurred tumors, and site of metastasis. In this cohort of over 100 patients, median time to recurrence was 3 years (range 1-17 years). Our analyses of primary tumor microarray cores revealed that 14-3-3zeta status was significantly correlated with tumor grade, size, and ERalpha. Women with 14-3-3zeta-positive and ERalpha-negative tumors had the earliest time to recurrence (median 1 yr, p < 0.001, hazard ratio 2.89), while median time to recurrence was 7 years for 14-3-3zeta-negative and ER-positive tumors. Of recurred tumors, 70-75 % were positive for 14-3-3zeta, up from the 45 % positivity of primary tumors. High expression of 14-3-3zeta also correlated with site of recurrence and showed a propensity for distant metastases to lung and chest wall. Multifactor correlation regression analysis revealed 14-3-3zeta to be a non-redundant, independent variable that adds clinical strength in predicting risk for early recurrence in ER-positive and -negative breast cancers, providing information beyond that of all other clinical pathological features examined. Thus, high expression of 14-3-3zeta in the primary tumor was significantly associated with earlier time to recurrence and with distant metastasis. Furthermore, even when the primary breast cancers were negative-low for 14-3-3zeta, the majority acquired increased expression in the recurrence. The findings underscore the detrimental role played by 14-3-3zeta in tumor aggressiveness and suggest that reducing its expression or interfering with its actions might substantially improve the clinical outcome for breast cancer patients.

 

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[334]

TÍTULO / TITLE:  - The HSP90 inhibitor NVP-AUY922-AG inhibits the PI3K and IKK signalling pathways and synergizes with cytarabine in acute myeloid leukaemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Haematol. 2013 Jan 29. doi: 10.1111/bjh.12215.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bjh.12215

AUTORES / AUTHORS:  - Walsby EJ; Lazenby M; Pepper CJ; Knapper S; Burnett AK

INSTITUCIÓN / INSTITUTION:  - Cardiff Experimental Cancer Medicine Centre, Institute of Cancer and Genetics, Institute of Cancer and Genetics, School of Medicine, Cardiff University, ardiff, UK.

RESUMEN / SUMMARY:  - Heat shock protein 90 (HSP90; HSP90AA1) is a molecular chaperone involved in signalling pathways for cell proliferation, survival, and cellular adaptation. Inhibitors of HSP90 are being examined as anti-cancer agents, but the critical molecular mechanism(s) of their activity remains unresolved. HSP90 inhibition potentially facilitates the simultaneous targeting of multiple molecules within tumour cells and represents an attractive therapeutic proposition. Here, we investigated HSP90 as a molecular target for acute myeloid leukaemia (AML) using  the novel HSP90 inhibitor NVP-AUY922-AG. NVP-AUY922-AG induced dose-dependent killing in myeloid cell lines and primary AML blasts. In primary blasts, cell death in response to NVP-AUY922-AG was seen at concentrations almost 2 logs lower than cytarabine (Ara-C) (50% lethal dose = 0.12 mu mol/l +/- 0.28). NVP-AUY922-AG was significantly less toxic to normal bone marrow (P = 0.02). In vitro response  to NVP-AUY922-AG did not correlate with response to Ara-C (r(2) = 0.0006). NVP-AUY922-AG was highly synergistic with Ara-C in cell lines and in 20/25 of the primary samples tested. NVP-AUY922-AG induced increases in HSP70 expression and depletion of total AKT, IKKalpha and IKKbeta in cell lines and primary blasts. This study shows that the novel HSP90 inhibitor NVP-AUY922-AG has significant single agent activity in AML cells and is synergistic with Ara-C.

 

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[335]

TÍTULO / TITLE:  - Binding partners for curcumin in human schwannoma cells: Biologic Implications.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Bioorg Med Chem. 2012 Dec 13. pii: S0968-0896(12)00969-8. doi: 10.1016/j.bmc.2012.12.008.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bmc.2012.12.008

AUTORES / AUTHORS:  - Angelo LS; Maxwell DS; Wu JY; Sun D; Hawke DH; McCutcheon IE; Slopis JM; Peng Z; Bornmann WG; Kurzrock R

INSTITUCIÓN / INSTITUTION:  - Department of Investigational Cancer Therapeutics, (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address:  lsangelo39@gmail.com.

RESUMEN / SUMMARY:  - Curcumin (diferuloylmethane) is a potent anti-inflammatory and anti-tumorigenic agent that has shown preclinical activity in diverse cancers. Curcumin up-regulates heat shock protein 70 (hsp70) mRNA in several different cancer cell  lines. Hsp70 contributes to an escape from the apoptotic effects of curcumin by several different mechanisms including prevention of the release of apoptosis inducing factor from the mitochondria and inhibition of caspases 3 and 9. Previously we showed that the combination of curcumin plus a heat shock protein inhibitor was synergistic in its down-regulation of the proliferation of a human  schwannoma cell line (HEI-193) harboring an NF2 mutation, possibly because curcumin up-regulated hsp70, which also binds merlin, the NF2 gene product. In order to determine if curcumin also interacts directly with hsp70 and to discover other binding partners of curcumin, we synthesized biotinylated curcumin (bio-curcumin) and treated HEI-193 schwannoma cells. Cell lysates were prepared and incubated with avidin-coated beads. Peptides pulled down from this reaction were sequenced and it was determined that biotinylated curcumin bound hsp70, hsp90, 3-phosphoglycerate dehydrogenase, and a beta-actin variant. These binding  partners may serve to further elucidate the underlying mechanisms of curcumin’s actions.

 

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[336]

TÍTULO / TITLE:  - Propofol induces apoptosis of hepatocellular carcinoma cells by upregulation of microRNA-199a expression.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Biol Int. 2012 Dec 27:1-6. doi: 10.1002/cbin.10034.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cbin.10034

AUTORES / AUTHORS:  - Zhang J; Wu GQ; Zhang Y; Feng ZY; Zhu SM

INSTITUCIÓN / INSTITUTION:  - Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Rd., Hangzhou 310003, China.

RESUMEN / SUMMARY:  - Propofol is one of the extensively commonly used intravenous anaesthetic agents.  The effects of Propofol on hepatocellular carcinoma (HCC) growth inhibition and apoptosis have been examined. The techniques used were the MTT assay, flow cytometry, real-time PCR to assess miR-199a expression, as also caspase-8 and caspase-9 activity in HepG2 cells treated with Propofol. Finally, we evaluated the effect of miR-199a on Propofol-induced anti-tumour activity using anti-miR-199a. Propofol efficiently inhibited the growth of HCC cells, but was less toxic to normal hepatic cells. It induced apoptosis and increased expression of miR-199a. Activation of caspase-8 and caspase-9 suggested that both extrinsic  and intrinsic pathways are involved in Propofol-induced apoptosis. Anti-miR-199a  reversed the effect of Propofol on apoptosis and activation of caspase-8 and caspase-9 in HepG2 cells. Propofol can effectively induce apoptosis of HCC cells  and modulation of miR-199a possibly contributes to the anti-tumour action of Propofol. Hence, Propofol might be an effective drug for HCC.

 

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[337]

TÍTULO / TITLE:  - CpG oligodeoxynucleotide induces apoptosis and cell cycle arrest in A20 lymphoma  cells via TLR9-mediated pathways.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Immunol. 2013 Jan 25;54(3-4):327-337. doi: 10.1016/j.molimm.2013.01.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.molimm.2013.01.001

AUTORES / AUTHORS:  - Qi XF; Zheng L; Kim CS; Lee KJ; Kim DH; Cai DQ; Qin JW; Yu YH; Wu Z; Kim SK

INSTITUCIÓN / INSTITUTION:  - Key Laboratory for Regenerative Medicine of the Ministry of Education, Department of Developmental & Regenerative Biology, Ji Nan University School of Life Science and Technology, Guangzhou 510632, People’s Republic of China. Electronic address: qixufeng@jnu.edu.cn.

RESUMEN / SUMMARY:  - Recent studies have suggested that the anti-cancer activity of CpG-oligodeoxynucleotides (CpG-ODNs) is owing to their immunomodulatory effects in tumor-bearing host. The purpose of this study is to investigate the directly cytotoxic activity of KSK-CpG, a novel CpG-ODN with an alternative CpG motif, against A20 and EL4 lymphoma cells in comparison with previously used murine CpG  motif (1826-CpG). To evaluate the potential cytotoxic effects of KSK-CpG on lymphoma cells, cell viability assay, confocal microscopy, flow cytometry, DNA fragmentation, Western blotting, and reverse transcription-polymerase chain reaction (RT-PCR) analysis were used. We found that KSK-CpG induced direct cytotoxicity in A20 lymphoma cells, but not in EL4 lymphoma cells, at least in part via TLR9-mediated pathways. Apoptotic cell death was demonstrated to play an important role in CpG-ODNs-induced cytotoxicity. In addition, both mitochondrial  membrane potential decrease and G1-phase arrest were involved in KSK-CpG-induced  apoptosis in A20 cells. The activities of apoptotic molecules such as caspase-3,  PARP, and Bax were increased, but the activation of p27 Kip1 and ERK were decreased in KSK-CpG-treated A20 cells. Furthermore, autocrine IFN-gamma partially contributed to apoptotic cell death in KSK-CpG-treated A20 cells. Collectively, our findings suggest that KSK-CpG induces apoptotic cell death in A20 lymphoma cells at least in part by inducing G1-phase arrest and autocrine IFN-gamma via increasing TLR9 expression, without the need for immune system of tumor-bearing host. This new understanding supports the development of TLR9-targeted therapy with CpG-ODN as a direct therapeutic agent for treating B lymphoma.

 

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[338]

TÍTULO / TITLE:  - Estrogen receptor beta (ERbeta) is a novel prognostic marker of recurrence survival in non-muscle-invasive bladder cancer potentially by inhibiting cadherin switch.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Urol. 2013 Jan 26.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00345-012-1020-0

AUTORES / AUTHORS:  - Han B; Cui D; Jing Y; Hong Y; Xia S

INSTITUCIÓN / INSTITUTION:  - Department of Urology, School of Medicine, The First People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People’s Republic of China.

RESUMEN / SUMMARY:  - OBJECTIVE: The function and significance of estrogen receptor beta (ERbeta) in bladder cancer remains a field of hot debate. In this study, we aimed to (a) evaluate ERbeta as a novel prognostic marker of recurrence free survival; and (b) digest the underlying mechanism by elucidating the relationship between ERbeta expression and cadherin switch. METHODS: We examined the expression levels of ERbeta, E-cadherin and N-cadherin in 42 initial non-muscle-invasive urothelial bladder carcinomas via immunohistochemistry. Correlation analysis was performed among ERbeta expression, cadherin switch and recurrence free survival. Moreover,  in vitro studies were performed to validate the identified correlation using two  bladder cancer cell lines RT4 and 253J. Upon stimulation with an ERbeta selective agonist diarylpropionitrile, E-cadherin, N-cadherin expressions; cell migration and invasion capacity were assessed. RESULTS: Expression of ERbeta protein was seen in 34 bladder cancer cases (80.9 %), and 21 (50 %) specimens showed non-cadherin switch (positive E-cadherin and negative N-cadherin). ERbeta expression and the non-cadherin switch are both accompanied with better recurrence free survival. Also, the least ERbeta expression was observed in specimens that undergo cadherin switch. Moreover, these results were consistent with our observations in bladder cancer RT4 and 253J cell lines studies. Diarylpropionitrile stimulation resulted in an increase in E-cadherin, a decrease in N-cadherin expression and abolished cell migration and invasion. CONCLUSION: ERbeta is a prognostic marker of recurrence free rate in non-muscle-invasive bladder cancer, potentially through suppressing cadherin switch, and may act as a potential target for bladder cancer therapy.

 

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[339]

TÍTULO / TITLE:  - Exploration of 1-(3-chloro-4-(4-oxo-4H-chromen-2-yl)phenyl)-3-phenylurea derivatives as selective dual inhibitors of Raf1 and JNK1 kinases for anti-tumor  treatment.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Bioorg Med Chem. 2013 Feb 1;21(3):824-31. doi: 10.1016/j.bmc.2012.04.006. Epub 2012 Apr 11.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bmc.2012.04.006

AUTORES / AUTHORS:  - Jin F; Gao D; Zhang C; Liu F; Chu B; Chen Y; Chen YZ; Tan C; Jiang Y

INSTITUCIÓN / INSTITUTION:  - Department of Chemistry, Tsinghua University, Beijing 100084, China; The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.

RESUMEN / SUMMARY:  - Based on the roles of Raf1 and JNK1 in hepatocarcinoma development, scaffold-based drug design was employed to produce a series of compounds, which subsequently were synthesized and explored as potential dual inhibitors Raf1 and  JNK1 kinases for anti-tumor treatment. The compound 1-(3-chloro-4-(6-ethyl-4-oxo-4H-chromen-2-yl)phenyl)-3-(4-chloro-phenyl)urea (3d) showed 66%, 67% and 13% inhibition rate at 50muM against Raf1, JNK1 and p38-alpha, respectively, but no effect on ERK1 and ERK2, and inhibited the expression of pERK1/2 markedly and HepG2 cells proliferation with IC(50) at 8.3muM. Furthermore, 3d showed lower toxicity against normal liver cell-lines QSG7701 and HL7702. Molecular docking study further showed that 3d can fit into binding domain of JNK1 and Raf1. Our data suggested the activities of 3d were associated with dual inhibition of JNK1 and Raf1 kinases.

 

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[340]

TÍTULO / TITLE:  - Human antibodies reactive to NeuGcGM3 ganglioside have cytotoxic anti-tumor properties.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Immunol. 2013 Jan 14. doi: 10.1002/eji.201242693.

            ●● Enlace al texto completo (gratuito o de pago) 1002/eji.201242693

AUTORES / AUTHORS:  - Rodriguez-Zhurbenko N; Martinez D; Blanco R; Rondon T; Grinan T; Hernandez AM

INSTITUCIÓN / INSTITUTION:  - Tumor Immunology Direction, Center of Molecular Immunology, Havana, Cuba.

RESUMEN / SUMMARY:  - N-glycolylated gangliosides are not naturally expressed in healthy human tissues  but are overexpressed in several tumors. We demonstrate the existence of antibodies that bind (N-glycolylneuraminyl)-lactosylceramide (NeuGcGM3) and are detectable in the sera from 65 of the 100 donors (65%) tested by ELISA. From those 65 NeuGcGM3 antibody-positive donors, 35 had antibodies that were able to recognize and kill NeuGcGM3-expressing tumor cells by a complement-mediated mechanism. After complement inactivation, 11 of the 35 positive sera showed a direct cytotoxic effect on the tumor cells. This complement-independent cytotoxicity was dependent on the presence of antigen on the membrane and resembles an oncotic necrosis cell death. Both the levels of anti-NeuGcGM3 antibodies in the sera as well as the percentage of healthy donors with this immunity decreased with age of the donor. In contrast to age and gender-matched healthy donors, we could only detect low reactivity against NeuGcGM3 in the sera  of 6 out of 53 non-small cell lung cancer patients. These results suggest the existence of antibodies against NeuGcGM3 with anti-tumor immune surveillance functions, reinforcing the importance of N-glycolylated gangliosides as anti-tumor targets.

 

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[341]

TÍTULO / TITLE:  - Smh-3 induces G(2)/M arrest and apoptosis through calciummediated endoplasmic reticulum stress and mitochondrial signaling in human hepatocellular carcinoma Hep3B cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):751-62. doi: 10.3892/or.2012.2166. Epub 2012 Dec 5.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2166

AUTORES / AUTHORS:  - Liu CY; Yang JS; Huang SM; Chiang JH; Chen MH; Huang LJ; Ha HY; Fushiya S; Kuo SC

INSTITUCIÓN / INSTITUTION:  - Graduate Institute of Pharmaceutical Chemistry, China Medical University Hospital, Taichung 404, Taiwan, ROC.

RESUMEN / SUMMARY:  - In the present study, we investigated the antitumor effects of Smh-3 on the viability, cell cycle and apoptotic cell death in human hepatocellular carcinoma  Hep3B cells in vitro. We also investigated the molecular mechanisms involved in the effects of Smh-3 on human hepatoma Hep3B cells, including the effects on protein and mRNA levels which were determined by western blotting and DNA microarray methods, respectively. The results demonstrated that Smh-3 induced growth inhibition, cell morphological changes and induction of G(2)/M arrest and  apoptosis in Hep3B cells. DNA microarray assay identified numerous differentially expressed genes related to angiogenesis, autophagy, calcium-mediated ER stress signaling, cell adhesion, cell cycle and mitosis, cell migration, cytoskeleton organization, DNA damage and repair, mitochondrial-mediated apoptosis and cell signaling pathways. Furthermore, Smh-3 inhibited CDK1 activity, mitochondrial membrane potential (DeltaPsim) and increased the cytosolic Ca(2+) release and caspase-4, caspase-9 and caspase-3 activities in Hep3B cells. Western blot analysis demonstrated that Smh-3 increased the protein levels of caspase-4 and GADD153 that may lead to ER stress and consequently apoptosis in Hep3B cells. Taken together, Smh-3 acts against human hepatocellular carcinoma Hep3B cells in  vitro through G(2)/M phase arrest and induction of calcium-mediated ER stress and mitochondrial-dependent apoptotic signaling pathways.

 

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[342]

TÍTULO / TITLE:  - Physangulidine A, a Withanolide from Physalis angulata, Perturbs the Cell Cycle and Induces Cell Death by Apoptosis in Prostate Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Nat Prod. 2013 Jan 25;76(1):2-7. doi: 10.1021/np300457g. Epub 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1021/np300457g

AUTORES / AUTHORS:  - Reyes-Reyes EM; Jin Z; Vaisberg AJ; Hammond GB; Bates PJ

INSTITUCIÓN / INSTITUTION:  - Department of Medicine, University of Louisville , Louisville, Kentucky 40202, United States.

RESUMEN / SUMMARY:  - Recently, our group reported the discovery of three new withanolides, physangulidines A-C, from Physalis angulata. In this study, the biological effects of physangulidine A (1), which was the most active and abundant of the three new constituents, are described. It was found that 1 significantly reduces  survival in clonogenic assays for two hormone-independent prostate cancer cell lines. Flow cytometry and confocal microscopy studies in DU145 human prostate cancer cells indicated that 1 induces cell cycle arrest in the G(2)/M phase and causes defective mitosis. It was determined also that 1 produces programed cell death by apoptosis, as evidenced by biochemical markers and distinct changes in cell morphology. These results imply that the antimitotic and proapoptotic effects of 1 may contribute significantly to the biological activities and potential medicinal properties of its plant of origin.

 

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[343]

TÍTULO / TITLE:  - The targeted co-delivery of DNA and doxorubicin to tumor cells via multifunctional PEI-PEG based nanoparticles.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biomaterials. 2013 Mar;34(10):2547-64. doi: 10.1016/j.biomaterials.2012.12.038. Epub 2013 Jan 17.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biomaterials.2012.12.038

AUTORES / AUTHORS:  - Liu C; Liu F; Feng L; Li M; Zhang J; Zhang N

INSTITUCIÓN / INSTITUTION:  - Department of Pharmaceutics, School of Pharmaceutical Science, Shandong University, 44 West culture Road, Ji’nan 250012, Shandong Province, China.

RESUMEN / SUMMARY:  - Co-delivery of nucleic acids and chemotherapeutics has a potential to efficaciously treat human diseases via their synergetic effects. Activable therapeutic tools at the nanoscale are suitable platforms for combination therapy. In this study, we have developed a multifunctional nanoscaled delivery system simultaneously integrated with passive and active tumor targeting, cell membrane translocation, pH-triggered drug release and co-delivery strategies. Poly (ethyleneimine) (PEI)-polyethylene glycol (PEG) copolymer was synthesized with coupling TAT to the distal end of PEG for membrane activity. The functional  amino group of PEI was used to chemically conjugate doxorubicin (DOX) via a pH-sensitive hydrazone linkage. Meanwhile, the cationic PEI backbone could complex DNA to DOX loaded-TAT modified polyion complex micelles (NPIC). To achieve double targeting effect to tumor vascular endothelial cells and tumor cells either by active or passive targeting, a virus mimetic shell functioned with NGR was conferred by electrostatic adsorption of sulfamerazine (SA)-PEG-NGR  on the surface of NPIC to obtain DOX loaded targeted PIC micelles (TPIC). The multifunctional nanoscaled delivery system was established to comprehensively improve the efficacy of cancer therapy through the synergistic effect of gene therapy with chemotherapy. Consequently, the system was shown to be a promising carrier for the co-delivery of DNA and DOX, leading to the efficiency of gene transfection and anti-tumor activity in vitro.

 

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[344]

TÍTULO / TITLE:  - Curcumin induces FasL-related apoptosis through p38 activation in human hepatocellular carcinoma Huh7 cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Life Sci. 2013 Jan 24. pii: S0024-3205(13)00023-4. doi: 10.1016/j.lfs.2013.01.013.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.lfs.2013.01.013

AUTORES / AUTHORS:  - Wang WZ; Li L; Liu MY; Jin XB; Mao JW; Pu QH; Meng MJ; Chen XG; Zhu JY

INSTITUCIÓN / INSTITUTION:  - Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, P. R. China; Guangzhou Higher Education Mega Centre Health Industrial Science and Technology Park Investment Management Co.Ltd., Guangzhou, P. R. China; School of Pubic Heath and Tropical Medicine, Southern Medical University, Guangzhou, P. R. China. Electronic address: wwzss@163.com.

RESUMEN / SUMMARY:  - Aim The aim of this study is to explore the underlying molecular mechanism of curcumin-induced apoptosis in human hepatocellular carcinoma (HCC) Huh7 cells. Main methods Fas and FasL mRNA expression was analyzed by reverse transcription PCR. Western blot was applied to detect the protein expression of Bcl-2 family members, MAPK family members, c-Jun, c-Fos, ATF-2, caspase-3, PARP, TNF receptor  family members and the respective ligands. Apoptotic cells were assayed with annexin V/PI double staining and flow cytometry. Key findings Curcumin treatment  resulted in a fast and significant increase of Fas and Fas ligand (FasL) along with activation of caspase-3 and cleavage of PARP in Huh7 cells. Inhibition of caspase-3 activity by the specific inhibitor Z-DEVD-FMK rescued Huh7 cells from curcumin-induced apoptosis. Neutralization of FasL significantly protected the cells from curcumin-induced caspase-3 activation and apoptosis in a dose-dependent manner. Moreover, p38 was rapidly activated in response to curcumin, and inactivation of p38 by pharmacologic inhibitor SB203580 dramatically suppressed curcumin-induced FasL expression and apoptosis. Significance Our results demonstrated that curcumin induces apoptosis through p38-denpendent up-regulation of FasL in Huh7 cells.

 

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[345]

TÍTULO / TITLE:  - Sensitization of TRAIL-induced apoptosis in human hepatocellular carcinoma HepG2  cells by phytochemicals.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Life Sci. 2013 Jan 24. pii: S0024-3205(13)00045-3. doi: 10.1016/j.lfs.2013.01.017.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.lfs.2013.01.017

AUTORES / AUTHORS:  - El Naga RN; Azab SS; El-Demerdash E; Shaarawy S; El-Merzabani M; Ammar ES

INSTITUCIÓN / INSTITUTION:  - Department of pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.

RESUMEN / SUMMARY:  - AIMS: The present study investigated and compared the potential chemosensitizing  effect of indole-3-carbinol (I3C) and epigallocatechin-3-gallate (EGCG) on TRAIL-induced apoptosis in human hepatocellular carcinoma (HCC) HepG2 cells as well as the possible mechanisms underlying these modulatory effects, particularly their effects on TRAIL death receptors (DR), Bcl-2 and c-FLIP proteins expression. MATERIALS AND METHODS: HepG2 cells were treated with different concentrations of TRAIL ranging from 3 to 400ng/ml for 24h. For studying the modulatory effects of the phytochemicals on TRAIL-induced apoptosis, I3C and EGCG were used at concentrations that inhibit only 5% of the cells which were found to be 110muM and 70mug/ml, respectively. KEY FINDINGS: It was found that 24h pre-treatment of HepG2 cells with either 110muM I3C or 70mug/ml EGCG significantly enhanced TRAIL cytotoxicity. EGCG induced more reduction in IC(50)  of TRAIL compared to I3C. Nevertheless, I3C was more efficient than EGCG in enhancing TRAIL cytotoxicity at higher concentrations of TRAIL. Both I3C and EGCG significantly increased caspase-3 activity, DNA fragmentation percentage, DR4 and DR5 protein expression as well as decreased Bcl-2 protein expression when compared to control groups. SIGNIFICANCE: Both I3C and EGCG chemosensitized HCC HepG2 cells to TRAIL-induced apoptosis. These modulatory effects were partially attributed to the up-regulation of caspase-3 activity and DR4 and DR5 expression, as well as down-regulation of Bcl-2 expression. Only EGCG was able to induce a significant decrease in c-FLIP expression level.

 

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[346]

TÍTULO / TITLE:  - MAPK signaling pathways regulate mitochondrial-mediated apoptosis induced by isoorientin in human hepatoblastoma cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Food Chem Toxicol. 2012 Dec 5;53C:62-68. doi: 10.1016/j.fct.2012.11.048.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.fct.2012.11.048

AUTORES / AUTHORS:  - Yuan L; Wang J; Xiao H; Wu W; Wang Y; Liu X

INSTITUCIÓN / INSTITUTION:  - Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.

RESUMEN / SUMMARY:  - Isoorientin (ISO) (CAS RN: 4261-42-1) is a flavonoid compound that can be extracted from several plant species, such as Phyllostachys pubescens, Patrinia,  and Drosophyllum lusitanicum. ISO is able to induce apoptosis through mitochondrial dysfunction and inhibition of PI3K/Akt signaling pathway in HepG2 cells, however, the effects of ISO on MAPK signaling pathways remain unknown. The present study investigated the effects of ISO on this pathway, and the roles of MAPK kinases on mitochondrial-mediated apoptosis in HepG2 cells. The results showed that ISO induced cell death in a dose- and time-dependent manner, and induction apoptosis is main cause for ISO-induced cytotoxicity in HepG2 cells. ISO significantly inhibited the levels of ERK1/2 kinase and increased the expression of JNK and p38 kinases. Furthermore, U0126 (an ERK1/2 inhibitor) significantly enhanced the ISO-induced the Bax/Bcl-2 ratio, the release of cytochrome c to the cytosol fraction, and the levels of cleaved caspase-3. While  SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor) markedly prevented the  expression of these proteins induced by ISO. Furthermore, the ROS inhibitor (NAC) notably promoted the inhibited effect of ISO on the ERK1/2 kinase. NAC also suppressed the p-JNK and p-p38, but failed to reverse the effects of ISO. These results demonstrated for the first time that ISO induces apoptosis in HepG2 cells through inactivating ERK1/2 kinase and activating JNK and p38 kinases, and ROS stimulated by ISO is able to activate the MAPK singaling pathway as the upstream  signaling molecules. Initiating event of the mitochondrial-mediated apoptosis induced by ISO is MAPK signals.

 

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[347]

TÍTULO / TITLE:  - ROS-mediated activation of AKT induces apoptosis via pVHL in prostate cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Cell Biochem. 2013 Jan 12.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11010-012-1549-7

AUTORES / AUTHORS:  - Chetram MA; Bethea DA; Odero-Marah VA; Don-Salu-Hewage AS; Jones KJ; Hinton CV

INSTITUCIÓN / INSTITUTION:  - Center for Cancer Research and Therapeutic Development, Clark Atlanta University, 223 James P. Brawley Drive, SW, Atlanta, GA, 30314, USA.

RESUMEN / SUMMARY:  - Reactive oxygen species (ROS) play a central role in oxidative stress, which leads to the onset of diseases, such as cancer. Furthermore, ROS contributes to the delicate balance between tumor cell survival and death. However, the mechanisms by which tumor cells decide to elicit survival or death signals during oxidative stress are not completely understood. We have previously reported that  ROS enhanced tumorigenic functions in prostate cancer cells, such as transendothelial migration and invasion, which depended on CXCR4 and AKT signaling. Here, we report a novel mechanism by which ROS facilitated cell death  through activation of AKT. We initially observed that ROS enhanced the expression of phosphorylated AKT (p-AKT) in 22Rv1 human prostate cancer cells. The tumor suppressor PTEN, a negative regulator of AKT signaling, was rendered catalytically inactive through oxidation by ROS, although the expression levels remained consistent. Despite these events, cells still underwent apoptosis. Further investigation into apoptosis revealed that expression of the tumor suppressor pVHL increased, and contains a target site for p-AKT phosphorylation.  pVHL and p-AKT associated in vitro, and knockdown of pVHL rescued HIF1alpha expression and the cells from apoptosis. Collectively, our study suggests that in the context of oxidative stress, p-AKT facilitated apoptosis by inducing pVHL function.

 

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[348]

TÍTULO / TITLE:  - Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Med Chem. 2013 Jan 10;56(1):123-49. doi: 10.1021/jm3013097. Epub 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1021/jm3013097

AUTORES / AUTHORS:  - La Regina G; Bai R; Rensen WM; Di Cesare E; Coluccia A; Piscitelli F; Famiglini V; Reggio A; Nalli M; Pelliccia S; Da Pozzo E; Costa B; Granata I; Porta A; Maresca B; Soriani A; Iannitto ML; Santoni A; Li J; Miranda Cona M; Chen F; Ni Y; Brancale A; Dondio G; Vultaggio S; Varasi M; Mercurio C; Martini C; Hamel E; Lavia P; Novellino E; Silvestri R

INSTITUCIÓN / INSTITUTION:  - Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Universita di Roma , Piazzale Aldo Moro 5, I-00185 Roma, Italy.

RESUMEN / SUMMARY:  - New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited  tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC(50) = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.

 

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[349]

TÍTULO / TITLE:  - Promoter methylation of WNT inhibitory factor-1 and expression pattern of WNT/beta-catenin pathway in human astrocytoma: pathologic and prognostic correlations.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mod Pathol. 2013 Jan 18. doi: 10.1038/modpathol.2012.215.

            ●● Enlace al texto completo (gratuito o de pago) 1038/modpathol.2012.215

AUTORES / AUTHORS:  - Kim SA; Kwak J; Nam HY; Chun SM; Lee BW; Lee HJ; Khang SK; Kim SW

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

RESUMEN / SUMMARY:  - WNT inhibitory factor-1 (WIF1) is an antagonist of the WNT signaling pathway. We  investigated the relationship between WIF1 promoter methylation and regulation of the WNT/beta-catenin signaling pathway, tumor grade, and survival in patients with astrocytoma. This study included 86 cases of astrocytoma, comprising 20 diffuse astrocytomas and 66 glioblastomas. In addition, 17 temporal lobectomy specimens from patients with epilepsy were included as controls. The ratio of methylated DNA to total methylated and unmethylated DNA (% methylation) was measured by methylation- and unmethylation-specific PCR. Representative tumor tissue was immunostained for WIF1, beta-catenin, cyclin D1, c-myc, and isocitrate dehydrogenase 1. Levels of WIF1 promoter methylation, mRNA expression, and protein expression in a glioblastoma cell line were compared before and after demethylation treatment. The mean percent methylation of the WIF1 promoter in astrocytomas was higher than that in control brain tissue. WIF1 protein expression was lower in the tumor group with >5% methylation than in the group with <5% methylation. Cytoplasmic beta-catenin staining was more frequently observed in tumors with a low WIF1 protein expression level. Demethylation treatment of a glioblastoma cell line increased WIF1 mRNA and protein expression. Increased WIF1 promoter methylation and decreased WIF1 protein expression were not related to patient survival. In conclusion, WIF1 expression is downregulated  by promoter methylation and is an important mechanism of aberrant WNT/beta-catenin pathway activation in astrocytoma pathogenesis.Modern Pathology  advance online publication, 18 January 2013; doi:10.1038/modpathol.2012.215.

 

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[350]

TÍTULO / TITLE:  - Gonadotropin-releasing hormone neuropeptides and receptor in human breast cancer: Correlation to poor prognosis parameters.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Peptides. 2012 Dec 31. pii: S0196-9781(12)00500-1. doi: 10.1016/j.peptides.2012.12.016.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.peptides.2012.12.016

AUTORES / AUTHORS:  - Pazaitou-Panayiotou K; Chemonidou C; Poupi A; Koureta M; Kaprara A; Lambropoulou M; Constantinidis TC; Galaktidou G; Koffa M; Kiziridou A; Kakolyris S; Kolios G; Kortsaris A; Chatzaki E

INSTITUCIÓN / INSTITUTION:  - Department of Endocrinology - Endocrine Oncology, “Theagenio” Cancer Hospital, Thessaloniki, Greece.

RESUMEN / SUMMARY:  - Expression of the two gonadotropin-releasing hormone homologue peptides GnRHI and GnRHII and their receptor GnRHR has been demonstrated in a number of malignancies. In hormone-dependent breast cancer, GnRH analogs are used for therapy in premenopausal women. Gene expression of GnRHI, II and R was studied in breast biopsies from primary breast adenocarcinoma obtained from the tumor and the adjacent benign tissue. Levels were evaluated by a multiplex real-time RT-PCR. GnRHI transcripts were detected in 14.7% of the benign and 29.4% malignant biopsies and GnRHII in 21.2% benign and 44.1% malignant biopsies. GnRHR was also more frequent in the malignant (54.2%) than in the benign (24.0%) biopsies, at similar expression levels. No transcripts were detected in biopsies  from healthy individuals. There was a strong correlation between the presence of  GnRHI and GnRHII transcripts and their receptor in the benign and the malignant biopsies. GnRHI, II and R expression correlated significantly with poor prognosis pathological parameters. Immunohistochemistry for GnRHR revealed expression in malignant cells and in epithelial cells of mammary ducts of the adjacent area with pre-cancerous features. In contrast, GnRH I and II peptides were rarely expressed at low levels in breast cancer cells. In conclusion GnRH peptides and receptor are expressed more frequently in breast tumors than in the adjacent mammary tissue, representing a malignant feature their expression correlated to tumor characteristics of poor prognosis and was therefore related to more aggressive malignancies. Concomitant expression of peptides and receptor supports an autocrine/paracrine regulating role.

 

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[351]

TÍTULO / TITLE:  - Non-gastric advanced mucosa-associated lymphoid tissue (MALT) lymphoma has worse  prognosis than gastric MALT lymphoma even when treated with rituximab-containing  chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2012.754023

AUTORES / AUTHORS:  - Ueda K; Terui Y; Yokoyama M; Sakajiri S; Nishimura N; Tsuyama N; Takeuchi K; Hatake K

INSTITUCIÓN / INSTITUTION:  - Department of Hematology Oncology , Cancer Institute Hospital, Tokyo , Japan.

RESUMEN / SUMMARY:  - The aim of this study was to assess the clinical characteristics, treatment results, and analyze the prognostic factors among patients with extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). We retrospectively reviewed 98 patients with MALT lymphoma consecutively diagnosed at the Cancer Institute Hospital. Eighty-one patients (82%) had localized disease and 17 patients (17%) had advanced disease. The primary site was gastric in 52, and extra-gastric in 46. With a median follow-up  of 40 months, the estimated 3-year overall survival (OS) and progression free survival (PFS) of the entire group were 100% and 89%, respectively. Three-year PFS was significantly better in patients with gastric lymphoma than in those with non-gastric lymphoma (95% vs. 82%, p = 0.043). Patients with localized disease had significantly better 3-year PFS than those with advanced disease (94% vs. 73%, p = 0.026). Upon multivariate analysis, non-gastric lymphoma retained prognostic significance for PFS.

 

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[352]

TÍTULO / TITLE:  - Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 15;19(2):450-61. doi: 10.1158/1078-0432.CCR-12-1067. Epub 2012 Dec 3.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-1067

AUTORES / AUTHORS:  - Endo M; Yamamoto H; Setsu N; Kohashi K; Takahashi Y; Ishii T; Iida K; Matsumoto Y; Hakozaki M; Aoki M; Iwasaki H; Dobashi Y; Nishiyama K; Iwamoto Y; Oda Y

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Departments of Anatomic Pathology and Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University; Department of Pathology,  National Kyushu Cancer Center; Department of Pathology, Fukuoka University Faculty of Medicine, Fukuoka; Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima; and Department of Pathology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.

RESUMEN / SUMMARY:  - PURPOSE: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. MPNSTs occur frequently in patients with neurofibromatosis type 1 (NF1), in which NF1 gene deficiency leads to Ras hyperactivation. Ras activation causes the subsequent activation of the AKT/mTOR  and Raf/MEK/ERK pathways and regulates cellular functions. However, the activation profiles of the AKT/mTOR and MAPK pathways in MPNSTs are poorly understood. The purposes of this study are to examine the correlation between the activation of these pathways and clinicopathologic or prognostic factors and to identify candidate target molecules in MPNST. Moreover, we assessed the antitumor effects of the inhibitor of candidate target. EXPERIMENTAL DESIGN: Immunohistochemistry was conducted to evaluate the activation profiles of AKT/mTOR and MAPK pathways using 135 tumor specimens. Immunohistochemical expressions were confirmed by Western blotting. Then, an in vitro study was conducted to examine the antitumor effect of the mTOR inhibitor on MPNST cell lines. RESULTS: Phosphorylated-AKT (p-AKT), p-mTOR, p-S6RP, p-p70S6K, p-4E-BP1, p-MEK1/2, and p-ERK1/2 expressions were positive in 58.2%, 47.3%, 53.8%, 57.1%, 62.6%, 93.4%, and 81.3% of primary MPNSTs, respectively. Positivity for each factor showed no difference between NF1-related and sporadic MPNSTs. Univariate prognostic analysis revealed that p-AKT, p-mTOR, and p-S6RP expressions were associated with poor prognosis. Furthermore, activation of each p-mTOR and p-S6RP was an independent poor prognostic factor by multivariate analysis. mTOR inhibition by Everolimus showed antitumor activity on MPNST cell lines in vitro.  CONCLUSION: mTOR inhibition is a potential treatment option for both NF1-related  and sporadic MPNSTs. Clin Cancer Res; 19(2); 450-61. ©2012 AACR.

 

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[353]

TÍTULO / TITLE:  - Letter to the Editor: High dose cytarabine with rituximab is an effective first-line therapy for mantle cell lymphoma and produces ample stem cell harvest  yields after multiple chemotherapy cycles.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Jan 24.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2013.769536

AUTORES / AUTHORS:  - Forbes A; Farrell K; McKay P; Bolam S; Rule S

 

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[354]

TÍTULO / TITLE:  - Is the Standardized Uptake Value of FDG-PET/CT Predictive of Pathological Complete Response in Locally Advanced Rectal Cancer Treated with Capecitabine-Based Neoadjuvant Chemoradiation?.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncology. 2013 Jan 15;84(4):191-199.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000345601

AUTORES / AUTHORS:  - Bampo C; Alessi A; Fantini S; Bertarelli G; de Braud F; Bombardieri E; Valvo F; Crippa F; Di Bartolomeo M; Mariani L; Milione M; Biondani P; Avuzzi B; Chiruzzi C; Pietrantonio F

INSTITUCIÓN / INSTITUTION:  - Department of Nuclear Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

RESUMEN / SUMMARY:  - Objectives: Our aim was to assess FDG-PET/CT as a surrogate biomarker of the pathological complete response in locally advanced rectal cancer treated with neoadjuvant chemoradiation. Methods: T3-4 and/or N+ rectal cancer patients were treated prospectively with capecitabine-based chemoradiation and total mesorectal excision 7-8 weeks later. FDG-PET/CT uptake was obtained at baseline, after 2 weeks, and 6 weeks following treatment completion, calculating the maximum standardized uptake value (SUV) and percentage difference to identify the early and late metabolic ‘response index’. Results: Thirty-one patients were treated from January 2009 to January 2012 at the Istituto Nazionale dei Tumori of Milan.  One patient was excluded due to surgery refusal. The pathological complete response rate was 30%. Early FDG-PET/CT was performed in 24 consenting patients and failed to show predictive utility. On the contrary, significant differences in late SUV value and response index were observed between complete and noncomplete pathological responders (p = 0.0006 and 0.03). In multivariate analysis including most relevant SUV parameters, none of them was independently associated with a pathological complete response. With receiver operating characteristic curve analysis, a late SUV threshold <5.4 had 81% sensitivity and  100% specificity, with 90% overall accuracy. Conclusions: We evidenced a possible predictive role of late FDG-PET/CT for the assessment of pathological response in locally advanced rectal cancer following neoadjuvant chemoradiation.

 

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[355]

TÍTULO / TITLE:  - Potential role of acid ceramidase in conversion of cytostatic to cytotoxic end-point in pancreatic cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-012-2050-4

AUTORES / AUTHORS:  - Morad SA; Messner MC; Levin JC; Abdelmageed N; Park H; Merrill AH Jr; Cabot MC

INSTITUCIÓN / INSTITUTION:  - Department of Experimental Therapeutics, John Wayne Cancer Institute, 2200 Santa  Monica Blvd, Santa Monica, CA, 90404, USA.

RESUMEN / SUMMARY:  - PURPOSE: Acid ceramidase (AC) occupies an important place in the control of cancer cell proliferation. We tested the influence of AC inhibition on the effects of PSC 833, a P-glycoprotein antagonist with potent ceramide-generating capacity, to determine whether AC could be a therapeutic target in pancreatic cancer. METHODS: Ceramide metabolism was followed using (3)H-palmitate, and molecular species were determined by mass spectroscopy. Apoptosis was measured by DNA fragmentation, autophagy by acridine orange staining, and cell cycle was assessed by flow cytometry and RB phosphorylation. AC was measured in intact cells using fluorescent substrate. RESULTS: Exposure of human PANC-1 or MIA-PaCa-2 cells to PSC 833 promoted increases in de novo (dihydro)ceramides, (dihydro)glucosylceramides, and (dihydro)sphingomyelins, demarking ceramide generation and robust metabolism. Despite the multifold increases in (dihydro)ceramide levels, cells were refractory to PSC 833. However, PSC 833 produced a dose-dependent decrease in DNA synthesis and dose- and time-dependent  decreases in RB phosphorylation, consistent with cell cycle arrest as demonstrated at G1. Cytostatic effects of PSC 833 were converted to cytotoxic end-point by acid ceramidase inhibition. Cytotoxicity was accompanied by formation of acridine orange-stained acidic vesicles and an increase in LC3 expression, indicative of autophagic response. Cell death was not reversed by preexposure to myriocin, which blocks PSC 833-induced ceramide generation. CONCLUSION: Although the role of ceramide in end-point cytotoxicity is unclear, our results suggest that acid ceramidase is a viable target in pancreatic cancer. We propose that AC inhibition will be effective in concert with other anticancer  therapies.

 

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[356]

TÍTULO / TITLE:  - HPV16 L1 and L2 DNA methylation predicts high grade cervical intraepithelial neoplasia in women with mildly abnormal cervical cytology.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Cancer. 2013 Jan 21. doi: 10.1002/ijc.28050.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.28050

AUTORES / AUTHORS:  - Lorincz AT; Brentnall AR; Vasiljevic N; Scibior-Bentkowska D; Castanon A; Fiander A; Powell N; Tristram A; Cuzick J; Sasieni P

INSTITUCIÓN / INSTITUTION:  - Queen Mary University of London, Centre for Cancer Prevention, Wolfson Institute  of Preventive Medicine, Barts and The London School of Medicine, EC1M 6BQ London  UK. a.lorincz@qmul.ac.uk.

RESUMEN / SUMMARY:  - DNA methylation changes in human papillomavirus type 16 (HPV16) DNA are common and might be important for identifying women at increased risk of cervical cancer. Using recently published data from Costa Rica we developed a classification score to differentiate women with cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) from those with no evident high grade lesions. Here we aim to investigate the performance of the score using data from the UK. Exfoliated cervical cells at baseline and six-months follow-up were analyzed in 84 women selected from a randomized clinical trial of women undergoing surveillance for low grade cytology. Selection of women for the methylation study was based on detectable HPV16 in the baseline sample. Purified DNA was bisulfite  converted, amplified and pyrosequenced at selected CpG sites in the viral genome  (URR, E6, L1 and L2), with blinding of laboratory personnel to the clinical data. The primary measure was a predefined score combining the mean methylation in L1 and any methylation in L2. At the second follow-up visit 73/84 (87%) women were HPV16 positive and of these 25 had a histo-pathological diagnosis of CIN2/3. The  score was significantly associated with CIN2/3 (area under curve = 0.74, p=0.002). For a cut-off with 92% sensitivity, colposcopy could have been avoided  in 40% (95%CI 27-54%) of HPV16 positive women without CIN2/3; positive predictive value was 44% (32-58%) and negative predictive value was 90% (71-97%). We conclude that quantitative DNA methylation assays could help to improve triage among HPV16 positive women.

 

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[357]

TÍTULO / TITLE:  - TRAIL and osteoprotegerin (OPG) expression in bladder urothelial carcinoma: correlation with clinicopathological parameters and prognosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pathology. 2013 Feb;45(2):138-44. doi: 10.1097/PAT.0b013e32835c9891.

            ●● Enlace al texto completo (gratuito o de pago) 1097/PAT.0b013e32835c9891

AUTORES / AUTHORS:  - Levidou G; Thymara I; Saetta AA; Papanastasiou P; Pavlopoulos P; Sakellariou S; Fragkou P; Patsouris E; Korkolopoulou P

INSTITUCIÓN / INSTITUTION:  - First Department of Pathology, Laiko General Hospital, Athens, University School  of Medicine, Athens, Greece.

RESUMEN / SUMMARY:  - AIMS: : To investigate the expression of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin (OPG) in bladder urothelial carcinomas (UCs) and assess possible interrelations with other regulators of TRAIL induced apoptosis (p65/NF-kappaB, p-ERK1/2, p-AKT) and FGFR3, as well as to elucidate their potential involvement in bladder tumourigenesis and determine their potential prognostic utility. METHODS: : Paraffin embedded transurethral resection tissue from 128 patients with UC was immunostained for TRAIL and OPG as well as for p65/NF-kappaB, p-ERK1/2, p-AKT and FGFR3. RESULTS: : TRAIL and OPG were coexpressed in 96.6% of cases and positively interrelated. OPG expression was significantly different among histological grades, being higher in low-grade  UCs and was inversely correlated with the presence of lymphovascular invasion (LVI). TRAIL also displayed an inverse relationship with histological grade, T-category and LVI. Both OPG and TRAIL expression were positively correlated with FGFR3 expression, the former relationship being marginal. Moreover, increased TRAIL expression was marginally correlated with lower NF-kappaB/p65 nuclear expression. Increased OPG expression adversely affected survival both in univariate and multivariate analysis. CONCLUSIONS: : OPG and TRAIL are frequently expressed and coexpressed in UCs, supporting the involvement of OPG in the resistance to TRAIL-driven apoptosis. Inhibition of NF-kappaB activation may also play a similar role, although less important. OPG emerged as an independent prognostic marker of adverse significance.

 

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[358]

TÍTULO / TITLE:  - Predictors of reduced relative dose intensity and its relationship to mortality in women receiving multi-agent chemotherapy for epithelial ovarian cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Gynecol Oncol. 2012 Dec 21. pii: S0090-8258(12)00965-1. doi: 10.1016/j.ygyno.2012.12.017.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ygyno.2012.12.017

AUTORES / AUTHORS:  - Hanna RK; Poniewierski MS; Laskey RA; Lopez MA; Shafer A; Van Le L; Crawford J; Dale DC; Gehrig PA; Secord AA; Havrilesky LJ; Lyman GH

INSTITUCIÓN / INSTITUTION:  - Henry Ford Hospital, Detroit MI, USA.

RESUMEN / SUMMARY:  - OBJECTIVE: There is limited information concerning the role of relative dose intensity (RDI) on clinical outcomes in solid tumors. The objectives of our study were to evaluate the prognostic significance of RDI and predictors of reduced RDI in women with newly diagnosed advanced stage epithelial ovarian carcinoma (EOC) treated with platinum-based chemotherapy. METHODS: A multi-center retrospective study of women with FIGO stage III-IV epithelial ovarian cancer treated postoperatively with multi-agent intravenous chemotherapy between 1995 and 2009 was conducted. Data were obtained to include the first four chemotherapy cycles administered. Outcomes included: (1) planned and delivered relative dose intensity (RDI), (2) progression-free (PFS) and overall (OS) survival. Survival estimates were based on Kaplan and Meier method, and multivariate analyses were based on logistic regression and Cox proportional hazards regression. RESULTS: Evaluable subjects included 325 women. With median follow-up of 34months (range,  0.4-170), progression or recurrence was recorded in 241 (73.9%) and death in 179  (54.9%). In multivariate analysis, predictors of reduced planned RDI were: treatment off research protocols (odds ratio [OR]=4.3; P<0.001) and BSA >2m(2) (OR=6.14; P<0.001); predictors of reduced delivered RDI were: BMI over 30kg/m(2)  (OR=2.35; P=0.008) and use of carboplatin (OR=2.71; P=0.008). In multivariate analysis, the following factors were independently associated with OS: delivered  RDI <85% (hazard ratio [HR]=1.71; P=0.003) and elevated CA-125 at cycle 1 (HR=2.29; P=0.017). CONCLUSION: In this retrospective analysis, reduced chemotherapy RDI for ovarian cancer was associated with lower OS, but not PFS, despite adjustment for established prognostic factors.

 

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[359]

TÍTULO / TITLE:  - Triptolide induces S phase arrest via the inhibition of cyclin E and CDC25A and triggers apoptosis via caspase- and mitochondrial-dependent signaling pathways in A375.S2 human melanoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar;29(3):1053-60. doi: 10.3892/or.2013.2230. Epub 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2230

AUTORES / AUTHORS:  - Hung FM; Chen YL; Huang AC; Hsiao YP; Yang JS; Chung MT; Chueh FS; Lu HF; Chung JG

INSTITUCIÓN / INSTITUTION:  - Department of Surgical Intensive Care Unit, Far Eastern Memorial Etaospital, Taipei, Taiwan, R.O.C.

RESUMEN / SUMMARY:  - Triptolide (TPL), a diterpene triepoxide compound, extracted from Tripterygium wilfordii Hook F. [a traditional Chinese medicinal herb (TCM)], has demonstrated  great chemotherapeutic potential for the treatment of tumors. However, the anticancer mechanisms of action of TPL in human skin cancer remain to be further  investigated. In this study, we used A375.S2 human melanoma skin cancer cells as  a model to investigate the effect of TPL on cell death. A375.S2 cells were treated with various concentrations of TPL for different periods of time and investigated the effects on cell cycle distribution and apoptosis were investigated. The data showed that TPL induced cell morphological changes, decreased the percentage of viable cells, and induced S phase arrest and apoptosis in A375.S2 cells in a concentration- and time-dependent manner. Furthermore, we used flow cytometry analysis and the data showed that TPL promoted reactive oxygen species, NO and Ca2+ production, decreased the mitochondrial membrane potential (DeltaPsim) and increased the activity of caspase-3, -8 and -9 in the A375.S2 cells. Western blot analysis showed that TPL  promoted the expression of p21 and p27 but inhibited that of cyclin A and CDC25A, leading to S phase arrest. Furthermore, the data also showed that TPL promoted the expression of Fas and FasL and increased the activity of caspase-3, -8 and -9, cytochrome c, Bax, apoptosis-inducing factor (AIF) and endonuclease G (Endo G); however, the expression of Bax was decreased, leading to apoptosis. Based on  these observations, TPL induces apoptosis in A375.S2 cells through Fas-, caspase- and mitochondrial-mediated pathways.

 

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[360]

TÍTULO / TITLE:  - Lipoxygenase inhibitor MK886 potentiates TRAIL-induced apoptosis through CHOP- and p38 MAPK-mediated up-regulation of death receptor 5 in malignant glioma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2012 Dec 19. pii: S0006-291X(12)02395-9. doi: 10.1016/j.bbrc.2012.11.134.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.11.134

AUTORES / AUTHORS:  - Woo JS; Kim SM; Jeong CH; Ryu CH; Jeun SS

INSTITUCIÓN / INSTITUTION:  - Department of Biomedical Science, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Republic of Korea.

RESUMEN / SUMMARY:  - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers specific apoptosis in tumor cells and is one of the most promising candidates for cancer gene therapy. However, resistance to TRAIL is one of the main impediments to use  of TRAIL in cancer treatment. We showed previously that the lipoxygenase inhibitor MK886 in combination with TRAIL exhibits enhanced antitumor activities  compared with each agent alone in human glioma cells. In this study, we elucidated the molecular mechanisms responsible for MK886-mediated sensitization  to TRAIL-induced apoptosis. We found that MK886 sensitized glioma cells to TRAIL-induced apoptosis by upregulating the death receptor 5 (DR5) and that specific knockdown of DR5 attenuated cell death. The mechanisms underlying this sensitization involved activation of the MK886-induced p38 mitogen-activated protein kinase (MAPK) pathway and subsequent DR5 overexpression. However, treatment with a specific inhibitor or gene silencing of p38 MAPK abolished both  the DR5 induction and the increase in apoptosis caused by TRAIL. Taken together,  our findings indicate that the increased expression of DR5 in a p38 MAPK-dependent manner plays an important role in the sensitization of MK886 to TRAIL-induced apoptosis.

 

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[361]

TÍTULO / TITLE:  - Anti-apoptotic proteins on guard of melanoma cell survival.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2013 Jan 20. pii: S0304-3835(13)00035-9. doi: 10.1016/j.canlet.2013.01.010.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2013.01.010

AUTORES / AUTHORS:  - Hartman ML; Czyz M

INSTITUCIÓN / INSTITUTION:  - Department of Molecular Biology of Cancer, Medical University of Lodz, Poland.

RESUMEN / SUMMARY:  - Apoptosis plays a pivotal role in sustaining proper tissue development and homeostasis. Evading apoptosis by cancer cells is a part of their adaption to microenvironment and therapies. Cellular integrity is predominantly maintained by pro-survival members of Bcl-2 family and IAPs. Melanoma cells are characterized by a labile and stage-dependent phenotype. Pro-survival molecules can protect melanoma cells from apoptosis and mediate other processes, thus enhancing aggressive phenotype. The essential role of Bcl-2, Mcl-1, Bcl-X(L), livin, survivin and XIAP was implicated for melanoma, often in a tumor stage-dependent fashion. In this review, the current knowledge of pro-survival machinery in melanoma is discussed.

 

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[362]

TÍTULO / TITLE:  - TAP expression level in tumor cells defines the nature and processing of MHC class I peptides for recognition by tumor-specific cytotoxic T lymphocytes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann N Y Acad Sci. 2013 Jan 9. doi: 10.1111/j.1749-6632.2012.06777.x.

            ●● Enlace al texto completo (gratuito o de pago) 1111/j.1749-6632.2012.06777.x

AUTORES / AUTHORS:  - El Hage F; Durgeau A; Mami-Chouaib F

INSTITUCIÓN / INSTITUTION:  - Chimie et Sciences de la Vie et de la Terre, Universite Saint-Esprit de Kaslik, Jounieh, Lebanon. Integrated Research Cancer Institute in Villejuif, Institut de  Cancerologie Gustave Roussy, Villejuif, France.

RESUMEN / SUMMARY:  - We identified that the antigen preprocalcitonin (ppCT) is recognized on a human lung carcinoma by a cytotoxic T lymphocyte clone derived from autologous tumor-infiltrating lymphocytes. The antigenic peptide ppCT(16-25) is encoded by the gene calcitonin-related polypeptide alpha (CALCA), which codes for CT and is  overexpressed in several lung carcinomas compared with normal tissues. The ppCT peptide is derived from the C-terminal region of the signal peptide and is processed independently of proteasomes and the transporter associated with antigen processing (TAP)1/TAP2 heterodimeric complexes. Instead, processing occurs within the endoplasmic reticulum by a novel mechanism involving signal pepsidase (SP) and signal peptide peptidase (SPP). Although lung cancer cells bearing the ppCT(16-25) epitope displayed low levels of TAP, restoration of TAP expression by interferon (IFN)-gamma treatment or by TAP1/TAP2 gene transfer inhibited ppCT antigen presentation. Thus, the ppCT(16-25) human tumor epitope requires low TAP expression for efficient presentation. These results indicate that emerging SP-generated peptides represent alternative T cell targets that permit cytotoxic T lymphocytes to destroy TAP-impaired tumors, a process that helps to overcome tumor escape from CD8(+) T cell immunity. Additionally, our data suggest that ppCT is a promising candidate for cancer immunotherapy.

 

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[363]

TÍTULO / TITLE:  - Anticancer effects of O-desmethylangolensin are mediated through cell cycle arrest at the G2/M phase and mitochondrial-dependent apoptosis in Hep3B human hepatocellular carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Med. 2013 Mar;31(3):726-30. doi: 10.3892/ijmm.2013.1230. Epub 2013 Jan  8.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijmm.2013.1230

AUTORES / AUTHORS:  - Choi EJ; Lee JI; Kim GH

INSTITUCIÓN / INSTITUTION:  - Plant Resources Research Institute, Duksung Women’s University, Tobong-ku, Seoul  132-714, Republic of Korea.

RESUMEN / SUMMARY:  - In the present study, in order to investigate the anticancer effects of O-desmethylangolensin (O-DMA) on human hepatocellular carcinoma Hep3B cells, we first examined the antiproliferative effect of O-DMA. When Hep3B cells were treated with O-DMA at various concentrations (5-200 microM) for 24, 48 or 72 h, cell proliferation decreased significantly in a dose- and time-dependent manner.  Moreover, O-DMA exposure at the IC50 concentration for 72 h arrested cells at the G2/M phase, which was accompanied by a reduction in CDK1, and an increase in cyclin A and B. Under the same conditions, O-DMA significantly increased the number of sub-G1 phase cells. Additionally, an Annexin V assay revealed that exposure to O-DMA affected the rate of cell apoptosis. O-DMA caused the downregulation of Bcl-2 and upregulation of Bax, which led to cytochrome c release from the mitochondria and activation of caspase-3. Taken together, these  data suggest that O-DMA exhibits anticancer activity by arresting the cell cycle  at G2/M phase and causing mitochondrial-dependent apoptosis in Hep3B cells.

 

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[364]

TÍTULO / TITLE:  - A phase II study of biweekly paclitaxel and cisplatin chemotherapy for recurrent  or metastatic esophageal squamous cell carcinoma: ERCC1 expression predicts response to chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):343. doi: 10.1007/s12032-012-0343-4. Epub 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0343-4

AUTORES / AUTHORS:  - Huang J; Zhou Y; Zhang H; Qu T; Mao Y; Zhu H; Quan L; Xing P; Wang J; He J; Xu N; Sun Y

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100021, China, huangjingwg@163.com.

RESUMEN / SUMMARY:  - Recurrent or metastatic esophageal cancer has poor prognosis. This study was to assess the efficacy and safety of biweekly paclitaxel and cisplatin combination for patients with recurrent or metastatic esophageal squamous cell carcinoma. The excision repair cross-complementation group 1 (ERCC1) expression to predict response is also assessed. Forty-six eligible patients were enrolled. Paclitaxel  was given at 150 mg/m(2) over 3 h on day 1, and cisplatin was given at 50 mg/m(2) on day 2, every 2 weeks as one cycle. ERCC1 protein expression was assessed by immunohistochemistry staining. The overall response rate was 56.5 % (26/46, 95 %  CI 42.2-70.8 %). Progression-free survival was 5.6 months (95 % CI, 2.8-8.4 months), and the median actuarial survival time was 17.0 months (95 % CI, 12.3-21.7 months). There was a significant difference in median actuarial survival between the patients with a response compared to the non-responders (22.8 months vs. 7.4 months, P < 0.0001). Overall survival at 1 year was 65.0 %,  and at 2 years was 34.0 %, respectively. The most frequent toxicity for all patients was neutropenia (37.0 and 23.9 % for grades 3 and 4, respectively). Patients with ERCC1 negative tumors had a higher treatment response than the ERCC1 positive group (radiological response rates; 92.3 % vs.50 %, P = 0.013). Biweekly chemotherapy with paclitaxel and cisplatin was found to be active and generally well tolerated. Our study indicates that the expression of ERCC1 evaluated by immunohistochemistry is a promising predictive marker for response in patients with metastatic ESCC receiving cisplatin-paclitaxel regimen.

 

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[365]

TÍTULO / TITLE:  - Mutants of lymphotoxin-alpha with augmented cytotoxic activity via TNFR1 for use  in cancer therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cytokine. 2012 Dec 11. pii: S1043-4666(12)00775-2. doi: 10.1016/j.cyto.2012.11.005.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.cyto.2012.11.005

AUTORES / AUTHORS:  - Morishige T; Yoshioka Y; Narimatsu S; Ikemizu S; Tsunoda SI; Tsutsumi Y; Mukai Y; Okada N; Nakagawa S

INSTITUCIÓN / INSTITUTION:  - Laboratory of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.

RESUMEN / SUMMARY:  - The cytokine lymphotoxin-alpha (LTalpha) is a promising candidate for use in cancer therapy. However, the instability of LTalphain vivo and the insufficient levels of tumor necrosis factor receptor 1 (TNFR1)-mediated bioactivity of LTalpha limit its therapeutic potential. Here, we created LTalpha mutants with increased TNFR1-mediated bioactivity by using a phage display technique. We constructed a phage library displaying lysine-deficient structural variants of LTalpha with randomized amino acid residues. After affinity panning, we screened  three clones of lysine-deficient LTalpha mutant, and identified a LTalpha mutant  with TNFR1-mediated bioactivity that was 32times that of the wild-type LTalpha (wtLTalpha). When compared with wtLTalpha, the selected clone showed augmented affinity to TNFR1 due to slow dissociation rather than rapid association. In contrast, the mutant showed only 4times the TNFR2-mediated activity of wtLTalpha. In addition, the LTalpha mutant strongly and rapidly activated caspases that induce TNFR1-mediated cell death, whereas the mutant and wtLTalpha activated nuclear factor-kappa B to a similar extent. Our data suggest that the kinetics of LTalpha binding to TNFR1 play an important role in signal transduction patterns,  and a TNFR1-selective LTalpha mutant with augmented bioactivity would be a superior candidate for cancer therapy.

 

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[366]

TÍTULO / TITLE:  - TWIST interacts with beta-catenin signaling on osteosarcoma cell survival against cisplatin.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Carcinog. 2012 Dec 31. doi: 10.1002/mc.21991.

            ●● Enlace al texto completo (gratuito o de pago) 1002/mc.21991

AUTORES / AUTHORS:  - Wu J; Liao Q; He H; Zhong D; Yin K

INSTITUCIÓN / INSTITUTION:  - Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Spine, Xiangya Hospital, Central South University, Changsha, Hunan, China.

RESUMEN / SUMMARY:  - Both TWIST and Wnt/beta-catenin signaling reportedly play important roles in osteosarcoma development. In the present study, we explored the regulatory effect of TWIST on beta-catenin in osteosarcoma cells and assessed how the functional interaction between TWIST and beta-catenin would impact osteosarcoma cell survival against chemotherapy agent cisplatin. Overexpression and knockdown of TWIST were respectively performed in Saos-2 and MG-63 osteosarcoma cells. Overexpression of TWIST in Saos-2 cells significantly decreased the soluble beta-catenin level, phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) at serine 9, the mRNA level of beta-catenin signaling target genes, and cell survival against cisplatin, which was strengthened by knocking down beta-catenin. Knockdown of TWIST in MG-63 cells significantly increased the soluble beta-catenin level, phosphorylation of GSK-3beta at serine 9, the mRNA level of beta-catenin signaling target genes, and cell survival against cisplatin, which was reversed by knocking down beta-catenin or phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. In conclusion, we demonstrate that TWIST decreases osteosarcoma cell survival against cisplatin by decreasing the soluble beta-catenin level through a PI3K-dependent manner. This study provides the first evidence of a functional link between TWIST and beta-catenin signaling in osteosarcoma cells, which adds fresh insights into the molecular mechanism of osteosarcoma development. © 2012 Wiley Periodicals, Inc.

 

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[367]

TÍTULO / TITLE:  - Zebularine-induced apoptosis in Calu-6 lung cancer cells is influenced by ROS and GSH level changes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Tumour Biol. 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s13277-013-0656-8

AUTORES / AUTHORS:  - You BR; Park WH

INSTITUCIÓN / INSTITUTION:  - Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, Jeonju, 561-180, Republic of Korea.

RESUMEN / SUMMARY:  - Zebularine (Zeb) is a DNA methyltransferase (DNMT) inhibitor that has various biological properties including anti-cancer effect. In the present study, we evaluated the effects of Zeb on the growth and death of Calu-6 lung cancer cells  in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. Zeb inhibited the growth of Calu-6 cells with an IC(50) of approximately 150 muM at 72 h in a dose-dependent manner. Zeb induced an S phase arrest of the cell cycle  and apoptosis in Calu-6 cells. Pan-caspase inhibitor (Z-VAD) and caspase-8 inhibitor (Z-IETD) significantly rescued some cells from Zeb-induced Calu-6 cell  death. In relation to ROS and GSH levels, O(2) (*-) level was significantly increased in Zeb-treated Calu-6 cells and caspase inhibitors reduced O(2) (*-) level in these cells. Zeb induced GSH depletion in HeLa cells, which was attenuated by caspase inhibitors. L-buthionine sulfoximine (BSO), a GSH synthesis inhibitor, intensified the apoptotic cell death, ROS level, and GSH depletion in  Zeb-treated Calu-6 cells. In addition, BSO increased Bax protein and decreased Bcl-2 protein in Zeb-treated Calu-6 cells. In conclusion, Zeb inhibited the growth of Calu-6 lung cancer cells via cell cycle arrest and caspase-dependent apoptosis and its cell death was influenced by ROS and GSH level changes.

 

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[368]

TÍTULO / TITLE:  - Efficacy and Safety of Tumor Necrosis Factor Inhibitors in Acute Generalized Pustular Psoriasis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Arch Dermatol. 2012 Dec 1;148(12):1423-1425.

            ●● Enlace al texto completo (gratuito o de pago) 1001/2013.jamadermatol.80

AUTORES / AUTHORS:  - Viguier M; Aubin F; Delaporte E; Pages C; Paul C; Beylot-Barry M; Goujon C; Rybojad M; Bachelez H

 

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[369]

TÍTULO / TITLE:  - The prevalence of immunohistochemically determined oestrogen receptor positivity  in primary breast cancer is dependent on the choice of antibody and method of heat-induced epitope retrieval - prognostic implications?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Acta Oncol. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 3109/0284186X.2012.762994

AUTORES / AUTHORS:  - Grabau DA; Bendahl PO; Ryden L; Stal O; Ferno M

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Skane University Hospital , Lund , Sweden.

RESUMEN / SUMMARY:  - Background. Oestrogen receptor (ER) status is important for the choice of systemic treatment of breast cancer patients. However, most data from randomised  trials on the effect of adjuvant endocrine therapy according to ER status are based on the cytosol methods. Comparisons with immunohistochemical methods have given similar results. The aim of the present study was to examine whether different ER antibodies and heat-induced epitope retrieval (HIER) methods influence the prevalence of ER-positivity in primary breast cancer. Material and  methods. This study is based on patients included in a clinical trial designed to compare the effect of two years of adjuvant tamoxifen versus no adjuvant systemic treatment in premenopausal women. From 1986 to 1991, 564 patients from two study  centres in Sweden were enrolled and randomised. Patients were randomised independently of ER status. In the present study, ER status was assessed on tissue microarrays with the three different ER antibody/HIER combinations: 1D5 in citrate pH 6 (n = 390), SP1 in Tris pH 9 (n = 390) and PharmDx in citrate pH 6 (n = 361). Results. At cut-offs of 1% and 10%, respectively, the prevalence of ER-positivity was higher with SP1 (75% and 72%) compared with 1D5 (68% and 66%) and PharmDx (66% and 62%). At these cut-offs, patients in the discordant groups (SP1-positive and 1D5-negative) seem to have a prognosis intermediate between those of the double-positive and double-negative groups. Comparison with the ER status determined by the cytosol-based methods in the discordant group also showed an intermediate pattern. The repeatability was good for all antibodies and cut-offs, with overall agreement >/= 93%. Conclusion. The present study shows that the choice of antibody and HIER method influences the prevalence of ER-positivity. We suggest that this be taken into consideration when choosing a cut-off for clinical decision making.

 

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[370]

TÍTULO / TITLE:  - In silico analysis of molecular mechanisms of legume lectin-induced apoptosis in  cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Prolif. 2013 Feb;46(1):86-96. doi: 10.1111/cpr.12009.

            ●● Enlace al texto completo (gratuito o de pago) 1111/cpr.12009

AUTORES / AUTHORS:  - Shi Z; An N; Zhao S; Li X; Bao JK; Yue BS

INSTITUCIÓN / INSTITUTION:  - School of Life Sciences and Key Laboratory of Bio-resources and Eco-environment,  Ministry of Education, Sichuan University, Chengdu, 610064, China; School of Life Sciences, Guizhou Normal University, Guiyang, 550001, China.

RESUMEN / SUMMARY:  - OBJECTIVES: The legume lectin family, one of the most extensively studied plant lectin families, has received increasing attention for the remarkable anti-tumor  activities of its members for binding specific cancer cell surface glycoconjugates. MicroRNAs, a class of small, non-coding RNAs, control translation and stability of mRNAs at post-transcriptional and translational levels. To date, accumulating evidence has revealed that microRNAs are involved in progression of a number of human diseases, especially cancers. However, the molecular manners of microRNA-modulated apoptosis in legume lectin-treated cancer cells are still under investigation. MATERIALS AND METHODS: We performed in silico analyses to study the interactions between three typical legume lectins (ConA, SFL and SAL) and some specific sugar-containing receptors (for example, EGFR, TNFR1, HSP70 and HSP90). Additionally, we predicted some relevant microRNAs which could significantly regulate these aforementioned targetreceptors and thus  inhibiting down-stream cancer-related signaling pathways. RESULTS: The results showed that these three legume lectins could competitively bind sugar-containing  receptors such as EGFR, TNFR1, HSP70 and HSP90 in two ways, via anti-apoptotic or survival pathways. On the one hand, the legume lectins could induce cancer cell death through triggering receptor-mediated signaling pathways, which resulted from indirect binding between legume lectins and mannoses resided in receptors. On the other hand, direct binding between legume lectins and receptors could lead to steric hindrance, which would disturb efficient interactions between them, and thus, the legume lectins would induce cancer cell death by triggering receptor-mediated signaling pathways. In addition, we identified several relevant microRNAs that regulated these targeted receptors, thereby ultimately causing cancer cell apoptosis. CONCLUSIONS: These findings provide new perspectives for exploring microRNA-modulated cell death in legume lectin-treated cancer cells, which could be utilized in combination therapy for future cancer drug development.

 

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[371]

TÍTULO / TITLE:  - Resveratrol induces MMP-9 and cell migration via the p38 kinase and PI-3K pathways in HT1080 human fibrosarcoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):826-34. doi: 10.3892/or.2012.2151. Epub 2012 Nov 27.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2151

AUTORES / AUTHORS:  - Gweon EJ; Kim SJ

INSTITUCIÓN / INSTITUTION:  - Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Chungnam 314-701, Republic of Korea.

RESUMEN / SUMMARY:  - Trans-3,4’,5-trihydroxystilbene (resveratrol) is a grape polyphenol present in various plants, food products, red wine and grapes. Resveratrol has anti-inflammatory, anticarcinogenic, anti-oxidant and anti-aging properties. Matrix metalloproteinases (MMPs) are key enzymes involved in the degradation of the extracellular matrix, and their expression may be regulated in cancer metastasis. In the present study, we aimed to evaluate the effect of resveratrol  on MMPs and cell migration, and to understand the mechanism of action in HT1080 human fibrosarcoma cells. We found that resveratrol inhibited HT1080 cell viability at various concentrations as detected by the MTT assay and FACS analysis. However, resveratrol dramatically increased the activation and expression of MMP-9 in a dose- and time-dependent manner, as determined by gelatin zymography assay and western blot analysis. We also discovered that resveratrol enhanced the migratory ability of HT1080 cells, as determined by the  wound healing assay, and decreased the phosphorylation of p38 kinase. Moreover, the Akt kinase was inhibited by resveratrol in the HT1080 cells. The inhibition of p38 and Akt kinases with SB203580 and LY294002 further increased resveratrol-induced MMP-9 as well as cell migration in the HT1080 cells. Our results suggest that resveratrol regulates MMP-9 and migratory abilities through  the p38 kinase and PI-3K pathways in HT1080 human fibrosarcoma cells.

 

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[372]

TÍTULO / TITLE:  - PIVL, a new serine protease inhibitor from Macrovipera lebetina transmediterranea venom, impairs motility of human glioblastoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Matrix Biol. 2012 Dec 20. pii: S0945-053X(12)00152-7. doi: 10.1016/j.matbio.2012.11.015.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.matbio.2012.11.015

AUTORES / AUTHORS:  - Morjen M; Kallech-Ziri O; Bazaa A; Othman H; Mabrouk K; Zouari-Kessentini R; Sanz L; Calvete JJ; Srairi-Abid N; El Ayeb M; Luis J; Marrakchi N

INSTITUCIÓN / INSTITUTION:  - Laboratoire des Venins et Biomolecules Therapeutiques, Institut Pasteur de Tunis, Tunisia. Electronic address: maram.morjen@yahoo.fr.

RESUMEN / SUMMARY:  - A novel Kunitz-type serine proteinase inhibitor, termed PIVL, was purified to homogeneity from the venom of the Tunisian snake Macrovipera lebetina transmediterranea. It is a monomeric polypeptide chain cross-linked by three disulfide linkages with an isotope-averaged molecular mass of 7691.7Da. The 67-residue full-length PIVL sequence was deduced from a venom gland cDNA clone. Structurally, PIVL is built by a single Kunitz/BPTI-like domain. Functionally, it is able to specifically inhibit trypsin activity. Interestingly, PIVL exhibits an anti-tumor effect and displays integrin inhibitory activity without being cytotoxic. Here we show that PIVL is able to dose-dependently inhibit the adhesion, migration and invasion of human glioblastoma U87 cells. Our results also show that PIVL impairs the function of alphavbeta3 and to a lesser extent, the activity of alphavbeta6, alphavbeta5, alpha1beta1 and alpha5beta1 integrins.  Interestingly, we demonstrate that the (41)RGN(43) motif of PIVL is likely responsible for its anti-cancer effect. By using time lapse videomicroscopy, we found that PIVL significantly reduced U87 cells motility and affected cell directionality persistence by 68%. These findings reveal novel pharmacological effects for a Kunitz-type serine proteinase inhibitor.

 

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[373]

TÍTULO / TITLE:  - Initial Response to Chemotherapy, Not Delay in Diagnosis, Predicts Overall Survival in Inflammatory Breast Cancer Cases.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Clin Oncol. 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1097/COC.0b013e318271b34b

AUTORES / AUTHORS:  - Hoffman HJ; Khan A; Ajmera KM; Zolfaghari L; Schenfeld JR; Levine PH

INSTITUCIÓN / INSTITUTION:  - Department of Epidemiology and Biostatistics, The George Washington University School of Public Health and Health Services, Washington, DC.

RESUMEN / SUMMARY:  - OBJECTIVES:: To determine whether chemotherapy response and diagnostic delay affect overall survival (OS) of classic inflammatory breast cancer (IBC) cases receiving chemotherapy as initial treatment and to determine whether OS differs between classic and “atypical” IBC cases. METHODS:: This is a prospective cohort  study of 155 patients enrolled in the IBC Registry. “Classic” IBC cases met AJCC  or SEER case definitions. “Atypical” IBC cases exhibited classic features but involved <1/2 breast without documented dermal lymphatic invasion. Variables included OS (years from initial chemotherapy treatment until death or last contact), chemotherapy response (complete, partial, or none), diagnostic delay (days from first medical contact for signs/symptoms of abnormal breast to definitive pathologic IBC diagnosis), age at diagnosis (y), and triple-negative status (yes or no). OS curves stratified by individual predictors were estimated  and compared using Kaplan-Meier methods and log-rank tests. Associations between  OS and predictors were examined collectively using Cox proportional hazards regression. RESULTS:: Classic IBC cases with complete, partial, or no response had respective median [95% confidence interval (CI)] OS times of 10.30 (6.78, +), 6.27 (4.42, +), and 2.86 (1.11, 11.42) years (P=0.0072). Chemotherapy response was significantly associated with OS after controlling for covariates (P=0.003).  Women not responding to chemotherapy had a significantly higher hazard of death compared with women with complete [hazard ratio (HR)=5.76; 95% CI, 2.09-15.84] or partial (HR=3.40; 95% CI, 1.27-9.10) response. Diagnostic delay was not significantly associated with OS (HR=1.003; 95% CI, 0.999-1.007). OS did not differ significantly between classic and “atypical” IBC cases (P=0.60). CONCLUSIONS:: Response to standard IBC chemotherapy is a dominant prognostic factor in determining patient outcomes. In our study, with limited statistical power, delay in diagnosis defined as >60 days from the time of first physician contact did not seem to affect patient outcomes. Data support similarities between classic and “atypical” IBC.

 

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[374]

TÍTULO / TITLE:  - Comparison Between 18F-FDG PET Image-Derived Indices for Early Prediction of Response to Neoadjuvant Chemotherapy in Breast Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Nucl Med. 2013 Jan 17.

            ●● Enlace al texto completo (gratuito o de pago) 2967/jnumed.112.108837

AUTORES / AUTHORS:  - Hatt M; Groheux D; Martineau A; Espie M; Hindie E; Giacchetti S; de Roquancourt A; Visvikis D; Cheze-Le Rest C

INSTITUCIÓN / INSTITUTION:  - INSERM, UMR 1101 LaTIM, Brest, France.

RESUMEN / SUMMARY:  - The goal of this study was to determine the best predictive factor among image-derived parameters extracted from sequential (18)F-FDG PET scans for early  tumor response prediction after 2 cycles of neoadjuvant chemotherapy in breast cancer. METHODS: 51 breast cancer patients were included. Responder and nonresponder status was determined by histopathologic examination according to the tumor and node Sataloff scale. PET indices (maximum and mean standardized uptake value [SUV], metabolically active tumor volume, and total lesion glycolysis [TLG]), at baseline and their variation (Delta) after 2 cycles of neoadjuvant chemotherapy were extracted from the PET images. Their predictive value was investigated using Mann-Whitney U tests and receiver-operating-characteristic analysis. Subgroup analysis was also performed  by considering estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, triple-negative, and HER2-positive tumors separately. The impact of partial-volume correction was also investigated using an iterative  deconvolution algorithm. RESULTS: There were 24 pathologic nonresponders and 27 responders. None of the baseline PET parameters was correlated with response. After 2 neoadjuvant chemotherapy cycles, the reduction of each parameter was significantly associated with response, the best prediction of response being obtained with DeltaTLG (96% sensitivity, 92% specificity, and 94% accuracy), which had a significantly higher area under the curve (0.91 vs. 0.82, P = 0.01) than did DeltaSUV(max) (63% sensitivity, 92% specificity, and 77% accuracy). Subgroup analysis confirmed a significantly higher accuracy for DeltaTLG than DeltaSUV for ER-positive/HER-negative but not for triple-negative and HER2-positive tumors. Partial-volume correction had no impact on the predictive value of any of the PET image-derived parameters despite significant changes in their absolute values. CONCLUSION: Our results suggest that the reduction after 2 neoadjuvant chemotherapy cycles of the metabolically active volume of primary tumor measurements such as DeltaTLG predicts histopathologic tumor response with  higher accuracy than does DeltaSUV measurements, especially for ER-positive/HER2-negative breast cancer. These results should be confirmed in a larger group of patients as they may potentially increase the clinical value and  efficiency of (18)F-FDG PET for early prediction of response to neoadjuvant chemotherapy.

 

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[375]

TÍTULO / TITLE:  - Delivery of ursolic acid (UA) in polymeric nanoparticles effectively promotes the apoptosis of gastric cancer cells through enhanced inhibition of cyclooxygenase 2 (COX-2).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Pharm. 2013 Jan 30;441(1-2):261-8. doi: 10.1016/j.ijpharm.2012.11.034. Epub 2012 Nov 27.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ijpharm.2012.11.034

AUTORES / AUTHORS:  - Zhang H; Li X; Ding J; Xu H; Dai X; Hou Z; Zhang K; Sun K; Sun W

INSTITUCIÓN / INSTITUTION:  - Department of Geriartric Gerontology, The First Affiliated Hospital to Nanjing Medical University, Nanjing 210029, PR China.

RESUMEN / SUMMARY:  - It has been demonstrated that ursolic acid (UA) could effectively induces apoptosis of cancer cells by inhibiting the expression of cyclooxygenase 2 (COX-2), which constitutively expresses in gastric cancer. However, the hydrophobicity of UA increases the difficulty in its potential clinical application, which raises the possibility for its application as a novel model drug in nanoparticle-based delivery system. UA-loaded nanoparticles (UA-NPs) were prepared by a nano-precipitation method using amphilic methoxy poly(ethylene glycol)-polycaprolactone (mPEG-PCL) block copolymers as drug carriers. UA was effectively transported into SGC7901 cells by nanoparticles and localized around  the nuclei in the cytoplasms. The in vitro cytotoxicity and apoptosis test indicated that UA-NPs significantly elicited more cell death at almost equivalent dose and corresponding incubation time. Moreover, UA-NPs led to more cell apoptosis through stronger inhibition of COX-2 and activation of caspase 3. The most powerful evidence from this report is that the significant differences between the cytotoxicity of free UA and UA-NPs are closely related to the expression levels of COX-2 and caspase-3, which demonstrates the superiority of UA-NPs over free UA through penetrating cell membrane. Therefore, the study offer an effective way to improve the anticancer efficiency of UA through nano-drug delivery system.

 

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[376]

TÍTULO / TITLE:  - Effects of propranolol on the proliferation and apoptosis of hemangioma-derived endothelial cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Pediatr Surg. 2012 Dec;47(12):2216-23. doi: 10.1016/j.jpedsurg.2012.09.008.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jpedsurg.2012.09.008

AUTORES / AUTHORS:  - Ji Y; Li K; Xiao X; Zheng S; Xu T; Chen S

INSTITUCIÓN / INSTITUTION:  - Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai, 201102, China.

RESUMEN / SUMMARY:  - BACKGROUND/PURPOSE: Propranolol, a non-selective beta-blocker, has recently been  introduced as a novel treatment modality for proliferating hemangiomas. However,  the mechanism of action of this therapy is unknown. In this study, we investigated propranolol in the etiology of hemangiomas that are associated with  the proliferation and apoptosis of hemangioma-derived endothelial cells (HemECs). METHODS: HemECs were isolated from freshly resected hemangioma specimens. We studied propranolol-treated HemECs in vitro. We measured the effect of propranolol on HemEC viability using the Cell Counting Kit-8 (CCK-8) assay and proliferation and apoptosis using a BrdU labeling assay, annexin-V-fluorescein isothiocyanate/propidium iodide flow cytometry, and Hoechst 33342 fluorescent staining. We explored the potential mechanisms of propranolol-induced HemEC dysfunction using western blot analysis, a caspase assay kit, and real-time quantitative PCR. RESULTS: We observed that propranolol had inhibitory effects on the viability and proliferation of HemECs. HemEC apoptosis significantly increased with 100 muM propranolol treatment. Vascular endothelial growth factor  (VEGF) expression was down-regulated by propranolol in a dose-dependent manner. We also demonstrated activation of the caspase cascade, including caspase-9 and caspase-3 of the intrinsic pathway, and an increased p53 gene expression and Bax/Bcl-xL ratio in HemECs treated with 100 muM propranolol. CONCLUSIONS: We obtained novel data that suggests propranolol could inhibit HemEC proliferation and induce apoptosis. The effects were likely mediated through the suppression of VEGF expression, activation of caspase-9 and caspase-3, up-regulation of the pro-apoptotic genes p53 and Bax and down-regulation of the anti-apoptotic gene Bcl-xL.

 

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[377]

TÍTULO / TITLE:  - UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Gastroenterol. 2012 Dec 7;18(45):6635-44. doi: 10.3748/wjg.v18.i45.6635.

            ●● Enlace al texto completo (gratuito o de pago) 3748/wjg.v18.i45.6635

AUTORES / AUTHORS:  - Wang Y; Shen L; Xu N; Wang JW; Jiao SC; Liu ZY; Xu JM

INSTITUCIÓN / INSTITUTION:  - Department of GI Oncology, Cancer Center, 307 Hospital of PLA, Academy of Military Medical Science, Beijing 100071, China.

RESUMEN / SUMMARY:  - AIM: To evaluate effects of UDP-glucuronosyltransferase1A1 (UGT1A1) and thymidylate synthetase (TS) gene polymorphisms on irinotecan in metastatic colorectal cancer (mCRC). METHODS: Two irinotecan- and fluorouracil-based regimens, FOLFIRI and IFL, were selected as second-line therapy for 138 Chinese mCRC patients. Genomic DNA was extracted from peripheral blood samples before treatment. UGT1A1 and TS gene polymorphisms were determined by direct sequencing  and restriction fragment length polymorphism, respectively. Gene polymorphisms of UGT1A1*28, UGT1A1*6 and promoter enhancer region of TS were analyzed. The relationship between genetic polymorphisms and clinical outcome, that is, response, toxicity and survival were assessed. Pharmacokinetic analyses were performed in a subgroup patients based on different UGT1A1 genotypes. Plasma concentration of irinotecan and its active metabolite SN-38 and inactive metabolite SN-38G were determined by high performance liquid chromatography. Differences in irinotecan and its metabolites between UGT1A1 gene variants were compared. RESULTS: One hundred and eight patients received the FOLFIRI regimen, 29 the IFL regimen, and one irinotecan monotherapy. One hundred and thirty patients were eligible for toxicity and 111 for efficacy evaluation. One hundred  and thirty-six patients were tested for UGT1A1*28 and *6 genotypes and 125 for promoter enhancer region of TS. Patients showed a higher frequency of wild-type UGT1A1*28 (TA6/6) compared with a Caucasian population (69.9% vs 45.2%). No significant difference was found between response rates and UGT1A1 genotype, although wild-type showed lower response rates compared with other variants (17.9% vs 24.2% for UGT1A1*28, 15.7% vs 26.8% for UGT1A1*6). When TS was considered, the subgroup with homozygous UGT1A1*28 (TA7/7) and non-3RG genotypes  showed the highest response rate (33.3%), while wild-type UGT1A1*28 (TA6/6) with  non-3RG only had a 13.6% response rate, but no significant difference was found.  Logistic regression showed treatment duration was closely linked to clinical response. In toxicity comparison, UGT1A1*28 TA6/6 was associated with lower incidence of grade 2-4 diarrhea (27.8% vs 100%), and significantly reduced the risk of grade 4 neutropenia compared with TA7/7 (7.8% vs 37.5%). Wild-type UGT1A1*6 (G/G) tended to have a lower incidence of grade ¾ diarrhea vs homozygous mutant (A/A) genotype (13.0% vs 40.0%). Taking UGT1A1 and TS genotypes together, lower incidence of grade 2-4 diarrhea was found in patients with non-3RG TS genotypes, when TA6/6 was compared with TA7/7 (35.3% vs 100.0%). No significant association with time to progression (TTP) and overall survival (OS)  was observed with either UGT1A1 or TS gene polymorphisms, although slightly longer TTP and OS were found with UGT1A1*28 (TA6/6). Irinotecan PK was investigated in 34 patients, which showed high area under concentration curve (AUC) of irinotecan and SN-38, but low AUC ratio (SN-38G / SN-38) in those patients with UGT1A1*28 TA7/7. CONCLUSION: A distinct distribution pattern of UGT1A1 genotypes in Chinese patients might contribute to relatively low toxicity  associated with irinotecan and 5-fluorouracil in mCRC patients.

 

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[378]

TÍTULO / TITLE:  - c-Jun N-terminal kinase is required for thermotherapy-induced apoptosis in human  gastric cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Gastroenterol. 2012 Dec 28;18(48):7348-56. doi: 10.3748/wjg.v18.i48.7348.

            ●● Enlace al texto completo (gratuito o de pago) 3748/wjg.v18.i48.7348

AUTORES / AUTHORS:  - Xiao F; Liu B; Zhu QX

INSTITUCIÓN / INSTITUTION:  - Feng Xiao, Bin Liu, Qing-Xian Zhu, Department of Pathology, Medical School, Nanchang University, Nanchang 330006, Jiangxi Province, China.

RESUMEN / SUMMARY:  - AIM: To investigate the role of c-Jun N-terminal kinase (JNK) in thermotherapy-induced apoptosis in human gastric cancer SGC-7901 cells. METHODS:  Human gastric cancer SGC-7901 cells were cultured in vitro. Following thermotherapy at 43 degrees C for 0, 0.5, 1, 2 or 3 h, the cells were cultured for a further 24 h with or without the JNK specific inhibitor, SP600125 for 2 h.  Apoptosis was evaluated by immunohistochemistry [terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)] and flow cytometry (Annexin vs propidium iodide). Cell proliferation was determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. The production of p-JNK, Bcl-2, Bax and caspase-3 proteins was evaluated by Western blotting. The expression of JNK at mRNA level was determined by reverse transcription polymerase chain reaction. RESULTS: The proliferation of gastric carcinoma SGC-7901 cells was significantly inhibited following thermotherapy, and was 32.7%, 30.6%, 43.8% and 52.9% at 0.5, 1, 2 and 3 h post-thermotherapy, respectively. Flow cytometry analysis revealed an increased population of SGC-790l cells in G0/G1 phase, but a reduced population in S phase following thermotherapy for 1 or 2 h, compared to untreated cells (P < 0.05). The increased number of SGC-790l cells in G0/G1 phase was consistent with induced apoptosis (flow cytometry) following thermotherapy for 0.5, 1, 2 or 3 h, compared to the untreated group (46.5% +/- 0.23%, 39.9% +/- 0.53%, 56.6% +/- 0.35% and 50.4% +/-  0.29% vs 7.3% +/- 0.10%, P < 0.01), respectively. This was supported by the TUNEL assay (48.2% +/- 0.4%, 40.1% +/- 0.2%, 61.2% +/- 0.29% and 52.0% +/- 0.42% vs 12.2% +/- 0.22%, P < 0.01) respectively. More importantly, the expression of p-JNK protein and JNK mRNA levels were significantly higher at 0.5 h than at 0 h  post-treatment (P < 0.01), and peaked at 2 h. A similar pattern was detected for  Bax and caspase-3 proteins. Bcl-2 increased at 0.5 h, peaked at 1 h, and then decreased. Furthermore, the JNK specific inhibitor, SP600125, suppressed p-JNK, Bax and caspase-3 at the protein level in SGC790l cells following thermotherapy,  compared to mock-inhibitor treatment, which was in line with the decreased rate of apoptosis. The expression of Bcl-2 was consistent with thermotherapy alone. CONCLUSION: Thermotherapy induced apoptosis in gastric cancer cells by promoting  p-JNK at the mRNA and protein levels, and up-regulated the expression of Bax and  caspase-3 proteins. Bcl-2 may play a protective role during thermotherapy. Activation of JNK via the Bax-caspase-3 pathway may be important in thermotherapy-induced apoptosis in gastric cancer cells.

 

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[379]

TÍTULO / TITLE:  - Genetic Polymorphism of XRCC1 Correlated with Response to Oxaliplatin-based Chemotherapy in Advanced Colorectal Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Invest. 2013 Jan;31(1):24-8. doi: 10.3109/07357907.2012.716468.

            ●● Enlace al texto completo (gratuito o de pago) 3109/07357907.2012.716468

AUTORES / AUTHORS:  - Lv H; Li Q; Qiu W; Xiang J; Wei H; Liang H; Sui A; Liang J

INSTITUCIÓN / INSTITUTION:  - Cancer Center, The Affiliated Hospital of Qingdao University Medical College , Qingdao , P. R. China,1.

RESUMEN / SUMMARY:  - In this study, we investigated the association between genetic polymorphisms of XRCC1 Arg399Gln (G-->A) and response to oxaliplatin-based chemotherapy in advanced colorectal cancer. XRCC1 genotypes of totally 99 patients (37 stage III  and 62 stage IV) with advanced colorectal cancer treated with oxaliplatin-based chemotherapy were detected by the TaqMan-MGB probe allelic discrimination method, and clinical response of 62 patients in stage IV after 2 to 3 cycles of chemotherapy were evaluated. Also, time to progression (TTP) of all patients was  evaluated. The results showed that of the genotype frequencies in all patients, up to 52.53% were G/G genotype, 9.09% were A/A genotype, and 38.38% were G/A genotype. The response rate (CR + PR) of 62 patients in stage IV was 61.29% (19/31). Patients with G/G genotype showed enhanced response to chemotherapy compared with those with G/A + A/A (x(2) = 5.6, p = .029; Odds Ratio (OR) = 3.845, 95% Confidence Interval (CI) = 1.231 approximately 12.01, p = .018). Individuals with the G/G genotype had a TTP of 10.0 (8.88-11.12) months, and those with the G/A + A/A genotype had a TTP of 5.0 (4.26-5.74) months. The Log-Rank test was marginally significant (x(2) = 29.20, p < .01). The Cox proportional hazards model, adjusted for stage, performance status, and chemotherapy regimen showed that only XRCC1 G/G genotype increases the OR significantly (OR = 3.555; 95% CI, 2.119 approximately 5.963; p < .01). These results indicate that XRCC1 Arg399Gln polymorphism is associated with response to oxaliplantin-based chemotherapy and TTP in advanced colorectal cancer in Chinese  population. It is proposed that the XRCC1 Arg399Gln polymorphism should be routinely detected to screen patients who are more likely to benefit from oxaliplantin-based treatment.

 

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[380]

TÍTULO / TITLE:  - Effects of baicalein on apoptosis, cell cycle arrest, migration and invasion of osteosarcoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Food Chem Toxicol. 2012 Dec 22;53C:325-333. doi: 10.1016/j.fct.2012.12.019.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.fct.2012.12.019

AUTORES / AUTHORS:  - Zhang Y; Song L; Cai L; Wei R; Hu H; Jin W

INSTITUCIÓN / INSTITUTION:  - Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.

RESUMEN / SUMMARY:  - Baicalein is a bioactive flavonoid that is widely used in ancient China. However, its effects on the most common primary malignant bone tumor, osteosarcoma, remain unknown. In the present study, we investigated the effects of baicalein in osteosarcoma cells. Our results indicate baicalein might be an efficacious anti-osteosarcoma drug. We found that baicalein could inhibit cell proliferation  in a time- and dose-dependent manner. Additionally, we demonstrated that baicalein promotes osteosarcoma cell apoptosis, and our mechanistic studies suggest that this is mediated by caspase activation, especially caspase-3. We also showed that the down-regulation of Bcl-2 and concurrent increase in Bax and  Bim levels contribute to the apoptosis induced by baicalein. In addition, we observed that baicalein induces G1 cell cycle arrest by decreasing cyclin D1 and  cyclin-dependent kinase 4 (CDK4). Furthermore, our data verifies that baicalein can reduce osteosarcoma cell adhesion, migration and invasion in vitro, which indicates its potential to inhibit osteosarcoma metastasis. The decrease in expression of matrix metalloproteinases (MMP)-2 and MMP-9 may contribute to the effects of baicalein. Taken together, our results provide evidence that baicalein plays important roles in anti-osteosarcoma therapy, and thus may serve as a novel and efficient candidate agent for osteosarcoma treatment.

 

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[381]

TÍTULO / TITLE:  - HLA-G expression in acute lymphoblastic leukemia: a significant prognostic tumor  biomarker.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):460. doi: 10.1007/s12032-013-0460-8. Epub 2013 Jan 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-013-0460-8

AUTORES / AUTHORS:  - Alkhouly N; Shehata I; Ahmed MB; Shehata H; Hassan S; Ibrahim T

INSTITUCIÓN / INSTITUTION:  - Medical Biochemistry, Faculty of Medicine, Ain Shams University, Abbasia, Cairo,  Egypt.

RESUMEN / SUMMARY:  - Human leukocyte antigen G (HLA-G) is a non-classical major histocompatibility class Ib antigen with multiple immune regulatory functions including the induction of immune tolerance in malignancies. The goal of our study was to investigate the expression of membrane form of HLA-G in acute lymphoblastic leukemia (ALL) before and after therapy in a trial to evaluate its role as a tumor escape mechanism and prognosis. So we measured its expression by reverse transcription (RT)-PCR in peripheral blood mononuclear cells of 25 (ALL) patients and 15 healthy controls and correlated our findings with a variety of clinical and laboratory variables and two important cytokines, IL-10 and INF-gamma, and with natural killer (NK) cells. Serum levels of IL-10 and INF-gamma were measured by ELISA. NK cells were quantitated by flow cytometry. The best cutoff values for the investigated markers were determined by ROC curve. The current study showed that membrane-bound HLA-G expression levels and positivity rates above the cutoff value 0.37 were significantly higher in ALL patients at diagnosis compared to after therapy and both showed significant higher levels than in normal control group (P < 0.01). Moreover, IL-10 and INF-gamma serum levels were significantly elevated in ALL patients at time of diagnosis compared to healthy controls with a significant reduction in their levels in ALL patients after receiving chemotherapy. Membrane HLA-G expression showed a significant positive correlation with lactate dehydrogenase, peripheral and bone marrow blast cells and with IL-10 and INF-gamma. The positive correlation of membrane HLA-G expression with both IL-10 and INF-gamma serum levels supports the speculation that both cytokines may be involved in the control of HLA-G expression. HLA-G showed a negative correlation with NK cells confirming its importance in tumor escape through down-regulation of NK cells. In conclusion, HLA-G expression could be used as a prognostic tumor marker to monitor disease state and improvement in ALL.

 

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[382]

TÍTULO / TITLE:  - Hepatocyte nuclear factor 1beta is a novel prognostic marker independent of the milan criteria in transplantable hepatocellular carcinoma: A retrospective analysis based on tissue microarrays.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Liver Transpl. 2012 Dec 2. doi: 10.1002/lt.23584.

            ●● Enlace al texto completo (gratuito o de pago) 1002/lt.23584

AUTORES / AUTHORS:  - Shim JH; Lee HC; Han S; Kang HJ; Yu E; Lee SG

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

RESUMEN / SUMMARY:  - OBJECTIVES: We retrospectively investigated the prognostic value of hepatocyte nuclear factor-1 (HNF1) proteins in 159 liver transplant patients with hepatocellular carcinomas (HCC), including 36 (22.6%) exceeding the Milan criteria. METHODS: Expression of alpha-fetoprotein (AFP), HNF1alpha, and HNF1beta was examined by immunohistochemistry on duplicate tissue microarray slides containing the HCC tumor explants. Times to recurrence and cancer death were analyzed based on the Cox regression model and compared according to expression of markers of interest. We compared risk predictions using area under the receiver operator curves (AU-ROCs) and c statistics. RESULTS: AFP, HNF1alpha, and HNF1beta were positive in 22.6%, 46.5%, and 61%, respectively, of the tumor immunoprofiles. Although several variables were associated with times to recurrence and cancer death in univariate Cox analyses, only AFP expression for time to recurrence, and the Milan criteria and HNF1beta expression for times to recurrence and cancer death, remained significant after multivariate adjustment.  Expression of HNF1beta, but not of HNF1alpha, was related to serum AFP >/=200 ng/mL, microvascular invasion, and AFP expression (p<0.05). A subgroup analysis showed that in the within-Milan group, recurrence and cancer death rates at 10 years in the HNF1beta-negative patients were approximately one-tenth of those in  the HNF1beta-positive patients, but the difference was not significant in the non-Milan group. Addition of HNF1beta expression to the Milan criteria increased  the c statistics and AU-ROCs for both recurrence and mortality (p<0.05). CONCLUSIONS: Immunohistological detection of HNF1beta predicts recurrence and death specific for HCC post-transplant, and provides an additive benefit over the Milan selection criteria on their own. © 2012 American Association for the Study of Liver Diseases.

 

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[383]

TÍTULO / TITLE:  - Interleukin-32 expression is associated with a poorer prognosis in head and neck  squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Carcinog. 2013 Jan 28. doi: 10.1002/mc.21996.

            ●● Enlace al texto completo (gratuito o de pago) 1002/mc.21996

AUTORES / AUTHORS:  - Guenin S; Mouallif M; Hubert P; Jacobs N; Krusy N; Duray A; Ennaji MM; Saussez S; Delvenne P

INSTITUCIÓN / INSTITUTION:  - Laboratory of Experimental Pathology, GIGA Cancer, University of Liege, Liege, Belgium.

RESUMEN / SUMMARY:  - Head and neck squamous cell carcinoma (HNSCC) represent the sixth most common malignancy diagnosed worldwide. Patient’s survival is low due the high frequency  of tumor recurrence. Inflammation promotes carcinogenesis as well as the formation of metastasis. Indeed, proinflammatory mediators are known to stimulate the expression of specific transcription factors such as Snai1 and to increase the ability of tumor cells to migrate into distant organs. The atypical interleukin-32 (IL32) was mainly described to exacerbate inflammatory responses in rheumatoid arthritis and inflammatory bowel diseases. IL32 is expressed in various cancers but its role in HNSCC physiology is still unexplored. Here, we analyzed the expression of IL32 and its implication on HNSCC aggressiveness. We showed that patients with tumor expressing high amounts of IL32 exhibit decreased disease-free periods (20.5 mo vs. 41 mo, P = 0.0041) and overall survival (P = 0.0359) in comparison with individuals with weak IL32 tumor expression. This overexpression was negatively correlated with gender (P = 0.0292) and p53 expression (P = 0.0307). In addition, in vitro data linked IL32 expression to metastasis formation since IL32 inhibition decreased Snai1 expression and tumor cell migration in a Boyden chamber assay. Our data provide new insight into the role of IL32 in HNSCC aggressiveness. © 2013 Wiley Periodicals, Inc.

 

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[384]

TÍTULO / TITLE:  - DC-81-enediyne induces apoptosis of human melanoma A375 cells: involvement of the ROS, p38 MAPK, and AP-1 signaling pathways.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Biol Toxicol. 2013 Jan 5.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10565-012-9238-6

AUTORES / AUTHORS:  - Chen CY; Chen YK; Wang JJ; Hsu CC; Tsai FY; Sung PJ; Lin HC; Chang LS; Hu WP

INSTITUCIÓN / INSTITUTION:  - Graduate Institute of Pharmacy, Faculty of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.

RESUMEN / SUMMARY:  - Melanoma is one of the most chemoresistant cancers in patient care. The remission rate of current therapy remains low. DC-81, an antitumor antibiotic produced by Streptomyces species, belongs to pyrrolo[2,1-c][1,4]benzodiazepine (PBD), which is a potent inhibitor of nucleic acid synthesis. An enediyne contains either DNA  intercalating groups or DNA minor groove binding functions and these are potent DNA-damaging agents due to their ability to generate benzenoid diradicals. We have previously reported an efficient synthesis and antitumor activity of a series of novel PBD hybrids linked with enediyne. The purpose of this study was to examine the mechanism of the antiproliferative effect of DC-81-enediyne agent  on human melanoma A375 cells. DC-81-enediyne induced an increase in Ca(2+) level  and reactive oxygen species (ROS) generation as detected by flow cytometric assay. Western blot analysis showed that DC-81-enediyne induced the phosphorylation of p38 and activating transcription factor 2 (ATF-2). By using the luciferase reporter assay, activating protein-1 (AP-1) activity was further enhanced after A375 cells were treated with graded concentrations of DC-81-enediyne. DC-81-enediyne treatment-induced A375 cell apoptosis was significantly abrogated by the addition of Ca(2+), ROS, and p38 inhibitors. Collectively, our studies indicate that DC-81-enediyne induces A375 cell apoptosis through an increased Ca(2+) and ROS generation, which involves p38 phosphorylation and enhanced ATF-2/AP-1 expressions, leading to caspase-3 activity, poly(ADP-ribose)polymerase cleavage, M30 CytoDeath staining, and subsequent apoptotic cell death.

 

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[385]

TÍTULO / TITLE:  - How sensitive are epidermal growth factor receptor-tyrosine kinase inhibitors for squamous cell carcinoma of the lung harboring EGFR gene-sensitive mutations?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Thorac Oncol. 2013 Jan;8(1):89-95. doi: 10.1097/JTO.0b013e31827690b5.

            ●● Enlace al texto completo (gratuito o de pago) 1097/JTO.0b013e31827690b5

AUTORES / AUTHORS:  - Hata A; Katakami N; Yoshioka H; Kunimasa K; Fujita S; Kaji R; Notohara K; Imai Y; Tachikawa R; Tomii K; Korogi Y; Iwasaku M; Nishiyama A; Ishida T

INSTITUCIÓN / INSTITUTION:  - Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.

RESUMEN / SUMMARY:  - INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations are found mostly  in adenocarcinoma, and rarely in squamous cell carcinoma (SQC). Little is known about SQC harboring EGFR mutations. METHODS: Between April 2006 and October 2010, we investigated the incidence of EGFR activating mutations in SQC of the lung using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) was retrospectively evaluated in patients with EGFR-mutated SQC. Further pathologic analyses were performed using immunohistochemistry. RESULTS: Thirty-three of 249  patients with SQC (13.3%) had EGFR mutations, including exon 19 deletion (19 of 33 patients, 58%), L858R point mutation in exon 21 (12 of 33, 36%), and G719S point mutation in exon 18 (2 of 33, 6%). Twenty of these 33 patients received EGFR-TKI therapy, and five of these 20 responded to EGFR-TKIs with a response rate of 25.0% (95% confidence interval [CI], 8.7%-49.1%). The patients’ median progression-free survival and median overall survival were 1.4 months (95% CI, 0.7-5.8 months) and 14.6 months (95% CI, 2.9-undeterminable months), respectively. Approximately one third of the EGFR-mutated SQC patients achieved progression-free survival for longer than 6 months. Some of these patients had high carcinoembryonic antigen levels or a history of never smoking, or were positive for thyroid transcription factor-1. CONCLUSIONS: Although EGFR-TKIs seem to be generally less effective in EGFR-mutated SQC than in EGFR-mutated adenocarcinoma, some EGFR-mutated SQC patients can obtain clinical benefit from EGFR-TKIs. To better identify these patients, not only EGFR mutation status, but  also clinical factors and pathologic findings should be taken into consideration.

 

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[386]

TÍTULO / TITLE:  - Injectable hyaluronic acid-tyramine hydrogels incorporating interferon-alpha2a for liver cancer therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Control Release. 2013 Jan 14. pii: S0168-3659(13)00025-4. doi: 10.1016/j.jconrel.2013.01.008.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jconrel.2013.01.008

AUTORES / AUTHORS:  - Xu K; Lee F; Gao SJ; Chung JE; Yano H; Kurisawa M

INSTITUCIÓN / INSTITUTION:  - Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, 138669, Singapore.

RESUMEN / SUMMARY:  - We report an injectable hydrogel system that incorporates interferon-alpha2a (IFN-alpha2a) for liver cancer therapy. IFN-alpha2a was incorporated in hydrogels composed of hyaluronic acid-tyramine (HA-Tyr) conjugates through the oxidative coupling of Tyr moieties with hydrogen peroxide (H(2)O(2)) and horseradish peroxidase (HRP). IFN-alpha2a-incorporated HA-Tyr hydrogels of varying stiffness  were formed by changing the H(2)O(2) concentration. The incorporation of IFN-alpha2a did not affect the rheological properties of the hydrogels. The activity of IFN-alpha2a was furthermore well-maintained in the hydrogels with lower stiffness. Through the caspase-3/7 pathway in vitro, IFN-alpha2a released from HA-Tyr hydrogels inhibited the proliferation of liver cancer cells and induced apoptosis. In the study of the pharmacokinetics, a higher concentration of IFN-alpha2a was shown in the plasma of mice treated with IFN-alpha2a-incorporated hydrogels after 4h post injection, with a much higher amount of IFN-alpha2a delivered at the tumor tissue comparing to that of injecting an IFN-alpha2a solution. The tumor regression study revealed that IFN-alpha2a-incorporated HA-Tyr hydrogels effectively inhibited tumor growth, while the injection of an IFN-alpha2a solution did not demonstrate antitumor efficacy. Histological studies confirmed that tumor tissues in mice treated with  IFN-alpha2a-incorporated HA-Tyr hydrogels showed lower cell density, with more apoptotic and less proliferating cells compared with tissues treated with an IFN-alpha2a solution. In addition, the IFN-alpha2a-incorporated hydrogel treatment greatly inhibited the angiogenesis of tumor tissues.

 

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[387]

TÍTULO / TITLE:  - The anti-mitotic drug griseofulvin induces apoptosis of human germ cell tumor cells through a connexin 43-dependent molecular mechanism.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Apoptosis. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10495-012-0800-8

AUTORES / AUTHORS:  - Mauro V; Carette D; Pontier-Bres R; Dompierre J; Czerucka D; Segretain D; Gilleron J; Pointis G

INSTITUCIÓN / INSTITUTION:  - INSERM U 1065, Centre Mediterraneen de Medecine Moleculaire, 06204, Nice Cedex 3, France.

RESUMEN / SUMMARY:  - Griseofulvin, a widely used antifungal antimitotic drug has been proposed as an anti-tumoral treatment by way of in vitro experiments. Recently, in vivo demonstration of griseofulvin efficacy against multiple myeloma in mice argues for its potential as therapeutics for cancer. Nevertheless, the molecular mechanisms by which griseofulvin disrupts cancerous cell progression are far from being understood. In the present study, we found that griseofulvin inhibits human germ cell tumor cell growth through activation of mitochondrial caspase pathway (caspase 9 and 3) leading to the activation of apoptosis rather than an alteration of cell proliferation. Strikingly, we demonstrated that griseofulvin triggered the expression level of connexin 43 (mRNA and protein), a well described tumor-suppressor gene, known to participate in apoptosis regulation. Consistently, together with microtubule instability, a mechanism classically associated with cell death in response to griseofulvin, we observed a disruption  of connexin 43/tubulin association concomitant of an enhanced translocation of connexin 43, or an immunoreactive fragment of the protein, from the cytoplasm to  the nucleus. Finally, by using siRNA approaches we demonstrated the requirement of connexin 43 in the apoptotic induction of griseofulvin on our tumor cell model. Altogether, these results described a new molecular mechanism connexin 43-dependent targeted by griseofulvin leading to apoptosis of human germ cell tumor cells.

 

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[388]

TÍTULO / TITLE:  - Relationship Between Imaging Biomarkers of Stage I Cervical Cancer and Poor-Prognosis Histologic Features: Quantitative Histogram Analysis of Diffusion-Weighted MR Images.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - AJR Am J Roentgenol. 2013 Feb;200(2):314-20. doi: 10.2214/AJR.12.9545.

            ●● Enlace al texto completo (gratuito o de pago) 2214/AJR.12.9545

AUTORES / AUTHORS:  - Downey K; Riches SF; Morgan VA; Giles SL; Attygalle AD; Ind TE; Barton DP; Shepherd JH; Desouza NM

INSTITUCIÓN / INSTITUTION:  - CRUK/EPSRC Cancer Imaging Centre, MRI Unit, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Royal Marsden Hospital, Downs Rd, Sutton, Surrey SM2 5PT, UK.

RESUMEN / SUMMARY:  - OBJECTIVE: The purpose of this study was to determine whether histogram analysis  of apparent diffusion coefficient (ADC) values from diffusion-weighted MRI can be used to differentiate cervical tumors according to their histologic characteristics. SUBJECTS AND METHODS: Sixty patients with International Federation of Gynecology stage I cervical cancer underwent MRI at 1.5 T with a 37-mm-diameter endovaginal coil. T2-weighted images (TR/TE, 2000-2368/90) followed by diffusion-weighted images (TR/TE, 2500/69; b values, 0, 100, 300, 500, and 800 s/mm(2)) were acquired. An expert observer drew regions of interest  around a histologically confirmed tumor on ADC maps by referring to the T2-weighted images. Pixel-by-pixel ADCs were calculated with a monoexponential fit of data from b values of 100-800 s/mm(2), and ADC histograms were obtained from the entire tumor volume. An independent samples Student t test was used to compare differences in ADC percentile values, skew, and kurtosis between squamous cell carcinoma and adenocarcinoma, well or moderately differentiated and poorly differentiated tumors, and absence and presence of lymphovascular space invasion. RESULTS: There was no statistically significant difference in ADC percentiles between squamous cell carcinoma and adenocarcinoma, but the median was significantly higher in well or moderately differentiated tumors (50th percentile, 1113 +/- 177 x 10(-6) mm(2)/s) compared with poorly differentiated tumors (50th percentile, 996 +/- 184 x 10(-6) mm(2)/s) (p = 0.049). Histogram skew was significantly less positive for adenocarcinoma compared with squamous cell carcinoma (p = 0.016) but did not differ between tumor grades. There was no  significant difference between any parameter with regard to lymphovascular space  invasion. CONCLUSION: Median ADC is lower in poorly compared with well or moderately differentiated tumors, while lower histogram-positive skew in adenocarcinoma compared with squamous cell carcinoma is likely to reflect the glandular content of adenocarcinoma.

 

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[389]

TÍTULO / TITLE:  - Cancer-associated fibroblasts do not respond to combined irradiation and kinase inhibitor treatment.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):785-90. doi: 10.3892/or.2012.2180. Epub 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2180

AUTORES / AUTHORS:  - Affolter A; Schmidtmann I; Mann WJ; Brieger J

INSTITUCIÓN / INSTITUTION:  - Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University, D-55101 Mainz, Germany. annette.affolter@web.de

RESUMEN / SUMMARY:  - The emergence of radioresistance is a significant issue in the treatment of squamous cell carcinoma. We recently demonstrated that post-radiogenic extracellular signal-regulated kinase (ERK) signaling might decrease radiosensitivity in this cancer type. To further elucidate how tumor-organizing cell types respond to irradiation and ERK pathway inhibition, we analyzed one oral squamous cell carcinoma and one lung cancer cell line (HNSCCUM-02T, A549), fibroblasts (NIH3T3), primary normal and cancer-associated fibroblasts (CAFs) in  vitro. Irradiated cells treated with mitogen-activated protein kinase (MAPK) inhibitor U0126 were screened for pERK levels. Post-radiogenic cellular responses were functionally analyzed by proliferation and colony assays. We found analogous pERK expression, proliferation and survival of tumor and normal fibroblast cells. CAFs did not show any response to treatment. We hypothesized that radiation and MAPK inhibition have no dose-limiting effect on tumor-surrounding normal tissue.  As CAFs are considered to influence the radioresponse of the entire tumor, but are not affected by treatment themselves, potential CAF-mediated tumor protection should be considered in further studies.

 

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[390]

TÍTULO / TITLE:  - Interim PET/CT-based prognostic model for the treatment of diffuse large B cell lymphoma in the post-rituximab era.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Hematol. 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00277-012-1640-x

AUTORES / AUTHORS:  - Yang DH; Ahn JS; Byun BH; Min JJ; Kweon SS; Chae YS; Sohn SK; Lee SW; Kim HW; Jung SH; Kim YK; Kim HJ; Bom HS; Lee JJ

INSTITUCIÓN / INSTITUTION:  - Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 160 Ilsimri, Hwasun, Jeollanamdo, 519-809, Republic of Korea.

RESUMEN / SUMMARY:  - The prognostic accuracy of interim (18)F-fluoro-2-dexoy-D-glucose positron emission tomography/computerized tomography (PET/CT) using three different methods of response assessments during rituximab, cyclophosphamide, doxorubicin,  vincristine, and prednisolone chemotherapy was investigated in 186 patients with  newly diagnosed diffuse large B cell lymphoma (DLBCL). The response of interim PET/CT was assessed based on a combined evaluation of the Deauville five-point scale (5-PS), the rates of reduction in the maximal standardized uptake value (DeltaSUVmax), and the rates of reduction in the metabolic tumor volume (DeltaMTV2.5). Positivity on the 5-PS, the optimal cutoff of DeltaSUVmax, or the  optimal cutoff of DeltaMTV2.5 could each predict disease progression. Over a median follow-up of 22.8 months, the assessment of responses based on the 5-PS, DeltaSUVmax, and DeltaMTV2.5 had prognostic value for progression-free survival.  When patients were allocated a score of 0 to 3 depending on the presence of an inadequate response by visual, DeltaSUVmax, or DeltaMTV2.5, the outcomes of patients with a score of 0 were significantly superior to those with a score of 1, 2, or 3. The interim PET/CT response based on visual, SUV-based, and MTV-based assessment had significant negative predictive value for disease progression and  a high potential for predicting outcomes of patients with DLBCL.

 

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[391]

TÍTULO / TITLE:  - Tumor necrosis factor alpha -238G/A (rs 361525) gene polymorphism predicts progression to type-2 diabetes in an Eastern Indian population with prediabetes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Diabetes Res Clin Pract. 2013 Jan 5. pii: S0168-8227(12)00505-0. doi: 10.1016/j.diabres.2012.12.007.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.diabres.2012.12.007

AUTORES / AUTHORS:  - Dutta D; Choudhuri S; Mondal SA; Maisnam I; Reza AH; Ghosh S; Chowdhury S; Bhattacharya B; Mukhopadhyay S

INSTITUCIÓN / INSTITUTION:  - Department of Endocrinology & Metabolism, IPGMER & SSKM Hospital, 244 AJC Bose Road, Kolkata 700020, India; Department of Biochemistry, Dr. B.C. Roy Post-graduate Institute of Basic Medical Education and Research, IPGMER, 244 AJC  Bose Road, Kolkata 700020, India. Electronic address: deepdutta2000@yahoo.com.

RESUMEN / SUMMARY:  - Prediabetes (IPD; n=122) and normoglycemic individuals (n=100) underwent assessment of polymorphisms of TNFalpha (-238, -308) and IL6 (-174). After 27.25+/-5.64 months, 16 IPD had reverted to normoglycemia and 18 progressed to diabetes. TNFalpha -238AA/GA genotypes were significantly more common in IPD, had higher TNFalpha, higher progression to diabetes and lower reversal.

 

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[392]

TÍTULO / TITLE:  - Sphingoid bases from sea cucumber induce apoptosis in human hepatoma HepG2 cells  through p-AKT and DR5.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar;29(3):1201-7. doi: 10.3892/or.2013.2223. Epub 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2223

AUTORES / AUTHORS:  - Hossain Z; Sugawara T; Hirata T

INSTITUCIÓN / INSTITUTION:  - Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada.

RESUMEN / SUMMARY:  - Biofunctional marine compounds have recently received substantial attention for their nutraceutical characteristics. In this study, we investigated the apoptosis-inducing effects of sphingoid bases prepared from sea cucumber using human hepatoma HepG2 cells. Apoptotic effects were determined by cell viability assay, DNA fragmentation assay, caspase-3 and caspase-8 activities. The expression levels of apoptosis-inducing death receptor-5 (DR5) and p-AKT were assayed by western blot analysis, and mRNA expression of bax, GADD45 and PPARgamma was assayed by quantitative RT-PCR analysis. Sphingoid bases from sea cucumber markedly reduced the cell viability of HepG2 cells. DNA fragmentation indicative of apoptosis was observed in a dose-dependent manner. The expression levels of the apoptosis inducer protein Bax were increased by the sphingoid bases from sea cucumber. GADD45, which plays an important role in apoptosis-inducing pathways, was markedly upregulated by sphingoid bases from sea cucumber. Upregulation of PPARgamma mRNA was also observed during apoptosis induced by the  sphingoid bases. The expression levels of DR5 and p-AKT proteins were increased and decreased, respectively, as a result of the effects of sphingoid bases from sea cucumber. The results indicate that sphingoid bases from sea cucumber induce  apoptosis in HepG2 cells through upregulation of DR5, Bax, GADD45 and PPARgamma and downregulation of p-AKT. Our results show for the first time the functional properties of marine sphingoid bases as inducers of apoptosis in HepG2 cells.

 

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[393]

TÍTULO / TITLE:  - Differential susceptibility of gastric cancer cells to TRAIL-induced apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar;29(3):1224-30. doi: 10.3892/or.2012.2183. Epub 2012 Dec 11.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2183

AUTORES / AUTHORS:  - Song NM; Jun S; Zang DY; Kim SG; Park HR; Kang D

INSTITUCIÓN / INSTITUTION:  - Ilsong Institute of Life Science, Hallym University, Anyang, Kyonggi-do 431-060,  Republic of Korea.

RESUMEN / SUMMARY:  - Understanding the molecular basis of the differential sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis is required to predict therapeutic outcomes and to improve the effectiveness of TRAIL-based therapy. This study aimed to compare the responsiveness of gastric cancer cells to TRAIL treatment and to investigate the  molecular basis of the differential TRAIL sensitivity of four gastric cancer cell lines. The TRAIL sensitivity of the four cell lines was ranked in the following order: SNU-16 approximately SNU-620 > SNU-5 >> SNU-1. The level of Annexin V binding and the activation profile of caspase-3, -8 and -9 corroborated the differential TRAIL susceptibility of the cell lines. To determine the molecular basis of the differential sensitivity to TRAIL, we examined the expression of signaling components involved in TRAIL-mediated apoptosis. The mRNA level and surface expression of death receptor 4 (DR4) were significantly decreased in the  SNU-1 cells compared to the other cell lines. Bid cleavage and X-linked inhibitor of apoptosis (XIAP) degradation were significantly increased in the SNU-16 and SNU-620 cells compared to the SNU-5 and SNU-1 cells, although Bid and XIAP were expressed at similar levels across the four cell lines. The expression and degradation of FLICE-inhibitory protein (FLIP) upon TRAIL treatment was independent of TRAIL sensitivity. In conclusion, the differential susceptibility  of the four gastric cancer cells to TRAIL may be ascribed to the differential expression of DR4 and the proper augmentation of the death signal by the truncation of Bid and degradation of XIAP.

 

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[394]

TÍTULO / TITLE:  - NP-1250, an ABCG2 inhibitor, induces apoptotic cell death in mitoxantrone-resistant breast carcinoma MCF7 cells via a caspase-independent pathway.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Jan 24. doi: 10.3892/or.2013.2249.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2249

AUTORES / AUTHORS:  - Ito M; Kajino K; Abe M; Fujimura T; Mineki R; Ikegami T; Ishikawa T; Hino O

INSTITUCIÓN / INSTITUTION:  - Department of Pathology and Oncology, Juntendo University School of Medicine, Bunkyo, Tokyo 113-8421, Japan.

RESUMEN / SUMMARY:  - Chemoresistance is one of the main obstacles to successful cancer therapy and is  frequently associated with multidrug resistance (MDR). One of the most studied mechanisms of MDR is the high expression of ATP-binding cassette (ABC) transporters. Here, we demonstrated that NP-1250, an ABCG2 inhibitor, induced apoptotic cell death in ABCG2-overexpressing multidrug-resistant MCF7/mitoxantrone-resistant (MX) human breast carcinoma cells via a caspase-independent pathway. Incubation of MCF7/MX cells with NP-1250 significantly reduced cell viability, while NP-1250 had little effect on the viability of drug-sensitive MCF7/wild-type cells. Although the target molecules of NP-1250 in cell death remain unknown, investigation of NP-1250 will aid in the elucidation of the molecular mechanism of drug resistance and NP-1250 may become  a new therapy for MDR cancers.

 

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[395]

TÍTULO / TITLE:  - Suppression of HER-2 via siRNA interference promotes apoptosis and decreases metastatic potential of SKOV3 human ovarian carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar;29(3):1133-9. doi: 10.3892/or.2012.2214. Epub 2012 Dec 28.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2214

AUTORES / AUTHORS:  - Lu YM; Rong ML; Shang C; Wang N; Li X; Zhao YY; Zhang SL

INSTITUCIÓN / INSTITUTION:  - Department of Gynaecology and Obstetrics, The Affiliated Shengjing Hospital, China Medical University, Shenyang, P.R. China.

RESUMEN / SUMMARY:  - The aberrant expression of human epidermal growth factor receptor-2 (HER-2) has been detected in ovarian cancer. However, the role of HER-2 in the development of ovarian cancer has not been sufficiently elucidated. The objective of this study  was to determine the role of HER-2 in the apoptosis and metastasis of SKOV-3 ovarian cancer cells. SKOV-3 cells were transfected with three doublestranded small interfering RNA (siRNA) molecules that target HER-2. Various sequences were synthesized by T7 transcription in vitro to select the most effective HER-2silencing siRNA. SKOV-3 cells were examined for growth inhibition using the  MTT proliferation assay and apoptosis was assessed using flow cytometry and TUNEL assay. The Matrigel basement memebrane matrix was used to assess invasion and chemotactic mobility, as a model of tumor cell metastasis. Western blot analysis  was used to detect the expression of matrix metallopeptidase-9 (MMP-9), E-cadherin, N-cadherin and vimentin. siRNA interference in HER-2 resulted in decreased cell proliferation and invasion and increased apoptosis. Western blot analysis demonstrated a marked increase in E-cadherin and MMP-9 and a reduction in N-cadherin and vimentin protein levels in the SKOV-3 cells. The suppression of HER-2 expression resulted in apoptosis and the inhibition of metastasis of SKOV-3 cells. Therefore, the overexpression of the HER-2 gene can enhance the metastatic potential of SKOV-3 cells by increasing the protein levels of MMP-9. Epithelial-mesenchymal transition may be involved in the HER-2 siRNA-induced invasion and migration of SKOV-3 cells. Taken together, these results suggest that HER-2 functions as an oncogene and may thus be an attractive therapeutic target in SKOV-3 ovarian cancer cells.

 

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[396]

TÍTULO / TITLE:  - Carfilzomib: a second-generation proteasome inhibitor for the treatment of relapsed and refractory multiple myeloma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Pharmacother. 2013 Jan;47(1):56-62. doi: 10.1345/aph.1R561. Epub 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 1345/aph.1R561

AUTORES / AUTHORS:  - Thompson JL

INSTITUCIÓN / INSTITUTION:  - Pharmaceutical Management Branch, Cancer Therapy Evaluation Program, Division of  Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Rockville, MD.

RESUMEN / SUMMARY:  - OBJECTIVE: To review and summarize data on carfilzomib, which was approved by the Food and Drug Administration (FDA) in July 2012 for the treatment of patients with relapsed and refractory multiple myeloma (MM) who received prior bortezomib  and thalidomide or lenalidomide. DATA SOURCES: A literature search through PubMed was conducted through October 2012 using the terms carfilzomib, PR-171, proteasome inhibitor (PI), and MM. Data were also obtained through the American Society of Clinical Oncology and American Society of Hematology abstracts and FDA briefing documents. STUDY SELECTION AND DATA EXTRACTION: The literature search was limited to human studies published in English. Priority was placed on trials  of carfilzomib in relapsed and refractory MM. DATA SYNTHESIS: Carfilzomib is a new PI that differs in pharmacology and pharmacokinetics from bortezomib, the first-in-class PI. The FDA approval was based on efficacy data from a Phase 2 study of carfilzomib in patients with relapsed and refractory MM (n = 266). All patients had received prior bortezomib and 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients were treated with intravenous carfilzomib 20 mg/m(2) (cycle 1) followed by 27 mg/m(2) (cycles >/=2) on days 1,  2, 8, 9, 15, and 16 of each 28-day cycle. The overall response rate was 23.7% (18.7-29.4), with a median duration of response of 7.8 (5.6-9.2) months. Safety data from an integrated analysis reported thrombocytopenia, anemia, fatigue, nausea, and diarrhea as the most common adverse events, with minimal dose-limiting neutropenia or peripheral neuropathy (PN) (n = 526). The incidence  of grade 3 or higher thrombocytopenia was 24.9%, while that of neutropenia was 11.9%, and the incidence of all grades of treatment-emergent PN was 13%. CONCLUSIONS: Carfilzomib is a safe and effective new treatment option for patients with relapsed MM refractory to bortezomib and thalidomide or lenalidomide. Randomized head-to-head trials with bortezomib will assist in formulary and treatment decisions in the context of PIs as a drug class.

 

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[397]

TÍTULO / TITLE:  - Jolkinolide B from Euphorbia fischeriana Steud induces in human leukemic cells apoptosis via JAK2/STAT3 pathways.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Clin Pharmacol Ther. 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 5414/CP201807

AUTORES / AUTHORS:  - Wang JH; Zhang K; Niu HY; Shu LH; Yue DM; Li DY; He P

RESUMEN / SUMMARY:  - Jolkinolide B from the roots of Euphorbia fischeriana Steud exhibits significant  antitumor activities against several tumor lines. Previous study has shown that Jolkinolide B could induce apoptosis in human leukemia cells. However, the exact  mechanism and signaling pathway involved in Jolkinolide B-induced apoptosis have  not been fully elucidated. In the present study, we found that Jolkinolide B reduced cell viability and induced apoptosis in dose- and time-dependent manner in human leukemic HL-60 and THP-1 cells. The induction of apoptosis was accompanied by the downregulation of JAK2/STAT3. Our results also suggest that expression of Bcl-2 and mitochondrial cytochrome c was dosedependently reduced following Jolkinolide B-treated THP-1 and HL-60 cells, whereas Jolkinolide B up-regulated the expression of Bax and cytosolic cytochrome c. Moreover, we observed that Jolkinolide B treatment resulted in activation of caspase-3, -8, and -9. JSI-124, a STAT-3 inhibitor, was able to block the negative effect of Jolkinolide B on cell apoptosis. Taken together, our study for the first time suggests that Jolkinolide B is able to enhance apoptosis of human leukemic HL-60  and THP-1 cells, at least in part, through downregulation of JAK2/STAT3 and bcl-2, and upregulation of Bax and cytosolic cytochrome c. Moreover, the triggering of caspase-3, -8, and -9 activation mediated apoptotic induction.

 

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[398]

TÍTULO / TITLE:  - High incidence of DNA ploidy abnormalities and increased Mcm2 expression may predict malignant change in oral proliferative verrucous leukoplakia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Histopathology. 2012 Sep 28. doi: 10.1111/his.12036.

            ●● Enlace al texto completo (gratuito o de pago) 1111/his.12036

AUTORES / AUTHORS:  - Gouvea AF; Santos Silva AR; Speight PM; Hunter K; Carlos R; Vargas PA; de Almeida OP; Lopes MA

INSTITUCIÓN / INSTITUTION:  - Department of Oral Diagnosis, Piracicaba Dental School, Campinas State University (UNICAMP), Sao Paulo, Brazil.

RESUMEN / SUMMARY:  - AIMS: To assess the DNA content of cases of oral proliferative verrucous leukoplakia (PVL) and correlate the DNA ploidy findings with the expression of Mcm2, geminin, and Ki67, and with clinicopathological data. METHODS AND RESULTS:  DNA quantification was performed by image cytometry using the ACIS III Automated  Cellular Imaging System. Expression of Ki67, Mcm2 and geminin was determined by immunohistochemistry. There were 21 cases of PVL, the female/male ratio was 6:1,  and the average age was 65.5 years. Seventeen patients (81.0%) did not report tobacco and alcohol consumption. Nine patients (42.9%) developed verrucous or squamous cell carcinoma. Levels of Mcm2 expression showed a positive correlation  with increasingly severe epithelial changes (P = 0.03). Twenty patients had their DNA examined by ACIS III, and 19 (95%) showed aneuploidy. The frequency and severity of aneuploidy (P < 0.0001), the mean values of the DNA heterogeneity index (P < 0.0001) and the 5n-exceeding fractions (P = 0.0007) increased according to epithelial alterations. Abnormal DNA content was observed even in the more indolent lesions. CONCLUSIONS: Mcm2 expression and DNA ploidy analysis could be used to predict areas of malignant transformation. The clinicopathological findings associated with the immunohistochemical and DNA ploidy results support the distinct and aggressive profile of this entity.

 

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[399]

TÍTULO / TITLE:  - RLIP76 is overexpressed in human glioblastomas and is required for proliferation, tumorigenesis and suppression of apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Carcinogenesis. 2013 Jan 15.

            ●● Enlace al texto completo (gratuito o de pago) 1093/carcin/bgs401

AUTORES / AUTHORS:  - Wang Q; Wang JY; Zhang XP; Lv ZW; Fu D; Lu YC; Hu GH; Luo C; Chen JX

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.

RESUMEN / SUMMARY:  - The guanosine triphosphatase-activating protein RLIP76 is overexpressed in many malignant tumor cells, but it is unclear if RLIP76 overexpression contributes to  the high proliferative potential of glioma cells. We demonstrate that RLIP76 messenger RNA and protein expression are positively correlated with glioma grade  and that higher RLIP76 expression correlates with shorter patient survival. Immunohistochemical staining revealed that RLIP76 expression was positively correlated with the expression of Ki-67, a biomarker for cell proliferation. Inhibition of RLIP76 expression in U87 and U251 glioma cell lines by stable transfection of a targeted siRNA suppressed anchorage-independent growth and enhanced apoptosis in vitro. Conversely, overexpression of RLIP76 in SW1088 and U251 cell lines enhanced proliferation and reduced apoptosis. Inhibition of RLIP76 in U251 cells also significantly suppressed tumorigenicity and induced apoptosis in an endotopic xenograft mouse model. Moreover, we demonstrate that knockdown of RLIP76 increases apoptosis in different human gliomas independently  of p53 status. In addition, a constitutively active Rac1 reversed both the suppression of proliferation and the promotion of apoptosis induced by the RLIP76-targeted siRNA, indicating that RLIP76 is an upstream activator of Rac1. Rac1-mediated suppression of apoptosis and promotion of proliferation were dependent on intact c-jun N-terminal kinase (JNK) signaling. Furthermore, we demonstrate that RLIP76 promotes proliferation and suppresses glioma cell apoptosis through a mechanism independent of Rho-selective GTPase-activating protein. Instead, we found that the adenosine triphosphatase function of Rlip76 modulates Rac1 activity by regulating Rac1 protein ubiquitylation and degradation. These data demonstrate that RLIP76 may suppress apoptosis and promote the proliferation of glioma cells by direct adenosine triphosphate-dependent xenobiotic transport and by activating the Rac1-JNK signaling pathway. Inhibition of RLIP76 signaling is a potential treatment for malignant glioma.

 

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[400]

TÍTULO / TITLE:  - Insulin-like growth factor-1 as a predictive biomarker for metastatic uveal melanoma in humans.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Invest Ophthalmol Vis Sci. 2013 Jan 17;54(1):490-3. doi: 10.1167/iovs.12-10228.

            ●● Enlace al texto completo (gratuito o de pago) 1167/iovs.12-10228

AUTORES / AUTHORS:  - Frenkel S; Zloto O; Pe’er J; Barak V

INSTITUCIÓN / INSTITUTION:  - Department of Ophthalmology and.

RESUMEN / SUMMARY:  - PURPOSE: High expression levels of insulin-like growth factor-1 (IGF-1) receptor  were associated with metastatic uveal melanoma (UM). The purpose of this study was to examine the potential of serum IGF-1 in early detection of liver metastasis. METHODS: IGF-1 SERUM LEVELS WERE ANALYZED USING ENZYME-LINKED IMMUNOSORBENT ASSAY FOR 118 SUBJECTS IN THREE DIFFERENT GROUPS: 55 disease-free (DF) UM patients who did not develop metastasis within 10 years of diagnosis; 22  metastatic patients; and 41 healthy subjects. Matched pairs univariate analysis was performed for sera of 19 metastatic patients 12 and 6 months before the diagnosis of metastasis and on the day of diagnosis, both as time groups and normalized levels per patient. IGF-1 levels were compared among groups by analysis of variance and Student t-test. RESULTS: Mean +/- SD IGF-1 serum levels  for the control, DF, and metastatic groups were 152.48 +/- 49.76, 119.92 +/- 60.66, and 96.99 +/- 56.91 ng/mL, respectively (P < 0.001). Normalized changes in IGF-1 per metastatic patient from 6 months prior to the diagnosis of metastases compared to the day of diagnosis of metastases showed a decreasing trend. CONCLUSIONS: IGF-1 levels in 10-years’ disease-free UM patients were significantly lower than those in healthy subjects and were even lower in metastatic patients. IGF-1 levels decreased toward the diagnosis of metastases. Therefore, serum IGF-1 level may be used as a predictive biomarker for metastatic UM when measured repeatedly.

 

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[401]

TÍTULO / TITLE:  - Induction of apoptosis of SW480 human colon cancer cells by (-)-epicatechin isolated from Bulnesia sarmienti.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Anticancer Res. 2012 Dec;32(12):5353-61.

AUTORES / AUTHORS:  - Kim D; Mollah ML; Kim K

INSTITUCIÓN / INSTITUTION:  - DVM, College of Veterinary Medicine, Kyungpook National University, #1370 Sangyeok-dong, Buk-gu, Daegu, 702-701, Republic of Korea.

RESUMEN / SUMMARY:  - BACKGROUND/AIM: (-)-Epicatechin is a major constituent of Bulnesia sarmienti, which is known to possess anticancer properties. Here we report that (-)-epicatechin isolated from B. Sarmienti inhibited growth and induced apoptosis of SW480 human colon cancer cells. MATERIALS AND METHODS: Cells were treated with different concentrations (0, 25, 50, and 100 mumol/ml) of (-)-epicatechin. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, 40,6-diamidine-20-phenylindole dihydrochloride (DAPI) staining, colony-forming assay, DNA fragmentation analysis, reverse transcription-polymerase chain reaction (RT-PCR), annexin V-fluorescein isothiocyanate (FITC) staining, and immunoblot analyses were then carried out. RESULTS: (-)-Epicatechin was found to  have cytotoxic activity, and cells treated with this compound had fragmented nuclei, fragmented DNA, and underwent apoptosis. mRNA and protein expression levels of BCL2-associated X protein (BAX) and p53 were up-regulated and those of  B-cell lymphoma-2 (BCL2) were down-regulated, while p21 mRNA levels were significantly increased in cells treated with (-)-epicatechin in a concentration-dependent manner. CONCLUSION: (-)-Epicatechin from B. Sarmienti inhibited colon cancer cell growth and induced apoptosis.

 

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[402]

TÍTULO / TITLE:  - Dihydroceramide desaturase knockdown impacts sphingolipids and apoptosis after photodamage in human head and neck squamous carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Anticancer Res. 2013 Jan;33(1):77-84.

AUTORES / AUTHORS:  - Breen P; Joseph N; Thompson K; Kraveka JM; Gudz TI; Li L; Rahmaniyan M; Bielawski J; Pierce JS; VAN Buren E; Bhatti G; Separovic D

INSTITUCIÓN / INSTITUTION:  - Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201, U.S.A. dseparovic@wayne.edu.

RESUMEN / SUMMARY:  - BACKGROUND: Dihydroceramide desaturase 1 (DES) is the enzyme responsible for converting dihydroceramide into ceramide in the de novo sphingolipid biosynthesis pathway. Dihydroceramide can inhibit ceramide channel formation to interfere with apoptosis. We have shown that following ceramide synthase knockdown, photodynamic therapy (PDT), a cancer treatment modality, is associated with decreased levels of ceramides and dihydroceramides in cells that are resistant to apoptosis. Aim:  Here we investigated the effect of DES knockdown on the sphingolipid profile and  apoptosis in human head and neck squamous carcinoma cells after PDT with the silicon phthalocyanine Pc 4. MATERIALS AND METHODS: Following siRNA transfection  and PDT treatment, quantitative real-time polymerase chain reaction for quantification of DES mRNA, immunoblotting for protein expression, mass spectrometry for sphingolipid analysis, spectrofluorometry for caspase 3-like (DEVDase) activity, flow cytometry for apoptosis detection, and trypan blue assay for cell viability evaluation, were performed. RESULTS: Down-regulation of DES led to a substantial increase in levels of dihydroceramides without affecting ceramide levels. PDT-induced accumulation of individual dihydroceramides and global ceramides was increased by DES knockdown. Concomitantly, mitochondrial depolarization, DEVDase activation, late-apoptosis and cell death were attenuated by DES knockdown. Early apoptosis, however, was enhanced. CONCLUSION: Our findings support the following: (i) dihydroceramide reduces pro-apoptotic effects of ceramide; (ii) cells adapt to DES knockdown to become more sensitive to ceramide and early-apoptosis; (iii) DES is a potential molecular target for regulating apoptotic resistance to PDT.

 

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[403]

TÍTULO / TITLE:  - hPNAS-4 inhibits proliferation through S phase arrest and apoptosis: underlying action mechanism in ovarian cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Apoptosis. 2013 Jan 16.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10495-012-0797-z

AUTORES / AUTHORS:  - Li L; Chen DB; Lin C; Cao K; Wan Y; Zhao XY; Nie CL; Yuan Z; Wei YQ

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, 1# Keyuan Road 4, Gaopeng Street, High  Technological Development Zone, Chengdu, 610041, China.

RESUMEN / SUMMARY:  - PNAS-4, a novel pro-apoptotic gene, was activated during the early response to DNA damage. Previous studies have shown that hPNAS-4 can inhibit tumor growth when over-expressed in ovarian cancer cells. However, the underlying action mechanism remains elusive. In this work, we found that hPNAS-4 expression was significantly increased in SKOV3 cells when exposed to cisplatin, methyl methanesulfonate or mitomycin C, and that its overexpression could induce proliferation inhibition, S phase arrest and apoptosis in A2780s and SKOV3 ovarian cancer cells. The S phase arrest caused by hPNAS-4 was associated with up-regulation of p21. p21 is p53-dispensable and correlates with activation of ERK, and activation of the Cdc25A-Cdk2-Cyclin E/Cyclin A pathway, while the pro-apoptotic effects of hPNAS-4 were mediated by activation of caspase-9 and -3  other than caspase-8, and accompanied by release of AIF, Smac and cytochrome c into the cytosol. Taken together, these data suggest a new mechanism by which hPNAS-4 inhibits proliferation of ovarian cancer cells by inducing S phase arrest and apoptosis via activation of Cdc25A-Cdk2-Cyclin E/Cyclin A axis and mitochondrial dysfunction-mediated caspase-dependent and -independent apoptotic pathways. To our knowledge, we provide the first molecular evidence for the potential application of hPNAS-4 as a novel target in ovarian cancer gene therapy.

 

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[404]

TÍTULO / TITLE:  - Tamoxifen Represses miR-200 MicroRNAs and Promotes Epithelial-to-Mesenchymal Transition by Up-Regulating c-Myc in Endometrial Carcinoma Cell Lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Endocrinology. 2013 Feb;154(2):635-45. doi: 10.1210/en.2012-1607. Epub 2013 Jan 7.

            ●● Enlace al texto completo (gratuito o de pago) 1210/en.2012-1607

AUTORES / AUTHORS:  - Bai JX; Yan B; Zhao ZN; Xiao X; Qin WW; Zhang R; Jia LT; Meng YL; Jin BQ; Fan DM; Wang T; Yang AG

INSTITUCIÓN / INSTITUTION:  - Department of Immunology, Fourth Military Medical University, 169 Changle West Road, Xi’an, Shaanxi Province 710032, China. agyang@fmmu.edu.cn; or wangt@fmmu.edu.cn.

RESUMEN / SUMMARY:  - Although tamoxifen (TAM), a selective estrogen receptor modulator, has been widely used in the treatment of hormone-responsive breast cancer, its estrogen-like effect increases the risk of endometrial cancer. However, the molecular mechanisms of TAM-induced endometrial carcinoma still remain unclear. In this report, we explored the role of microRNAs (miRNAs) in TAM-induced epithelial-mesenchymal transition (EMT) in ECC-1 and Ishikawa endometrial cancer  cell lines and found miR-200 is involved in this process via the regulation of c-Myc. When treated with TAM, ECC-1 and Ishikawa cells were characterized by higher invasiveness and motility and underwent EMT. miR-200, a miRNA family with  tumor suppressive functions in a wide range of cancers, was found reduced in response to TAM treatment. Consistent with zinc finger E-box binding homeobox 2,  which was confirmed as a direct target of miR-200b in endometrial cancer cell lines, some other key factors of EMT such as Snail and N-cadherin increased, whereas E-cadherin decreased in the TAM-treated cells, contributing to TAM-induced EMT in these endometrial cancer cells. In addition, we showed that c-Myc directly binds to and represses the promoter of miR-200 miRNAs, and its up-regulation in TAM-treated endometrial cancer cells leads to the down-regulation of miR-200 and eventually to EMT. Collectively, our data suggest  that TAM can repress the miR-200 family and induce EMT via the up-regulation of c-Myc in endometrial cancer cells. These findings describe a possible mechanism of TAM-induced EMT in endometrial cancer and provide a potential new therapeutic  strategy for it.

 

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[405]

TÍTULO / TITLE:  - Influence of Pharmacogenomic Profiling Prior to Pharmaceutical Treatment in Metastatic Colorectal Cancer on Cost Effectiveness : A Systematic Review.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pharmacoeconomics. 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s40273-012-0017-2

AUTORES / AUTHORS:  - Frank M; Mittendorf T

INSTITUCIÓN / INSTITUTION:  - Center for Health Economics Research Hannover, Leibniz University Hannover, Konigsworther Platz 1, 30167, Hannover, Germany, mf@ivbl.uni-hannover.de.

RESUMEN / SUMMARY:  - BACKGROUND: Metastatic colorectal cancer (mCRC) imposes a substantial health burden on individual patients and society. Furthermore, rising costs in oncology  cause a growing concern about reimbursement for innovations in this sector. The promise of pharmacogenomic profiling and related stratified therapies in mCRC is  to improve treatment efficacy and potentially save costs. Among other examples, the commonly used epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab are only effective in patients with kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type cancers. Hence, the adaptation of predictive biomarker testing might be a valid strategy for healthcare systems worldwide. OBJECTIVE: This study aims to review the clinical and economic evidence supporting pharmacogenomic profiling prior to the administration of pharmaceutical treatment in mCRC. Moreover, key drivers and areas of uncertainty  in cost-effectiveness evaluations are analysed. METHODS: A systematic literature  review was conducted to identify studies evaluating the cost effectiveness of predictive biomarkers and the result dependent usage of pharmaceutical agents in  mCRC. RESULTS: The application of predictive biomarkers to detect KRAS mutations  prior to the administration of EGFR antibodies saved treatment costs and was cost effective in all identified evaluations. However, because of the lack of data regarding cost-effectiveness analyses for predictive biomarker testing, e.g. for  first-line treatment, definitive conclusions cannot be stated. Key drivers and areas of uncertainty in current cost-effectiveness analyses are, among others, the consideration of predictive biomarker costs, the characteristics of single predictive biomarkers and the availability of clinical data for the respective pharmaceutical intervention. Especially the cost effectiveness of uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1) mutation analysis prior to irinotecan-based chemotherapy remains unclear. CONCLUSION: Pharmacogenomic profiling has the potential to improve the cost effectiveness of pharmaceutical treatment in mCRC. Hence, quantification of the economic impact of stratified medicine as well as cost-effectiveness analyses of pharmacogenomic profiling are  becoming more important. Nevertheless, the methods applied in cost-effectiveness  evaluations for the usage of predictive biomarkers for patient selection as well  as the level of evidence required to determine clinical effectiveness are areas for further research. However, mCRC is one of the first indications in which stratified therapies are used in clinical practice. Thus, clinical and economic experiences could be helpful when adopting pharmacogenomic profiling into clinical practice for other indications.

 

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[406]

TÍTULO / TITLE:  - Histone Methyltransferase Inhibitors: Novel Epigenetic Agents for Cancer Treatment.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Med Chem. 2012 Nov 26.

AUTORES / AUTHORS:  - Zagni C; Chiacchio U; Rescifina A

INSTITUCIÓN / INSTITUTION:  - Dipartimento di Scienze del Farmaco, Universita di Catania, Viale Andrea Doria 6, 95125 Catania, Italy. arescifina@unict.it.

RESUMEN / SUMMARY:  - Epigenetics is defined as heritable changes in gene activity and expression that  occur without alteration in DNA sequence. The gene transcription is strictly correlated to chromatin structure, which could undergo to covalent modifications  of histones involving acetylation, methylation, phosphorylation and ubiquitination. Alterations in histones are implicated in many diseases, included cancer, by leading to tumor suppressor silencing or pro-apoptotic proteins downregulation. Although post-translational addition of methyl groups to the histone lysine has been discovered three decades ago, the importance of this epigenetic modification is emerging only in the last few years. Thenceforward histone methyltransferase inhibitors have been developed as potential therapeutic cancer agents. It should not be long before some selective inhibitors make their  way into clinical trials. This review is mainly focused on the evolution in the development of new epigenetic modifier molecules modulating histone marks.

 

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[407]

TÍTULO / TITLE:  - Sentinel node tumour burden quantified based on cytokeratin 19 mRNA copy number predicts non-sentinel node metastases in breast cancer: Molecular whole-node analysis of all removed nodes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Cancer. 2012 Dec 19. pii: S0959-8049(12)00918-5. doi: 10.1016/j.ejca.2012.11.022.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2012.11.022

AUTORES / AUTHORS:  - Osako T; Iwase T; Kimura K; Horii R; Akiyama F

INSTITUCIÓN / INSTITUTION:  - Division of Pathology, The Cancer Institute of Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan; Department of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan. Electronic address: tomo.osako@jfcr.or.jp.

RESUMEN / SUMMARY:  - OBJECTIVE: The one-step nucleic acid amplification (OSNA) assay can assess an entire lymph node and detect clinically relevant metastases quantified based on cytokeratin 19 (CK19) mRNA copy number. The OSNA assay of all sentinel lymph nodes (SNs) and non-sentinel nodes (non-SNs) allows for the accurate measurement  of tumour burden in either situation. We aim to reveal the usefulness of the OSNA assay regarding the prediction of non-SN metastasis. METHODS: The subjects consisted of 185 breast cancer patients who underwent axillary dissection after a metastatic SN biopsy and whose SNs and non-SNs were examined using the OSNA whole-node assay between 2009 and 2011. The non-SN tumour burden was classified as macrometastasis (CK19 mRNA 5000 copies/mul) or micrometastasis (250-5000 copies/mul). The relationship between SN and non-SN tumour burdens and predictors of non-SN metastasis were investigated. RESULTS: Among these 185 patients, 38 patients (20.5%) had macrometastasis and 58 (31.4%) had micrometastasis only in the non-SNs. Non-SN macrometastasis rates increased in direct proportion to the SN copy number: approximately 5% in patients with SNs with 250-500 copies; 20%, 500-5000 copies and 30%, 5000 copies. However, non-SN micrometastasis rates were  approximately 30% regardless of the SN copy number. In multivariate analyses, the mean SN copy number, number of macrometastatic SN and lymphovascular invasion were significant for identifying non-SN macrometastases. CONCLUSIONS: The SN tumour burden quantified using the OSNA assay predicts non-SN metastases. A novel mathematical model to predict the non-SN tumour burden can be generated using the results of the OSNA assay.

 

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[408]

TÍTULO / TITLE:  - Retraction Note to: Non-thermal Plasma Induces Apoptosis in Melanoma Cells via Production of Intracellular Reactive Oxygen Species.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Biomed Eng. 2013 Jan 12.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10439-013-0740-7

AUTORES / AUTHORS:  - Sensenig R; Kalghatgi S; Cerchar E; Fridman G; Shereshevsky A; Torabi B; Arjunan KP; Podolsky E; Fridman A; Friedman G; Azizkhan-Clifford J; Brooks AD

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, College of Medicine, Drexel University, Philadelphia, PA,  19102, USA.

 

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[409]

TÍTULO / TITLE:  - Use of potassium channel tetramerization domain-containing 12 as a biomarker for  diagnosis and prognosis of gastrointestinal stromal tumor.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hum Pathol. 2013 Jan 2. pii: S0046-8177(12)00381-4. doi: 10.1016/j.humpath.2012.10.013.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.humpath.2012.10.013

AUTORES / AUTHORS:  - Hasegawa T; Asanuma H; Ogino J; Hirohashi Y; Shinomura Y; Iwaki H; Kikuchi H; Kondo T

INSTITUCIÓN / INSTITUTION:  - Department of Surgical Pathology, Sapporo Medical University School of Medicine,  Chuo-ku, Sapporo 060-8543, Japan. Electronic address: hasetada@sapmed.ac.jp.

RESUMEN / SUMMARY:  - Previously, we showed that the expression of potassium channel tetramerization domain-containing 12 (KCTD12), which was discovered by a proteomics approach, is  associated with high-risk behavior of gastrointestinal stromal tumors (GISTs). Here, we examined the distribution and expression of this protein by immunostaining with a commercially available polyclonal KCTD12 antibody in GISTs  (n = 64) and other types of malignancy (n = 168) to clarify its diagnostic and clinical significance. Diffuse KCTD12 immunoreactivity was found in most GISTs (52 cases; 81%). KCTD12 expression was observed primarily in vascular endothelial cells, Purkinje cells of the cerebellum, and some neurons scattered throughout the cerebral cortex. KCTD12 was absent from not only the interstitial cells of Cajal but also interstitial cells of Cajal hyperplasia that was encountered incidentally in colon diverticulitis. KCTD12 immunostaining was also seen in malignant peripheral nerve sheath tumors (2/10 cases; 20%), synovial sarcomas (2/10; 20%), solitary fibrous tumor (1/8; 13%), angiosarcoma (1/7; 14%), and colon adenocarcinoma (1/24; 4%). In survival analyses, the 5-year recurrence-free survival rate of patients without KCTD12 expression was only 16.7% compared with  95.6% in those with KCTD12 expression (P < .0001). Ki-67 and KCTD12 were significant predictors of recurrence-free survival, and KCTD12 expression provided additional information about recurrence-free survival after accounting for Ki-67 status. Overall, KCTD12 expression was specific for GISTs from neoplastic and nonneoplastic adult tissues other than brain and served as a predictor of GIST recurrence. These findings suggest that KCTD12 is a useful and  reliable biomarker for both the diagnosis and prognosis of GIST.

 

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[410]

TÍTULO / TITLE:  - The potential of self-assembled, pH-responsive nanoparticles of mPEGylated peptide dendron-doxorubicin conjugates for cancer therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biomaterials. 2013 Feb;34(5):1613-23. doi: 10.1016/j.biomaterials.2012.11.007. Epub 2012 Nov 26.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biomaterials.2012.11.007

AUTORES / AUTHORS:  - She W; Luo K; Zhang C; Wang G; Geng Y; Li L; He B; Gu Z

INSTITUCIÓN / INSTITUTION:  - National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.

RESUMEN / SUMMARY:  - Nanoparticles, such as dendritic polymers, are currently investigated as excellent candidates for drug delivery vehicles. In this study, we report the preparation and characterization of mPEGylated peptide dendron-doxorubicin (dendron-DOX) conjugate based vehicle carrying 14.0 wt% (weight percent) of doxorubicin (DOX). Dynamic light scattering (DLS), scanning electron microscope (SEM) and transmission electron microscope (TEM) studies demonstrated the dendron-DOX conjugate self-assembled into nanoscale particles with neutral charged surface. The globular morphology and compact nanoparticle with diameter around 80 nm were observed by SEM and TEM. The release rates of DOX from the nanoparticle at pH 5.0 were much faster than those at pH 7.4 due to the pH-sensitive cleavage of the hydrazone bonds. The nanoparticle was shown to effectively kill cancer cells in vitro. Importantly, the nanoparticle resulted in strong antitumor activity and induced apoptosis on the 4T1 breast tumor model. In vivo toxicity evaluation demonstrated that drug-free dendron and drug-loading nanoparticle provided good biosafety in healthy or tumor-bearing mice, because no significant systematic toxicity was revealed via histological analysis. The functionalized peptide dendron-DOX conjugate based nanoparticle may be therefore  a potential candidate for drug delivery vehicle for cancer therapy.

 

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[411]

TÍTULO / TITLE:  - Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: results from a large, consecutive Norwegian series.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Oncol. 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 1093/annonc/mds614

AUTORES / AUTHORS:  - Merok MA; Ahlquist T; Royrvik EC; Tufteland KF; Hektoen M; Sjo OH; Mala T; Svindland A; Lothe RA; Nesbakken A

INSTITUCIÓN / INSTITUTION:  - Department of Gastrointestinal Surgery, Oslo University Hospital-Aker, Oslo.

RESUMEN / SUMMARY:  - BackgroundMicrosatellite instability (MSI) was suggested as a marker for good prognosis in colorectal cancer in 1993 and a systematic review from 2005 and a meta-analysis from 2010 support the initial observation. We here assess the prognostic impact and prevalence of MSI in different stages in a consecutive, population-based series from a single hospital in Oslo, Norway.Patients and methodsOf 1274 patients, 952 underwent major resection of which 805 were included in analyses of MSI prevalence and 613 with complete resection in analyses of outcome. Formalin-fixed tumor tissue was used for PCR-based MSI analyses.ResultsThe overall prevalence of MSI was 14%, highest in females (19%) and in proximal colon cancer (29%). Five-year relapse-free survival (5-year RFS)  was 67% and 55% (P = 0.030) in patients with MSI and MSS tumors, respectively, with the hazard ratio (HR) equal to 1.60 (P = 0.045) in multivariate analysis. The improved outcome was confined to stage II patients who had 5-year RFS of 74%  and 56% respectively (P = 0.010), HR = 2.02 (P = 0.040).Examination of 12 or more lymph nodes was significantly associated with proximal tumor location (P < 0.001).ConclusionsMSI has an independent positive prognostic impact on stage II colorectal cancer patients after complete resection.

 

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[412]

TÍTULO / TITLE:  - Photodynamic treatment induces cell death by apoptosis or autophagy depending on  the melanin content in two B16 melanoma cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar;29(3):1196-200. doi: 10.3892/or.2012.2190. Epub 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2190

AUTORES / AUTHORS:  - Sparsa A; Bellaton S; Naves T; Jauberteau MO; Bonnetblanc JM; Sol V; Verdier M; Ratinaud MH

INSTITUCIÓN / INSTITUTION:  - EA 3842 Cellular Homeostasis and Pathology, Faculty of Medicine, University of Limoges, 87025 Limoges Cedex, France.

RESUMEN / SUMMARY:  - Photodynamic therapy (PDT) is now a well-established treatment modality for cutaneous carcinomas and is based on the administration of a light-activated drug followed by illumination of the pathological area. The treatment of metastatic melanoma remains a therapeutic challenge. To define the possible role of melanin  in relative phototoxicity of 5-aminolevulinic acid (5-ALA), a photosensitizer used in PDT in vivo, we studied cell death in two variants (with or without melanin, B16F10 and B16G4F cells, respectively) of a melanoma cell line. Concentrations of 5-Ala up to 10 mM induced similar cytostatic effects in the B16G4F and B16F10 cells. PDT and high 5-ALA concentrations induced photocytotoxicity in both melanoma cell lines (at 10 mM for B16F10 cells and at 5 mM for B16G4F cells). Cell death corresponded to p53-dependent apoptotic signaling in pigmented B16F10 cells, whereas an autophagic response leading to a  caspase-independent death was detected in non-pigmented B16G4F cells. Therefore,  the PDT-induced cell death pathway appeared to correlate with melanin synthesis capacity in melanoma cells. To reduce the cytotoxicity of 5-ALA without irradiation, a low drug concentration could be used. Consequently, in combination with current therapeutics, a moderate concentration of 5-ALA and PDT may constitute a supplementary promising approach to eliminate metastatic melanoma.

 

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[413]

TÍTULO / TITLE:  - Potent antitumor activity of zoledronic acid-induced Vgamma9Vdelta2 T cells against primary effusion lymphoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2013 Jan 12. pii: S0304-3835(13)00005-0. doi: 10.1016/j.canlet.2012.12.021.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2012.12.021

AUTORES / AUTHORS:  - Goto H; Matsuda K; Srikoon P; Kariya R; Hattori S; Taura M; Katano H; Okada S

INSTITUCIÓN / INSTITUTION:  - Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Honjo,  Kumamoto, Japan.

RESUMEN / SUMMARY:  - Primary effusion lymphoma (PEL) is a subtype of aggressive and resistant non-Hodgkin lymphoma that occurs predominantly in patients with advanced AIDS. In this study, we examined the antitumor activity of zoledronic acid (Zol)-induced Vgamma9Vdelta2 T cells against PEL cells in vitro and in vivo. Vgamma9Vdelta2 T cells recognized endogenous mevalonate metabolites and MICA/B of PEL cell lines,  inducing cytotoxicity via granule exocytosis and TRAIL-mediated pathway. Vgamma9Vdelta2 T cells suppressed the development of PEL cells and existed in a PEL xenograft mouse model. These results show that immunotherapy with Zol-induced Vgamma9Vdelta2 T cells could demonstrate an efficient strategy for PEL.

 

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[414]

TÍTULO / TITLE:  - Increased expression of forkhead box M1 protein is associated with poor prognosis in clear cell renal cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):346. doi: 10.1007/s12032-012-0346-1. Epub 2012 Dec 22.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0346-1

AUTORES / AUTHORS:  - Wu XR; Chen YH; Liu DM; Sha JJ; Xuan HQ; Bo JJ; Huang YR

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, No. 145 Middle Shandong Road, Shanghai, 200001, China.

RESUMEN / SUMMARY:  - Forkhead box protein M1 (FoxM1) is crucial in the regulation of various biological processes, including cell proliferation, organogenesis, and angiogenesis. Overexpression of FoxM1 is associated with carcinogenesis. In this  study, immunohistochemistry was carried out to examine FoxM1 expression in clear  cell renal cell carcinoma (ccRCC), and these data were examined for correlation with clinicopathological parameters and prognosis. FoxM1 protein had high expression in 37 of 87 cases of ccRCC (42.5 %), which was significantly higher than in normal tissues, and FoxM1 overexpression was significantly associated with tumor stage (P = 0.005) and recurrence (P = 0.027). The Kaplan-Meier survival analysis demonstrated that FoxM1 expression was significantly associated with shorter recurrence-free survival and overall survival (P = 0.007 and P = 0.008, respectively). Multivariate analysis further demonstrated that FoxM1 was an independent prognostic factor for patients with ccRCC. So FoxM1 might be a potential molecular marker to predict the prognosis of patients with ccRCC.

 

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[415]

TÍTULO / TITLE:  - Immunohistochemical analysis of prognostic protein markers for primary localized  clear cell renal cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Invest. 2013 Jan;31(1):56-64. doi: 10.3109/07357907.2012.749267.

            ●● Enlace al texto completo (gratuito o de pago) 3109/07357907.2012.749267

AUTORES / AUTHORS:  - Weber T; Meinhardt M; Zastrow S; Wienke A; Fuessel S; Wirth MP

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Technical University of Dresden , Dresden , Germany,1.

RESUMEN / SUMMARY:  - Recurrence is not reliably predictable in localized clear cell renal cell carcinoma. Proteinmarkers could improve predictive accuracy. Tissue-microarrays from 132 patients with primary localized ccRCC were immunohistochemically analyzed for VHL, Ki67, p53, p21, survivin, and, for microvessel-density, UEA-1.  Nuclear stainings of Ki67, p21, and survivin were significantly associated with disease-specific survival and increased predictive ability from 74% to 76%, 77%,  and 78%, respectively in a multivariate model including T-stage and Fuhrman grade. A score-variable, combining Ki67-, p21-, and nS-staining identified a subset of patients with high risk of disease recurrence and increased predictive  ability in the multivariate model to 84%.

 

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[416]

TÍTULO / TITLE:  - High-grade prostate cancer and biochemical recurrence after radical prostatectomy among men using 5alpha-reductase inhibitors and alpha-blockers.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Prostate. 2013 Jan 17. doi: 10.1002/pros.22638.

            ●● Enlace al texto completo (gratuito o de pago) 1002/pros.22638

AUTORES / AUTHORS:  - Murtola TJ; Kujala PM; Tammela TL

INSTITUCIÓN / INSTITUTION:  - Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Department of Surgery, Central Finland Central Hospital, Jyvaskyla, Finland. teemu.murtola@uta.fi.

RESUMEN / SUMMARY:  - BACKGROUND: Two clinical trials have shown that users of 5alpha-reductase inhibitors finasteride and dutasteride (5-ARIs) have reduced overall prostate cancer risk, while the proportion of high-grade tumors is increased. We studied tumor characteristics, risk of biochemical recurrence and mortality after radical prostatectomy in 5-ARI and alpha-blocker users. METHODS: The study cohort consisted of 1,315 men who underwent radical prostatectomy at the Tampere University Hospital during 1995-2009. Biochemical relapse was defined as serum PSA >/= 0.2 ng/ml after the operation. Information on mortality and medication purchases was obtained from national registries. Cox proportional regression was  used to analyze hazard ratios (HRs) and 95% confidence intervals (95% CI) of biochemical relapse and death. RESULTS: The proportion of high-grade (Gleason 7-10) tumors was significantly elevated among men who had used 5-ARIs for 4 years or longer compared to the non-users (83.3% vs. 53.3%, respectively). Survival curves for biochemical relapse-free survival differed between long-term and short-term 5-ARI users, but the hazard ratio remained statistically non-significant. Risk of biochemical recurrence was elevated among alpha-blocker  users (HR 1.68, 95% CI 1.37-2.06), but in sensitivity analyses this was evident only in men using alpha-blockers after prostatectomy. Mortality was not associated with medication usage. CONCLUSIONS: Long-term users of finasteride or  dutasteride had more often high-grade prostate cancer. Our results suggest also worse progression-free survival. The association between risk of biochemical recurrence and post-operative alpha-blocker usage suggests that voiding or storage symptoms after prostatectomy may predict biochemical relapse. Prostate © 2013 Wiley Periodicals, Inc.

 

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[417]

TÍTULO / TITLE:  - Autophagy induced by p53-reactivating molecules protects pancreatic cancer cells  from apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Apoptosis. 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10495-012-0790-6

AUTORES / AUTHORS:  - Fiorini C; Menegazzi M; Padroni C; Dando I; Dalla Pozza E; Gregorelli A; Costanzo C; Palmieri M; Donadelli M

INSTITUCIÓN / INSTITUTION:  - Department of Life and Reproduction Sciences, Section of Biochemistry, University of Verona, Strada Le Grazie 8, 37134, Verona, Italy.

RESUMEN / SUMMARY:  - TP53 mutations compromising p53 transcriptional function occur in more than 50 %  of human cancers, including pancreatic adenocarcinoma, and render cancer cells more resistant to conventional therapy. In the last few years, many efforts have  been addressed to identify p53-reactivating molecules able to restore the wild-type transcriptionally competent conformation of the mutated proteins. Here, we show that two of these compounds, CP-31398 and RITA, induce cell growth inhibition, apoptosis, and autophagy by activating p53/DNA binding and p53 phosphorylation (Ser15), without affecting the total p53 amount. These effects occur in both wild-type and mutant p53 pancreatic adenocarcinoma cell lines, whereas they are much less pronounced in normal human primary fibroblasts. Furthermore, CP-31398 and RITA regulate the axis SESN1-2/AMPK/mTOR by inducing AMPK phosphorylation on Thr172, which has a crucial role in the autophagic response. The protective role of autophagy in cell growth inhibition by CP-31398  and RITA is supported by the finding that the AMPK inhibitor compound C or the autophagy inhibitors chloroquine or 3-methyladenine sensitize both pancreatic adenocarcinoma cell lines to the apoptotic response induced by p53-reactivating molecules. Our results demonstrate for the first time a survival role for autophagy induced by p53-reactivating molecules, supporting the development of an anti-cancer therapy based on autophagy inhibition associated to p53 activation.

 

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[418]

TÍTULO / TITLE:  - A small-molecule induces apoptosis and suppresses metastasis in pancreatic cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Pharm Sci. 2013 Jan 10. pii: S0928-0987(13)00002-X. doi: 10.1016/j.ejps.2012.12.023.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejps.2012.12.023

AUTORES / AUTHORS:  - Li D; Liu Z; Zhao W; Zheng X; Wang J; Wang E

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China.

RESUMEN / SUMMARY:  - Pancreatic cancer is one of the most malignant tumor diseases with the characters of aggressive growth and metastasis. With the inefficiency of the current therapeutics, new potential targets and new therapeutic agents for healing of pancreatic cancer are critically needed. We have previously found a small molecule, named 4-tert-butyl-2-[(cyclohexylamino) methyl]-6-methylphenol (TBMMP,  NSC number: 48160), which can freeze the intermediate of Ras-GTP hydrolysis in the open non-signaling conformation with high affinity and high specificity in silico. In this work, we studied the effect and mechanism of TBMMP on two pancreatic cancer cell lines, CFPAC-1 and BxPC-3. The results showed that TBMMP could restrain the growth of the pancreatic cancer cells with IC(50) value 84.3muM for CPFAC-1 and 94.5muM for BxPC-3, respectively. Additionally, TBMMP increased cytochrome c release, reduced mitochondrial membrane potential, activated caspase-3, -9, elevated ROS and increased expression of the Bax in the  pancreatic cancer cell lines. Collectively, the results indicated that TBMMP induced the apoptosis of pancreatic cancer cells through the mitochondrial pathway. Further, we also found that TBMMP could suppress the metastasis of both  pancreatic cancer cells in vitro. Taken together, we proposed that TBMMP might be a therapeutic potential lead for treating patients with pancreatic cancer.

 

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[419]

TÍTULO / TITLE:  - The crude extract of Corni Fructus induces apoptotic cell death through reactive  oxygen species-modulated pathways in U-2 OS human osteosarcoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Environ Toxicol. 2012 Dec 12. doi: 10.1002/tox.21832.

            ●● Enlace al texto completo (gratuito o de pago) 1002/tox.21832

AUTORES / AUTHORS:  - Liao CL; Hsu SC; Yu CC; Yang JS; Tang NY; Wood WG; Lin JG; Chung JG

INSTITUCIÓN / INSTITUTION:  - Graduate Institute of Chinese Medicine, China Medical University, Taichung 404, Taiwan, Republic of China.

RESUMEN / SUMMARY:  - Crude extract of Corni Fructus (CECF) has been used in Traditional Chinese medicine for the treatment of different diseases for hundreds of years. The purpose of this study was to investigate the cytotoxic effects of CECF on U-2 OS  human osteosarcoma cells. Flow cytometry was used for measuring the percentage of viable cells, cell-cycle distribution, apoptotic cells in sub-G1 phase, reactive  oxygen species (ROS), Ca(2+) levels, and mitochondrial membrane potential (DeltaPsi(m) ). Comet assay and 4’-6-diamidino-2-phenylindole staining were used  for examining DNA damage and condensation. Western blotting was used to examine apoptosis-associated protein levels in U-2 OS cells after exposed to CECF. Immunostaining and confocal laser system microscope were used to examine protein  translocation after CECF incubation. CECF decreased the percentage of viability,  induced DNA damage and DNA condensation, G(0) /G(1) arrest, and apoptosis in U-2  OS cells. CECF-stimulated activities of caspase-8, caspase-9, and caspase-3, ROS, and Ca(2+) production, decreased DeltaPsi(m) levels of in U-2 OS cells. CECF increased protein levels of caspase-3, caspase-9, Bax, cytochrome c, GRP78, AIF,  ATF-6alpha, Fas, TRAIL, p21, p27, and p16 which were associated with cell-cycle arrest and apoptosis. These findings suggest that CECF triggers apoptosis in U-2  OS cells via ROS-modulated caspase-dependent and -independent pathways. © 2012  Wiley Periodicals, Inc. Environ Toxicol, 2012.

 

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[420]

TÍTULO / TITLE:  - The Tumor Suppressor, p53, Contributes to Radiosensitivity of Lung Cancer Cells by Regulating Autophagy and Apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Biother Radiopharm. 2012 Dec 26.

            ●● Enlace al texto completo (gratuito o de pago) 1089/cbr.2012.1297

AUTORES / AUTHORS:  - Guanghui C; Dejuan K; Xue H; Bing L; Mengzi H; Nan L; Shumei M; Xiaodong L

INSTITUCIÓN / INSTITUTION:  - 1 Department of Radiation Oncology, China-Japan Union Hospital, Jilin University  , Changchun, China .

RESUMEN / SUMMARY:  - Abstract Purpose: Cell death is one of the most important endpoints of radiosensitivity. The tumor suppressor p53 participates not only in regulation of apoptosis, but also in autophagy mechanism. In this study, H1299-P53 (with wild-type p53) and H1299-175H (with mutant 175H) were used, and the effects of p53 on radiosensitivity were analyzed. Methods: Cell models with different p53 status were established by gene engineering, and cell viability was examined by colony formation assay, and cell counting kit-8 (CCK-8), 3-Methyladenine, and Z-VAD were used to block autophagy and apoptosis, respectively. Western blot was  used to detect protein expression; monodansylcadaverine (MDC) staining was used to analyze autophagy rate; DAPI/Propidium Iodide (PI) staining and flow cytometry were used to assess apoptosis and necrosis. Results: In parental H1299, H1299-P53, and H1299-175H cells, radiosensitivity exhibited different by colony formation and CCK-8 assay (D0: 1.764 Gy, 1.407 Gy and 1.695 Gy; Dq: 2.977 Gy, 1.199 Gy and 2.312 Gy in turn). The radiosensitization of p53 was associated with the increase of MDM2 and P21 expression. The ionizing radiation (IR)-induced apoptosis was significant in H1299-P53 compared with in H1299 and H199-175H (p<0.05) by flow cytometry, and the expression of cleaved-caspase3 was increased  in H1299-P53 cells. While the IR-induced autophagy was significant in H1299 cells (p<0.01) and decreased in H1299-P53 and H1299-175H cells (p<0.01) by MDC staining, the expression of MAPLC3II and Beclin-1 increased in H1299, but not in  H1299-p53 and H199-175H cells. The IR-induced cell survival was significantly increased by Z-VAD-FMK and decreased by 3MA in H1299-P53 cells; IR- induced autophagy was significantly increased by Z-VAD-FMK in H1299-P53 cells (p<0.01), but not changed in H1299 cells. Conclusion: p53 could regulate radiosensitivity by inhibiting autophagy and activating apoptosis; autophagy provides a prosurvival mechanism, and p53 potently abrogated the IR-induced autophagy, while mutant 175H shown no effect on radiosensitivity, suggesting that individual treatment strategies should be based on p53 status in patients.

 

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[421]

TÍTULO / TITLE:  - Overexpression of Smac Promotes Cisplatin-Induced Apoptosis by Activating Caspase-3 and Caspase-9 in Lung Cancer A549 Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Biother Radiopharm. 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 1089/cbr.2012.1261

AUTORES / AUTHORS:  - Qin S; Yang C; Wang X; Xu C; Li S; Zhang B; Ren H

INSTITUCIÓN / INSTITUTION:  - 1 Department of Thoracic Surgery, First Affiliated Hospital, School of Medicine,  Xi’an Jiaotong University , Xi’an, P.R. China.

RESUMEN / SUMMARY:  - Abstract Second mitochondrial-derived activator of caspase (Smac) plays crucial roles in mitochondrial apoptosis pathways and promotes chemotherapy-induced apoptosis. In this study, Smac levels were examined in various lung cancer cell lines, and the effects of overexpressed Smac in the nonsmall-cell lung cancer cell line A549 were assayed by stable transfection of Smac. Subsequently, MTT assays, cell counting, and flow cytometry were applied to show that overexpression of Smac inhibits cell viability and cell growth and enhances apoptosis after cisplatin treatment. Western blotting was performed before and after cisplatin treatment to demonstrate that drug treatment could release Smac from mitochondria into the cytosol and promote apoptosis by activating caspase-3  and caspase-9. Promotion of apoptosis by cytosolic Smac could be blocked by pretreating cells with the caspase-9 inhibitor z-LEHD-FMK. Our findings indicate  that overexpressed Smac significantly inhibited A549 cell growth and promoted apoptosis following cisplatin treatment due to the release of Smac from mitochondria into the cytosol, which increased the activities of caspase-3 and caspase-9.

 

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[422]

TÍTULO / TITLE:  - Biomarker Analysis of Neoadjuvant Doxorubicin/Cyclophosphamide Followed by Ixabepilone or Paclitaxel in Early-stage Breast Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-1359

AUTORES / AUTHORS:  - Horak CE; Pusztai L; Xing G; Trifan OC; Saura C; Tseng LM; Chan S; Welcher R; Liu D

INSTITUCIÓN / INSTITUTION:  - Clinical Biomarkers - Oncology, Bristol-Myers Squibb.

RESUMEN / SUMMARY:  - Background: Predictive biomarkers offer the potential to improve the benefit:risk ratio of a therapeutic agent. Ixabepilone achieves comparable pathologic complete response (pCR) rates to other active drugs in the neoadjuvant setting. This phase II trial was designed to investigate potential biomarkers that differentiate response to this agent. Patients and methods: Women with untreated, histologically-confirmed primary invasive breast adenocarcinoma received neoadjuvant doxorubicin/cyclophosphamide, followed by 1:1 randomization to ixabepilone (n = 148) or paclitaxel (n = 147). Rates of pCR were compared between treatment arms based on pre-defined biomarker sets: TUBB3, TACC3 and CAPG gene expression, a 20- and 26-gene expression model, MDR1 protein expression and other potential markers of sensitivity. betaIII-tubulin protein expression is reported  separately, but is referred to here for completeness. All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis prior to chemotherapy. Gene expression profiling data was used for molecular subtyping. RESULTS: There was no significant difference in the rate of pCR in both treatment arms in betaIII-tubulin-positive patients. Higher pCR rates were observed among betaIII-tubulin-positive patients compared with betaIII-tubulin-negative patients. Furthermore, no correlation was evident between TUBB3, TACC3 and CAPG gene expression, MDR1 protein expression, multi-gene expression models, and the efficacy of ixabepilone or paclitaxel, even within the estrogen-receptor-negative subset. CONCLUSION: These results indicate that betaIII-tubulin protein and mRNA  expression, MDR1 protein expression, TACC3 and CAPG gene expression, and multi-gene expression models (20- and 26-gene) are not predictive markers for differentiating treatment benefit between ixabepilone and paclitaxel in early-stage breast cancer.

 

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[423]

TÍTULO / TITLE:  - Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 15;108(1):72-81. doi: 10.1038/bjc.2012.559. Epub 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2012.559

AUTORES / AUTHORS:  - Shen YC; Ou DL; Hsu C; Lin KL; Chang CY; Lin CY; Liu SH; Cheng AL

INSTITUCIÓN / INSTITUTION:  - 1] Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan [2] Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan [3] Department Medical Research, National Taiwan University Hospital, Taipei, Taiwan [4] National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.

RESUMEN / SUMMARY:  - Background:Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma (HCC). The bioenergetic propensity of cancer cells has been correlated to anticancer drug resistance, but such correlation is unclear in sorafenib resistance of HCC.Methods:Six sorafenib-naive HCC cell lines and one sorafenib-resistant HCC cell line (Huh-7R; derived from sorafenib-sensitive Huh-7) were used. The bioenergetic propensity was calculated by measurement of lactate in the presence or absence of oligomycin. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, and siRNA of hexokinase 2 (HK2) were used to target relevant pathways of cancer metabolism. Cell viability, mitochondrial membrane potential, and sub-G1 fraction were measured for in vitro  efficacy. Reactive oxygen species (ROS), adenosine triphosphate (ATP) and glucose uptake were also measured. A subcutaneous xenograft mouse model was used for in vivo efficacy.Results:The bioenergetic propensity for using glycolysis correlated with decreased sorafenib sensitivity (R(2)=0.9067, among sorafenib-naive cell lines; P=0.003, compared between Huh-7 and Huh-7 R). DCA reduced lactate production and increased ROS and ATP, indicating activation of oxidative phosphorylation (OXPHOS). DCA markedly sensitised sorafenib-resistant HCC cells to sorafenib-induced apoptosis (sub-G1 (combination vs sorafenib): Hep3B, 65.4+/-8.4% vs 13+/-2.9%; Huh-7 R, 25.3+/- 5.7% vs 4.3+/-1.5%; each P<0.0001), whereas siRNA of HK2 did not. Sorafenib (10 mg kg(-1) per day) plus DCA (100 mg kg(-1) per day) also resulted in superior tumour regression than sorafenib alone  in mice (tumour size: -87% vs -36%, P<0.001).Conclusion:The bioenergetic propensity is a potentially useful predictive biomarker of sorafenib sensitivity, and activation of OXPHOS by PDK inhibitors may overcome sorafenib resistance of HCC.

 

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[424]

TÍTULO / TITLE:  - Combination of AT-101/cisplatin overcomes chemoresistance by inducing apoptosis and modulating epigenetics in human ovarian cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Biol Rep. 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11033-012-2469-z

AUTORES / AUTHORS:  - Karaca B; Atmaca H; Bozkurt E; Kisim A; Uzunoglu S; Karabulut B; Sezgin C; Sanli UA; Uslu R

INSTITUCIÓN / INSTITUTION:  - Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine,  Ege University, 35100, Bornova, Izmir, Turkey, karacaburcak@hotmail.com.

RESUMEN / SUMMARY:  - We investigated the effects of AT-101/cisplatin combination treatment on the expression levels of apoptotic proteins and epigenetic events such as DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzyme activities in OVCAR-3 and MDAH-2774 ovarian cancer cells. XTT cell viability assay was used to  evaluate cytotoxicity. For showing apoptosis, both DNA Fragmentation and caspase  3/7 activity measurements were performed. The expression levels of apoptotic proteins were assessed by human apoptosis antibody array. DNMT and HDAC activities were evaluated by ELISA assay and mRNA levels of DNMT1 and HDAC1 genes were quantified by qRT-PCR. Combination of AT-101/cisplatin resulted in strong synergistic cytotoxicity and apoptosis in human ovarian cancer cells. Combination treatment reduced some pivotal anti-apoptotic proteins such as Bcl-2, HIF-1A, cIAP-1, XIAP in OVCAR-3 cells, whereas p21, Bcl-2, cIAP-1, HSP27, Clusterin and XIAP in MDAH-2774 cells. Among the pro-apoptotic proteins, Bad, Bax, Fas, phospho-p53 (S46), Cleaved caspase-3, SMAC/Diablo, TNFR1 and Cytochrome c were induced in OVCAR-3 cells, whereas, Bax, TRAILR2, FADD, p27, phospho-p53 (S46), Cleaved caspase-3, Cytochrome c, SMAC/Diablo and TNFR1 were induced in MDAH-2774  cells. Combination treatment also inhibited both DNMT and HDAC activities and also mRNA levels in both ovarian cancer cells. AT-101 exhibits great potential in sensitization of human ovarian cancer cells to cisplatin treatment in vitro, suggesting that the combination of AT-101 with cisplatin may hold great promise for development as a novel chemotherapeutic approach to overcome platinum-resistance in human ovarian cancer.

 

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[425]

TÍTULO / TITLE:  - PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pharmacol Res. 2013 Jan 23. pii: S1043-6618(13)00015-7. doi: 10.1016/j.phrs.2013.01.005.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.phrs.2013.01.005

AUTORES / AUTHORS:  - Kim W; Youn H; Kwon T; Kang J; Kim E; Son B; Yang HJ; Jung Y; Youn B

INSTITUCIÓN / INSTITUTION:  - Department of Biological Sciences, Pusan National University, Busandaehak-ro 63,  Geumjeong-gu, Busan, 609-735, South Korea. Electronic address: kkhjjang01@pusan.ac.kr.

RESUMEN / SUMMARY:  - Radiotherapy plays a critical role in the treatment of non-small cell lung cancer (NSCLC). However, radioresistance is a major barrier against increasing the efficiency of radiotherapy for NSCLC. To understand the mechanisms underlying NSCLC radioresistance, we previously focused on the potential involvement of PIM1, PRAS40, FOXO3a, 14-3-3, and protein phosphatases. Among these proteins, PIM1 functioned as an oncogene and was found to act as a crucial mediator in radioresistant NSCLC cells. Therefore, we investigated the use of PIM1-specific inhibitors as novel therapeutic drugs to regulate radiosensitivity in NSCLC. After structure-based drug selection, SGI-1776, ETP-45299, and tryptanthrin were  selected as candidates of PIM1 inhibitors that act as radiosensitizers. With irradiation, these drugs inhibited only PIM1 kinase activity without affecting PIM1 mRNA/protein levels or cellular localization. When PIM1 kinase activity was  suppressed by these inhibitors, PRAS40 was not phosphorylated. Consequently, unphosphorylated PRAS40 did not form trimeric complexes with 14-3-3 and FOXO3a, leading to increased nuclear localization of FOXO3a. Nuclear FOXO3a promoted the  expression of pro-apoptotic proteins such as Bim and FasL, resulting in a radiosensitizing effect on radioresistant NSCLC cells. Moreover, an in vivo xenograft mouse model confirmed this radiosensitizing effect induced by PIM1 inhibitors. In these model systems, tumor volume was significantly reduced by a combinational treatment with irradiation and PIM1 inhibitors compared to irradiation alone. Taken together, our findings provided evidence that PIM1-specific inhibitors, SGI-1776, ETP-45299, and tryptanthrin, can act as novel radiosensitizers to enhance the efficacy of radiotherapy by inhibiting irradiation-induced signaling pathway associated with radioresistance.

 

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[426]

TÍTULO / TITLE:  - Hydroxyl radical (.OH) played a pivotal role in oridonin-induced apoptosis and autophagy in human epidermoid carcinoma A431 cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biol Pharm Bull. 2012;35(12):2148-59.

AUTORES / AUTHORS:  - Yu Y; Fan SM; Song JK; Tashiro S; Onodera S; Ikejima T

INSTITUCIÓN / INSTITUTION:  - China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.

RESUMEN / SUMMARY:  - Oridonin, a diterpenoid compound extracted and purified from Rabdosia rubescen, has been reported to induce tumor cell apoptosis through tyrosine kinase pathway. To further examine the mechanism of oridonin, we selected human epidermoid carcinoma A431 cell as a test object. Besides apoptosis, oridonin also induced A431 cell autophagy, and this autophagy antagonized apoptosis and played a protective role for A431 cells. Reactive oxygen species (ROS) played a pivotal role in induction of cytotoxicity. Therefore, a ROS scavenger, N-acetylcysteine (NAC) combined with oridonin was appiled. Results of morphologic observation, flow cytometric analysis and Western blot analysis showed that NAC could significantly reverse both ROS generation and down-regulation of mitochondrial membrane potential in oridonin treated cells. NAC inhibited oridonin induced apoptosis through both the intrinsic and extrinsic apoptotic pathways. NAC effectively inhibited both oridonin-induced apoptosis and autophagy by reducing intracellular oxidative stress. To further examine the mechanism of ROS, exogenous enzyme antioxidants (superoxide dismutase (SOD), catalase (CAT)) and non-enzyme antioxidants (glutathione (GSH)) were applied to detect the effect of  oridonin on ROS generation. Only GSH exerted a similar role with NAC, suggesting  that hydroxyl radical (.OH) played the major role in oridonin-induced cell death. Oridonin could decrease the GSH level in A431 cells in a dose-dependent manner. In addition, after treatment with .OH donor, Fenton reagent, the changes in A431cells were similar to the results of oridonin treatment. All the results proved that .OH played the pivotal role in oridonin induced apoptosis and autophagy in A431 cells.

 

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[427]

TÍTULO / TITLE:  - Targeting matrix metalloproteinases: design of a bifunctional inhibitor for presentation by tumour-associated galectins.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chemistry. 2013 Feb 4;19(6):1896-902. doi: 10.1002/chem.201203794. Epub 2012 Dec  27.

            ●● Enlace al texto completo (gratuito o de pago) 1002/chem.201203794

AUTORES / AUTHORS:  - Bartoloni M; Dominguez BE; Dragoni E; Richichi B; Fragai M; Andre S; Gabius HJ; Arda A; Luchinat C; Jimenez-Barbero J; Nativi C

INSTITUCIÓN / INSTITUTION:  - Department of Chemistry, University of Florence, Via della Lastruccia, 13 50019 Sesto F.no Firenze (Italy).

RESUMEN / SUMMARY:  - A new strategy to exploit galectin presence to target matrix metalloproteinases (MMPs) is presented. A bifunctional conjugate with lactose and an inhibitor for MMPs is able to bind MMP and Gal-3 simultaneously. This compound might allow the  lectin to attract the MMP inhibitor to the tumour site and to block protumoural activities of the lectin at the same time.

 

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[428]

TÍTULO / TITLE:  - Performance comparison of machine learning methods for prognosis of hormone receptor status in breast cancer tissue samples.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Comput Methods Programs Biomed. 2013 Jan 19. pii: S0169-2607(12)00314-8. doi: 10.1016/j.cmpb.2012.12.005.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.cmpb.2012.12.005

AUTORES / AUTHORS:  - Kalinli A; Sarikoc F; Akgun H; Ozturk F

INSTITUCIÓN / INSTITUTION:  - Erciyes University, Engineering Faculty, Department of Computer Engineering, 38039 Kayseri, Turkey. Electronic address: kalinlia@erciyes.edu.tr.

RESUMEN / SUMMARY:  - We examined the classification and prognostic scoring performances of several computer methods on different feature sets to obtain objective and reproducible analysis of estrogen receptor status in breast cancer tissue samples. Radial basis function network, k-nearest neighborhood search, support vector machines, naive bayes, functional trees, and k-means clustering algorithm were applied to the test datasets. Several features were employed and the classification accuracies of each method for these features were examined. The assessment results of the methods on test images were also experimentally compared with those of two experts. According to the results of our experimental work, a combination of functional trees and the naive bayes classifier gave the best prognostic scores indicating very good kappa agreement values (kappa=0.899 and kappa=0.949, p<0.001) with the experts. This combination also gave the best dichotomization rate (96.3%) for assessment of estrogen receptor status. Wavelet  color features provided better classification accuracy than Laws texture energy and co-occurrence matrix features.

 

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[429]

TÍTULO / TITLE:  - TGF-beta1 Secreted by Hepatocellular Carcinoma Induces the Expression of the Foxp3 Gene and Suppresses Antitumor Immunity in the Tumor Microenvironment.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Dig Dis Sci. 2013 Jan 30.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10620-012-2550-4

AUTORES / AUTHORS:  - Wang Y; Deng B; Tang W; Liu T; Shen X

INSTITUCIÓN / INSTITUTION:  - The Department of Gastroenterology of Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, People’s Republic of China.

RESUMEN / SUMMARY:  - AIM: The purpose of this study was to explore the mechanisms of TGF-beta1 mediated immunosuppression in tumor stroma. METHODS: The expression of TGF-beta1  was investigated in Huh7, Hep 3B, SGC-7901, Eca-109 and Hepa1-6 cell lines using  immunofluorescence. Knocked-down TGF-beta1 of the Hepa1-6 cell line was established through lentivirus-based RNA interference. The interference efficiency of the TGF-beta1 gene was tested by real-time PCR and ELISA; the expression of Foxp3, IFN-gamma and CD83 in CD4(+), CD8(+) or dendritic cells was  examined via flow cytometry; and the tumorigenic ability of the cancer cells was  investigated in the animal experiments. RESULTS: The diverse digestive cancer cells were found to secrete TGF-beta1, mRNA of which was knocked down by 78 % thanks to lentivirus-based interference in Hepa1-6 cells. Flow cytometry showed that CD4(+)CD25(+)Foxp3(+) regulatory T cells significantly increased in hepatocellular carcinoma patients when compared with those in the healthy controls. The supernatant from Hepa1-6 cells and recombinant TGF-beta1 significantly induced the expression of Foxp3 gene in vitro, while that from sh TGF-beta1 Hepa1-6 cells restored it. Hepa1-6 cells inhibited IFN-gamma and CD83 expression in CD8(+) or dendritic cells by secreting TGF-beta1. The animal experiments indicated that the knockdown TGF-beta1 gene impaired the tumorigenic  ability of Hepa1-6 cells. CONCLUSION: TGF-beta1, expressed in cancer cells, might be a potential therapeutic target for cancer treatment.

 

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[430]

TÍTULO / TITLE:  - Loss of trefoil factor 1 is regulated by DNA methylation and is an independent predictive factor for poor survival in advanced gastric cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Mar;42(3):894-902. doi: 10.3892/ijo.2013.1759. Epub 2013 Jan 3.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2013.1759

AUTORES / AUTHORS:  - Tanaka T; Nakamura J; Kitajima Y; Kai K; Miyake S; Hiraki M; Ide T; Koga Y; Noshiro H

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.

RESUMEN / SUMMARY:  - Trefoil factor 1 (TFF1) is considered to be a tumor suppressor gene in gastric cancer. However, the role of TFF1 expression and its regulation in gastric cancer patients remain unclear. The aims of this study were to clarify the clinical significance of TFF1 and to determine its regulatory mechanisms. We assessed the  immunohistochemical expression of TFF1 in 182 gastric cancer patients and examined whether or not TFF1 is associated with the clinicopathological factors and patient survival. In vitro study using TFF1 knockdown gastric cancer cells evaluated the role of TFF1 in cancer invasion. Bisulfite sequencing was performed to assess DNA methylation of TFF1 in cells and resected tissues. Patients with low expression of TFF1 showed a significantly deeper invasion of the tumor than those with high expression (p=0.037). Low expression of TFF1 was also associated  with a poor survival (p=0.029) in 108 patients who were treated by surgery alone. Both TFF1 expression and lymph node metastasis are independent predictive factors for diseasespecific survival in a multivariate analysis. In an in vitro study, invasive power of the cells was significantly increased in the TFF1deficient cells compared with the control cells. Bisulfate sequencing showed that TFF1 expression is strongly dependent on DNA methylation in both gastric cancer cells  and tissues. Interestingly, methylation status of two specific CpG sites, which are located close to a TATA box and hypoxia response element (HRE), determined the TFF1 expression in the resected tissues. TFF1 expression is silenced by DNA methylation and is associated with tumor invasion and a poor survival in gastric  cancer patients. The expression andor methylation status of TFF1 may, therefore,  serve as a useful biomarker for predicting survival in patients with advanced gastric cancer.

 

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[431]

TÍTULO / TITLE:  - ApoG2 as the most potent gossypol derivatives inhibits cell growth and induces apoptosis on gastric cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biomed Pharmacother. 2012 Nov 19. pii: S0753-3322(12)00108-4. doi: 10.1016/j.biopha.2012.10.016.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biopha.2012.10.016

AUTORES / AUTHORS:  - Xin J; Zhan YH; Xia LM; Zhu HW; Nie YZ; Liang JM; Tian J

INSTITUCIÓN / INSTITUTION:  - School of Life Sciences and Technology, Xidian University, Xi’an, 710071 Shaanxi, China.

RESUMEN / SUMMARY:  - Gastric cancer is one of the most common types of malignancies and proteins from  the Bcl-2 family are highly expressed in human gastric cancer. Apogossypolone (ApoG2), the most potent gossypol derivative, has been defined as a novel small-molecule inhibitor of anti-apoptotic Bcl-2 family proteins. However, whether or not it can inhibit the growth and proliferation of gastric cancer cell lines has not been demonstrated to date. Here, we assessed the effects of anti-growth of ApoG2 on gastric cancer cell lines in vitro and explored the possible molecular mechanisms of ApoG2. Using the MTT assay and flow cytometry, we found that ApoG2 has the significant anti-growth effect on MKN28, MKN45 and AGS cell lines in a time- and dose-dependent manner. Compared to (-)-gossypol, MTT assay and flow cytometry results showed that anti-growth effect of ApoG2 is inferior, but the colony formation ability of ApoG2 is superior. Furthermore, western blot results revealed that ApoG2 inhibits the growth and proliferation of gastric cancer cells by down-regulating of Bcl-2 protein expression, up-regulating of Bax and activating of Caspase-3. Taken together, albeit the ApoG2 inferior to (-)-gossypol in many ways on gastric cancer in vitro, our results suggest that ApoG2 could effectively inhibit the growth and proliferation of gastric cancer cell lines through the mitochondrial pathway of apoptosis.

 

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[432]

TÍTULO / TITLE:  - c-Cbl shRNA-expressing adenovirus sensitizes TRAIL-induced apoptosis in prostate  cancer DU-145 through increases of DR4/5.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Gene Ther. 2013 Jan 11. doi: 10.1038/cgt.2012.88.

            ●● Enlace al texto completo (gratuito o de pago) 1038/cgt.2012.88

AUTORES / AUTHORS:  - Kim SY; Kim JH; Song JJ

INSTITUCIÓN / INSTITUTION:  - 1] Institute for Cancer Research, College of Medicine, Yonsei University, Seoul,  Korea [2] Brain Korea 21 Project for Medical Science, College of Medicine, Yonsei University, Seoul, Korea.

RESUMEN / SUMMARY:  - We previously demonstrated that the downregulation of Casitas B-lineage lymphoma  (c-Cbl) can sensitize tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in two different ways. One way is to block the rapid degradation of TRAIL receptors, which can sustain TRAIL-induced apoptosis for a long time. Here, we designed a replication-defective adenovirus expressing the short hairpin RNA (shRNA) against c-Cbl to test the possibility of developing a cancer gene therapy that can act as a sensitizer of TRAIL. As expected from the results of our previous study that used a stable cell line with downregulated c-Cbl, infection with the c-Cbl shRNA-expressing adenovirus led to an increase in the death receptor 4 (DR4) and DR5 levels, which is known to be a cause for the increase of TRAIL-induced apoptosis. In conclusion, we demonstrated that c-Cbl shRNA-expressing adenovirus is able to sensitize TRAIL-induced apoptosis in vivo  as well as in vitro.Cancer Gene Therapy advance online publication, 11 January 2013; doi:10.1038/cgt.2012.88.

 

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[433]

TÍTULO / TITLE:  - Synergistic effects of histone deacetylase inhibitor in combination with mTOR inhibitor in the treatment of prostate carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Med. 2013 Feb;31(2):339-46. doi: 10.3892/ijmm.2012.1221. Epub 2012 Dec  21.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijmm.2012.1221

AUTORES / AUTHORS:  - Thelen P; Krahn L; Bremmer F; Strauss A; Brehm R; Loertzer H

INSTITUCIÓN / INSTITUTION:  - Department of Urology, University Medical Center Gottingen, Georg-August-University, D-37075 Gottingen, Germany.

RESUMEN / SUMMARY:  - The aim of this study was to elucidate whether the treatment of a prostate carcinoma cell line (LNCaP) and LNCaP-derived tumors with the histone deacetylase (HDAC) inhibitor valproate in combination with the mammalian target of rapamycin  (mTOR) inhibitor temsirolimus resulted in synergistic effects on cell proliferation and tumor growth. LNCaP cells were treated with valproate, temsirolimus or a combination of both. The proliferation rates and the expression of key markers of tumorigenesis were evaluated. In in vivo experiments, LNCaP cells were implanted into immune-suppressed male nude mice. Mice were treated with valproate (per os), temsirolimus (intravenously) or with a combination of both. Tumor volumes were calculated and mRNA expression was quantified. The incubation of LNCaP cells with the combination of valproate and temsirolimus resulted in a decrease of cell proliferation with an additive effect of both drugs in comparison to the single treatment. In particular, the combined application of valproate and temsirolimus led to a significant upregulation of insulin-like growth factor-binding protein-3 (IGFBP-3), which mediates apoptosis  and inhibits tumor cell proliferation. In the mouse model, we found no significant differences in tumor growth between the different treatment arms but  immunohistological analyses showed that tumors treated with a combination of valproate and temsirolimus, but not with the single drugs alone, exhibited a significant lower proliferation capacity.

 

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[434]

TÍTULO / TITLE:  - Comparison of EGFR and KRAS mutations in primary and unpaired metastatic lung adenocarcinoma with potential chemotherapy effect.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hum Pathol. 2013 Jan 18. pii: S0046-8177(12)00397-8. doi: 10.1016/j.humpath.2012.10.016.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.humpath.2012.10.016

AUTORES / AUTHORS:  - Munfus-McCray D; Cui M; Zhang Z; Gabrielson E; Askin F; Li QK

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287.

RESUMEN / SUMMARY:  - Several recent studies have suggested that EGFR and KRAS mutations may be different in primary and metastatic tumors. It is also not well studied whether or not conventional chemotherapy has any effect on EGFR or KRAS mutations. In this study, we compared EGFR and KRAS mutations in primary and unrelated metastatic lung adenocarcinomas from retrospectively collected clinical cases. We also examined the potential effect of chemotherapy on EGFR and KRAS mutations in  these 2 groups based on available clinical information. Using Johns Hopkins Hospital archives, 379 lung adenocarcinomas with EGFR and KRAS mutational analyses were included. Mutational status was determined by sequencing exons 18 to 21 of EGFR and codons 12 and 13 of KRAS. Clinical information was correlated.  The overall mutational rates in primary and metastatic tumors were comparable. In 213 primary tumors, there was no significant difference of EGFR and KRAS mutational rates in the prechemotherapy and postchemotherapy groups (P > .05), whereas in 166 metastatic tumors, EGFR and KRAS mutations were 12.8% and 36.1% in the prechemotherapy group and 27.3% and 18.2% in the postchemotherapy group (P <  .05). Although our study is an unpaired study, it suggests that mutational status in metastatic tumors may need to be tested, especially if the patient had chemotherapy before the test. Additional studies are needed to further investigate the mechanism and clinical significance of the findings.

 

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[435]

TÍTULO / TITLE:  - Lx2-32c, a novel taxane derivative, exerts anti-resistance activity by initiating intrinsic apoptosis pathway in vitro and inhibits the growth of resistant tumor in vivo.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biol Pharm Bull. 2012;35(12):2170-9.

AUTORES / AUTHORS:  - Zhou Q; Li Y; Jin J; Lang L; Zhu Z; Fang W; Chen X

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.

RESUMEN / SUMMARY:  - Resistance to anticancer drugs is a major obstacle to successful chemotherapy. Thus, the exploration of new drugs and strategies in combating resistance is of great importance. In this study, we investigated the anti-tumor drug resistance (anti-resistance for short) activity of Lx2-32c, a novel taxane, and its possible mechanisms. Lx2-32c was cytotoxic to various drug-resistant tumor cell lines, and significantly suppressed the growth of tumor xenografts in paclitaxel-resistant MX-1 nude mice. It promoted microtubule polymerization and G(2)/M phase arrest in MX-1/T cells. Moreover, it induced typical apoptotic characteristics indicated by morphological changes and DNA fragmentation. Apoptosis was associated with loss of mitochondrial membrane potential, enhancement of mitochondrial cytochrome c and apoptosis-inducing factor (AIF) release, elevation of the Bax/Bcl-2 ratio, activation of caspase-9,-3 but not caspase-8 and Fas/FasL, and degradation of poly(ADP-ribose) polymerase (PARP). In conclusion, Lx2-32c is an effective microtubule-stabilizing agent in overcoming paclitaxel resistance by inducing apoptosis via the intrinsic apoptotic pathway. It also displayed robust anti-paclitaxel-resistance activity in vivo. Therefore, these findings provide new insight into the strategy to overcome resistance by manipulating dysregulated apoptosis pathway.

 

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[436]

TÍTULO / TITLE:  - Enhancement of cisplatin-induced apoptosis by beta-elemene in resistant human ovarian cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):424. doi: 10.1007/s12032-012-0424-4. Epub 2013 Jan 1.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0424-4

AUTORES / AUTHORS:  - Li QQ; Lee RX; Liang H; Zhong Y; Reed E

INSTITUCIÓN / INSTITUTION:  - Beihai Institute of Endocrine and Metabolic Diseases, Beihai, 536000, Guangxi, China, quentinli2004@yahoo.com.

RESUMEN / SUMMARY:  - beta-Elemene is a new anticancer compound extracted from the Chinese medicinal herb Rhizoma zedoariae. We have shown previously that beta-elemene increases cisplatin cytotoxicity and enhances cisplatin sensitivity via blocking cell cycle progression at G2/M phase in resistant ovarian tumor cells. In the current study, we asked whether beta-elemene-augmented cisplatin activity in ovarian carcinoma cells is mediated through the induction of apoptosis. Here, we show that beta-elemene triggered apoptotic cell death in chemoresistant human ovarian cancer A2780/CP and MCAS cells in a dose- and time-dependent fashion, as assessed by six different apoptosis assays. Intriguingly, beta-elemene was a stronger inducer of apoptosis than cisplatin in this model system, and a synergistic effect on induction of cell death was observed when the tumor cells were treated  with both agents. Furthermore, beta-elemene plus cisplatin exposure significantly disrupted the mitochondrial transmembrane potential (DeltaPsi (m)) and increased  the release of cytochrome c from mitochondria into the cytoplasm. The combination treatment with both compounds also induced increases in caspase-3/8/9 activities  and caspase-9 cleavage, enhanced protein expression of Bax and phosphorylation of Bcl-2 at Ser-70, and reduced the protein levels of Bcl-2 and Bcl-X(L) in the platinum-resistant ovarian cancer cells. Taken together, these data indicate that beta-elemene sensitizes chemoresistant ovarian carcinoma cells to cisplatin-induced apoptosis and that the augmented effect of beta-elemene on cisplatin cytotoxicity and sensitivity in resistant ovarian tumor cells is mediated through a mitochondria- and caspase-dependent cell death pathway.

 

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[437]

TÍTULO / TITLE:  - A phase 2 study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Jan 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-013-2079-z

AUTORES / AUTHORS:  - Antonarakis ES; Heath EI; Posadas EM; Yu EY; Harrison MR; Bruce JY; Cho SY; Wilding GE; Fetterly GJ; Hangauer DG; Kwan MF; Dyster LM; Carducci MA

INSTITUCIÓN / INSTITUTION:  - Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB1-1M45, Baltimore, MD, 21231-1000, USA, eantona1@jhmi.edu.

RESUMEN / SUMMARY:  - PURPOSE: KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, prostate-specific antigen (PSA) declines were seen in patients with advanced prostate cancer. We conducted a single-arm phase 2 study evaluating KX2-391 in men with chemotherapy-naive bone-metastatic castration-resistant prostate cancer (CRPC). METHODS: We treated  31 patients with oral KX2-391 (40 mg twice-daily) until disease progression or unacceptable toxicity. The primary endpoint was 24-week progression-free survival (PFS); a 50 % success rate was pre-defined as clinically significant. Secondary endpoints included PSA progression-free survival (PPFS) and PSA response rates. Exploratory outcomes included pharmacokinetic studies, circulating tumor cell (CTC) enumeration, and analysis of markers of bone resorption [urinary N-telopeptide (uNTx); C-telopeptide (CTx)] and formation [bone alkaline phosphatase (BAP); osteocalcin]. RESULTS: The trial closed early after accrual of 31 patients, due to a pre-specified futility rule. PFS at 24 weeks was 8 %, and median PFS was 18.6 weeks. The PSA response rate (>/=30 % decline) was 10 %, and  median PPFS was 5.0 weeks. Additionally, 18 % of men with unfavorable (>/=5) CTCs at baseline converted to favorable (<5) CTCs with treatment. The proportion of men with declines in bone turnover markers was 32 % for uNTx, 21 % for CTx, 10 %  for BAP, and 25 % for osteocalcin. In pharmacokinetic studies, median C (max) was 61 (range 16-129) ng/mL, and median AUC was 156 (35-348) ng h/mL. Common toxicities included hepatic derangements, myelosuppression, fatigue, nausea, and  constipation. CONCLUSION: KX2-391 dosed at 40 mg twice-daily lacks antitumor activity in men with CRPC, but has modest effects on bone turnover markers. Because a C (max) of >/=142 ng/mL is required for tubulin polymerization inhibition (defined from preclinical studies), higher once-daily dosing will be used in future trials.

 

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[438]

TÍTULO / TITLE:  - Sphingosine Induces Apoptosis in MKN-28 Human Gastric Cancer Cells in an SDK-Dependent Manner.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Physiol Biochem. 2012 Sep 20;30(4):987-994.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000341475

AUTORES / AUTHORS:  - Kanno T; Nishimoto T; Fujita Y; Gotoh A; Nakano T; Nishizaki T

INSTITUCIÓN / INSTITUTION:  - Division of Bioinformation, Department of Physiology, Hyogo College of Medicine,  1-1 Mukogawa-cho, Nishinomiya Department of Thoracic Oncology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Japan.

RESUMEN / SUMMARY:  - Background/Aims: Evidence has pointed to the role of sphingosine in cellular differentiation, cell growth, and apoptosis. The present study investigated sphingosine-induced apoptosis in human gastric cancer cells. Methods: Well differentiated MKN-28 and poorly differentiated MKN-45 human gastric cancer cells were cultured. MTT assay, TUNEL staining, Western blotting, and assay of caspase-3, -8, and -9 activities were carried out in cells transfected with and without the siRNA to silence the protein kinase C (PKC)-delta-targeted gene. Results: Sphingosine induced apoptosis in MKN-28 cells, with the potential much.

 

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[439]

TÍTULO / TITLE:  - Interaction between Gambogic Acid and Dihydrofolate Reductase and Synergistic Lethal Effects with Methotrexate on Hepatoma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Anticancer Res. 2013 Jan;33(1):133-42.

AUTORES / AUTHORS:  - Deschatrette J; Ng-Bonaventure K; Philippe L; Wolfrom C

INSTITUCIÓN / INSTITUTION:  - UMR 757 INSERM, University Paris-Sud, Orsay F-91405, France. jean.deschatrette@u-psud.fr.

RESUMEN / SUMMARY:  - Gambogic acid (GA), a natural xanthone, has a wide spectrum of pharmacological activities, including repression of telomerase expression and induction of apoptosis of cancer cells. GA has also been reported to reduce the steady-state level of thymidylate synthetase mRNA in a gastric carcinoma cell line. Therefore, it has recently emerged as a candidate for use in cancer treatment. Using hepatoma cells with a dihydrofolate reductase (DHFR) gene amplification and cells transfected with an inducible DHFR transgene, we observed a negative relationship between DHFR expression and resistance to GA. Furthermore, DHFR assays in vitro indicated that in the presence of GA, DHFR activity was slightly inhibited and the affinity of the enzyme for dihydrofolate was markedly decreased. Treatment of rat hepatoma and other human and murine cancer cell lines with methotrexate and GA revealed that the two drugs displayed a marked synergistic lethal effect.

 

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[440]

TÍTULO / TITLE:  - Effects of voltage-gated K+ channel blockers in gefitinib-resistant H460 non-small cell lung cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Anticancer Res. 2012 Dec;32(12):5279-84.

AUTORES / AUTHORS:  - Jeon WI; Ryu PD; Lee SY

INSTITUCIÓN / INSTITUTION:  - DVM, Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 151-742, South Korea.

RESUMEN / SUMMARY:  - Voltage-gated K(+) (Kv) channels are known to be associated with the proliferation of several types of cancer cells, including lung adenocarcinoma cells, and certain Kv channel blockers inhibit cancer cell proliferation. In the  present study, we investigated the effects of Kv channel blockers in gefitinib-resistant H460 non-small cell lung cancer (NSCLC) cells. Treatment with dendrotoxin-kappa (DTX-kappa), which is a Kv1.1-specific blocker, reduced H460 cell viability and arrested cells in G(1)/S transition during cell-cycle progression. We administered DTX-kappa in a xenograft model using nude mice. The  tumor volume was reduced by the injection of DTX-kappa into the tumor tissues compared to the control group. These results indicate that DTX-kappa has antitumor effects in gefitinib-resistant H460 cells through the pathway governing the G(1)/S transition both in vitro and in vivo. These findings suggest that Kv1.1 could serve as a novel therapeutic target for gefitinib-resistant NSCLC.

 

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[441]

TÍTULO / TITLE:  - All Subunits of the Interleukin-2 Receptor are Expressed by Canine Cutaneous Mast Cell Tumours.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Comp Pathol. 2012 Dec 28. pii: S0021-9975(12)00420-3. doi: 10.1016/j.jcpa.2012.11.232.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jcpa.2012.11.232

AUTORES / AUTHORS:  - Meyer A; Gruber AD; Klopfleisch R

INSTITUCIÓN / INSTITUTION:  - Department of Veterinary Pathology, Freie Universitat Berlin, Robert-von-Ostertag-Strasse 15, 14163 Berlin, Germany.

RESUMEN / SUMMARY:  - Cutaneous mast cell tumours (MCTs) are among the most important skin tumours in dogs. Apart from c-KIT mutations, which are present in <18% of MCTs, little is known of the mechanisms of MCT development and independent growth of tumour cells. Recently, the alpha-subunit (CD25) of the interleukin (IL)-2 receptor (IL-2R) has been found to be expressed by canine cutaneous MCTs and this expression is negatively correlated with tumour grade. We thus hypothesized that  the other two subunits of the IL-2R and the ligand IL-2 are also expressed and that IL-2-dependent pathways may have an impact on MCT development and independent tumour cell growth. Messenger RNA and protein expression levels of the IL-2R beta-subunit (CD122), the IL-2R gamma-subunit (CD132) and IL-2 were analyzed in canine cutaneous MCTs and compared with tumour grade and c-KIT mutation status. Eighty-six percent of the tumours expressed both subunits of the IL-2R and 64% expressed IL-2. In addition, neoplastic mast cells seem able to bind IL-2. IL-2Rgamma and IL-2 protein expression levels were significantly decreased in higher grade tumours and IL-2 expression was significantly decreased in c-KIT mutated tumours. Thus, expression of the complete IL-2R and its ligand by canine cutaneous MCTs indicates a potential impact of IL-2R signalling in MCT  development and tumour cell proliferation. The decrease in IL-2R expression with  increasing histological evidence of malignancy suggests that the IL-2R may be more relevant for early MCT development and well-differentiated tumours.

 

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[442]

TÍTULO / TITLE:  - Correlation between expressions of ERCC1/TS mRNA and effects of gastric cancer to chemotherapy in the short term.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Jan 25.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-013-2083-3

AUTORES / AUTHORS:  - Chen L; Li G; Li J; Fan C; Xu J; Wu B; Liu K; Zhang C

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China.

RESUMEN / SUMMARY:  - PURPOSE: To study the correlation between expression levels of ERCC1/TS mRNA and  the susceptibility of preoperative chemotherapy for patients with gastric cancer. METHODS: A total of forty cases with advanced gastric cancer of T3-4N1-2M0 were treated with preoperative chemotherapy according to FLEEOX regimen based on endarterial-intravenous coadministration. Sufficient, fresh gastric tissue specimens were obtained with the help of gastroscope, and the expression levels of ERCC1/TS mRNA were detected by qRT-PCR before chemotherapy. The chemotherapeutic response was evaluated with Choi Criteria after chemotherapy, and pathologic remission extent was observed after surgery. The correlation between the expression levels of ERCC1/TS mRNA before chemotherapy and the chemotherapeutic effect based on imageology and pathology was analyzed. RESULTS:  The response rate of Chemotherapy in this cohort was 80.0 % based on imageology and 51.43 % based on pathology. The expression levels of ERCC1/TS mRNA were significantly associated with imageology remission extent (P = 0.033, P = 0.025)  and pathologic remission extent (P = 0.044, P = 0.016), respectively. The chemotherapeutic effect on patients with low-expression levels of ERCC1/TS mRNA was better. CONCLUSIONS: From the perspective of pathology and imageology evaluating the preoperative chemotherapeutic response for patients with gastric cancer, ERCC1 and TS were used as the molecular predictors and provided prognostic information in this study.

 

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[443]

TÍTULO / TITLE:  - Snake (Walterinnesia aegyptia) venom-loaded silica nanoparticles induce apoptosis and growth arrest in human prostate cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Apoptosis. 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10495-012-0787-1

AUTORES / AUTHORS:  - Badr G; Al-Sadoon MK; Rabah DM; Sayed D

INSTITUCIÓN / INSTITUTION:  - Princess Johara Alibrahim Center for Cancer Research, Prostate Cancer Research Chair, College of Medicine King Saud University, P.O. Box 7805, Riyadh, 11472, Saudi Arabia, badr73@yahoo.com.

RESUMEN / SUMMARY:  - Prostate cancer (PCa) is the most commonly diagnosed cancer in men. The progression and invasion of PCa are normally mediated by the overexpression of chemokine receptors (CKRs) and the interaction between CKRs and their cognate ligands. We recently demonstrated that venom extracted from Walterinnesia aegyptia (WEV) either alone or in combination with silica nanoparticles (WEV+NP)  mediated the growth arrest and apoptosis of breast cancer cells. In the present study, we evaluated the impact of WEV alone and WEV+NP on the migration, invasion, proliferation and apoptosis of prostate cancer cells. We found that WEV alone and WEV+NP decreased the viability of all cell types tested (PCa cells isolated from patient samples, PC3 cells and LNCaP cells) using an MTT assay. The IC(50) values were determined to be 10 and 5 mug/mL for WEV alone and WEV+NP, respectively. WEV+NP decreased the surface expression of the CKRs CXCR3, CXCR4, CXCR5 and CXCR6 to a greater extent than WEV alone and subsequently reduced migration and the invasion response of the cells to the cognate ligands of the CKRs (CXCL10, CXCL12, CXCL13 and CXCL16, respectively). Using a CFSE proliferation assay, we found that WEV+NP strongly inhibited epidermal growth factor-mediated PCa cell proliferation. Furthermore, analysis of the cell cycle indicated that WEV+NP strongly altered the cell cycle of PCa cells and enhanced the induction of apoptosis. Finally, we demonstrated that WEV+NP robustly decreased the expression of anti-apoptotic effectors, such as B cell Lymphoma-2 (Bcl-2), B cell Lymphoma-extra large (Bcl-(XL)) and myeloid cell leukemia sequence-1 (Mcl-1), and increased the expression of pro-apoptotic effectors, such as Bcl-2 homologous antagonist/killer (Bak), Bcl-2-associated X protein (Bax) and Bcl-2-interacting mediator of cell death (Bim). WEV+NP also altered the membrane  potential of mitochondria in the PCa cells. Our data reveal the potential of nanoparticle-sustained delivery of snake venom as effective treatments for prostate cancer.

 

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[444]

TÍTULO / TITLE:  - Modulation of CYP3A4 activity and induction of apoptosis, necrosis and senescence by the anti-tumour imidazoacridinone C-1311 in human hepatoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Biol Int. 2013 Feb;37(2):109-20. doi: 10.1002/cbin.10018. Epub 2013 Jan 14.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cbin.10018

AUTORES / AUTHORS:  - Augustin E; Pawlowska M; Polewska J; Potega A; Mazerska Z

INSTITUCIÓN / INSTITUTION:  - Chemical Faculty, Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Narutowicza Str. 11/12, 80-233 Gdansk, Poland.

RESUMEN / SUMMARY:  - There is increasing evidence that the expression level of drug metabolic enzymes  affects the final cellular response following drug treatment. Moreover, anti-tumour agents may modulate enzymatic activity and/or cellular expression of  metabolic enzymes in tumour cells. We have investigated the influence of CYP3A4 overexpression on the cellular response induced by the anti-tumour agent C-1311 in hepatoma cells. C-1311-mediated CYP3A4 activity modulation and the effect of CYP3A4 overexpression on C-1311 metabolism have also been examined. With the HepG2 cell line and its CYP3A4-overexpressing variant, Hep3A4, experiments involving DAPI staining, cell cycle analysis, phosphatidylserine externalisation  and senescence-associated (SA)-beta-galactosidase expression, were used to monitor the effects of C-1311 exposure. C-1311 cellular metabolism and CYP3A4 activity were investigated by high-performance liquid chromatography. C-1311 metabolism was very low in both hepatoma cell lines and slightly influenced by CYP3A4 expression. Interestingly, in HepG2 cells, C-1311 was an effective modulator of CYP3A4 enzymatic activity, being the inhibitor of this isoenzyme in  Hep3A4 cells. Cell cycle analysis showed that HepG2 cells underwent a rather stable G(2) /M arrest following C-1311 exposure, whereas CYP3A4-overexpressing cells accumulated only slightly in this compartment. C-1311-treated cells died by apoptosis and necrosis, whereas surviving cells underwent senescence; however, these effects occurred faster and more intensely in Hep3A4 cells. Although CYP3A4 did not influence C-1311 metabolism, changes in CYP3A4 levels affected the C-1311-induced response in hepatoma cells. Therefore, inter-patient differences in CYP3A4 levels should be considered when assessing the potential therapeutic effects of C-1311.

 

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[445]

TÍTULO / TITLE:  - Is exon mutation analysis needed for adjuvant treatment of gastrointestinal stromal tumor?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Gastroenterol. 2013 Jan 7;19(1):144-6. doi: 10.3748/wjg.v19.i1.144.

            ●● Enlace al texto completo (gratuito o de pago) 3748/wjg.v19.i1.144

AUTORES / AUTHORS:  - Sendur MA; Ozdemir NY; Akinci MB; Uncu D; Zengin N; Aksoy S

INSTITUCIÓN / INSTITUTION:  - Mehmet Ali Nahit Sendur, Nuriye Yildirim Ozdemir, Muhammed Bulent Akinci, Dogan Uncu, Nurullah Zengin, Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara 06100, Turkey.

RESUMEN / SUMMARY:  - Gastrointestinal stromal tumors (GISTs) are the most common soft tissue sarcoma of the gastrointestinal tract, resulting from an activating mutation of stem cell factor receptor (KIT), and an activating mutation of the homologous platelet-derived growth factor receptor alpha (PDGFRA) kinase. Most GISTs (90%-95%) are KIT-positive. About 5% of GISTs are truly negative for KIT expression. GISTs have been documented to resistant conventional chemotherapeutics. Due to the KIT activation that occurs in the majority of the cases, KIT inhibition is the primary treatment approach in the adjuvant treatment of metastatic GISTs. Imatinib mesylate is an oral agent that is a selective protein tyrosine kinase inhibitor of the KIT protein tyrosine kinase, and it has  demonstrated clinical benefit and objective tumor responses in most GIST patients in phase II and III trials. The presence and the type of KIT or PDGFRA mutation are predictive of response to imatinib therapy in patients with advanced and metastatic disease. Molecular analysis in phase I-II trials revealed significant  differences in objective response, progression-free survival, and overall survival between GISTs with different kinase mutations. The aim of this letter is to touch on the need for exon mutation analysis for adjuvant treatment with imatinib in GIST patients.

 

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[446]

TÍTULO / TITLE:  - Long-term effect of interferon-alpha combined with homoharringtonine on chronic myelogenous leukemia in chronic phase.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2012.745521

AUTORES / AUTHORS:  - Zhu J; Ding B; Li Y

INSTITUCIÓN / INSTITUTION:  - Department of Hematology , Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu , P. R. China.

RESUMEN / SUMMARY:  - To evaluate the efficacy of interferon-alpha (IFN-alpha) combined with homoharringtonine (HHT) in the treatment of patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CML), an IFN-alpha combined with HHT  scheme was used as induction and maintenance therapy for 42 patients with CML in  chronic phase. Thirty-five patients treated with IFN-alpha alone were used as the control group. It was found that the cytogenetic response rate and estimated 2-year survival rate were higher in the IFN-alpha + HHT group than in the IFN-alpha group (52.4% vs. 28.6% and 90% vs. 73%, respectively). No grade 3 or 4  hematological toxicity, severe infections, hemorrhage or non-hematological adverse reactions were observed. From this research it can be concluded that an IFN-alpha combined with HHT scheme is safe and effective for CML induction and long-term maintenance therapy. It may be a good choice for patients with CML who  cannot accept a hematopoietic stem cell transplant and imatinib or who fail IFN-alpha therapy.

 

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[447]

TÍTULO / TITLE:  - Antioxidant and In Vitro Anticancer Effect of 2-Pyrrolidinone Rich Fraction of Brassica oleracea var. capitata Through Induction of Apoptosis in Human Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Phytother Res. 2013 Jan 4. doi: 10.1002/ptr.4908.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ptr.4908

AUTORES / AUTHORS:  - Thangam R; Suresh V; Rajkumar M; Vincent JD; Gunasekaran P; Anbazhagan C; Kaveri K; Kannan S

INSTITUCIÓN / INSTITUTION:  - Proteomics and Molecular cell Physiology Lab, Department of Zoology, Bharathiar University, Coimbatore, TN, India; Department of Virology, King Institute of Preventive Medicine and Research, Chennai, TN, India. thangam1985@yahoo.co.in.

RESUMEN / SUMMARY:  - The aim of this study was to analyze if the 2-pyrrolidinone rich fraction of Brassica oleracea var. capitata exhibiting antioxidant and in vitro anticancer activities. 2-Pyrrolidinone is an active compound present in Brassica oleracea var. capitata. Our findings explored the potential use of 2-pyrrolidinone in cancer treatment. This compound was identified and isolated by gas chromatography-mass spectrometry and high-performance liquid chromatography from  the leaf of Brassica oleracea var. capitata. The resultant rich active compound exhibited in vitro cytotoxicity in HeLa and PC-3 human cancer cell lines, and it  also exhibited antioxidant activity in cell free assays. DAPI staining, an apoptotic analysis and cell cycle analysis were performed to evaluate the anticancer activity of 2-pyrrolidinone against the above cell lines. The IC(50) value of 2-pyrrolidinone was determined to be of 2.5 microg/ml for HeLa, 3 microg/ml for PC-3 cells at 24 h and 1.5 microg/ml for HeLa and 2 microg/ml for PC-3 cells at 48 h, respectively. However, cell cycle analysis revealed that the  anti-proliferative effects of the 2-pyrrolidinone were mediated through cell cycle arrest in the G0/G1 phase. These results from the current study suggest that the 2-pyrrolidinone have potential anticancer effects, which will lead to the development of new anticancer agents for arresting cancer cells growth in vitro. Copyright © 2013 John Wiley & Sons, Ltd.

 

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[448]

TÍTULO / TITLE:  - Cyclin-dependent kinase-associated protein phosphatase is overexpressed in alcohol-related hepatocellular carcinoma and influences xenograft tumor growth.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar;29(3):903-10. doi: 10.3892/or.2012.2208. Epub 2012 Dec 24.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2208

AUTORES / AUTHORS:  - Lin WR; Lai MW; Yeh CT

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, R.O.C.

RESUMEN / SUMMARY:  - The cyclin-dependent kinase (Cdk)-associated protein phosphatase (KAP) is a dual-specificity phosphatase that dephosphorylates Cdk2 and inhibits cell cycle progression. The overexpression of KAP has been found in breast, prostate and renal cell carcinomas. However, the role of KAP in hepatocellular carcinoma (HCC) remains unclear. Therefore, the aim of this study was to investigate the expression of KAP in HCC and elucidate its role in tumorigenesis. HCC tissues from 117 patients undergoing surgical resection were collected for western blot analysis and immuno-histochemichal analysis to establish clinical correlation. The antisense-mediated inhibition of KAP expression was performed in Huh-7 cell lines for tumorigenicity and growth regulation experiments. Clinicopathological analysis indicated that KAP was overexpressed in HCC tissue from alcoholic patients (P<0.001). It was significantly overexpressed in patients with a tumor number of <3 (P=0.0271), suggesting the potential role of KAP in tumorigenesis during earlystage alcohol-related HCC. Additionally, the antisense-mediated inhibition of KAP in Huh-7 HCC cells interfered with cell cycle progression, decreased cell proliferation, reduced the colonyforming ability of the cells and  increased apoptosis. Tumorigenicity experiments showed that the KAP knockdown in  Huh-7 cells generated smaller tumors in nude mice compared with the mock controls (P=0.018). In the cells in which KAP had been knocked down, the physical inter-action between KAP and Cdk2 significantly increased, despite the reduced expression levels of KAP. The phosphorylation of cell proliferation and apoptosis-associated proteins, including phosphatase and tensin homolog (PTEN), glycogen synthase kinase (GSK), p44/42 and Akt, was decreased. Therefore, it can  be concluded that KAP is overexpressed in alcohol-related HCC. The antisense-mediated knockdown of KAP in Huh-7 cells decreased cell proliferation,  reduced the colonyforming ability of the cells, interfered with cell cycle progression and suppressed xenograft tumor formation, partly through enhanced KAP and Cdk2 interaction.

 

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[449]

TÍTULO / TITLE:  - Antitumoral efficacy of four histone deacetylase inhibitors in hepatoma in vitro  and in vivo.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Anticancer Res. 2012 Dec;32(12):5263-9.

AUTORES / AUTHORS:  - Ganslmayer M; Konturek P; Herold C; Neurath MF; Zopf S

INSTITUCIÓN / INSTITUTION:  - Department of Medicine I, University hospital Erlangen, Ulmenweg 18, D-91054 Erlangen, Germany. marion.ganslmayer@uk-erlangen.de

RESUMEN / SUMMARY:  - BACKGROUND: Histone deacetylase (HDAC) inhibitors are promising antitumoral drugs. Currently there are no data regarding the comparison of different HDAC inhibitors on hepatoma cells. MATERIALS AND METHODS: Hepatoma cells were incubated with the HDAC inhibitors MS-275, SAHA, FK901228 and trichostatin. Proliferation was assessed via BrdU incorporation and apoptosis rate via flow cytometry. Trichostatin, SAHA and MS-275 were applied in a rat hepatoma model. RESULTS: The agents showed antiproliferative and pro-apoptotic effects time- and  dose-dependently. SAHA and MS-275 were moderately effective at 10 muM, while trichostatin A and FK901228 showed higher potency. Caspases 3 and 8 were activated upon treatment with the drugs. The agents increased the acetylation rate. Hyperacetylation did not correlate with antitumoral efficacy. In vivo, SAHA was superior to MS-275 and trichostatin A. CONCLUSION: The HDAC inhibitors were effective both in vitro and in vivo. The potency of SAHA and MS-275 was similar.  In spite of differing affinity to the 11 known HDACs, the agents induced comparable effects. These findings suggest that these agents have further antitumoral effects apart from HDAC inhibition.

 

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[450]

TÍTULO / TITLE:  - Two-weekly dose-adjusted (DA)-EPOCH-like chemotherapy with high-dose dexamethasone plus rituximab (DA-EDOCH14-R) in poor-prognostic untreated diffuse  large B-cell lymphoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Haematol. 2012 Dec 11. doi: 10.1111/bjh.12144.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bjh.12144

AUTORES / AUTHORS:  - Garcia-Suarez J; Flores E; Callejas M; Arribas I; Fernandez JJ; Olmedilla G; Curto N; Guillen H; Casco CR; Martin Y; Burgaleta C

INSTITUCIÓN / INSTITUTION:  - Haematology Service, Department of Medicine, Principe de Asturias University Hospital, University of Alcala, Alcala de Henares, Madrid, España.

RESUMEN / SUMMARY:  - The activity and safety of two-weekly dose-adjusted (DA)-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin)-like chemotherapy with high-dose dexamethasone plus rituximab (DA-EDOCH14-R) was explored in 20 patients with previously untreated poor prognosis diffuse large B-cell lymphoma (DLBCL). The main outcomes were compared with those of 27 poor-prognosis patients enrolled into a previous trial of 3-weekly DA-EPOCH-R. Toxicity was manageable and there were no therapy-related deaths. Three-year progression-free survival (PFS) was superior in the DA-EDOCH14-R group (95% vs. 74%, P = 0.08). Importantly, this improvement in PFS with the two-weekly DA-EDOCH14-R was particularly notable in patients with an age-adjusted International Prognostic Index of 3 (100% vs. 30%,  P < 0.001).

 

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[451]

TÍTULO / TITLE:  - Apoptotic events induced by synthetic naphthylchalcones in human acute leukemia cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochimie. 2012 Dec 17. pii: S0300-9084(12)00477-4. doi: 10.1016/j.biochi.2012.12.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biochi.2012.12.001

AUTORES / AUTHORS:  - Maioral MF; Gaspar PC; Rosa Souza GR; Mascarello A; Chiaradia LD; Licinio MA; Moraes AC; Yunes RA; Nunes RJ; Santos-Silva MC

INSTITUCIÓN / INSTITUTION:  - Laboratorio de Oncologia Experimental e Hemopatias, Departamento de Analises Clinicas, Universidade Federal de Santa Catarina, Campus Trindade, CEP 88040-900, Florianopolis, SC, Brazil. Electronic address: marimaioral@gmail.com.

RESUMEN / SUMMARY:  - Acute leukemia is a disorder of the hematopoietic system characterized by the expansion of a clonal population of cells blocked from differentiating into mature cells. Recent studies have shown that chalcones and their derivatives induce apoptosis in different cell lines. Since new compounds with biological activity are needed, the aim of this study was to evaluate the cytotoxic effect of three synthetic chalcones, derived from 1-naphthaldehyde and 2-naphthaldehyde, on human acute myeloid leukemia K562 cells and on human acute lymphoblastic leukemia Jurkat cells. Based on the results, the most cytotoxic compound (A1) was chosen for further analysis in six human acute leukemia cells and in a human colon adenocarcinoma cell line (HT-29). Chalcone A1 significantly reduced the cell viability of K562, Jurkat, Kasumi, U937, CEM and NB4 cells in a concentration and time-dependent manner when compared with the control group (IC(50) values between approximately 1.5 muM and 40 muM). It was also cytotoxic to HL-29 cells. To further examine its effect on normal cells, peripheral blood lymphocytes collected from healthy volunteers were incubated with the compound. It has also been incubated with human fibroblasts cultured from bone marrow (JMA). Chalcone A1 is non-cytotoxic to PBL cells and to JMA cells. A1 caused significant cell cycle arrest in all phases according to the cell line, and increased the proportion of cells in the sub G0/G1 phase. To evaluate whether this chalcone induced cell death via an apoptotic or necrotic pathway, cell morphology was examined using fluorescence microscopy. Cells treated with A1 at IC(50) demonstrated the morphological characteristic of apoptosis, such as chromatin condensation and formation of apoptotic bodies. Apoptosis was confirmed by externalization of phosphatidylserine, which was detected by the Annexin V-FITC method, and by DNA fragmentation. The results suggest that chalcone A1 has potential as a new lead compound for cancer therapy.

 

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[452]

TÍTULO / TITLE:  - Pharmacogenetic analysis in the treatment of Hodgkin’s lymphoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Jan 17.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2012.752080

AUTORES / AUTHORS:  - Altes A; Pare L; Esquirol A; Xicoy B; Ramila E; Vicente L; Lopez R; Orriols J; Vall-Llovera F; Sanchez-Gonzalez B; Del Rio E; Sureda A; Paez D; Baiget M

RESUMEN / SUMMARY:  - Abstract About 15-20% of patients with Hodgkin’s lymphoma (HL) treated with ABVD  chemotherapy +/- radiotherapy still die following relapse or progressive disease. Outcome might be influenced by gene polymorphisms influencing chemotherapy metabolism. We studied 126 patients with HL treated with ABVD regimen. We analyzed glutathione S-transferases (GSTT1, GSTM1 and GSTP1), cytochromes P450 (CYP3A4, CYP2D6), UGT1A1 and BLMH gene polymorphisms and their association with clinical and outcome variables. Patients with a GSTM1 genotype associated with extensive or ultrahigh activity had a probability of 93.8% to achieve complete response, while the rest of the patients had a probability of 82.3% (P=0.04). This variable maintained its statistical significance in multivariate analysis (HR 3.7, CI 95% 1 - 13, p= 0.05). Patients with an extensive or ultrahigh GSTM1 genotype had better prognostic factors than those with poor or intermediate genotypes (Hb level, P=0.003; serum albumin, P=0.05; and IPS, P=0.038). Thus, in  the treatment of HL, clinical determinants might be more relevant than the pharmacogenetic parameters analyzed to date.

 

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[453]

TÍTULO / TITLE:  - TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Haematol. 2013 Jan 9. doi: 10.1111/bjh.12203.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bjh.12203

AUTORES / AUTHORS:  - Kulasekararaj AG; Smith AE; Mian SA; Mohamedali AM; Krishnamurthy P; Lea NC; Gaken J; Pennaneach C; Ireland R; Czepulkowski B; Pomplun S; Marsh JC; Mufti GJ

INSTITUCIÓN / INSTITUTION:  - Department of Haematological Medicine, King’s College London, School of Medicine, London, UK; Department of Haematology, King’s College Hospital, London, UK.

RESUMEN / SUMMARY:  - This study aimed to determine the incidence/prognostic impact of TP53 mutation in 318 myelodysplastic syndrome (MDS) patients, and to correlate the changes to cytogenetics, single nucleotide polymorphism array karyotyping and clinical outcome. The median age was 65 years (17-89 years) and median follow-up was 45 months [95% confidence interval (CI) 27-62 months]. TP53 mutations occurred in 30 (9.4%) patients, exclusively in isolated del5q (19%) and complex karyotype (CK) with -5/5q-(72%), correlated with International Prognostic Scoring System intermediate-2/high, TP53 protein expression, higher blast count and leukaemic progression. Patients with mutant TP53 had a paucity of mutations in other genes  implicated in myeloid malignancies. Median overall survival of patients with TP53 mutation was shorter than wild-type (9 versus 66 months, P < 0.001) and it retained significance in multivariable model (Hazard Ratio 3.8, 95%CI 2.3-6.3,P < 0.001). None of the sequentially analysed samples showed a disappearance of the mutant clone or emergence of new clones, suggesting an early occurrence of TP53 mutations. A reduction in mutant clone correlated with response to 5-azacitidine, however clones increased in non-responders and persisted at relapse. The adverse  impact of TP53 persists after adjustment for cytogenetic risk and is of practical importance in evaluating prognosis. The relatively common occurrence of these mutations in two different prognostic spectrums of MDS, i.e. isolated 5q- and CK  with -5/5q-, possibly implies two different mechanistic roles for TP53 protein.

 

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[454]

TÍTULO / TITLE:  - Sulfation of keratan sulfate proteoglycan reduces radiation-induced apoptosis in  human Burkitt’s lymphoma cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - FEBS Lett. 2013 Jan 16;587(2):231-7. doi: 10.1016/j.febslet.2012.12.002. Epub 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.febslet.2012.12.002

AUTORES / AUTHORS:  - Nakayama F; Umeda S; Ichimiya T; Kamiyama S; Hazawa M; Yasuda T; Nishihara S; Imai T

INSTITUCIÓN / INSTITUTION:  - Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan. Electronic address: f_naka@nirs.go.jp.

RESUMEN / SUMMARY:  - This study focuses on clarifying the contribution of sulfation to radiation-induced apoptosis in human Burkitt’s lymphoma cell lines, using 3’-phosphoadenosine 5’-phosphosulfate transporters (PAPSTs). Overexpression of PAPST1 or PAPST2 reduced radiation-induced apoptosis in Namalwa cells, whereas the repression of PAPST1 expression enhanced apoptosis. Inhibition of PAPST slightly decreased keratan sulfate (KS) expression, so that depletion of KS significantly increased radiation-induced apoptosis. In addition, the repression  of all three N-acetylglucosamine-6-O-sulfotransferases (CHST2, CHST6, and CHST7)  increased apoptosis. In contrast, PAPST1 expression promoted the phosphorylation  of p38 MAPK and Akt in irradiated Namalwa cells. These findings suggest that 6-O-sulfation of GlcNAc residues in KS reduces radiation-induced apoptosis of human Burkitt’s lymphoma cells.

 

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[455]

TÍTULO / TITLE:  - Potential predictive biomarkers for individualizing treatment for men with castration-resistant prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer J. 2013 Jan;19(1):25-33. doi: 10.1097/PPO.0b013e31827e0b9c.

            ●● Enlace al texto completo (gratuito o de pago) 1097/PPO.0b013e31827e0b9c

AUTORES / AUTHORS:  - Bitting RL; Armstrong AJ

INSTITUCIÓN / INSTITUTION:  - From the Duke Cancer Institute and the Duke Prostate Center, Durham, NC.

RESUMEN / SUMMARY:  - ABSTRACT: With the surge in therapeutic options for men with castration-resistant prostate cancer (CRPC) comes increasingly complicated treatment decision making,  highlighting the need for biomarkers that can identify appropriate patients for specific treatments and accurately assess disease response. Predictive biomarkers are factors related to the disease or the host that are associated with improvements in outcomes, such as survival, due to specific therapies. Such biomarkers have become of paramount importance in oncology to maximize the benefits of novel systemic agents while minimizing harm to individual patients and the costs to society. Given the number of newly approved and expensive systemic therapies, including novel hormonal therapies, chemotherapies, immunotherapies, and bone microenvironment-targeting therapies, predictive biomarkers are needed to give physicians a more rational sense of matching the right patient to the right therapy sequence at a given time. There are currently  no validated predictive biomarkers in CRPC. We discuss potential predictive biomarkers in men with CRPC and how these may be developed in the context of therapeutic clinical trials.

 

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[456]

TÍTULO / TITLE:  - The T393C polymorphism of GNAS1 is a predictor for relapse and survival in resectable non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Lung Cancer. 2013 Feb;79(2):151-5. doi: 10.1016/j.lungcan.2012.11.003. Epub 2012  Nov 29.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.lungcan.2012.11.003

AUTORES / AUTHORS:  - Uzunoglu FG; Heumann A; Musici S; Kutup A; Koenig A; Roch N; Thomssen A; Dohrmann T; Tsui TY; Mann O; Izbicki JR; Vashist YK

INSTITUCIÓN / INSTITUTION:  - Department of General, Visceral and Thoracic Surgery, University Medical Centre of Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

RESUMEN / SUMMARY:  - INTRODUCTION: The GNAS1 T393C single nucleotide polymorphism (T393C-SNP) correlates with Galphas mRNA stability and protein expression and augmented apoptosis. Genetic germ line variations as stable and reproducible markers potentially serve as prognostic marker in oncology. The aim of this study was to  evaluate the potential prognostic value of T393C-SNP in complete resected non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In total 163 Caucasian  patients, who had been surgically treated for NSCLC between 1998 and 2010, were included in this study. Genotyping of peripheral blood cells was performed by polymerase chain reaction and digestion using the restriction enzyme FokI. The T393C-SNP was correlated with clinic-pathological parameters and survival. Chi-square test, Kaplan-Meier estimator and cox regression hazard model were used to assess the prognostic value of the T393C-SNP. RESULTS: C-allele carriers had a higher recurrence rate (p=0.018) and a shorter disease-free survival compared to  homozygous T-allele carriers (12.26 months vs. 44.65 months, p=0.009). The overall survival in homozygous C allele carriers was shorter (19.10 months vs. 53.95 months, p=0.019). Multivariate Cox regression identified the CC genotype as a negative independent prognostic factor for recurrence (hazard ratio 2.36, p=0.007) and survival (hazard ratio 2.51, p=0.008). CONCLUSION: Determination of  T393C-SNP preoperatively potentially allows allocation of NSCLC patients into different risk profiles and may influence the therapeutic strategy.

 

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[457]

TÍTULO / TITLE:  - A novel marine drug, SZ-685C, induces apoptosis of MMQ pituitary tumor cells by downregulating miR-200c.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Med Chem. 2013 Jan 4.

AUTORES / AUTHORS:  - Chen CH; Xiao WW; Jiang XB; Wang JW; Mao ZG; Lei N; Fan X; Song BB; Liao CX; Wang HJ; She ZG; Zhu YH

INSTITUCIÓN / INSTITUTION:  - Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, China. zhuyongh@mail.sysu.edu.cn.

RESUMEN / SUMMARY:  - Objective: We found a novel marine drug, SZ-685C, that was isolated from the secondary metabolites of a mangrove endophytic fungus (No. 1403) collected from the South China Sea, which has been reported to inhibit the proliferation of certain tumor cells. However, its anticancer mechanism remains unknown. The aims  of this study were to observe the effectiveness of SZ-685C on pituitary adenoma cells and determine the underlying mechanisms of action. Methods: A rat prolactinoma cell line, MMQ, was used in this study. A dose escalation of SZ-685C was performed on this cell line, and cell viability was assessed using an MTT assay. Hoechst 33342, Annexin V-FITC/PI, TUNEL staining and flow cytometry were used to evaluate the extent of apoptosis at each concentration of SZ-685C. The effect of SZ-685C on prolactin expression was also evaluated using RT-PCR and immunoblotting. Quantitative RT-PCR was used to detect the expression of miR-200c in SZ-685C-stimulated MMQ cells and pituitary adenoma tissues. This miRNA was then overexpressed in MMQ cells via transfection of a miR-200c mimic to identify  the mechanism underling the anti-tumor effect of SZ-685C. Results: SZ-685C inhibited MMQ cell growth in a dose-dependent manner but showed little toxicity toward rat pituitary cells (RPCs). The IC50s of SZ-685C in MMQ cells and RPCs were 13.2 +/- 1.3 muM and 49.1 +/- 11.5 muM, respectively, which was statistically significant. Increasing numbers of apoptotic cells were observed in response to escalating concentrations of SZ-685C, and the expression level of prolactin (PRL) was inhibited. Nevertheless, the level of PRL mRNA was unchanged. Additionally, miR-200c was upregulated in MMQ cells compared with RPCs, and downregulation of miR-200c was observed in SZ-685C-treated MMQ cells. Furthermore, the overexpression of miR-200c weakened the effect of SZ-685C-induced apoptosis of MMQ cells. Conclusions: Our results suggest that SZ-685C induces MMQ cell apoptosis in a miR-200c-dependent manner. Therefore, SZ-685C might be a useful alternative treatment for pituitary adenoma.

 

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[458]

TÍTULO / TITLE:  - Sulfocoumarins (1,2-Benzoxathiine-2,2-dioxides): A Class of Potent and Isoform-Selective Inhibitors of Tumor-Associated Carbonic Anhydrases.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Med Chem. 2013 Jan 10;56(1):293-300. doi: 10.1021/jm301625s. Epub 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1021/jm301625s

AUTORES / AUTHORS:  - Tars K; Vullo D; Kazaks A; Leitans J; Lends A; Grandane A; Zalubovskis R; Scozzafava A; Supuran CT

INSTITUCIÓN / INSTITUTION:  - Biomedical Research and Study Center, Ratsupites 1, LV 1067, Riga, Latvia.

RESUMEN / SUMMARY:  - Coumarins were recently shown to constitute a novel class of mechanism-based carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. We demonstrate that sulfocoumarins (1,2-benzoxathiine 2,2-dioxides) possess a similar mechanism of action, acting as effective CA inhibitors. The sulfocoumarins were hydrolyzed by  the esterase CA activity to 2-hydroxyphenyl-vinylsulfonic acids, which thereafter bind to the enzyme in a region rarely occupied by other classes of inhibitors. The X-ray structure of one of these compounds in adduct with a modified CA II enzyme possessing two amino acid residues from the CA IX active site, allowed us  to decipher the inhibition mechanism. The sulfonic acid was observed anchored to  the zinc-coordinated water molecule, making favorable interactions with Thr200 and Pro201. Some other sulfocoumarins incorporating substituted-1,2,3-triazole moieties were prepared by using click chemistry and showed low nanomolar inhibitory action against the tumor-associated isoforms CA IX and XII, being less effective against the cytosolic CA I and II.

 

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[459]

TÍTULO / TITLE:  - Leptin stimulates ovarian cancer cell growth and inhibits apoptosis by increasing cyclin D1 and Mcl-1 expression via the activation of the MEK/ERK1/2 and PI3K/Akt  signaling pathways.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Mar;42(3):1113-9. doi: 10.3892/ijo.2013.1789. Epub 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2013.1789

AUTORES / AUTHORS:  - Chen C; Chang YC; Lan MS; Breslin M

INSTITUCIÓN / INSTITUTION:  - Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan, R.O.C.

RESUMEN / SUMMARY:  - Obesity is known to be an important risk factor for many types of cancer, such as breast, prostate, liver and endometrial cancer. Recently, epidemiological studies have indicated that obesity correlates with an increased risk of developing ovarian cancer, the most lethal gynecological cancer in developed countries. Leptin is predominantly produced by adipocytes and acts as a growth factor and serum leptin levels positively correlate with the amount of body fat. In this study, we investigated the effects of leptin on the growth of ovarian cancer cells and the underlying mechanism(s) of action. Our results showed that leptin stimulated the growth of the OVCAR-3 ovarian cancer cell line using MTT assay and trypan blue exclusion. Using western blot analysis, we found that leptin enhanced the expression of cyclin D1 and Mcl-1, which are important regulators of cell proliferation and the inhibition of apoptosis. To investigate the signaling pathways that mediate the effects of leptin, cells were treated with leptin plus  specific inhibitors of JAK2, PI3KAkt and MEK/ERK1/2 and analysis of the phosphorylation state of proteins was carried out by western blot assays. We showed that the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways were involved in the growth-stimulating effect of leptin on ovarian cancer cell growth and the specific inhibitors of PI3K/Akt and MEK/ERK1/2 revealed that these two pathways interacted with each other. Our data demonstrate that leptin upregulates the expression of cyclin D1 and Mcl-1 to stimulate cell growth by activating the  PI3K/Akt and MEK/ERK1/2 pathways in ovarian cancer.

 

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[460]

TÍTULO / TITLE:  - Mutant TP53 enhances the resistance of glioblastoma cells to temozolomide by up-regulating O(6)-methylguanine DNA-methyltransferase.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Neurol Sci. 2012 Dec 8.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10072-012-1257-9

AUTORES / AUTHORS:  - Wang X; Chen JX; Liu YH; You C; Mao Q

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, West China Hospital, Sichuan University, 37 Guo Xuexiang, Chengdu, 610041, Sichuan, China.

RESUMEN / SUMMARY:  - The “gain of function” of mutant TP53 is an important determinant in human tumor  development and progression. This study aimed to investigate the possible mechanism of mutant TP53 inducing temozolomide resistance in glioblastoma cells.  Three established human glioma cell lines, T98G, U87, and U138, were chemoresistant cells. The mRNA of cells was sequenced to confirm the status of TP53. Synthetic small interfering RNA (siRNA) was used to knock down TP53 in cells. TP53 mRNA was detected “silenced” by reverse transcriptase-polymerase chain reaction (RT-PCR) in five consecutive days. Viable cell survival was measured when these cells were exposed to temozolomide or semustine in step-up concentrations. The expression of O(6)-methylguanine DNA-methyltransferase (MGMT) at mRNA level was also determined. T98G, U87, and U138 cells were resistant to temozolomide. T98G and U138 cells expressed mutant-type TP53 with positive MGMT,  while U87 cell expressed wild-type TP53 with negative MGMT. TP53-siRNA knocked down TP53 effectively (P = 0.021) in five consecutive days. Knockdown of mutant TP53 in T98G and U138 cells led to a fivefold increase in chemosensitivity to temozolomide, but not semustine. Knockdown of wild TP53 in U87 cell did not affect the chemoresistance. In addition, mutant TP53 knockdown induced a dramatic decrease of MGMT expression (P = 0.0000034). TP53 mutation decreases the chemosensitivity of malignant gliomas to temozolomide. This “gain of function” in drug resistance may be obtained by increasing MGMT expression.

 

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[461]

TÍTULO / TITLE:  - The activity against Ehrlich’s ascites tumors of doxorubicin contained in self assembled, cell receptor targeted nanoparticle with simultaneous oral delivery of the green tea polyphenol epigallocatechin-3-gallate.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biomaterials. 2013 Jan 25. pii: S0142-9612(13)00024-0. doi: 10.1016/j.biomaterials.2012.12.044.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biomaterials.2012.12.044

AUTORES / AUTHORS:  - Ray L; Kumar P; Gupta KC

INSTITUCIÓN / INSTITUTION:  - CSIR-Indian Institute of Toxicology Research, M.G. Marg, Post Box No. 80, Lucknow 226001, U.P., India.

RESUMEN / SUMMARY:  - Doxorubicin (DOX) is a well-known anticancer drug used for the treatment of a wide variety of cancers. However, undesired toxicity of DOX limits its uses. To address the issue of minimizing toxicity of DOX by making it targeted towards cancer cells, DOX was entrapped in self-assembled 6-O-(3-hexadecyloxy-2-hydroxypropyl)-hyaluronic acid (HDHA) nanoparticles. We hypothesized that by encapsulating the drug in biodegradable nanoparticles, its therapeutic efficacy would improve, if targeted against cancer cells. We synthesized cell receptor targeted, DOX loaded HDHA nanoparticles (NPs) and non-targeted DOX loaded O-hexadecylated dextran (HDD) nanoparticles (NPs) and characterized them for their entrapment efficiency, percent yield, drug load, surface morphology, particle size and in vitro drug release. The anticancer efficacy of DOX loaded HDHA-NPs was evaluated by measuring the changes in tumor volumes, tumor weights, and mean survival rate of Swiss albino mice grafted with  Ehrlich’s ascites carcinoma (EAC) cells. For this, the animals were given HDHA-DOX-NPs (1.5 mg/kg b.wt.) intravenously and a green tea polyphenol, Epigallocatechin-3-gallate (EGCG) (20 mg/kg b.wt.), orally through gavage. The targeted NP dose with EGCG significantly increased mean survival time of the animals and enhanced the therapeutic efficacy of the drug compared to the non-targeted NPs and free DOX. Further, we showed that these NPs (HDD and HDHA) were more active in the presence of EGCG than DOX alone in inducing apoptosis in  EAC cells as evident by an increase in sub-G1 cells (percent), Annexin V positive cells and chromatin condensation along with the reduction in mitochondrial membrane potential (MMP). The study demonstrates that DOX loaded HDHA-NPs along with EGCG significantly inhibit the growth of EAC cells with approximately 38-fold dose advantage compared to DOX alone and thus opens a new dimension in cancer chemotherapy.

 

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[462]

TÍTULO / TITLE:  - VITAMIN D RECEPTOR GENOTYPE rs731236 (TAQ1) AND BREAST CANCER PROGNOSIS.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Epidemiol Biomarkers Prev. 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1055-9965.EPI-12-0970-T

AUTORES / AUTHORS:  - Perna L; Butterbach K; Haug U; Schottker B; Muller H; Arndt V; Holleczek B; Burwinkel B; Brenner H

INSTITUCIÓN / INSTITUTION:  - 1Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ).

RESUMEN / SUMMARY:  - Several studies have suggested that the anti-cancerogenous effects of vitamin D might be modulated by genetic variants in the vitamin D receptor (VDR) gene. The  association of VDR polymorphisms with breast cancer-specific and all-cause mortality after a breast cancer diagnosis remains, however, largely unexplored. We assessed the association of genetic variants in VDR (rs731236, rs1989969, rs2228570, 11568820) with breast cancer survival in a sample of 498 breast cancer patients with a mean age at diagnosis of 61 years from Saarland, Germany, who were followed for up to 5 years with respect to total and breast cancer-specific  mortality (56 and 48 events, respectively). Adjusted hazard ratios with 95% confidence intervals (CI) were estimated by Cox regression models. We found that  breast cancer patients homozygous for the rare allele of rs731236 (15% of the women in our cohort) had a tendency toward an increased risk for breast cancer-specific mortality. The hazard ratio (95% CI) adjusted for age and breast  cancer stage was 2.8 (1.1-7.2) for breast cancer-specific mortality and 2.1 (0.9-4.9) for total mortality. Additional adjustment for family history of breast cancer, radical mastectomy, and body mass index changed only marginally the estimates. No association was found for rs1989969, rs2228570, and rs11568820. Our analysis suggests that VDR polymorphism rs731236 might be associated with breast  cancer-specific mortality and if our findings are confirmed in future and bigger  studies rs731236 might deserve consideration as a prognostic factor in clinical care of breast cancer patients.

 

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[463]

TÍTULO / TITLE:  - Association of tissue inhibitor of metalloproteinases-1 and Ki67 in estrogen receptor positive breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Acta Oncol. 2013 Jan;52(1):82-90. doi: 10.3109/0284186X.2012.734922. Epub 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 3109/0284186X.2012.734922

AUTORES / AUTHORS:  - Bjerre C; Knoop A; Bjerre K; Larsen MS; Henriksen KL; Lyng MB; Ditzel HJ; Rasmussen BB; Brunner N; Ejlertsen B; Laenkholm AV

INSTITUCIÓN / INSTITUTION:  - Sino-Danish Breast Cancer Research Centre at Section of Pathobiology, Department  of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. chab@life.ku.dk

RESUMEN / SUMMARY:  - BACKGROUND: The role of tissue inhibitor of metalloproteinases-1 (TIMP-1) in estrogen receptor (ER) positive breast cancer remains to be fully elucidated. We  evaluated TIMP-1 as a prognostic marker in patients treated with adjuvant tamoxifen and investigated TIMP-1s association with Ki67 and ER/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) profiles. MATERIAL  AND METHODS: TIMP-1 expression was evaluated by immunohistochemistry (IHC) on formalin fixed paraffin embedded primary tumor tissue in two independent cohorts  comprised of 236 and 192 patients, respectively. RESULTS: No differences in disease free survival (HR 0.98; 95% CI 0.63-1.53; p = 0.92) and overall survival  (HR 0.94; 95% CI 0.63-1.43; p = 0.79) were observed according to TIMP-1 status. A significant negative association between TIMP-1 and Ki67 was identified (p = 0.015). TIMP-1 expression did not differ significantly according to ER/PR/HER2 profiles. When analyzed as separate variables PR and HER2 status tended to have a positive but non-significant association with TIMP-1 (PR: p = 0.08; OR 2.54; 95%  CI 0.91-7.10, HER2: p = 0.08; OR 0.48; 95% CI 0.21-1.08) whereas ER status was not associated with TIMP-1 expression (p = 0.48; OR 0.68; 95% CI 0.23-1.99). CONCLUSION: TIMP-1 does not appear to be prognostic in breast cancer patients receiving adjuvant tamoxifen. We identified a negative association between TIMP-1 and Ki67. We did not confirm our previous in vitro findings of a negative association between TIMP-1 and PR.

 

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[464]

TÍTULO / TITLE:  - Decitabine represses translocated MYC oncogene in Burkitt lymphoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Pathol. 2013 Jan 23. doi: 10.1002/path.4164.

            ●● Enlace al texto completo (gratuito o de pago) 1002/path.4164

AUTORES / AUTHORS:  - Guan H; Xie L; Klapproth K; Weitzer CD; Wirth T; Ushmorov A

INSTITUCIÓN / INSTITUTION:  - Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, China; Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.

RESUMEN / SUMMARY:  - Burkitt lymphoma (BL) is caused by translocation of the MYC gene to an immunoglobulin locus resulting in its constitutive expression depending on the activity of the immunoglobulin (Ig) enhancer elements. Treatment of BL cell lines with epigenetic modifiers is known to repress B-cell specific genes and to up-regulate B-cell-inappropriate genes including the transcription repressor ID2  expression. We found that DNA methyltransferase inhibitor decitabine/5-aza-2-deoxycytidine (5-aza-dC) represses the MYC oncogene on RNA and protein levels by inducing ID2. Down-regulation of MYC was associated with repression of transcriptional activity of the Ig locus and with inhibition of proliferation. The induction of ID2 can be in part explained by activation of the transcription factor NF-kappaB. We conclude that up-regulation of ID2 contributes to antitumor activity of 5-aza-dC via repression of Ig locus activity and consequently MYC expression. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

 

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[465]

TÍTULO / TITLE:  - Sensitization of Tumor to (212)Pb Radioimmunotherapy by Gemcitabine Involves Initial Abrogation of G2 Arrest and Blocked DNA Damage Repair by Interference With Rad51.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Radiat Oncol Biol Phys. 2012 Nov 29. pii: S0360-3016(12)03592-4. doi: 10.1016/j.ijrobp.2012.09.015.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ijrobp.2012.09.015

AUTORES / AUTHORS:  - Yong KJ; Milenic DE; Baidoo KE; Brechbiel MW

INSTITUCIÓN / INSTITUTION:  - Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

RESUMEN / SUMMARY:  - PURPOSE: To elucidate the mechanism of the therapeutic efficacy of targeted alpha-particle radiation therapy using (212)Pb-TCMC-trastuzumab together with gemcitabine for treatment of disseminated peritoneal cancers. METHODS AND MATERIALS: Mice bearing human colon cancer LS-174T intraperitoneal xenografts were pretreated with gemcitabine, followed by (212)Pb-TCMC-trastuzumab and compared with controls. RESULTS: Treatment with (212)Pb-TCMC-trastuzumab increased the apoptotic rate in the S-phase-arrested tumors induced by gemcitabine at earlier time points (6 to 24 hours). (212)Pb-TCMC-trastuzumab after gemcitabine pretreatment abrogated G2/M arrest at the same time points, which may be associated with the inhibition of Chk1 phosphorylation and, in turn, cell cycle perturbation, resulting in apoptosis. (212)Pb-TCMC-trastuzumab treatment after gemcitabine pretreatment caused depression of DNA synthesis, DNA  double-strand breaks, accumulation of unrepaired DNA, and down-regulation of Rad51 protein, indicating that DNA damage repair was blocked. In addition, modification in the chromatin structure of p21 may be associated with transcriptionally repressed chromatin states, indicating that the open structure  was delayed at earlier time points. CONCLUSION: These findings suggest that the cell-killing efficacy of (212)Pb-TCMC-trastuzumab after gemcitabine pretreatment  may be associated with abrogation of the G2/M checkpoint, inhibition of DNA damage repair, and chromatin remodeling.

 

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[466]

TÍTULO / TITLE:  - Reduction in the recurrence of meningiomas by combining somatostatin receptor scintigraphy of 99mTc-HYNIC-octreotide SPECT/CT and radio guidance with a hand-held gamma-probe during surgery.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Nucl Med Commun. 2013 Mar;34(3):249-53. doi: 10.1097/MNM.0b013e32835bdfc9.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MNM.0b013e32835bdfc9

AUTORES / AUTHORS:  - Wang S; Yang W; Deng J; Zhang J; Ma F; Wang J

INSTITUCIÓN / INSTITUTION:  - Departments of aNuclear Medicine bNeurosurgery cPathology, Xijing Hospital, Fourth Military Medical University, Xi’an, China.

RESUMEN / SUMMARY:  - PURPOSE: The aim of this study was to determine whether recurrence of meningiomas could be reduced by combining somatostatin receptor scintigraphy (SRS) of Tc-HYNIC-octreotide SPECT/CT and radio guidance with a hand-held gamma-probe during surgery. MATERIALS AND METHODS: Thirty patients with meningiomas diagnosed by MRI and considered as the study group were treated with Tc-HYNIC-octreotide SPECT/CT preoperatively and pathologically examined postoperatively. Another 60 patients considered as the control group underwent only an MRI preoperatively and a pathological examination postoperatively. For the patients in the study group,  meningiomas were removed by a hand-held gamma-probe 4-12 h after SRS; these patients were followed up by MRI examination each year for 5 years to monitor the recurrence rate of the meningiomas. For the control group, routine operations without radio guidance were performed and followed up with MRI examination simultaneously. RESULTS: All patients in the study group, comprising 20 with grade I and 10 with grade II meningiomas, showed high Tc-HYNIC-octreotide accumulation with a sensitivity of 100% for SRS; four patients (13.3%) relapsed after a 5-year follow-up, including one (5%) patient with a grade I and three (30%) patients with a grade II meningioma. However, among the 60 control patients, 30 were of grade I and 30 were of grade II; 18 patients (30%) experienced recurrence, including five (16.7%) grade I patients and 13 (43.3%) grade II patients. There were significant differences in recurrence between the study group and the control group when considering all the patients and those in  grade I and grade II (all P values were below 0.001). CONCLUSION: Tc-HYNIC-octreotide SPECT/CT SRS is a sensitive technique for detecting meningiomas, and radio guidance using a hand-held gamma-probe with Tc-HYNIC-octreotide during surgery can significantly reduce the recurrence of meningiomas.

 

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[467]

TÍTULO / TITLE:  - Inhibition of leukemic U937 cell growth by induction of apoptosis, cell cycle arrest and suppression of VEGF, MMP-2 and MMP-9 activities by cytotoxin protein NN-32 purified from Indian spectacled cobra (Naja naja) venom.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Toxicon. 2013 Jan 18. pii: S0041-0101(13)00022-6. doi: 10.1016/j.toxicon.2013.01.004.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.toxicon.2013.01.004

AUTORES / AUTHORS:  - Das T; Bhattacharya S; Biswas A; Gupta SD; Gomes A; Gomes A

INSTITUCIÓN / INSTITUTION:  - Drug Development, Diagnostics & Biotechnology Division, CSIR-Indian Institute of  Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India.

RESUMEN / SUMMARY:  - A cytotoxin NN-32 (6.7 kDa) from Indian cobra (Naja naja) venom inhibited human leukemic U937 cell growth as observed by Trypan blue dye exclusion method and cytotoxicity was confirmed by MTT assay. NN-32 induced apoptosis of U937 cell and cell cycle arrest of sub-G1 phase were revealed by FACS analysis. Increased Bax/Bcl-2 ratio, increased caspase 3 and 9 activities, cleaved PARP, decreased VEGF, MMP-2 and MMP-9 activities were observed after NN-32 treatment of U937 cell. Antileukemic activity of NN-32 on U937 cell may be due to activation of apoptosis, arresting cell cycle and antiangiogenesis activities.

 

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[468]

TÍTULO / TITLE:  - PGRMC2, a yet uncharacterized protein with potential as tumor suppressor, migration inhibitor, and regulator of cytochrome P450 enzyme activity.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Steroids. 2012 Dec 28. pii: S0039-128X(12)00333-9. doi: 10.1016/j.steroids.2012.12.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.steroids.2012.12.002

AUTORES / AUTHORS:  - Wendler A; Wehling M

INSTITUCIÓN / INSTITUTION:  - University of Heidelberg, Clinical Pharmacology Mannheim, Maybachstr. 14, 68169 Mannheim, Germany.

RESUMEN / SUMMARY:  - PGRMC2 (progesterone receptor membrane component 2) is highly homologous if compared with PGRMC1, a cytochrome-related protein, which is induced in several cancers and linked to cell growth in these cancers. Further it seems to be involved in progesterone signalling and cytochrome P450 binding. For PGRMC2 only  sparse information is available. Recent data show that PGRMC1 and 2 share several similar characteristics, but there are also important differences in expression and function of the both proteins. Several findings point to the fact that PGRMC2 might play a role in cancer as well. The protein influences the migration rate of ovarian cancer cells and a loss of PGRMC2 might result in higher metastasis rates. In contrast to PGRMC1 it seems more likely to act as a tumor suppressor than a promoter. Altered PGRMC2 expression was further detected in the context of term and preterm labour, though the implications of this finding are currently unknown and need further examination. PGRMC2 further might play a role in gynaecologic diseases like preterm labour and endometriosis. PGRMC2 shares the cellular localisation and the ability to bind cytochrome enzymes with PGRMC1. Further the protein was shown to influence the activity of CYP3A4. In conclusion, though not much is known about PGRMC2 so far, it deserves further examination as  data point to a role of PGRMC2 as tumor suppressor, migration inhibitor and regulator of cytochrome P450 proteins.

 

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[469]

TÍTULO / TITLE:  - Prognostic impact of immune status and hematopoietic recovery before and after fludarabine, IV busulfan, and antithymocyte globulins (FB2 regimen) reduced-intensity conditioning regimen (RIC) allogeneic stem cell transplantation (allo-SCT).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Haematol. 2013 Jan 10. doi: 10.1111/ejh.12049.

            ●● Enlace al texto completo (gratuito o de pago) 1111/ejh.12049

AUTORES / AUTHORS:  - Le Bourgeois A; Lestang E; Guillaume T; Delaunay J; Ayari S; Blin N; Clavert A; Tessoulin B; Dubruille V; Mahe B; Roland V; Gastinne T; Le Gouill S; Moreau P; Mohty M; Planche L; Chevallier P

INSTITUCIÓN / INSTITUTION:  - Centre Hospitalier et Universitaire (CHU) de Nantes, Hematologie Clinique, Centre d’Investigation Clinique en Cancerologie (CI2C), Nantes, France.

RESUMEN / SUMMARY:  - This retrospective analysis aimed to assess hematopoietic and immune recovery in  a cohort of 53 patients [males: n = 33; median age: 59 yr (range: 22-70)] who received a FB2 (fludarabine 120-150 mg/m(2) + IV busulfan 6.4 mg/kg + antithymocyte globulin thymoglobulin 5 mg/kg) reduced-intensity conditioning (RIC) allo-stem cells transplantations (SCT). With a median follow-up of 19 months (range: 2-53), the 2-yr overall survival, disease-free survival (DFS), relapse incidence, and non-relapse mortality were 63%, 59.5%, 35%, and 6%, respectively. In univariate analysis, the factors correlated with a significantly higher 2-yr OS and DFS were a higher total circulating lymphocytes count at transplant (>730/mm(3) ; OS: 81% vs. 43%, P = 0.02; DFS: 73% vs. 45.5%, P = 0.03) and a higher recovery of leukocytes (>5300/mm(3) ) (2-yr OS: 81% vs. 44%, P = 0.007; 2-yr DFS: 72% vs. 46%, P = 0.08), neutrophils (>3200/mm(3) ) (2-yr OS: 76% vs. 50%, P = 0.03; 2-yr DFS: 67% vs. 52.0%, P = 0.1), and monocytes (>590/mm(3) ; 2-yr OS: 80% vs. 45%, P = 0.004; 2-yr DFS: 76% vs. 42%, P = 0.01) at day +30 post-transplant. In multivariate analysis, the only independent factors associated with a significantly higher OS and DFS were a better immune status at  transplant (lymphocytes count >730/mm(3) ) and a higher monocytes count (>590/mm(3) ) at day +30 post-transplant. These results suggest that immune status and hematopoietic recovery before and after FB2 RIC allo-SCT can be significant predictors of outcome. This paves the way for future studies aiming to closely monitor the kinetics of immune recovery after RIC allo-SCT and to evaluate the impact of growth factors and other immunostimulatory cytokines in the setting of RIC allo-SCT.

 

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[470]

TÍTULO / TITLE:  - Ambient UVA-induced Expression of p53 and Apoptosis in Human Skin Melanoma A375 Cell Line by Quinine.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Photochem Photobiol. 2013 Jan 22. doi: 10.1111/php.12047.

            ●● Enlace al texto completo (gratuito o de pago) 1111/php.12047

AUTORES / AUTHORS:  - Yadav N; Dwivedi A; Mujtaba SF; Kushwaha HN; Singh SK; Ray RS

INSTITUCIÓN / INSTITUTION:  - Photobiology Division, CSIR-Indian Institute of Toxicology Research.

RESUMEN / SUMMARY:  - The present study aimed to analyze the phototoxic mechanism and photostability of quinine in human skin cell line A375 under ambient intensities of UVA (340-400 nm). Photosensitized quinine produced a photoproduct 6-methoxy-quinoline-4-ylmethyl-oxonium identified through LC-MS/MS. Generation of (1) O(2) , O(2) (*-) , and (*) OH was measured and further substantiated through  their respective quenchers. Photosensitized Quinine (Q) caused degradation of 2-deoxyguanosine, the most sensitive nucleotide to UV radiation. The intracellular ROS was increased in a concentration dependent manner. Significant  reduction in metabolic status measured in terms of cell viability (54%) at 25mug  mL(-1) was observed through MTT assay. Results of MTT assay accord NRU assay. Single strand DNA breaks and apoptosis were increased significantly (P<0.01) as observed through comet assay and EB/AO double staining. Photosensitized quinine caused cells to arrest in G2 phase of cell cycle and induced apoptosis (5.08%) as revealed through FACS. Real-Time PCR showed up regulation of p21 (4.56 folds) and p53 (2.811 folds) genes expression. Thus, our study suggests that generation of reactive oxygen species by quinine under ambient intensity of UVA may result into deleterious phototoxic effects among human population. © 2013 Wiley Periodicals, Inc. Photochemistry and Photobiology © 2013 The American Society of Photobiology.

 

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[471]

TÍTULO / TITLE:  - Phase I/II study of amrubicin in combination with S-1 as second-line chemotherapy for non-small-cell lung cancer without EGFR mutation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-012-2061-1

AUTORES / AUTHORS:  - Murakami S; Oshita F; Sugiura M; Kondo T; Saito H; Yamada K

INSTITUCIÓN / INSTITUTION:  - Department of Thoracic Oncology, Kanagawa Cancer Center, Nakao 1-1-2, Asahi-ku, Yokohama, 241-0815, Japan.

RESUMEN / SUMMARY:  - INTRODUCTION: Both amrubicin (Am) and S-1 are effective against non-small-cell lung cancer (NSCLC), and preclinical studies have demonstrated that the effect of tegafur/uracil, the original compound of S-1, in combination with Am significantly inhibits tumor growth. METHODS: We conducted a phase I/II study of  Am and S-1 against pretreated NSCLC without EGFR mutation. We fixed the dose of S-1 at 40 mg/m(2) on days 1-14 and escalated the Am dose in increments of 5 mg/m(2) from a starting dose of 30 mg/m(2)/day on days 1-3 and repeated the cycle every 4 weeks. RESULTS: Twenty-six patients were registered. In phase I, at an Am dose of 35 mg/m(2)/day, three patients experienced grade 2 leukopenia during S-1  administration, and S-1 was withdrawn. Another patient developed grade 2 serum bilirubin in the first cycle. DLTs were observed in four of six patients at this  dose level, and therefore, 30 mg/m(2)/day was set as the recommended dose for Am. Twenty patients received this recommended Am dose. Febrile neutropenia was observed in two patients, and one patient developed a grade 4 increase in serum creatinine. Grade 3 vomiting, infection, hypotension, and urinary retention were  observed in one patient each, respectively. Other toxicities were mild, and there were no treatment-related deaths. Two patients showed a CR, three showed a PR, and the overall response rate was 25.0 %. The median progression-free and the median survival times were 3.8 and 15.6 months, respectively, and the 1-year survival rate was 60 %. CONCLUSION: Am and S-1 every 4 weeks is an effective combination for pretreated NSCLC without EGFR mutation.

 

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[472]

TÍTULO / TITLE:  - Vimentin as a poor prognostic factor for triple-negative breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Cancer Res Clin Oncol. 2013 Jan 26.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00432-013-1376-6

AUTORES / AUTHORS:  - Yamashita N; Tokunaga E; Kitao H; Hisamatsu Y; Taketani K; Akiyoshi S; Okada S; Aishima S; Morita M; Maehara Y

INSTITUCIÓN / INSTITUTION:  - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

RESUMEN / SUMMARY:  - PURPOSE: Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, is a highly heterogeneous disease. Recent studies suggest that there  are links between TNBC and the epithelial-mesenchymal transition (EMT). To identify prognostic biomarkers and novel therapeutic targets, vimentin, one of the most major factors associated with EMT was investigated in TNBC. MATERIALS AND METHODS: Sporadic invasive ductal carcinoma specimens were obtained from 659  Japanese patients, and 90 (14 %) cases were diagnosed as TNBC. The vimentin mRNA  and protein expression levels were evaluated by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. RESULTS: The mRNA expression of vimentin was significantly upregulated in the basal-type breast cancer cell line. Immunohistochemically, the vimentin expression was significantly higher (p = 0.0042) in TNBC compared with the other subtypes. Vimentin expression was associated with a younger age (p = 0.016), high nuclear grade (p = 0.023) and high Ki67 expression (p < 0.0001), and a poorer prognosis in terms of both the recurrence-free survival (RFS) (p = 0.0058) and overall survival (OS) (p = 0.013) in TNBC patients. A multivariate analysis showed that vimentin expression was an independent prognostic factor for the RFS (p = 0.043). Vimentin expression was also associated with a significantly shorter RFS (p = 0.021) and OS (p = 0.017) in patients with basal-like breast cancer (BLBC). CONCLUSIONS: The elevated expression of vimentin contributes to the aggressive phenotype and poor prognosis in TNBC. Vimentin expression might be useful as a biomarker for the prognosis of TNBC.

 

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[473]

TÍTULO / TITLE:  - Conversion to sirolimus in kidney transplant recipients with squamous cell cancer and changes in immune phenotype.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Nephrol Dial Transplant. 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 1093/ndt/gfs474

AUTORES / AUTHORS:  - Carroll RP; Hester J; Wood KJ; Harden PN

INSTITUCIÓN / INSTITUTION:  - 1Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford,Oxford, UK.

RESUMEN / SUMMARY:  - BackgroundConversion to sirolimus from calcineurin inhibitor- (CNI), azathioprine- (AZA) and mycophenolate-based regimens reduces the risk of development of squamous cell carcinoma of the skin (SCC) in kidney transplant recipients (KTRs). Sirolimus conversion may also be protective by permitting beneficial changes in immune phenotype. It is not known how sirolimus will affect immune phenotype in KTRs with SCC.MethodsThirty-two KTRs with SCC were enrolled into this single-blinded randomized study and 13 KTRs randomized to sirolimus (4-10 ng/mL) and prednisolone 5 mg/day.ResultsSix-month post conversion to sirolimus FOXP3(+) CD127(low)CD25(high)CD69(-), the number of T cells (putative Treg) increased significantly (P = 0.008). Natural killer (NK) and CD56(bright) NK cells also increased significantly (P = 0.039 and 0.02). T-cell number only significantly increased in those KTRs where CNI was ceased as part of the conversion to mammalian target of rapamycin inhibitors (mTORi’s) (P = 0.031) implying CNI cessation rather than mTORi initiation induced an increase in T-cell number. Increases in the NK cell number was only significant in those KTRs where  AZA was ceased (P = 0.040), implying AZA cessation rather than mTORi initiation caused the NK cell number to increase. At 6 months, sirolimus conversion reduces  new SCC/year, rate ratio 0.49 (95%CI: 0.15-1.63), P = 0.276. On therapy analysis  and intention-to-treat analysis over 24 months, the rate ratios were 0.84 and 0.87, respectively, and did not reach significance.ConclusionsConversion to mTORi from CNI may reveal a pre-existing high Treg phenotype by unmasking CNI inhibition of FOXP3 expression. Cessation of AZA leads to increased NK cell number. High FOXP3(+) T-cell number on conversion to mTORi may predict those KTRs who continue to accrue SCC.

 

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[474]

TÍTULO / TITLE:  - Effect of siRNAs targeting T790M mutation and wild type EGFR in non-small cell lung cancer cell line resistant to gefitinib or erlotinib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2012 Dec 22. pii: S0006-291X(12)02418-7. doi: 10.1016/j.bbrc.2012.12.070.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.12.070

AUTORES / AUTHORS:  - Chen G; Kronenberger P; Teugels E; Umelo IA; De Greve J

INSTITUCIÓN / INSTITUTION:  - Laboratory of Medical and Molecular Oncology, Department of Medical Oncology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium; Department of Pathology, First Affiliated Hospital, Guangxi Medical University, Shuangyong Road 6, 530021 Nanning, Guangxi, PR China.

RESUMEN / SUMMARY:  - The epidermal growth factor receptor (EGFR) is a validated therapeutic target in  non-small cell lung cancer (NSCLC). However, some mutations confer resistance to  current available agents, especially the T790M mutation. In the current study, we have examined in a NSCLC cell line H1975 containing both L858R and T790M mutations, the effect of T790M-specific-siRNAs. T790M-specific-siRNAs were able to inhibit T790M and EGFR mRNA, to reduce EGFR protein expression, as well as to  reduce the cell growth and induce cell caspase activity in H1975 cells. However,  this effect showed less potency compared to the EGFR-specific-siRNAs. EGFR-specific-siRNAs offered strong activity to inhibit cell growth and induce apoptosis in H358, H1650, H292, HCC827 and also H1975 cells, which showed weak response to tyrosine kinase inhibitors (TKIs) or cetuximab. The addition of T790M-specific-siRNAs could rescue the sensitivity of T790M mutant H1975 cells to TKIs. The combination of T790M-specific-siRNAs and cetuximab also additively enhanced cell growth regression and induction of apoptosis in H1975 cells. Among  the anti-EGFR agents tested, the strongest biological effect was observed when afatinib combined with T790M-specific-siRNAs. Afatinib also offered extra effect  when combined with cetuximab in H1975 cells. In a conclusion, knock-down of T790M transcript by siRNAs further decreases the cell growth of T790M mutant lung cancer cells that are treated with TKIs or cetuximab alone. The combination of a  potent, irreversible kinase inhibitor such as afatinib, with T790M-specific-siRNAs should be further investigated as a new strategy in the treatment of lung cancer containing the resistant T790M mutation.

 

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[475]

TÍTULO / TITLE:  - Antitumor efficacy on glioma models of PHA-848125, a multikinase inhibitor able to cross the blood brain barrier.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Pharmacol. 2013 Jan 24. doi: 10.1111/bph.12112.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bph.12112

AUTORES / AUTHORS:  - Albanese C; Alzani R; Amboldi N; Degrassi A; Festuccia C; Fiorentini F; Gravina GL; Mercurio C; Pastori W; Brasca MG; Pesenti E; Galvani A; Ciomei M

INSTITUCIÓN / INSTITUTION:  - BU Oncology, Nerviano Medical Sciences, Nerviano, Milano, Italy.

RESUMEN / SUMMARY:  - BACKGROUND & PURPOSE: Malignant gliomas, the most common primary brain tumors, are highly invasive and neurologically destructive neoplasms with a very bad prognosis due to the difficulty to remove completely the mass by surgery and the  limited activity of current therapeutic agents. PHA-848125 is a multikinase inhibitor with broad antitumor activity in preclinical studies and good tolerability in Phase 1 studies, that could affect two main pathways involved in  glioma pathogenesis, the G1-S phase progression control pathway through the inhibition of CDKs and the signaling pathways mediated by tyrosine kinase growth  factor receptors, such as tropomyosin receptors. For this reason we tested PHA-848125 in glioma models. EXPERIMENTAL APPROACH: PHA-848125 was tested on a panel of glioma cell lines in vitro to evaluate inhibition of proliferation and mechanism of action. In vivo efficacy was evaluated on two glioma models both as  single agent and in combination with standard therapy. KEY RESULTS: When tested on a subset of representative glioma cell lines, PHA-848125 blocked cell proliferation, DNA synthesis and inhibited both cell cycle and signal transduction markers. Relevantly, PHA-848125 was also able to induce cell death through authophagy in all cell lines. Good antitumor efficacy was observed by oral route in different glioma models both with subcutaneous and intracranial implantation. Indeed, we demonstrate that the drug is able to cross the blood brain barrier. Moreover, the combination of PHA-848125 with temozolomide resulted in a synergistic effect and a clear therapeutic gain was also observed with a triple treatment adding PHA-848125 to radiotherapy and temozolomide. CONCLUSIONS  & IMPLICATIONS: All the preclinical data obtained so far suggest that PHA-848125  may become a useful agent in chemotherapy regimens for glioma patients and support its evaluation in phase 2 trials for this indication.

 

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[476]

TÍTULO / TITLE:  - Expression of Adiponectin Receptor 1 Is Indicative of Favorable Prognosis in Non-small Cell Lung Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Tohoku J Exp Med. 2013;229(2):153-62.

AUTORES / AUTHORS:  - Abdul-Ghafar J; Soo Oh S; Park SM; Wairagu P; Nyung Lee S; Jeong Y; Eom M; Yong SJ; Jung SH

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Yonsei University Wonju College of Medicine.

RESUMEN / SUMMARY:  - Lung cancer is a major cause of cancer-related death worldwide. It is believed that obesity-related malignancies such as breast, endometrial, colorectal, and kidney carcinomas have lower plasma level and/or tissue expression of adiponectin receptors. However, the association between adiponectin receptors and lung cancer, a non obesity-related malignancy, is still unknown. We evaluated the tissue expression of adiponectin receptor (AdipoR) 1 and AdipoR2 in 83 cases of non-small cell lung carcinoma (NSCLC) and matched non-neoplastic lung tissues by  immunohistochemistry and real-time polymerase chain reaction (PCR). Clinicopathological data, including smoking history, smoker’s bronchiolitis, emphysema, lymph node metastasis, and T-stage were collected and evaluated. Expression of immunohistochemically stained AdipoR1 and AdipoR2 was observed in all samples of non-neoplastic lung tissues. Both receptors showed higher mRNA expression in non-neoplastic than neoplastic tissues (p < 0.05). In NSCLC tissues, AdipoR1 immunohistochemical expression was not observed in most of patients with squamous cell carcinoma and current smoking history (31/42, p = 0.04 and 25/29, p = 0.003, respectively). Additionally, AdipoR1 mRNA expression was significantly lower in patients with lymph node metastasis (p = 0.05). Meanwhile, AdipoR2 immunohistochemical stain expression was inversely correlated  with T-stage (p = 0.05) and AdipoR2 mRNA expression was significantly lower in patients with smoker’s bronchiolitis (p = 0.01) and emphysema (p = 0.03). Patients with expression of AdipoR1 had longer overall survival. AdipoR2 expression was not correlated with patients’ survival. In conclusion, we suggest  that expression of AdipoR1 is indicative of favorable prognosis and may be used as prognostic marker in NSCLC.

 

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[477]

TÍTULO / TITLE:  - Identification of an AKT-dependent signalling pathway that mediates tamoxifen-dependent induction of the pro-metastatic protein anterior gradient-2.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2013 Jan 24. pii: S0304-3835(13)00077-3. doi: 10.1016/j.canlet.2013.01.034.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2013.01.034

AUTORES / AUTHORS:  - Hrstka R; Murray E; Brychtova V; Fabian P; Hupp TR; Vojtesek B

INSTITUCIÓN / INSTITUTION:  - Masaryk Memorial Cancer Institute, Regional Centre for Applied Molecular Oncology, Zluty kopec 7, 656 53 Brno, Czech Republic.

RESUMEN / SUMMARY:  - The pro-metastatic protein anterior gradient-2 (AGR2) was previously demonstrated as a predictive factor of poor response to tamoxifen treatment. In this study we  aimed to delineate the key signalling pathway that may contribute to regulation of AGR2 protein induction in order to identify novel targets to overcome tamoxifen resistance in tumour cells. Together, our data identify PDPK1-AKT as a  pro-oncogenic signalling pathway that triggers AGR2 protein induction in response to tamoxifen and suggest that AKT inhibitors could be used as part of a therapeutic strategy to treat tamoxifen resistant, AGR2 over-expressing cancers.

 

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[478]

TÍTULO / TITLE:  - Phosphodiesterase-5 Inhibitors Could Be Efficacious in the Treatment of Erectile  Dysfunction after Radiotherapy for Prostate Cancer: A Systematic Review and Meta-Analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Urol Int. 2012 Dec 5.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000343730

AUTORES / AUTHORS:  - Yang L; Qian S; Liu L; Pu C; Yuan H; Han P; Wei Q

INSTITUCIÓN / INSTITUTION:  - Department of Urology, West China Hospital, Sichuan University, Chengdu, China.

RESUMEN / SUMMARY:  - Objective: This systematic review was performed to evaluate the efficacy and safety of phosphodiesterase-5 inhibitors (PDE5i) in the treatment of erectile dysfunction (ED) after radiotherapy for prostate cancer (PCa). Methods: A systematic search of PubMed, Embase and the Cochrane Library was performed to identify all randomized controlled trials (RCTs). All relevant studies on the outcomes and complications of PDE5i in the treatment of ED after radiotherapy for PCa were assessed. The outcomes and complications analyzed for this study included the International Index of Erectile Function (IIEF) questionnaire, Global Efficacy Questions (GEQs), Sexual Encounter Profile (SEP) diary and side effects. The Cochrane Collaboration Review Manager software (RevMan 5.1.4) was used for statistical analysis of the outcomes and complications. Results: A total of 4 RCTs were identified from the search strategy. Compared with placebo, the trials indicated that PDE5i significantly improved the IIEF scores, with the exception of two questions (questions 6 and 13), and statistically significantly  more positive answers for the GEQs and SEP diary were acquired in intervention groups. Furthermore, almost all the side effects in both groups were mild or moderate, transient and well tolerated. Except for headache, flushing and dyspepsia, all other adverse events did not differ significantly between the two  groups. Conclusions: The systematic review suggested significant advantages in the efficacy and safety of PDE5i in the treatment of ED after radiotherapy for PCa. PDE5i should be considered as the first choice for the treatment of PCa patients with ED after radiotherapy.

 

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[479]

TÍTULO / TITLE:  - Ubiquitin-specific protease 4 promotes TNF-alpha-induced apoptosis by deubiquitination of RIP1 in head and neck squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - FEBS Lett. 2013 Jan 8. pii: S0014-5793(13)00004-5. doi: 10.1016/j.febslet.2012.12.016.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.febslet.2012.12.016

AUTORES / AUTHORS:  - Hou X; Wang L; Zhang L; Pan X; Zhao W

INSTITUCIÓN / INSTITUTION:  - Department of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Department of Otorhinolaryngology, General Hospital of Jinan Military Region of PLA, Jinan, Shandong 250014, China.

RESUMEN / SUMMARY:  - Head and neck squamous cell carcinoma (HNSCC) is a common type of cancer. Better  understanding of molecular aberrations associated with HNSCC might identify new diagnostic and therapeutic strategies for this disease. In this study, we found ubiquitin-specific protease 4 (USP4) was significantly upregulated in HNSCC. USP4 negatively regulates RIP1-mediated NF-kappaB activation and promotes TNF-alpha-induced apoptosis in FaDu cells. USP4 directly interacts with receptor-interacting protein 1 (RIP1) and deubiquitinates K63-linked ubiquitination from RIP1. Therefore, our results indicate that USP4 has tumor suppressor roles in HNSCC and suggest USP4 as a potential therapeutic target for  HNSCC. STRUCTURED SUMMARY OF PROTEIN INTERACTIONS: RIP1physically interacts with  USP4 by anti tag coimmunoprecipitation (View Interaction: 1, 2, 3) RIP1physically interacts with USP4 by anti bait coimmunoprecipitation (View interaction).

 

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[480]

TÍTULO / TITLE:  - Efficacy analysis of (131)I therapy and predictive value of preablation stimulated thyroglobulin for lung metastases from differentiated thyroid cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Endocrinol (Paris). 2013 Jan 18. pii: S0003-4266(12)01213-9. doi: 10.1016/j.ando.2012.11.007.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ando.2012.11.007

AUTORES / AUTHORS:  - Wu S; Wang H

INSTITUCIÓN / INSTITUTION:  - Department of Nuclear Medicine, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, 1665, Kong Jiang road, Shanghai 200092, China.

RESUMEN / SUMMARY:  - OBJECTIVE: Our objective was to investigate the clinical efficacy of (131)I therapy for lung metastases from differentiated thyroid cancer (DTC) and assess whether the preablation stimulated thyroglobulin (Tg) could have predictive value for the outcome. METHODS AND MATERIALS: Fifty-two DTC patients (mean 44.5+/-19.2years; 33 females and 19 males) with lung metastases treated with (131)I were retrospectively analysed. The therapeutic efficacy was evaluated based on the change in serum Tg. Fifty patients’ preablation stimulated Tg were collected with negative Tg antibody levels and estimated using the t-test method. RESULTS: After (131)I therapy, a significant decrease in serum Tg was seen in 30  patients (effective rate, 57.6%), and changes in serum Tg that indicated stabilization and ineffectiveness were both seen in 11 patients (21.2%). Only patients with age under 45years were more likely to respond to serum Tg changes (P=0.046). But binary logistic regression revealed that none of the six factors (age, patient gender, pathological type, local lymph node involvement, size of metastases, and (131)I uptake by metastases) had statistically significant impacts on the efficacy analysis (all P>0.05). For analysing with the preablation stimulated Tg, the “Fine miliaric” and (131)I uptake positive with great prognosis group was much lower than any other group (all the P<0.05). CONCLUSION: (131)I therapy is a feasible and effective treatment for DTC lung metastases. A better prognosis would be accomplished in those who had low level of preablation  stimulated Tg in DTC patient with lung metastases.

 

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[481]

TÍTULO / TITLE:  - Prognostic significance of epigenetic inactivation of p16, p15, MGMT and DAPK genes in follicular lymphoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):441. doi: 10.1007/s12032-012-0441-3. Epub 2012 Dec 30.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0441-3

AUTORES / AUTHORS:  - Krajnovic M; Radojkovic M; Davidovic R; Dimitrijevic B; Krtolica K

INSTITUCIÓN / INSTITUTION:  - Institute of Nuclear Sciences “Vinca”, University of Belgrade, 11001, Belgrade, Serbia, lena2mkd@yahoo.com.

RESUMEN / SUMMARY:  - In this study, methylation-specific polymerase chain reaction was used to investigate the role and potential prognostic significance of the methylation status of p16, p15, MGMT and DAPK genes in 32 specimens of follicular lymphoma (FL). Hypermethylation of p15 gene was associated with lower hemoglobin level (P  = 0.020) and MGMT/DAPK comethylation with relapsed disease (P = 0.018). Among all patients with FL, there was no significant difference in the overall survival between those with hypermethylated and unmethylated of any examined genes. Therefore, we analyzed methylation in the different groups according to FL International Prognostic Index (FLIPI) and tumor grade. In the high-risk group, patients with hypermethylated p16 gene had significant lower overall survival than those with unmethylated p16 (P = 0.006) and trend toward shorter failure-free survival (P = 0.068). In the same risk group, there was a trend toward longer overall survival for patients with hypermethylated MGMT gene, compared to those with unmethylated MGMT gene (P = 0.066). p15 methylation had impact on shorter overall survival in grade I group of patients (P = 0.013), and  DAPK methylation tended to have impact on shorter failure-free survival in the whole examined group (P = 0.079). Our results suggest that promoter methylation of p16 and MGMT genes could have prognostic value when used in combination with the FLIPI and p15 methylation in combination with tumor grade. Concurrent methylation of MGMT and DAPK genes could be the marker of tumor chemoresistance and disease recurrence.

 

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[482]

TÍTULO / TITLE:  - Ly6/uPAR-Related Protein C4.4A as a Marker of Solid Growth Pattern and Poor Prognosis in Lung Adenocarcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Thorac Oncol. 2013 Feb;8(2):152-160.

            ●● Enlace al texto completo (gratuito o de pago) 1097/JTO.0b013e318279d503

AUTORES / AUTHORS:  - Jacobsen B; Muley T; Meister M; Dienemann H; Christensen IJ; Santoni-Rugiu E; Laerum OD; Ploug M

INSTITUCIÓN / INSTITUTION:  - *The Finsen Laboratory, Rigshospitalet, Copenhagen Biocenter, Copenhagen, Denmark; daggerBiotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark; double daggerTranslational Research Unit, section signDepartment of Surgery, Thoraxklinik-Heidelberg gGmbH, University of Heidelberg, Heidelberg, Germany; ||Department of Pathology, Rigshospitalet, Copenhagen, Denmark; paragraph signThe Gade Institute, University of Bergen/Department of Pathology, Haukeland University Hospital, Bergen, Norway; #Danish-Chinese Centre for Proteases and Cancer **Translational Lung Reseach Center Heidelberg (TLRC-H), Member of the German Centre of Lung Research (DZL).

RESUMEN / SUMMARY:  - INTRODUCTION:: We have recently shown that the protein C4.4A is induced in early  precursor lesions of pulmonary adenocarcinomas and squamous cell carcinomas. In the present study, we aimed at analyzing the impact of C4.4A on the survival of non-small cell lung cancer patients and determining whether its unexpected expression in adenocarcinomas could be attributed to a specific growth type (lepidic, acinar, papillary, micropapillary, solid). METHODS:: Sections from the  center and periphery of the primary tumor, as well as N2-positive lymph node metastases, were stained by immunohistochemistry for C4.4A and scored semi-quantitatively for intensity and frequency of positive tumor cells. RESULTS:: C4.4A score (intensity x frequency) in the tumor center was a highly significant prognostic factor in adenocarcinomas (n = 88), both in univariate (p  = 0.004; hazard ratio [95% confidence interval] = 1.44 [1.12-1.85]) and multivariate statistical analysis (p = 0.0005; hazard ratio = 1.65 [1.24-2.19]),  demonstrating decreasing survival with increasing score. In contrast, C4.4A did not provide prognostic information in squamous cell carcinomas (n = 104). Pathological stage was significant in both groups. In the adenocarcinomas, C4.4A  expression was clearly associated with, but a stronger prognostic factor than, solid growth. CONCLUSIONS:: The present results substantiate the potential value  of C4.4A as a prognostic marker in pulmonary adenocarcinomas seen earlier in a smaller, independent patient cohort. Importantly, we also show that C4.4A is a surrogate marker for adenocarcinoma solid growth. Recent data suggest that C4.4A  is negatively regulated by the tumor suppressor liver kinase B1, which is inactivated in some adenocarcinomas, providing a possible link to the impact of C4.4A on the survival of these patients.

 

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[483]

TÍTULO / TITLE:  - Mucin-producing Sweat Gland Carcinoma of the Eyelid: Diagnostic and Prognostic Considerations.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Ophthalmol. 2012 Dec 3. pii: S0002-9394(12)00686-1. doi: 10.1016/j.ajo.2012.09.030.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ajo.2012.09.030

AUTORES / AUTHORS:  - Hoguet A; Warrow D; Milite J; McCormick SA; Maher E; Dellarocca R; Dellarocca D; Goldbaum A; Milman T

INSTITUCIÓN / INSTITUTION:  - Ophthalmology, New York Eye and Ear Infirmary, New York, New York.

RESUMEN / SUMMARY:  - PURPOSE: To describe the clinical and pathologic characteristics of mucin-producing sweat gland carcinoma of the eyelid and to determine whether neuroendocrine differentiation is of prognostic significance. DESIGN: Retrospective interventional case series. METHODS: Search of the New York Eye and Ear Infirmary pathology database between 1990 and 2011 identified 16 patients with mucin-producing sweat gland carcinoma. Clinical, histopathologic, and immunohistochemical analyses were performed on all identified cases. RESULTS: The patients presented with vascularized, focally cystic, nonulcerated eyelid margin  lesions. Histopathologic evaluation showed that 4 lesions (25%) had a cystic, papillary, and solid growth pattern with an in situ component, 7 (44%) were pure  invasive mucinous carcinomas, and 5 (31%) demonstrated both growth patterns. Immunohistochemical analysis of 15 tumors showed that pure cystic/papillary lesions had a significantly greater percentage of synaptophysin-immunoreactive cells (P = .036). There was no significant difference in the number of neuroendocrine markers expressed or in the intensity of immunostaining among the  3 different growth patterns. Re-excision for margin clearance was performed in 8  of 13 cases (61.5%). Two of 13 lesions recurred (15%); 1 of these was an in situ  tumor with cystic morphology and neuroendocrine differentiation and the other was pure invasive mucinous carcinoma. None of the lesions metastasized. CONCLUSIONS:  Mucin-producing sweat gland carcinoma pathologically represents a continuum, from an in situ lesion to a classic, invasive mucinous carcinoma. Immunohistochemical  evidence of neuroendocrine differentiation can be observed in all lesions and does not appear to have a prognostic significance, arguing against the utility of immunohistochemical subtyping of mucinous sweat gland carcinomas.

 

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[484]

TÍTULO / TITLE:  - Expression of seven-in-absentia homologue 1 and hypoxia-inducible factor 1 alpha: Novel prognostic factors of nasopharyngeal carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2012 Dec 8. pii: S0304-3835(12)00719-7. doi: 10.1016/j.canlet.2012.12.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2012.12.002

AUTORES / AUTHORS:  - Kitagawa N; Kondo S; Wakisaka N; Zen Y; Nakanishi Y; Tsuji A; Endo K; Murono S; Yoshizaki T

INSTITUCIÓN / INSTITUTION:  - Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa, Ishikawa 920-8640, Japan.

RESUMEN / SUMMARY:  - Nasopharyngeal carcinoma (NPC) is an EBV-associated cancer. We analysed Siah1 expression as well as LMP1 and HIF1alpha expression by immuno-histochemical staining in 74 NPC biopsy specimens and found that the expression of Siah1 was significantly correlated with advanced tumour status and stage. Moreover, Siah1-positive and HIF1alpha-positive cases had significantly worse prognoses. The expression score for LMP1 was remarkably correlated with that of Siah1, whereas there was little correlation between LMP1 expression and the other markers evaluated. This is the first study to evaluate the pattern and clinical significance of Siah1 and HIF1alpha expression in NPC, and such an evaluation is  valuable for identifying those patients at a high risk for a poor prognosis.

 

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[485]

TÍTULO / TITLE:  - Toward the goal of personalized therapy in pancreatic cancer by targeting the molecular phenotype.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Adv Exp Med Biol. 2013;779:91-143. doi: 10.1007/978-1-4614-6176-0_5.

            ●● Enlace al texto completo (gratuito o de pago) 1007/978-1-4614-6176-0_5

AUTORES / AUTHORS:  - Yee NS

INSTITUCIÓN / INSTITUTION:  - Division of Hematology-Oncology, Department of Medicine, Penn State College of Medicine, Penn State Hershey Cancer Institute, Milton S. Hershey Medical Center,  Pennsylvania State University, Hershey, PA, USA, nyee@hmc.psu.edu.

RESUMEN / SUMMARY:  - The purpose of this article is to provide a critical review of the molecular alterations in pancreatic cancer that are clinically investigated as therapeutic  targets and their potential impact on clinical outcomes. Adenocarcinoma of exocrine pancreas is generally associated with poor prognosis and the conventional therapies are marginally effective. Advances in understanding the genetic regulation of normal and neoplastic development of pancreas have led to development and clinical evaluation of new therapeutic strategies that target the signaling pathways and molecular alterations in pancreatic cancer. Applications have begun to utilize the genetic targets as biomarkers for prediction of therapeutic responses and selection of treatment options. The goal of accomplishing personalized tumor-specific therapy with tolerable side effects for patients with pancreatic cancer is hopefully within reach in the foreseeable future.

 

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[486]

TÍTULO / TITLE:  - The prognostic value of KRAS mutated plasma DNA in advanced non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Lung Cancer. 2012 Dec 10. pii: S0169-5002(12)00637-X. doi: 10.1016/j.lungcan.2012.11.016.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.lungcan.2012.11.016

AUTORES / AUTHORS:  - Nygaard AD; Garm Spindler KL; Pallisgaard N; Andersen RF; Jakobsen A

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Vejle Hospital, Kabbeltoft 25, DK-7100 Vejle, Denmark. Electronic address: anneli.nygaard@slb.regionsyddanmark.dk.

RESUMEN / SUMMARY:  - BACKGROUND: Lung cancer is one of the most common malignant diseases worldwide and associated with considerable morbidity and mortality. New agents targeting the epidermal growth factor system are emerging, but only a subgroup of the patients will benefit from the therapy. Cell free DNA (cfDNA) in the blood allows for tumour specific analyses, including KRAS-mutations, and the aim of the study  was to investigate the possible prognostic value of plasma mutated KRAS (pmKRAS)  in patients with non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Patients with newly diagnosed, advanced NSCLC eligible for chemotherapy were enrolled in a prospective biomarker trial. A pre-treatment blood sample was drawn and subsequently DNA was extracted and pmKRAS analysed. The patients received carboplatin (AUC5) i.v. day 1 and vinorelbine (30mg/m(2) i.v. day 1 and 60mg/m(2) p.o. day 8) for a maximum of six cycles. Response to chemotherapy was evaluated according to RECIST v.1.0 by CT scans of the chest and upper abdomen. The presence of pmKRAS at baseline was assessed by an in-house qPCR method. The primary endpoint was overall survival (OS). Secondary end-points were progression free survival (PFS) and overall response rate. RESULTS: The study included 246 patients receiving a minimum of 1 treatment cycle, and all but four were evaluable for response according to RECIST. Forty-three patients (17.5%) presented with a KRAS mutation. OS was 8.9 months and PFS by intention to treat 5.4 months. Patients with a detectable plasma-KRAS mutation had a significantly shorter OS and PFS compared to the wild type (WT) patients (median OS 4.8 months  versus 9.5 months, HR 1.87, 95% CI 1.23-2.84, p=0.0002 and median PFS 3.0 months  versus 5.6 months, HR 1.60, 95% CI 1.09-2.37, p=0.0043). A multivariate Cox regression analysis confirmed the independent prognostic value of pmKRAS in OS but not in PFS. The response rate to chemotherapy was significantly lower in the  group of patients with a mutation compared to WT (p<0.0001). CONCLUSION: The presence of KRAS mutations in plasma may be a marker of poor prognosis and may also hold predictive value. Further validation in an independent cohort is highly needed.

 

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[487]

TÍTULO / TITLE:  - Intravitreal Tumor Necrosis Factor-Alpha Inhibitors for Neovascular Age-Related Macular Degeneration Suboptimally Responsive to Antivascular Endothelial Growth Factor Agents: A Pilot Study from the Pan American Collaborative Retina Study Group.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Ocul Pharmacol Ther. 2012 Dec 5.

            ●● Enlace al texto completo (gratuito o de pago) 1089/jop.2012.0203

AUTORES / AUTHORS:  - Wu L; Arevalo JF; Hernandez-Bogantes E; Regatieri CV; Roca JA; Farah ME

INSTITUCIÓN / INSTITUTION:  - 1 Instituto de Cirugia Ocular , San Jose, Costa Rica .

RESUMEN / SUMMARY:  - Abstract Purpose: To compare the short-term visual and anatomic outcomes after intravitreal injections of 2 different tumor necrosis factor-alpha inhibitors to  continued antivascular endothelial growth factor (VEGF) therapy in eyes with choroidal neovascularization (CNV) secondary to age-related macular degeneration  that responded suboptimally to anti-VEGF agents. Methods: Retrospective comparative case series of 26 eyes. Eyes were injected intravitreally with 1 mg infliximab, 2 mg infliximab, 2 mg adalimumab, or 1.25 mg bevacizumab. The main outcomes measured were the best-corrected visual acuity (BCVA) and the central macular thickness (CMT) at 3 months of follow-up. Results: The mean log minimal angle of resolution BCVA changed from 1.04+/-0.23 at baseline to 1.06+/-0.51 at 3 months (P=0.9455) in the 1-mg infliximab group; 0.94+/-0.48 at baseline to 0.85+/-0.43 in the 2-mg infliximab group (P=0.2802); 1.58+/-0.50 at baseline to 1.38+/-0.43 in the adalimumab group (P=0.1116); and 1.08+/-0.1 at baseline to 1.03+/-0.16 in the bevacizumab group (P=0.9928). The mean CMT changed from 387+/-54 mum at baseline to 342+/-108 mum (P=0.1053) in the 1-mg infliximab group; 301+/-42 mum at baseline to 284+/-73 mum (P=0.4854) in the 2-mg infliximab group; remained unchanged at 348+/-106 mum (P=0.308) in the adalimumab group; and 362+/-66 mum to 340+/-27 mum in the bevacizumab group (P=0.4622). Adverse events  included uveitis in 37.5% (6/16) of eyes injected with infliximab. Conclusion: Intravitreal infliximab and adalimumab do not appear to benefit eyes with CNV that responded suboptimally to anti-VEGF agents. Intravitreal injections of infliximab may elicit a severe intraocular inflammatory reaction.

 

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[488]

TÍTULO / TITLE:  - Overexpression of Yes-associated protein confers doxorubicin resistance in hepatocellullar carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):840-6. doi: 10.3892/or.2012.2176. Epub 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2176

AUTORES / AUTHORS:  - Huo X; Zhang Q; Liu AM; Tang C; Gong Y; Bian J; Luk JM; Xu Z; Chen J

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, PR China.

RESUMEN / SUMMARY:  - Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies worldwide and is highly resistant to chemotherapy. Yes-associated protein (YAP) is the downstream effector of the Hippo signaling pathway, which is frequently overexpressed in many types of cancers. Amplification of the YAP gene and overexpression of YAP in HCC have previously been reported to contribute to hepatocyte malignant transformation and tumor progression. In this study, we aimed to investigate the potential role of YAP in HCC chemoresistance. Overexpression of YAP resulted in resistance against doxorubicin-induced apoptosis in HCC cell lines, whereas suppression of the endogenous YAP expression by RNA interference demonstrated the reverse effect. Western blotting revealed that, following exposure to doxorubicin, YAP-overexpressing cells exhibited decreased cleaved PARP, increased phosphorylation of Akt and ERK1/2, and elevated Bcl-xL expression in comparison to the vector control. Inhibition of YAP expression sensitized HCC cells to doxorubicin, by exhibiting increased cleaved PARP, decreased levels of phosphorylated Akt, phosphorylated ERK1/2 and Bcl-xL expression. In addition, pretreatment with the MEK1/2 inhibitor U0126 but not the PI3-K inhibitor LY294002 significantly enhanced doxorubicin-induced apoptosis and decreased Bcl-xL expression in YAP-overexpressing HCC cells. Our data provide evidence that overexpression of YAP plays an important role in conferring doxorubicin resistance to HCC, which is at least partially mediated by YAP-induced activation of the MAP kinase pathway. Targeting YAP may be a promising adjunct for overcoming doxorubicin resistance in HCC.

 

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[489]

TÍTULO / TITLE:  - Histone Deacetylase Inhibitors: An Attractive Strategy for Cancer Therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Med Chem. 2012 Dec 24.

AUTORES / AUTHORS:  - Li J; Li G; Xu W

INSTITUCIÓN / INSTITUTION:  - Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Baidi Road 238, Nankai, Tianjin, PRC. xuwenqing67@yahoo.com.cn.

RESUMEN / SUMMARY:  - Histone deacetylases are able to catalyze the hydrolysis of N-acetyl lysine residues of histones which package chromosomal DNA. Therefore they play an important role in mediating gene expression and cell proliferation. HDAC inhibitors have not only shown promise as antiparasitic, antineurodegenerative, antirheumatologic agents and immunosuppressant, but as potent anticancer agents by inducing cell cycle arrest, differentiation and apoptosis. This review highlights recent development in design, synthesis and biological evaluation of HDAC inhibitors for cancer therapy.

 

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[490]

TÍTULO / TITLE:  - L1 gene methylation in high-risk human papillomaviruses for the prognosis of cervical intraepithelial neoplasia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Gynecol Cancer. 2013 Feb;23(2):235-43. doi: 10.1097/IGC.0b013e31827da1f6.

            ●● Enlace al texto completo (gratuito o de pago) 1097/IGC.0b013e31827da1f6

AUTORES / AUTHORS:  - Oka N; Kajita M; Nishimura R; Ohbayashi C; Sudo T

INSTITUCIÓN / INSTITUTION:  - *Section of Translational Research, Hyogo Cancer Center, Akashi; daggerCentral Research Laboratories, Sysmex Corporation, Kobe; double daggerLaboratory of Molecular Pharmaceutics and Technology, Faculty of Pharmacy, Takasaki University  of Health and Welfare, Takasaki; section signDepartment of Gynecologic Oncology,  Hyogo Cancer Center, Akashi; and parallelDivision of Diagnostic Pathology, Kobe University Hospital, Kobe, Japan.

RESUMEN / SUMMARY:  - OBJECTIVE: The purpose of this study was to investigate the clinical significance of DNA methylation of the human papillomavirus (HPV) genome as a prognostic biomarker for cervical intraepithelial neoplasia (CIN). METHODS AND MATERIALS: Clinical samples (paraffin-embedded tissues obtained by conization/hysterectomy or initial punch biopsy) were collected from patients at the Gynecologic Oncology of the Hyogo Cancer Center with informed consent. We evaluated the methylation status of the L1 gene of the HPV genome by bisulfite sequencing, calculating the  methylation ratio (L1MR) as (number of methylated CpGs in the analyzed region of  the L1 gene) / (number of all CpGs in the analyzed region of the L1 gene) x 100.  The methylation analysis and in situ hybridization were performed with serial tissue-section slices. RESULTS: DNA methylation was observed in the L1 gene, but  not in the long control region of HPV-16, -18, or the other high-risk HPV types including HPV-31, -52, and -58. L1MR was associated with the CIN grade; the median L1MR was 2.3%, 11.2%, 35.2%, and 50.0% for CIN1, CIN2, CIN3, and squamous  cell carcinoma, respectively. L1MRs also seemed to indicate physical status (integrated or episomal form) of the HPV genome in the host cell. L1MR of the progression group was significantly higher than that of the regression group. CONCLUSIONS: L1MR was associated with the CIN grade and indicated the HPV genome  status in the host cell: high L1MR indicated HPV genome integration linked to progression from early-stage CINs, whereas low L1MR indicated an episomal HPV genome location in host cells. L1MR may be a prognostic indicator of CIN.

 

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[491]

TÍTULO / TITLE:  - Ephrin-A1 mRNA is associated with poor prognosis of colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Feb;42(2):549-55. doi: 10.3892/ijo.2012.1750. Epub 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2012.1750

AUTORES / AUTHORS:  - Yamamoto H; Tei M; Uemura M; Takemasa I; Uemura Y; Murata K; Fukunaga M; Ohue M; Ohnishi T; Ikeda K; Kato T; Okamura S; Ikenaga M; Haraguchi N; Nishimura J; Mizushima T; Mimori K; Doki Y; Mori M

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine,  Osaka University, Osaka, Japan.

RESUMEN / SUMMARY:  - We previously studied hypoxic tumor cells from hepatic metastases of colorectal cancer (CRC) and determined several potential prognostic factors, including expression of ephrin-A1 (EFNA1), which was highly induced by hypoxia. Here, we further evaluated the prognostic impact of EFNA1 expression. Samples from a total of 366 CRC patients from 11 institutes were analyzed by either microarray (n=220) or quantitative reverse-transcriptase polymerase chain reaction (n=146). EFNA1 was an independent prognostic factor for CRC (p<0.05). In vitro assays revealed that loss of EFNA1 following siRNA treatment was associated with reduced proliferative activity and decreased invasion and migration of CRC cell lines. EFNA1 expression is a useful marker for predicting high risk of relapse and cancer-related death in patients who have undergone curative resection for CRC.

 

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[492]

TÍTULO / TITLE:  - Combination of quercetin and tannic acid in inhibiting 26S proteasome affects S5a and 20S expression and accumulation of ubiquitin resulted in apoptosis in cancer  chemoprevention.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biol Chem. 2012 Dec 5. pii: /j/bchm.just-accepted/hsz-2012-0277/hsz-2012-0277.xml. doi: 10.1515/hsz-2012-0277.

            ●● Enlace al texto completo (gratuito o de pago) 1515/hsz-2012-0277

AUTORES / AUTHORS:  - Chang TL; Wang CH

RESUMEN / SUMMARY:  - Abstract To look for oral proteasome inhibitors, the daily food is best source for cancer chemoprevention. A combination of active components from vegetables, coffee, tea, and fruit could be more efficient to inhibit 26S proteasome activities for preventing cancer diseases. Tannic acid and quercetin have been shown to strongly inhibit 26S proteasome activity, but the molecular target involved remains unknown. Overlay assay, peptide assay, western blot, and 2-D gels were used to assess the combination of quercetin and tannic acid as a potential inhibitor. Here, we demonstrated that the combination of quercetin and  tannic acid (1) synergistically suppresses chymotrypsin-like, caspase-like, and trypsin-like proteolytic activities, (2) are tightly binding substrates, (3) do not perturb the proteasome structure, (4) inhibit the 26S proteasome affected by  ubiquitin, ATP, or beta-casein, and (5) inhibit beta-casein degradation by the 26S proteasome in vitro. Finally, inhibition of the proteasome by a combination of quercetin plus tannic acid in Hep-2 cells resulted in induction of S5a at low  dose, accumulation of ubiquitin, and the cleavage of pro-caspase-3, followed by induction of apoptotic cell death. Evaluating the combination of quercetin and tannic acid as an oral drug to prevent cancer may provide a pharmacological rationale to pursue preclinical trials of this combination.

 

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[493]

TÍTULO / TITLE:  - Comparison and validation of genomic predictors for anticancer drug sensitivity.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Am Med Inform Assoc. 2013 Jan 26.

            ●● Enlace al texto completo (gratuito o de pago) 1136/amiajnl-2012-001442

AUTORES / AUTHORS:  - Papillon-Cavanagh S; De Jay N; Hachem N; Olsen C; Bontempi G; Aerts HJ; Quackenbush J; Haibe-Kains B

INSTITUCIÓN / INSTITUTION:  - Bioinformatics and Computational Genomics Laboratory, Institut de recherches cliniques de Montreal, University of Montreal, Montreal, Quebec, Canada.

RESUMEN / SUMMARY:  - BACKGROUND: An enduring challenge in personalized medicine lies in selecting the  right drug for each individual patient. While testing of drugs on patients in large trials is the only way to assess their clinical efficacy and toxicity, we dramatically lack resources to test the hundreds of drugs currently under development. Therefore the use of preclinical model systems has been intensively  investigated as this approach enables response to hundreds of drugs to be tested  in multiple cell lines in parallel. METHODS: Two large-scale pharmacogenomic studies recently screened multiple anticancer drugs on over 1000 cell lines. We propose to combine these datasets to build and robustly validate genomic predictors of drug response. We compared five different approaches for building predictors of increasing complexity. We assessed their performance in cross-validation and in two large validation sets, one containing the same cell lines present in the training set and another dataset composed of cell lines that have never been used during the training phase. RESULTS: Sixteen drugs were found in common between the datasets. We were able to validate multivariate predictors  for three out of the 16 tested drugs, namely irinotecan, PD-0325901, and PLX4720. Moreover, we observed that response to 17-AAG, an inhibitor of Hsp90, could be efficiently predicted by the expression level of a single gene, NQO1. CONCLUSION: These results suggest that genomic predictors could be robustly validated for specific drugs. If successfully validated in patients’ tumor cells, and subsequently in clinical trials, they could act as companion tests for the corresponding drugs and play an important role in personalized medicine.

 

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[494]

TÍTULO / TITLE:  - MicroRNA-218 inhibits cell cycle progression and promotes apoptosis in colon cancer by downregulating oncogene BMI-1.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Med. 2012 Dec 12. doi: 10.2119/molmed.2012.00304.

            ●● Enlace al texto completo (gratuito o de pago) 2119/molmed.2012.00304

AUTORES / AUTHORS:  - He X; Dong Y; Wu CW; Zhao Z; Ng SS; Chan FK; Sung JJ; Yu J

INSTITUCIÓN / INSTITUTION:  - Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Departments of Surgery, First affiliated Hospital, Hebei Medical University, Shijiazhuang, China.

RESUMEN / SUMMARY:  - Deregulated miRNAs participate in colorectal carcinogenesis. In this study, miR-218 was found to be downregulated in human colorectal cancer (CRC) by miRNA profile assay. MiR-218 was silenced or downregulated in all 5 colon cancer cells  (Caco2, HT29, SW620, HCT116 and LoVo) relative to normal colon tissues. miR-218 expression was significantly lower in 46 CRC tumor tissues as compared to their adjacent normal tissues (P<0.001). Potential target genes of miR-218 were predicted and BMI-1, a polycomb ring finger oncogene, was identified as one of the potential targets. Upregulation of BMI-1 was detected in CRC tumors compared  to adjacent normal tissues (P<0.001), and in all 5 colon cancer cell lines. Transfection of miR-218 in colon cancer cell lines (HCT116, HT29) significantly reduced luciferase activity of the wild-type construct of BMI-1 3’UTR (P<0.001),  whereas this effect was not seen in the construct with mutant BMI-1 3’UTR, indicating a direct and specific interaction of miR-218 with BMI-1. Ectopic expression of miR-218 in HCT116 and HT29 cells suppressed BMI-1 mRNA and protein  expression. In addition, miR-218 suppressed protein expression of BMI-1 downstream targets of cyclin-dependent kinase 4, a cell cycle regulator, while up-regulated protein expression of p53. We further revealed that miR-218 induced  apoptosis (P< 0.01), inhibited cell proliferation (P<0.05) and promoted cell cycle arrest in G2 phase (P<0.01). In conclusion, miR-218 plays a pivotal role in colorectal cancer development through inhibiting cell proliferation and cycle progression and promoting apoptosis by downregulating BMI-1.

 

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[495]

TÍTULO / TITLE:  - From bevacizumab to tasquinimod: angiogenesis as a therapeutic target in prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer J. 2013 Jan;19(1):99-106. doi: 10.1097/PPO.0b013e31827e0b86.

            ●● Enlace al texto completo (gratuito o de pago) 1097/PPO.0b013e31827e0b86

AUTORES / AUTHORS:  - Schweizer MT; Carducci MA

INSTITUCIÓN / INSTITUTION:  - From the Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MDfs.

RESUMEN / SUMMARY:  - ABSTRACT: It was first posited in the 1970s that angiogenesis may prove to be a useful target for anticancer therapies. Since then, a number of agents have been  developed and tested across a range of tumor types; however, to date, there have  unfortunately been more failures than successes. Prostate cancer (PCa) is no exception in this regard, and despite a strong preclinical rationale for targeting angiogenesis in men with PCa, there has yet to be an antiangiogenic therapy proven to prolong survival in this group of patients. Drugs have been developed to target a host of angiogenesis mediators. These include vascular endothelial growth factor (VEGF), the VEGF receptors, antiangiogenic factors (e.g., thrombospondin-1), and downstream mediators of angiogenesis (e.g., hypoxia-inducible factor-1alpha and MET). At present, there are 2 drugs being tested in the phase III setting for men with PCa: cabozantinib and tasquinimod. Cabozantinib, a dual VEGF receptor-2/MET inhibitor, has shown dramatic beneficial effects on radiographically evident bone metastases and pain in the phase II setting. There are currently 2 large phase III trials underway to further investigate cabozantinib’s role in treating men with PCa. Both trials randomize subjects to cabozantinib versus mitoxantrone: one is designed to evaluate overall survival, and the other, pain response durability. The other drug, tasquinimod, has a somewhat poorly understood mechanism of action. It is thought to exert an antiangiogenic effect through the inhibition of myeloid-derived suppressor cells, key to the support of an angiogenic environment, and down-regulation of hypoxia-inducible factor-1alpha. A phase II trial randomizing men to tasquinimod  versus placebo revealed a median progression-free survival advantage in the experimental arm (7.6 vs. 3.3 months with placebo; P = 0.0042). Based on these encouraging phase II results, a randomized, double-blind, placebo-controlled trial in men with metastatic castration-resistant PCa was launched. That trial is powered for a primary endpoint of progression-free survival and is expected to enroll 1200 men.

 

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[496]

TÍTULO / TITLE:  - Expression of the potential cancer stem cell markers, CD133, CD44, ALDH1, and beta-catenin, in primary lung adenocarcinoma-their prognostic significance.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pathol Int. 2012 Dec;62(12):792-801. doi: 10.1111/pin.12019.

            ●● Enlace al texto completo (gratuito o de pago) 1111/pin.12019

AUTORES / AUTHORS:  - Okudela K; Woo T; Mitsui H; Tajiri M; Masuda M; Ohashi K

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Division of Pathology, Kanagawa Cardiovascular and Respiratory Center Hospital, Yokohama, Japan.

RESUMEN / SUMMARY:  - The present study investigated expression profiles of the potential CSC markers including CD133, CD44, ALDH1, and beta-catenin, and evaluated their prognostic value in lung adenocarcinomas. One-hundred-and-seventy-seven tumors (stage I) were immunohistochemically examined for the expression of these markers, and thresholds to subdivide expression levels were determined using receiver operating characteristics curves. Tumors with high levels of CD133 (adjusted hazard ratio (HR) 4.55 (95% confidence interval (CI) 1.26-16.40, P = 0.021), CD44 (HR 3.73, 95% CI 1.20-11.58, P = 0.023) or ALDH1 (HR 3.61, 95% CI 1.09-12.3, P =  0.036), but not beta-catenin (HR 2.43, 95% CI 0.59-10.8, P = 0.220), showed a significantly higher risk of recurrence than the corresponding low expressers. In conclusion, levels of CD133, CD44, and ALDH1 had independent prognostic value to  predict the recurrence of lung adenocarcinoma.

 

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[497]

TÍTULO / TITLE:  - THE IGF2 mRNA BINDING PROTEIN p62 IN HEPATOCELLULAR CARCINOMA: ANTI-APOPTOTIC ACTION IS INDEPENDENT OF IGF2/PI3-K SIGNALING.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Physiol Gastrointest Liver Physiol. 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1152/ajpgi.00005.2012

AUTORES / AUTHORS:  - Kessler SM; Pokorny J; Zimmer V; Laggai S; Lammert F; Bohle RM; Kiemer AK

INSTITUCIÓN / INSTITUTION:  - 1Saarland University.

RESUMEN / SUMMARY:  - Background and aims: The insulin-like growth factor II (IGF2) mRNA binding protein (IMP) p62/IMP2-2, originally isolated from an HCC patient, induces a steatotic phenotype when overexpressed in mouse livers. Still, p62 transgenic livers do not show liver cell damage but exhibit a pronounced induction of Igf2 and activation of the downstream survival kinase Akt. Aim of this study was to investigate the relation between p62 and IGF2 expression in the human system and  to study potential anti-apoptotic actions of p62. Methods: p62 and IGF2 mRNA levels in human paraffin-embedded tissue were assessed by real-time RT-PCR. For knockdown and overexpression experiments human hepatoma HepG2 and PLC/PRF/5 cells were transfected with siRNA or plasmid DNA. Phosphorylated AKT and ERK1/2 were analysed by Western blot. Results: Investigations of 32 human HCC tissues showed  a strong correlation between p62 and IGF2 expression. Of note, p62 expression was increased markedly in patients with poor outcome. In hepatoma cells overexpression of p62 lowered levels of doxorubicin-induced caspase-3-like activity. Vice versa, knockdown of p62 resulted in increased doxorubicin-induced  apoptosis. However, neither PI3-K inhibitors nor a neutralizing IGF2 antibody showed any effects. Western blot analysis revealed increased levels of phosphorylated ERK1/2 in hepatoma cells overexpressing p62 and decreased levels in p62 knockdown experiments. When p62 overexpressing cells were treated with ERK1/2 inhibitors, the apoptosis-protecting effect of p62 was completely abrogated. Conclusions: Our data demonstrate that p62 exerts IGF2-independent anti-apoptotic action, which is facilitated via phosphorylation of ERK1/2. Furthermore, p62 might serve as a new prognostic marker in HCC.

 

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[498]

TÍTULO / TITLE:  - Fatty acid synthase overexpression confers an independent prognosticator and associates with radiation resistance in nasopharyngeal carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Tumour Biol. 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s13277-012-0605-y

AUTORES / AUTHORS:  - Kao YC; Lee SW; Lin LC; Chen LT; Hsing CH; Hsu HP; Huang HY; Shiue YL; Chen TJ; Li CF

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.

RESUMEN / SUMMARY:  - Fatty acid synthase (FASN) is overexpressed in many human cancers and associated  with poor prognosis. However, the role of FASN in nasopharyngeal carcinoma (NPC)  has not been studied. We evaluated the expression of FASN immunohistochemically in 124 NPC specimens, stratified them into two groups (FASN-high and FASN-low), and examined the correlation with various clinicopathological parameters. In two  NPC cell lines, HONE1 and TW01, we targeted the FASN transcript by shRNAi and evaluated the effect on cell proliferation by WST-1 assay and radiation-induced apoptosis by measuring caspase-3 and caspase-7 activation. NPC with high FASN immunoexpression was correlated with advanced pT disease status and worse prognosis in terms of disease-specific survival, metastasis-free survival and local recurrence-free survival, compared to FASN-low group in both univariate and multivariate analyses. In the two NPC cell lines, endogenous FASN expression was  significantly higher than the non-tumor keratinocyte, DOK. When the expression of FASN was suppressed by shRNAi, the tumor cells showed decreased cell proliferation and increased apoptosis after radiation. Our results supported FASN as an adverse prognostic marker in NPC, possibly by conferring cell growth advantage and resistance to radiation-induced apoptosis on tumor cells. The inhibition of FASN expression might be investigated as an adjunct in treatment, especially in radiation resistant NPC.

 

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[499]

TÍTULO / TITLE:  - Tumor-associated Macrophages as Potential Diagnostic and Prognostic Biomarkers in Breast Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2013 Jan 21. pii: S0304-3835(13)00053-0. doi: 10.1016/j.canlet.2013.01.024.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2013.01.024

AUTORES / AUTHORS:  - Tang X

INSTITUCIÓN / INSTITUTION:  - National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College; College of Life Sciences, Sichuan University. Electronic address: xiaoqiangtang@ibsc.pumc.edu.cn.

RESUMEN / SUMMARY:  - Breast cancer development largely depends upon the essential contributions from the tumor microenvironment, where several inflammatory cell populations (e.g. macrophages) orchestrate breast cancer development. The majority of tumor-associated macrophages (TAMs) exhibit alternatively activated M2 properties, produce abundant anti-inflammatory factors and facilitate tumor development. Clinical evidences compellingly indicate the association between high TAMs influx and poor prognosis in patients with breast cancers. The pan-macrophages marker CD68 is now generally utilized to identify TAMs in diagnostic biopsy samples, and some other TAM-related biomarkers are also utilized in prognosis prediction, including CD163, vascular endothelial growth factor (VEGF), hypoxia-inducible factors (HIFs), proliferating cellular nuclear antigen (PCNA), ferritin light chain (FTL) and C-C motif chemokine ligand 18 (CCL18). In this review, we highlight the recent progress made in understanding the relationship between TAMs and clinicopathological parameters in human breast  cancer and address the potential value of TAMs as diagnostic and prognostic biomarkers.

 

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[500]

TÍTULO / TITLE:  - Predictive markers of capecitabine sensitivity identified from the expression profile of pyrimidine nucleoside-metabolizing enzymes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):451-8. doi: 10.3892/or.2012.2149. Epub 2012 Nov 27.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2149

AUTORES / AUTHORS:  - Yasuno H; Kurasawa M; Yanagisawa M; Sato Y; Harada N; Mori K

INSTITUCIÓN / INSTITUTION:  - Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura 247-8530, Japan.

RESUMEN / SUMMARY:  - Molecular markers predicting sensitivity to anticancer drugs are important and useful not only for selecting potential responders but also for developing new combinations. In the present study, we analyzed the difference in the sensitivity of xenograft models to capecitabine (Xeloda®), 5’-deoxy-5-fluorouridine (5’-DFUR, doxifluridine, Furtulon®) and 5-FU by comparing the mRNA levels of 12 pyrimidine nucleoside-metabolizing enzymes. Amounts of mRNA in the tumor tissues  of 80 xenograft models were determined by real-time RT-PCR and mutual correlations were examined. A clustering analysis revealed that the 12 enzymes were divided into two groups; one group consisted of 8 enzymes, including orotate phosphoribosyl transferase (OPRT), TMP kinase (TMPK) and UMP kinase (UMPK), and was related to the de novo synthesis pathway for nucleotides, with mRNA expression levels showing significant mutual correlation. In the other group, 4 enzymes, including thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD), were involved in the salvage/degradation pathway of the nucleotides, and the mRNA levels of this group were dispersed more widely than that of the de novo group. Antitumor activity was assessed in 24 xenograft models for each drug. The antitumor activity of capecitabine and 5’-DFUR correlated significantly with the mRNA levels of TP and with the TP/DPD ratio, whereas the activity of 5-FU correlated significantly with OPRT, TMPK, UMPK and CD. In a stepwise regression analysis, TP and DPD were found to be independent predictive  factors of sensitivity to capecitabine and 5’-DFUR, and UMPK was predictive of sensitivity to 5-FU. These results indicate that the predictive factors for sensitivity to capecitabine and 5’-DFUR in xenograft models may be different from those for 5-FU, suggesting that these drugs may have different responders in clinical usage.

 

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[501]

TÍTULO / TITLE:  - A possible role for micro-RNA 141 down-regulation in sunitinib resistant metastatic clear cell renal cell carcinoma through induction of epithelial-to-mesenchymal transition and hypoxia resistance.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Urol. 2012 Nov 30. pii: S0022-5347(12)05718-7. doi: 10.1016/j.juro.2012.11.133.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.juro.2012.11.133

AUTORES / AUTHORS:  - Berkers J; Govaere O; Wolter P; Beuselinck B; Schoffski P; van Kempen LC; Albersen M; Van den Oord J; Roskams T; Swinnen J; Joniau S; Van Poppel H; Lerut E

INSTITUCIÓN / INSTITUTION:  - Laboratory of Translational Cell & Tissue Research, Catholic University Leuven, Minderbroederstraat 12, 3000 Leuven, Belgium; Department of Urology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: johannes.berkers@uzleuven.be.

RESUMEN / SUMMARY:  - PURPOSE: To identify micro-RNA (miR) driven mechanisms in clear cell renal cell carcinoma (ccRCC) associated with tumour response to the multi-targeted receptor  tyrosine kinase inhibitor sunitinib. METHODS: Screening genome-wide miR RT-qPCR was performed on 20 fresh-frozen ccRCC tissue samples of patients who received sunitinib treatment as first-line targeted therapy. Poor responders were considered those patients with progressive disease within 6 months (n=9) after initiating therapy. Patients with progression-free survival of at least 1 year were considered good responders (n=11). MiR-141 function was studied in vitro by  stable up-regulation of miR-141, quantification of target gene expression and cell viability in normoxic as well as hypoxic conditions. Relative expression in  clinical and cell line samples was determined by qRT-PCR. Localization of miR-141 and its targets was assessed by miR in situ hybridization and immunohistochemistry. Hypoxia-induced cytotoxicity was assessed by a luminescence ATP detection assay. RESULTS: MiR-141 was significantly down-regulated in tumours of poor responders to sunitinib therapy as compared to good responders. This seemed spatially linked to epithelial-to-mesenchymal transition (EMT) in vivo. Reintroduction of miR-141 in vitro reversed EMT and decreased cell viability in hypoxic conditions. CONCLUSIONS: In our study miR-141 down-regulation-driven EMT  in ccRCC was linked to unfavourable response to sunitinib therapy. Reintroduction of miR-141 in vitro led to EMT reversal and increased sensibility to an hypoxic environment. Future experiments should be conducted in vivo to see whether miR-141-driven reversal of EMT could affect efficacy of sunitinib treatment.

 

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[502]

TÍTULO / TITLE:  - Value of metastin receptor immunohistochemistry in predicting metastasis after radical nephrectomy for pT1 clear cell renal cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Exp Metastasis. 2013 Jan 1.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10585-012-9564-3

AUTORES / AUTHORS:  - Shoji S; Nakano M; Tomonaga T; Kim H; Hanai K; Usui Y; Nagata Y; Miyazawa M; Sato H; Tang XY; Osamura YR; Uchida T; Terachi T; Takeya K

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Tokai University Hachioji Hospital, 1838 Ishikawa-machi, Hachioji city, Tokyo, 192-0032, Japan, sunashoj@mail.goo.ne.jp.

RESUMEN / SUMMARY:  - KISS-1 is a metastasis-suppressor gene of human melanoma, and encodes metastin, which was identified as the ligand of a G-protein-coupled receptor (metastin receptor). The precursor protein is cleaved to 54 amino acids, which may be further truncated into carboxy-terminal fragments. Previous studies showed that lack of metastin receptor in clear cell renal cell carcinoma (RCC) is associated  with tumor progression, but the prediction of metastasis in patients with pT1 clear cell RCC after radical nephrectomy is difficult. The objective of this study was to evaluate the usefulness of metastin receptor immunohistochemistry in predicting metastasis after nephrectomy for pT1 clear cell RCC. After verification of the correlation between immunostaining and mRNA expression, we evaluated the clinical value of metastin receptor immunohistochemistry. Fifty-four patients were enrolled in this study; following radical nephrectomy, seven patients were found to have lung metastasis. The sensitivity, specificity,  positive predictive value, and negative predictive value with negative immunostaining of metastin receptor were 85.7, 97.6, 46.2, and 97.6 %, respectively. Metastasis-free survival rates were significantly higher in patients with positive staining (97.6 %) than in patients with negative staining  (53.8 %) (P < 0.001). In univariate analysis for metastasis-free survival, negative immunostaining of metastin receptor was a significant risk factor for metastasis (P = 0.001). Furthermore, negative immunostaining of metastin receptor was an independent predictor for metastasis in multivariate analysis (hazard ratio, 3.735; 95 % CI 0.629-22.174; P = 0.002). In conclusion, our study suggests that negative expression of metastin receptor in clear cell RCC is significantly  related to metastasis.

 

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[503]

TÍTULO / TITLE:  - Hydrophobic flavonoids from Scutellaria baicalensis induce colorectal cancer cell apoptosis through a mitochondrial-mediated pathway.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Mar;42(3):1018-26. doi: 10.3892/ijo.2013.1777. Epub 2013 Jan 16.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2013.1777

AUTORES / AUTHORS:  - Wang CZ; Calway TD; Wen XD; Smith J; Yu C; Wang Y; Mehendale SR; Yuan CS

INSTITUCIÓN / INSTITUTION:  - Tang Center for Herbal Medicine Research, and Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637, USA.

RESUMEN / SUMMARY:  - Scutellaria baicalensis extract (SbE) has been shown to exert chemopreventive effects on several types of cancer. Baicalin, a hydrophilic flavonoid found in SbE, may have opposing effects that decrease the antitumor potential of SbE against colorectal cancer. In this study, after removing baicalin, we prepared an aglycone-rich fraction (ARF) of SbE and evaluated its anti-proliferative activity and mechanisms of action. The flavonoids found in ARF, baicalin fraction (BF) and SbE were determined by high-performance liquid chromato-graphy (HPLC). The effects of ARF, BF, SbE and representative flavonoids on the proliferation of HCT-116 and HT-29 human colorectal cancer cells were determined by an MTS assay.  The cell cycle, the expression of cyclins A and B1 and cell apoptosis were assayed using flow cytometry. Apoptosis-related gene expression was visualized by quantitative real-time polymerase chain reaction (PCR), and mitochondrial membrane potential was estimated following staining with JC-1. HPLC analysis showed that ARF contained two hydrophobic flavonoids, baicalein and wogonin, and  that BF contained only baicalin. SbE had little anti-proliferative effect on the  colorectal cancer cells; cancer cell growth was even observed at certain concentrations. ARF exerted potent anti-proliferative effects on the cancer cells. By contrast, BF increased cancer cell growth. ARF arrested cells in the S  and G2/M phases, increased the expression of cyclins A and B1, and significantly  induced cell apoptosis. Multiple genes in the mitochondrial pathway are involved  in ARF-induced apoptosis, and subsequent cellular functional analysis validated the involvement of this pathway. These results suggest that removing baicalin from SbE produces an ARF that significantly inhibits the growth of colorectal cancer cells, and that the mitochondrial apoptotic pathway plays a role in hydrophobic flavonoid-induced apoptosis.

 

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[504]

TÍTULO / TITLE:  - CYT-1 isoform of ErbB4 is an independent prognostic factor in serous ovarian cancer and selectively promotes ovarian cancer cell growth in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Gynecol Oncol. 2013 Jan 9. pii: S0090-8258(13)00003-6. doi: 10.1016/j.ygyno.2012.12.044.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ygyno.2012.12.044

AUTORES / AUTHORS:  - Paatero I; Lassus H; Junttila TT; Kaskinen M; Butzow R; Elenius K

INSTITUCIÓN / INSTITUTION:  - Department of Medical Biochemistry and Genetics, and MediCity Research Laboratory, University of Turku, Turku, Finland; Turku Doctoral Programme of Biomedical Sciences, University of Turku, Turku, Finland.

RESUMEN / SUMMARY:  - OBJECTIVE: ErbB4 is a member of the ErbB subfamily of receptor tyrosine kinases with a poorly understood biological role in ovarian cancer. Here, we have addressed the expression, subcellular localization, and prognostic relevance of ErbB4 and its alternatively spliced isoforms in serous ovarian adenocarcinoma. METHODS: A tissue microarray including 482 samples was analyzed by immunohistochemistry, and a series of 198 samples by isoform-specific real-time RT-PCR. The data were statistically analyzed for associations with clinicopathological markers and survival. The functional effect of expressing the relevant ErbB4 isoforms in ovarian cancer cells was addressed by measuring colony formation in soft agar. RESULTS: While ErbB4 immunoreactivity was present in 90%  of the samples, total ErbB4 protein expression was not significantly associated with prognostic markers. However, real-time RT-PCR analysis of serous ovarian cancer samples indicated the presence of two alternatively spliced cytoplasmic isoforms of ERBB4, CYT-1 and CYT-2, previously demonstrated to mediate significantly different cellular activities. Expression of CYT-1, but not of CYT-2, was significantly associated with tumor grade (P=0.014) and overall survival (P=0.0028). CYT-1 expression was also an independent prognostic factor (P=0.021) in multivariate analysis of survival. Consistent with a biological effect specific for the one isoform, overexpression of ErbB4 CYT-1, but not of ErbB4 CYT-2, increased anchorage-independent growth of ovarian adenocarcinoma cells in vitro. CONCLUSIONS: These results suggest that expression of a specific  ErbB4 isoform, CYT-1, is associated with poor survival and enhanced growth in serous ovarian cancer.

 

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[505]

TÍTULO / TITLE:  - Resveratrol suppresses tumor progression via the regulation of indoleamine 2,3-dioxygenase.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 3. pii: S0006-291X(12)02441-2. doi: 10.1016/j.bbrc.2012.12.093.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.12.093

AUTORES / AUTHORS:  - Noh KT; Chae SH; Chun SH; Jung ID; Kang HK; Park YM

INSTITUCIÓN / INSTITUTION:  - Department of Microbiology and Immunology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626-870, South Korea.

RESUMEN / SUMMARY:  - This study showed the potential of resveratrol to inhibit the expression and activity of interferon-gamma (IFN-gamma)-induced indoleamine 2,3-dioxygenase (IDO) in bone marrow-derived dendritic cells (BMDCs). The mechanism of suppression was associated with the activity of Janus kinase/signal transducers and activators of transcription (JAK/STAT) and protein kinase Cdelta (PKCdelta).  In addition, resveratrol-mediated IDO suppression in IFN-gamma-stimulated BMDCs appears to play a pivotal role in anti-tumor activity through the regulation of CD8(+) T cell polarization and cytotoxic T lymphocyte (CTL) activity. Systemic administration of resveratrol suppressed tumor growth in EG7 thymoma-bearing mice in an IDO-dependent manner. Taken together, resveratrol not only regulates immune response through the regulation of IDO in a JAK/STAT1- and PKCdelta-dependent manner, but also modulates the IDO-mediated immune tolerance in EG7 thymoma.

 

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[506]

TÍTULO / TITLE:  - Molecular docking and synthesis of novel quinazoline analogues as inhibitors of transcription factors NF-kappaB activation and their anti-cancer activities.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Bioorg Med Chem. 2013 Jan 15;21(2):540-6. doi: 10.1016/j.bmc.2012.10.051. Epub 2012 Nov 15.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bmc.2012.10.051

AUTORES / AUTHORS:  - Xu L; Russu WA

INSTITUCIÓN / INSTITUTION:  - Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA 95211, USA.

RESUMEN / SUMMARY:  - NF-kB is a transcription factor protein complex that can be found in almost all animal cell types and is a key player in some cancers and inflammatory responses. It can enhance the proliferation rate, reduce apoptosis, as well as creating more blood flow to ensure the survival of cancer, thus blocking the NF-kB pathway has  potential therapeutic benefit. We designed a series of compounds based on a quinazoline scaffold pharmacophore model which may have high binding affinity with the p50 subunit of NF-kB. The compound series with phenyl substitution at the 2 position of the quinazoline proved to be more effective at inhibiting NF-kB function both theoretically and experimentally. These compounds also reduce the proliferation of numerous tumor cell lines and the mean GI(50) for compound 2a is 2.88muM against the NCI-60 cell line. At the same time, compound 2a can induce significant apoptosis in EKVX cell line at the concentration of 1muM.

 

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[507]

TÍTULO / TITLE:  - Kras mutations and p53 overexpression in pseudomyxoma peritonei: association with phenotype and prognosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Surg Res. 2012 Nov 20. pii: S0022-4804(12)00972-9. doi: 10.1016/j.jss.2012.10.053.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jss.2012.10.053

AUTORES / AUTHORS:  - Shetty S; Thomas P; Ramanan B; Sharma P; Govindarajan V; Loggie B

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Creighton University Medical Center, Omaha, NE.

RESUMEN / SUMMARY:  - BACKGROUND: Little information exists on Kras mutations and p53 overexpression in pseudomyxoma peritonei (PMP). These genetic alterations are associated with poorer prognoses in colorectal cancer. We postulated that these mutations might be more frequent in high-grade (HG) PMP (peritoneal mucinous carcinomatosis) versus low-grade (LG) PMP (disseminated peritoneal adenomucinosis/peritoneal mucinous carcinomatosis), for which survival differences are well documented. METHODS: We collected data retrospectively on patients with PMP of appendiceal origin tested for Kras mutation (commercial assay) and p53 overexpression (immunohistochemistry). We used Fisher’s exact test, chi-square test, and Kaplan-Meier survival curves for analysis. RESULTS: Of 64 cases with Kras mutations, 25 were classified as LG and 39 as HG PMP. Median age at diagnosis was 53 +/- 11.5 y. We detected Kras mutations in 37 of 64 patients (57.8%). In LG PMP, 15 of 25 (60%) were Kras mutant versus 22 of 39 (56.4%) in HG PMP (P=0.80).  Nearly 89% of mutations were seen in codon 12. We noted overexpression of p53 in  44.3% (86 of 194) of patients overall, which was significantly different between  LG PMP and HG PMP: 35.5% (37 of 104) versus 54.4% (49 of 90), respectively (P=0.009). Kras mutations did not affect prognosis. Overexpression of p53 was associated with a worse outcome. CONCLUSIONS: Kras mutation and p53 overexpression rates are comparable to those of colorectal adenomas and mucinous  colorectal cancer. Codon 12 mutations may be associated with mucin production. Kras mutation status is not prognostic for overall survival. Overexpression of p53 was significantly correlated with female sex, higher-grade disease, and worse survival.

 

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[508]

TÍTULO / TITLE:  - The pan-Aurora kinase inhibitor, PHA-739358, induces apoptosis and inhibits migration in melanoma cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Melanoma Res. 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1097/CMR.0b013e32835df5e4

AUTORES / AUTHORS:  - Xie L; Meyskens FL Jr

INSTITUCIÓN / INSTITUTION:  - Departments of aMedicine bBiological Chemistry cPublic Health, Chao Family Comprehensive Cancer Center, University of California, Irvine, California, USA.

RESUMEN / SUMMARY:  - Treatment of metastatic melanoma has long been a challenge because of its resistance to traditional chemotherapeutics, leading to the search for alternative strategies. Aurora kinases are key mitotic regulators that are frequently overexpressed in various cancers including melanoma, making them ideal targets for drug development. Several Aurora kinase inhibitors have been developed and tested preclinically and clinically. PHA-739358 is currently one of the most advanced clinical compounds being tested in phase II clinical trials; however, its antitumor effect has not been tested in melanoma. In this study, the antiproliferative and anti-invasive effects of PHA-739358 were investigated in melanoma cell lines. The results demonstrated that PHA-739358 produces a time-dependent and dose-dependent inhibition of cell proliferation, induction of  apoptosis, and inhibition of cell migration. Downregulation of matrix metalloproteinase-2 by the inhibition of NFkappaB-signaling pathway may contribute to PHA-739358-induced inhibition of migration. Furthermore, PHA-739358 enhanced temozolomide and Plx4032-induced apoptosis. This study suggests that Aurora kinase inhibitors may provide a new strategy for the treatment of advanced melanoma.

 

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[509]

TÍTULO / TITLE:  - Dihydroartemisinin inhibits the Bcr/Abl oncogene at the mRNA level in chronic myeloid leukemia sensitive or resistant to imatinib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biomed Pharmacother. 2012 Nov 19. pii: S0753-3322(12)00109-6. doi: 10.1016/j.biopha.2012.10.017.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biopha.2012.10.017

AUTORES / AUTHORS:  - Lee J; Shen P; Zhang G; Wu X; Zhang X

INSTITUCIÓN / INSTITUTION:  - Department of clinical pharmacology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, Zhejiang 310000, China.

RESUMEN / SUMMARY:  - Due to the mutations of the Bcr/Abl oncogene that obstacle the binding of the protein with imatinib, the resistance to imatinib has developed in a significant  portion of chronic myeloid leukemia (CML) patients. It stimulated the search for  novel molecules for treatment of imatinib-resistance CML. Inhibiting the amplification of Bcr/Abl oncogene is believed to be a new effective strategy to override the imatinib resistance on CML cells. In present research, we demonstrated that dihydroartemisinin (DHA), a safe and effective antimalarial analog of artemisinin, could significantly inhibit the Bcr/Abl fusion gene at the mRNA level in CML cells sensitive or resistant to imatinib (including the primary CML cells with T315I mutation) and induce cell death. Moreover, dihydroartemisinin could also lead to the inhibition of the Bcr/Abl protein expression and tyrosine kinase activity, and strongly suppress on the downstream  signals of Bcr/Abl, which included inhibition of tyrosine kinase activity of AKT  and ERK, promotion of cytochrome c release from the mitochondria and the consequential activation of caspase-9/3 in imatinib-resistant CML cells. These results suggest for the first time that Dihydroartemisinin might be a potential novel drug candidate for treatment of imatinib-resistant CML and worthy of further study.

 

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[510]

TÍTULO / TITLE:  - Clear cell carcinomas of the ovary: a multi-institutional study of 129 cases in Korea with prognostic significance of Emi1 and Galectin-3.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Gynecol Pathol. 2013 Jan;32(1):3-14. doi: 10.1097/PGP.0b013e31825554e9.

            ●● Enlace al texto completo (gratuito o de pago) 1097/PGP.0b013e31825554e9

AUTORES / AUTHORS:  - Min KW; Park MH; Hong SR; Lee H; Kwon SY; Hong SH; Joo HJ; Park IA; An HJ; Suh KS; Oh HK; Yoo CW; Kim MJ; Chang HK; Jun SY; Yoon HK; Chang ED; Kim DW; Kim I

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Hanyang University, Seoul, Korea.

RESUMEN / SUMMARY:  - Accurate diagnosis of ovarian clear cell carcinoma (CCC) is important because of  its poor prognosis with chemoresistance and a high recurrent rate. The clinicopathologic characteristics and prognostic significance of the cell cycle regulator [early mitotic inhibitor-1 (Emi1)] and galactoside-binding protein (Galectin-3) were evaluated. Among 155 CCCs from 18 hospitals in Korea between 1995 and 2006, 129 pure CCCs were selected with consensus using immunohistochemical stains for hepatocyte nuclear factor-1beta, Wilms’ tumor protein, and estrogen receptor. The expressions of Emi1, Galectin-3, p53, and Ki-67 labeling index were analyzed with clinicopathologic parameters and the patient’s survival. The mean age of the patients was 49.6 yr; the tumors were bilateral in 10.9%, and the average size was 12 cm. Adenofibromatous component was found in 7%, and endometriosis in 48.1% of the cases. Psammoma body was seen  in 16.3%. Disease-free survival and overall survival rates were 78.3% and 79.1%,  respectively. The International Federation of Obstetrics and Gynecology (FIGO) stage was the most important prognostic indicator. Emi1 expression (>5%) was seen in 23.3% of CCCs, and associated with high FIGO grades and poor overall survival  (P<0.05). High Galectin-3 (>/=80%) expression was seen in 59.7% of CCCs, and associated with FIGO stages III and IV, and high Ki-67 labeling index. High Ki-67 labeling index (>/=50%) and p53 expression (>/=50%) were seen in 27.1% and 18.6%  of CCCs, respectively, but there was no clinicopathologic and prognostic significance. On the basis of the fact that the expression of Emi1 in CCC was correlated with a high histologic grade and worse overall survival, target therapy using inhibitors of Emi1 may be tried in the management of CCC patients with Emi1 expression.

 

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[511]

TÍTULO / TITLE:  - Promise of rapalogues versus mTOR kinase inhibitors in subset specific breast cancer: Old targets new hope.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Treat Rev. 2013 Jan 22. pii: S0305-7372(12)00241-1. doi: 10.1016/j.ctrv.2012.12.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ctrv.2012.12.002

AUTORES / AUTHORS:  - De P; Miskimins K; Dey N; Leyland-Jones B

INSTITUCIÓN / INSTITUTION:  - Edith Sanford Breast Cancer, Sanford Research, 2301 E 60th Street N, Sioux Falls, SD 57104, United States.

RESUMEN / SUMMARY:  - The PI3K-AKT-mTOR network has been the major focus of attention for cancer researchers (both in the clinic and the laboratory) in the last decade. An incomplete knowledge of the molecular biology of this complex network has seen an expansion of first generation allosteric mTOR inhibitors, rapalogues, but also biomarker studies designed to identify the best responders of these agents. Currently, research in this pathway has focused on the dual nature of mTOR that is integrated by mTOR-RAPTOR complex (mTORC1) and mTOR-RICTOR complex (mTORC2). These two complexes are regulated by different upstream proteins and also regulated by multiple different compensatory feedback loops. The related advantage of feedback regulation of signaling systems is that it allows diversification in signal response. This deeper understanding has facilitated the development of a novel second generation of inhibitors that are able to affect both mTORC1 and mTORC2, and their downstream effectors, through inhibition of their catalytic activity (ATP competitive inhibitors, attacking the kinase domain of this protein) than binding to the FKBP12 regulatory proteins as for rapalogues. This article reviews the newest insight in the signaling network of the mTOR pathway, preclinical/clinical status of mTOR inhibitors (including second generation of kinase inhibitors) and then focuses on the development of a  new wave of research related to combination therapies in subset specific breast tumors.

 

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[512]

TÍTULO / TITLE:  - Hybrid fluorescent conjugates of COX-2 inhibitors: search for a COX-2 isozyme imaging cancer biomarker.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Bioorg Med Chem Lett. 2013 Jan 1;23(1):163-8. doi: 10.1016/j.bmcl.2012.10.131. Epub 2012 Nov 9.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bmcl.2012.10.131

AUTORES / AUTHORS:  - Bhardwaj A; Kaur J; Sharma SK; Huang Z; Wuest F; Knaus EE

INSTITUCIÓN / INSTITUTION:  - Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.

RESUMEN / SUMMARY:  - The observation that the cyclooxygenase-2 (COX-2) isozyme is over-expressed in multiple types of cancer, relative to that in adjacent non-cancerous tissue, prompted this investigation to prepare a group of hybrid fluorescent conjugates wherein the COX inhibitors ibuprofen, (S)-naproxen, acetyl salicylic acid, a chlororofecoxib analog and celecoxib were coupled via a linker group to an acridone, dansyl or rhodamine B fluorophore. Within this group of compounds, the  ibuprofen-acridone conjugate (10) showed potent and selective COX-2 inhibition (COX-2 IC(50)=0.67 muM; SI=110.6), but its fluorescence emission (lambda(em)=417, 440 nm) was not suitable for fluorescent imaging of cancer cells that over-express the COX-2 isozyme. In comparison, the celecoxib-dansyl conjugate (25) showed a slightly lower COX-2 potency and selectivity (COX-2 IC(50)=1.1 muM; SI>90) than the conjugate 10, and it possesses a better fluorescence emission (lambda(em)=500 nm). Ultimately, a celecoxib-rhodamine B conjugate (28) that exhibited moderate COX-2 potency and selectivity (COX-2 IC(50)=3.9 muM; SI>25) having the best fluorescence emission (lambda(em)=580 nm) emerged as the most promising biomarker for fluorescence imaging using a colon cancer cell line that  over-expresses the COX-2 isozyme.

 

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[513]

TÍTULO / TITLE:  - Prognostic and diagnostic significance of tumor budding associated with beta-catenin expression in submucosal invasive colorectal carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Tohoku J Exp Med. 2013;229(1):53-9.

AUTORES / AUTHORS:  - Umemura K; Takagi S; Shimada T; Masuda T; Shiga H; Takahashi S; Takahashi S; Kinouchi Y; Shibuya D; Shimosegawa T

INSTITUCIÓN / INSTITUTION:  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. umekun@nyc.odn.ne.jp

RESUMEN / SUMMARY:  - Endoscopic resection has become a major curative treatment for early colorectal carcinoma without lymph node metastasis. However, lymph node metastasis, a poor prognostic factor in colorectal carcinoma, occurs in about 10% of the patients with submucosal invasive colorectal carcinoma. Therefore, it is important to identify a high-risk factor for lymph node metastasis in submucosal invasive colorectal carcinoma. This study was designed to identify the relationship between tumor budding with beta-catenin expression and lymph node metastasis in submucosal invasive colorectal carcinoma. We investigated the immunohistochemistry of tumor budding in the 142 patients who underwent surgical  resection for submucosal invasive colorectal carcinomas between 1984 and 1999 and the expression pattern of beta-catenin in budding tumor cells. Accordingly, all the patients were followed up for at least 10 years or until death. Among the 142 patients, lymph node metastasis was detected in 14 patients (9.9%). Univariate analysis showed that tumor budding with >/= 5 tumor cells or cell clusters with expression of beta-catenin in the nucleus was significantly associated with lymph node metastasis (P = 0.005). In contrast, tumor budding detected by hematoxylin and eosin staining was not associated with lymph node metastasis. Multivariate logistic regression analysis showed that tumor budding with >/= 5 tumor cells or  cell clusters with expression of beta-catenin in the nucleus was a significant risk factor for lymph node metastasis (odds ratio, 7.124; 95% confidence interval, 1.407-36.062). Thus, tumor budding associated with beta-catenin expression is a risk factor for lymph node metastasis in submucosal invasive colorectal carcinoma.

 

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[514]

TÍTULO / TITLE:  - MUC20 overexpression predicts poor prognosis and enhances EGF-induced malignant phenotypes via activation of the EGFR-STAT3 pathway in endometrial cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Gynecol Oncol. 2012 Dec 19. pii: S0090-8258(12)00960-2. doi: 10.1016/j.ygyno.2012.12.012.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ygyno.2012.12.012

AUTORES / AUTHORS:  - Chen CH; Wang SW; Chen CW; Huang MR; Hung JS; Huang HC; Lin HH; Chen RJ; Shyu MK; Huang MC

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan.

RESUMEN / SUMMARY:  - OBJECTIVE: Mucins play a critical role in the malignancy of various tumors and have been identified as diagnostic markers and as attractive therapeutic targets. However, the role of mucin (MUC) 20 in endometrial cancer (EC) is still unknown.  METHODS: The relationship between MUC20 expression and clinical characteristics of EC was analyzed in 97 EC tumors and 16 normal tissues by immunohistochemistry. Effects of MUC20 on EC cells, HEC-1A and RL95-2, were examined by in vitro cell growth, migration, and invasion assays, as well as in vivo tumor growth in SCID mouse model. Western blotting was performed to analyze signaling pathways modulated by MUC20. RESULTS: MUC20 expression was significantly higher in EC tumors compared with the normal tissue. High levels of MUC20 expression in EC tumors were correlated with an unfavorable histologic subtype. Furthermore, MUC20 was an independent prognostic factor for poor survival as evaluated by multivariate analyses. Overexpression of MUC20 in EC cells significantly enhanced cell growth, migration, and invasion, as well as tumor growth in vivo. The MUC20-enhanced invasive behavior was significantly blocked by erlotinib, an EGFR  inhibitor. Moreover, MUC20 overexpression enhanced EGF-mediated migration and invasion, suggesting a critical role of EGFR in MUC20-mediated effects. We found  that MUC20 overexpression could enhance EGF-induced phosphorylation of EGFR and STAT3. Inhibition of the STAT3 activity by its inhibitor Stattic significantly suppressed the MUC20-enhanced invasive behavior. CONCLUSIONS: MUC20 is novel prognostic factor for EC and its overexpression enhances EGF-triggered invasive behavior through activation of EGFR-STAT3 pathway.

 

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[515]

TÍTULO / TITLE:  - Knockdown of beta-catenin controls both apoptotic and autophagic cell death through LKB1/AMPK signaling in head and neck squamous cell carcinoma cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Signal. 2012 Dec 30. pii: S0898-6568(12)00357-9. doi: 10.1016/j.cellsig.2012.12.020.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.cellsig.2012.12.020

AUTORES / AUTHORS:  - Chang HW; Lee YS; Nam HY; Han MW; Kim HJ; Moon SY; Jeon H; Park JJ; Carey TE; Chang SE; Kim SW; Kim SY

INSTITUCIÓN / INSTITUTION:  - Department of Otolaryngology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Republic of Korea.

RESUMEN / SUMMARY:  - The Wnt/beta-catenin pathway regulates the viability and radiosensitivity of head and neck squamous cancer cells (HNSCC). Increased beta-catenin predisposes HNSCC  patients to poor prognosis and survival. This study was conducted to determine the mechanism by which beta-catenin regulates the viability of HNSCC. AMC-HN-3, -HN-8, UM-SCC-38, and -SCC-47 cells, which were established from human head and neck cancer specimens, and underwent cell death following beta-catenin silencing. beta-Catenin silencing significantly induced G1 arrest and increased the expression of Bax and active caspase-3, which demonstrates the sequential activation of apoptotic cascades following treatment of HNSCC with targeted siRNA. Intriguingly, beta-catenin silencing also induced autophagy. Here, we confirm that the number of autophagic vacuoles and the expression of type II light chain 3 were increased in cells that were treated with beta-catenin siRNA.  These cell death modes are most likely due to the activation of LKB1-dependent AMPK following beta-catenin silencing. The activated LKB1/AMPK pathway in AMC-HN-3 cells caused G1 arrest by phosphorylating p53 and suppressing mTOR signaling. In addition, treating AMC-HN-3 cells with LKB1 siRNA preserved cell viability against beta-catenin silencing-induced cytotoxicity. Taken together, these results imply that following beta-catenin silencing, HNSCC undergo both apoptotic and autophagic cell death that are under the control of LKB1/AMPK. To the best of our knowledge, these results suggest for the first time that novel crosstalk between beta-catenin and the LKB1/AMPK pathway regulates the viability  of HNSCC. This study thus presents new insights into our understanding of the cellular and molecular mechanisms involved in beta-catenin silencing-induced cell death.

 

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[516]

TÍTULO / TITLE:  - Inhibition of ZEB1 reverses the phenotype of epithelial-mesenchymal transition and chemoresistance in docetaxel-resistant human lung adenocarcinoma cell line SPC-A1/DTX.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Cell Biochem. 2012 Dec 17. doi: 10.1002/jcb.24481.

            ●● Enlace al texto completo (gratuito o de pago) 1002/jcb.24481

AUTORES / AUTHORS:  - Ren J; Chen Y; Song H; Chen L; Wang R

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China.

RESUMEN / SUMMARY:  - Docetaxel has been used as one of the first-line chemotherapies in solid tumors including advanced non-small cell lung cancer (NSCLC). However, limited responses to chemotherapy are observed in clinic and the molecular mechanisms have not been fully understood. Emerging evidence suggests that epithelial-mesenchymal transition (EMT) plays an important role in the processes of tumor metastasis as  well as resistance towards anticancer agents. In this study, it was observed that docetaxel-resistant human lung adenocarcinoma cell line (SPC-A1/DTX) was typical  of mesenchymal phenotype. SPC-A1/DTX cell line has increased migratory and invasive capacity both in vitro and in vivo. Among the master EMT-inducing transcriptional factors, ZEB1 was found to be significantly increased in SPC-A1/DTX cell line. ZEB1 knockdown with RNA interference could reverse the EMT  phenotype and inhibit the migratory ability of SPC-A1/DTX cells. Furthermore, inhibition of ZEB1 significantly enhanced the chemosensitivity of SPC-A1/DTX cells to docetaxel in vitro and in vivo and ectopic expression of ZEB1 increased  the chemoresistance of SPC-A1 cells to docetaxel. All these results provide experimental evidence that ZEB1 might be an attractive target for the treatment of human NSCLC. J. Cell. Biochem. © 2012 Wiley Periodicals, Inc.

 

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[517]

TÍTULO / TITLE:  - Effects of TRAIL and taurolidine on apoptosis and proliferation in human rhabdomyosarcoma, leiomyosarcoma and epithelioid cell sarcoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Mar;42(3):945-56. doi: 10.3892/ijo.2013.1772. Epub 2013 Jan 15.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2013.1772

AUTORES / AUTHORS:  - Karlisch C; Harati K; Chromik AM; Bulut D; Klein-Hitpass L; Goertz O; Hirsch T; Lehnhardt M; Uhl W; Daigeler A

INSTITUCIÓN / INSTITUTION:  - Department of Gynecology and Obstetrics, Marienhospital Witten, Ruhr-University,  D-58452 Witten, Germany.

RESUMEN / SUMMARY:  - Soft tissue sarcomas (STS) are a heterogeneous group of malignant tumours representing 1% of all malignancies in adults. Therapy for STS should be individualised and multimodal, but complete surgical resection with clear margins remains the mainstay of therapy. Disseminated soft tissue sarcoma still represents a therapeutic dilemma. Commonly used chemotherapeutic agents such as doxorubicin and ifosfamide have proven to be effective in fewer than 30% in these cases. Therefore, we tested the apoptotic and antiproliferative in vitro effects  of TNF-related apoptosis-inducing ligand (TRAIL) and taurolidine (TRD) on rhabdomyosarcoma (A-204), leiomyosarcoma (SK-LMS-1) and epithelioid cell sarcoma  (VA-ES-BJ) cell lines. Viability, apoptosis and necrosis were quantified by FACS  analysis (propidium iodide/Annexin V staining). Gene expression was analysed by DNA microarrays and the results validated for selected genes by rtPCR. Protein level changes were documented by western blot analysis. Cell proliferation was analysed by BrdU ELISA assay. The single substances TRAIL and TRD significantly induced apoptotic cell death and decreased proliferation in rhabdomyosarcoma and  epithelioid cell sarcoma cells. The combined use of TRAIL and TRD resulted in a synergistic apoptotic effect in all three cell lines, especially in rhabdomyosarcoma cells leaving 18% viable cells after 48 h of incubation (p<0.05). Analysis of the differentially regulated genes revealed that TRD and TRAIL influence apoptotic pathways, including the TNF-receptor associated and the mitochondrial pathway. Microarray analysis revealed remarkable expression changes in a variety of genes, which are involved in different apoptotic pathways and cross talk to other pathways at multiple levels. This in vitro study demonstrates that TRAIL and TRD synergise in inducing apoptosis and inhibiting proliferation in different human STS cell lines. Effects on gene expression differ relevantly in the sarcoma entities. These results provide experimental support for in vivo trials assessing the effect of TRAIL and TRD in STS and sustain the approach of individualized therapy.

 

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[518]

TÍTULO / TITLE:  - Markers of mitochondrial dysfunction during the diclofenac-induced apoptosis in melanoma cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochimie. 2012 Dec 26. pii: S0300-9084(12)00503-2. doi: 10.1016/j.biochi.2012.12.012.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biochi.2012.12.012

AUTORES / AUTHORS:  - Albano F; Arcucci A; Granato G; Romano S; Montagnani S; De Vendittis E; Ruocco MR

INSTITUCIÓN / INSTITUTION:  - Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli Federico II, Via S. Pansini 5, 80131 Napoli, Italy; Dipartimento  di Sanita Pubblica, Universita degli Studi di Napoli Federico II, Via S. Pansini  5, 80131 Napoli, Italy.

RESUMEN / SUMMARY:  - Melanoma is an aggressive cutaneous cancer, whose incidence is growing in recent  years, especially in the younger population. The favorable therapy for this neoplasm consists in its early surgical excision; otherwise, in case of late diagnosis, melanoma becomes very refractory to any conventional therapy. Nevertheless, the acute inflammatory response occurring after excision of the primary melanoma can affect the activation and/or regulation of melanoma invasion and metastasis. Nonsteroidal anti-inflammatory drugs (NSAIDs), widely employed in clinical therapy as cyclooxygenase inhibitors, also display a cytotoxic effect on some cancer cell lines; therefore, their possible usage in combination with conventional chemo- and radio-therapies of tumors is being considered. In particular, diclofenac, one of the most common NSAIDs, displays its anti-proliferative effect in many tumor lines, through an alteration of the cellular redox state. In this study, the possible anti-neoplastic potential of diclofenac on the human melanoma cell lines A2058 and SAN was investigated, and a comparison was made with the results obtained from the nonmalignant fibroblast cell line BJ-5ta. Either in A2058 or SAN, the diclofenac treatment caused typical apoptotic morphological changes, as well as an increase of the number of sub-diploid nuclei; conversely, the same treatment on BJ-5ta had only a marginal  effect. The observed decrease of Bcl-2/Bax ratio and a parallel increase of caspase-3 activity confirmed the pro-apoptotic role exerted by diclofenac in melanoma cells; furthermore, the drug provoked an increase of the ROS levels, a decrease of mitochondrial superoxide dismutase (SOD2), the cytosolic translocation of both SOD2 and cytochrome c, and an increase of caspase-9 activity. Finally, the cytotoxic effect of diclofenac was amplified, in melanoma  cells, by the silencing of SOD2. These data improve the knowledge on the effects  of diclofenac and suggest that new anti-neoplastic treatments should be based on  the central role of mitochondrion in cancer development; under this concern, the  possible involvement of SOD2 as a novel target could be considered.

 

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[519]

TÍTULO / TITLE:  - Delta-like 3 is silenced by methylation and induces apoptosis in human hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Mar;42(3):817-22. doi: 10.3892/ijo.2013.1778. Epub 2013 Jan 17.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2013.1778

AUTORES / AUTHORS:  - Maemura K; Yoshikawa H; Yokoyama K; Ueno T; Kurose H; Uchiyama K; Otsuki Y

INSTITUCIÓN / INSTITUTION:  - Department of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka,  Japan.

RESUMEN / SUMMARY:  - The genetic and epigenetic events of hepato-carcinogenesis are relatively poorly  understood. By analyzing genes from human hepatocellular carcinoma (HCC) with restriction landmark genomic scanning, several aberrantly methylated genes, including Delta-like 3 (DLL3), have been isolated. In this study, we investigated the function of DLL3 in hepatocarcinogenesis. Methylation of the DLL3 gene in HCC cell lines was investigated with methylation-specific PCR and expression of DLL3  mRNA in HCC cells was examined by RT-PCR. Reactivation of DLL3 expression by treatment with a demethylating agent was examined in methylation-silenced HuH2 cells. Human DLL3 cDNA was cloned and DLL3 function was examined by restoring DLL3 expression in HuH2 cells. The effects of DLL3 on cell growth were evaluated  by colony formation assay. Induction of cell death by overexpression of DLL3 was  examined by flow cytometric assay using Annexin V and PI. Apoptotic cells were detected by TUNEL staining and the amount of single-stranded DNA was measured by  ELISA. As a result, the promoter region of the DLL3 gene was methylated in four of ten HCC cell lines. This aberrant methyl-ation correlated well with the suppression of RNA expression and a demethylating agent reactivated DLL3 expression in methylation-silenced HCC cells. Interestingly, the restoration of DLL3 in the methylation-silenced HuH2 cells led to growth suppression on colony formation assay. Flow cytometric assay with Annexin V and PI showed that this growth suppression by DLL3 expression is associated with the induction of apoptosis. Furthermore, these apoptotic effects were confirmed by TUNEL staining  and measurement of single-stranded DNA. These results suggest that DLL3 was silenced by methylation in human HCC and that it negatively regulates the growth  of HCC cells.

 

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[520]

TÍTULO / TITLE:  - Pharmacological Inhibition of Carbonic Anhydrase xii Interferes with cell Proliferation and Induces cell Apoptosis in t-cell Lymphomas.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2013 Jan 21. pii: S0304-3835(13)00049-9. doi: 10.1016/j.canlet.2013.01.020.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2013.01.020

AUTORES / AUTHORS:  - Nadia L; Celia R; Marielle N; Didier M; Emmanuel G; Zouhour N; Johanna C; Hergen S; Hagenbeek Thijs J; Vahid A; Sally-Ann P; Supuran Claudiu T; Jean-Francois P; Veronique I

INSTITUCIÓN / INSTITUTION:  - INSERM, U1065, Centre Mediterraneen de Medecine Moleculaire (C3M), Team 4, Inflammation, Cancer, Cellules Souches Cancereuses, Nice, France; Universite de Nice-Sophia Antipolis, Faculte de Medecine, Nice, France.

RESUMEN / SUMMARY:  - The membrane-bound carbonic anhydrase isoforms CAIX and CAXII, underpin a pH-regulating system that enables hypoxic tumor cell survival. Here, we observed  for the first time an upregulation of CAXII in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LL) cells. First we showed that CAXII is overexpressed in thymocytes from tPTEN-/- mice suffering of T lymphoma and that its pharmacological inhibition decreased cell proliferation and induced apoptosis. The same results were observed with the SupT1 human T cell lymphoma line. In addition we observed an upregulation of CAXII in human T-ALL samples supporting the case that CAXII may represent a new therapeutic target for T-ALL/LL.

 

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[521]

TÍTULO / TITLE:  - Safety of tumor necrosis factor inhibitors use for rheumatoid arthritis and ankylosing spondylitis in Africa, the Middle East, and Asia: focus on severe infections and tuberculosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Rheumatol. 2012 Dec 15.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10067-012-2137-7

AUTORES / AUTHORS:  - Hammoudeh M; Alarfaj A; Chen DY; Djoudi H; Youseif E; Zhu J

INSTITUCIÓN / INSTITUTION:  - Hamad Medical Corporation, PO Box 3050, Doha, Qatar, mhamoudeh@hmc.org.qa.

RESUMEN / SUMMARY:  - Multiple studies of patients in Western countries with rheumatoid arthritis (RA)  and ankylosing spondylitis (AS) have indicated increased risk for active tuberculosis (TB) and other infections among these individuals. It has also been  consistently reported that patients receiving tumor necrosis factor (TNF) inhibitors for these conditions have higher rates of active TB and other infections than RA or AS patients not receiving these medications. These issues have been studied less extensively in the Asia and Africa-Middle East regions, and information from these regions is important because of higher rates of TB in  the general population. This paper reviews studies of RA and AS patients from Asia, Africa, and the Middle East who received TNF inhibitors. A literature search was conducted using http://www.ncbi.nlm.nih.gov/pubmed to collect and report these data. The years included in the PubMed literature search ranged from January 2000 to October 2011. Additionally, information from the China Hospital Knowledge Database was used to report data from Chinese patients with RA and AS treated with TNF inhibitors. Results from these studies indicate that the risk for active TB and other infections in AS and RA patients from Asia, Africa, and the Middle East are increased in patients receiving TNF inhibitors and that the risk is higher among those treated with monoclonal antibodies versus soluble TNF  receptor.

 

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[522]

TÍTULO / TITLE:  - Texture analysis in assessment and prediction of chemotherapy response in breast  cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Magn Reson Imaging. 2012 Dec 13. doi: 10.1002/jmri.23971.

            ●● Enlace al texto completo (gratuito o de pago) 1002/jmri.23971

AUTORES / AUTHORS:  - Ahmed A; Gibbs P; Pickles M; Turnbull L

INSTITUCIÓN / INSTITUTION:  - Centre for Magnetic Resonance Investigations, University of Hull, Hull, UK. arfanahmed@hotmail.com.

RESUMEN / SUMMARY:  - PURPOSE: To assess the efficacy of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-based textural analysis in predicting response to chemotherapy  in a cohort of breast cancer patients. MATERIALS AND METHODS: In all, 100 patients were scanned on a 3.0T HDx scanner immediately prior to neoadjuvant chemotherapy treatment. A software application to use texture features based on co-occurrence matrices was developed. Texture analysis was performed on precontrast and 1-5 minutes postcontrast data. Patients were categorized according to their chemotherapeutic response: partial responders corresponding to a decrease in tumor diameter over 50% (40) and nonresponders corresponding to a decrease of less than 50% (4). Data were also split based on factors that influence response: triple receptor negative phenotype (TNBC) (22) vs. non-TNBC (49); node negative (45) vs. node positive (46); and biopsy grade 1 or 2 (38) vs. biopsy grade 3 (55). RESULTS: Parameters f(2) (contrast), f(4) (variance), f(10)  (difference in variance), f(6) (sum average), f(7) (sum variance), f(8) (sum entropy), f(15) (cluster shade), and f(16) (cluster prominence) showed significant differences between responders and partial responders of chemotherapy. Differences were mainly seen at 1-3 minutes postcontrast administration. No significant differences were found precontrast administration. Node +ve, high grade, and TNBC are associated with poorer prognosis and appear to be more heterogeneous in appearance according to texture analysis. CONCLUSION: This work highlights that textural differences between groups (based on response, nodal status, and triple negative groupings) are apparent and appear to be most evident 1-3 minutes postcontrast administration. The fact that significant differences for certain texture parameters and groupings are consistently observed is encouraging. J. Magn. Reson. Imaging 2013. Esta es una cita bibliográfica que va por delante de la publicación en papel. La fecha indicada en la cita provista, NO corresponde con la fecha o la cita bibliográfica de la publicación en papel. La cita bibliográfica definitiva (con el volumen y su paginación) saldrá en 1 ó 2 meses a partir de la fecha de la emisión electrónica-online. *** This is a bibliographic record ahead of the paper publication. The given date in the bibliographic record does not correspond to the date or the bibliographic citation on the paper publication. The publisher will provide the final bibliographic citation (with the volume, and pagination) within 1 or 2 months from the date the record was published online. © 2013 Wiley Periodicals, Inc.

 

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[523]

TÍTULO / TITLE:  - Prognostic role of E-cadherin and Vimentin expression in various subtypes of soft tissue leiomyosarcomas.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):401. doi: 10.1007/s12032-012-0401-y. Epub 2013 Jan 5.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0401-y

AUTORES / AUTHORS:  - Tian W; Wang G; Yang J; Pan Y; Ma Y

INSTITUCIÓN / INSTITUTION:  - Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China, tianweiyh@yahoo.com.

RESUMEN / SUMMARY:  - The gain of E-cadherin and loss of Vimentin known as “Cadherin switching” resulting in epithelial differentiation play an important role in tumor cell invasion and metastasis. In soft tissue leiomyosarcoma (LMS), aberrant expression of E-cadherin and down-regulation of Vimentin-related Mesenchymal to Epithelial Reverting Transition was defined, but the role of these proteins in various subtypes of LMS have not been well demonstrated yet. The aim of this study was to evaluate the prognostic role of E-cadherin and Vimentin expression in 45 soft tissue leiomyosarcoma samples by Immunohistochemistry analysis. E-cadherin was positive in a small proportion of LMS, accounting for 15.6 % (7/45). All LMS samples expressed Vimentin, concluding 20 patients as strong positive group (44.4 %), 25 patients as week positive group (55.6 %). Although the aberrant expression of E-cadherin had no differences among various subtypes of LMS, it was significantly associated with early clinical stages. The patients with strong positive expression of Vimentin suffered significant high risk of recurrence and  metastasis and also had significant worse overall survival. These data suggest that the epithelial differentiation of LMS evaluated by E-cadherin expression does not belong to certain subtypes in LMS. The patients with the gain of E-cadherin and loss of Vimentin expression represent favorable trend of survival. They might serve as good biomarkers of the LMS clinical outcome after further investigations.

 

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[524]

TÍTULO / TITLE:  - The decrease of paclitaxel efflux by pretreatment of interferon-gamma and tumor necrosis factor-alpha after intracerebral microinjection.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Brain Res. 2013 Jan 9. pii: S0006-8993(13)00030-9. doi: 10.1016/j.brainres.2013.01.005.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.brainres.2013.01.005

AUTORES / AUTHORS:  - Lee NY; Kang YS

INSTITUCIÓN / INSTITUTION:  - College of Pharmacy and Research Center for Cell Fate Control, Sookmyung Women’s  University, Seoul 140-742, Korea.

RESUMEN / SUMMARY:  - Paclitaxel is highly efficacious in the treatment of patients suffering from a broad spectrum of neoplastic diseases. However, its efficacy against malignant glioma is very moderate. Paclitaxel is known to be a substrate for P-glycoprotein (P-gp), so this transporter may be due to insufficient access of paclitaxel to the brain. First, we investigated the brain-to-blood transport of paclitaxel across the blood-brain barrier (BBB) using the brain efflux index method. [(3)H]Paclitaxel was eliminated from rat brain with an efflux transport rate of 1.87x10(-2)+/-0.16x10(-2)min(-1). The elimination of [(3)H]paclitaxel was inhibited by unlabeled paclitaxel and verapamil, suggesting a carrier-mediated transport process via P-gp. Furthermore, TNF-alpha and IFN-gamma induced significant decrease of paclitaxel efflux 1 and 24h pre-treatment. These results  suggest that P-gp efflux function at the BBB is reduced by TNF-alpha and IFN-gamma. Therefore, the distribution of P-gp dependant drugs including paclitaxel in the central nervous system can be modulated by neurological diseases.

 

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[525]

TÍTULO / TITLE:  - Antiproliferative and apoptotic effects of compounds from the flower of Mammea siamensis (Miq.) T. Anders. on human cancer cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Bioorg Med Chem Lett. 2013 Jan 1;23(1):158-62. doi: 10.1016/j.bmcl.2012.10.127. Epub 2012 Nov 7.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bmcl.2012.10.127

AUTORES / AUTHORS:  - Tung NH; Uto T; Sakamoto A; Hayashida Y; Hidaka Y; Morinaga O; Lhieochaiphant S; Shoyama Y

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Nagasaki International University, 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan.

RESUMEN / SUMMARY:  - On the search for anti-cancer compounds from Thai traditional herb medicines, a bioassay-guided fractionation and chemical investigation of the methanol extract  of Mammea siamensis flower resulted in the isolation and identification of eight  compounds (1-8) including a novel geranylated coumarin, namely mammeanoyl (2), and seven known compounds (1 and 3-8). The structure of new compound 2 was elucidated based on the extensive spectroscopic and chemical methods. Among the isolated compounds, three structurally related coumarins 3, 4, and 5 showed significant antiproliferative activities against human leukemia and stomach cancer cell lines. However, these compounds did not affect the cell viabilities of colon cancer, hepatoma, and normal skin fibroblast cell lines. Further analysis demonstrated that the morphological features of apoptosis including DNA  fragmentation and chromatin condensation were observed in human leukemia HL-60 cells treated with compounds 3, 4, and 5. In addition, compound 3 led to caspase-3 activation and cleavage of poly (ADP-ribose) polymerase (PARP), and compound 3-induced DNA fragmentation was inhibited by caspase-specific inhibitors. These results suggest that compound 3, 4, and 5 exert antiproliferative actions through apoptotic cell death in leukemia cells and these compounds may have the potential to be developed into new anti-cancer drug  candidates.

 

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[526]

TÍTULO / TITLE:  - Immunohistochemical expression of metallothionein in pleomorphic adenoma of minor salivary glands: A role in the control of apoptosis?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Acta Histochem. 2013 Jan 16. pii: S0065-1281(12)00179-1. doi: 10.1016/j.acthis.2012.12.004.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.acthis.2012.12.004

AUTORES / AUTHORS:  - Miranda Viana AD; Ribeiro DC; Florencio TN; Santos VT; Sousa AA; Aguiar MC

INSTITUCIÓN / INSTITUTION:  - Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

RESUMEN / SUMMARY:  - Pleomorphic adenoma is the most common benign neoplasm of both the major and minor salivary glands. The histological features are diverse and are characterized by the involvement of epithelial-myoepithelial structures. Metallothionein is a cysteine-rich protein present in myoepithelial cells of several benign and malignant neoplasms. The function of metallothionein is associated with DNA protection, oxidative stress and apoptosis. The purpose of this study was to evaluate the expression of metallothionein in pleomorphic adenoma of the minor salivary glands. Additionally, we investigated the association of the clinicopathological features of the lesions with metallothionein, specifically its association with Bcl-2, in an attempt to evaluate the role of metallothionein in the control of apoptosis. Thirty-five cases of pleomorphic adenoma were selected and immunohistochemistry was performed for metallothionein and Bcl-2 proteins. The proteins were quantified by the Quickscore method. The samples showed epidemiological characteristics similar to  those described in the literature. We did not find an association between the clinicopathological characteristics of pleomorphic adenomas and the proteins studied, but an association between metallothionein and Bcl-2 was demonstrated. The results suggest that metallothionein may have a role in the control of apoptosis in pleomorphic adenoma.

 

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[527]

TÍTULO / TITLE:  - Over-expressing transporters associated with antigen processing increases antitumor immunity response in prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Immunol. 2012 Oct;279(2):167-73. doi: 10.1016/j.cellimm.2012.10.004. Epub 2012 Oct 29.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.cellimm.2012.10.004

AUTORES / AUTHORS:  - Qiu T; Wang L; Liu XH; Weng XD; Kuang YL; Chen ZY; Chen H; Zhu HC

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China.

RESUMEN / SUMMARY:  - As we know, prostate cancer down-regulates expression of HLA-1 Antigen Processing Machinery (APM) and has defects in the antigen presentation pathway. In vitro, the prostate cancer cell (PC-3 cells) infected with Lentivirus TAP1 can efficiently over-express TAP1 and Tapasin, and HLA-1 was also up-regulated on the surface of the infected cells. The lentivirus TAP1 infection increased the apoptosis rate of PC-3 cells. In addition, with the co-cluture PC-3 cells and lymphocytes, TAP1 augmented the expression of CD3(+)CD8(+)CD38(+) T cell. Importantly, administration of Lentivirus TAP1 to prostate cancer cells in a xenograft mouse model can prolong survival and increase the CD4(+) T cells, and CD8(+) T cells as well as decrease Foxp3(+) T cells in the tumor microenvironment. In summary, a recombinant lentivirus expressing TAP1 can effectively increase prostate cancer tumor-specific immune response.

 

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[528]

TÍTULO / TITLE:  - Extended preoperative chemotherapy, extent of liver resection and blood transfusion are predictive factors of liver failure following resection of colorectal liver metastasis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Surg Oncol. 2013 Jan 22. pii: S0748-7983(12)01379-0. doi: 10.1016/j.ejso.2012.12.020.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejso.2012.12.020

AUTORES / AUTHORS:  - Ribeiro HS; Costa WL Jr; Diniz AL; Godoy AL; Herman P; Coudry RA; Begnami MD; Mello CA; Silva MJ; Zurstrassen CE; Coimbra FJ

INSTITUCIÓN / INSTITUTION:  - Department of Abdominal Surgery, A.C. Camargo Cancer Hospital, Rua Antonio Prudente, 211 Liberdade, CEP 01501-900, Sao Paulo, Brazil. Electronic address: hsalvadorcr@gmail.com.

RESUMEN / SUMMARY:  - AIM: The aim of this study was to determine the incidence and prognostic factors  of postoperative liver failure in patients submitted to liver resection for colorectal metastases. METHOD: Patients with CLM who underwent hepatectomy from 1998 to 2009 were included in retrospective analysis. Postoperative liver failure was defined using either the 50-50 criteria or the peak of serum bilirubin level  above 7 mg/dL independently. RESULTS: Two hundred and nine (209) procedures were  performed in 170 patients. 120 surgeries were preceded by chemotherapy within six months. The overall morbidity rate was 53.1% and 90-day mortality was 2.3%. Postoperative liver failure occurred in 10% of all procedures, accounting for a mortality rate of 9.5% among this group of patients. In multivariate analysis, extent of liver resection, need of blood transfusion and more than eight preoperative chemotherapy cycles were independent prognostic factors of postoperative liver insufficiency. This complication was not related with the chemotherapy regimen used. CONCLUSION: We conclude that postoperative liver failure has a relatively low incidence (10%) after CLM resection, but a remarkable impact on postoperative mortality rate. The amount of liver resected,  the need of blood transfusion and extended preoperative chemotherapy are independent predictors of its occurrence and this knowledge can be used to prevent postoperative liver failure in a multidisciplinary approach.

 

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[529]

TÍTULO / TITLE:  - p75NTR: an enhancer of fenretinide toxicity in neuroblastoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Jan 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-013-2071-7

AUTORES / AUTHORS:  - Ganeshan V; Ashton J; Schor NF

INSTITUCIÓN / INSTITUTION:  - Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY, 14642, USA.

RESUMEN / SUMMARY:  - OBJECTIVE: Neuroblastoma is a common, frequently fatal, neural crest tumor of childhood. Chemotherapy-resistant neuroblastoma cells typically have Schwann cell-like (“S-type”) morphology and express the p75 neurotrophin receptor (p75NTR). p75NTR has been previously shown to modulate the redox state of neural  crest tumor cells. We, therefore, hypothesized that p75NTR expression level would influence the effects of the redox-active chemotherapeutic drug fenretinide on neuroblastoma cells. METHODS: Transfection and lentiviral transduction were used  to manipulate p75NTR expression in these cell lines. Sensitivity to fenretinide was determined by concentration- and time-cell survival studies. Apoptosis incidence was determined by morphological assessment and examination of cleavage  of poly-ADP ribose polymerase and caspase-3. Generation and subcellular localization of reactive oxygen species were quantified using species- and site-specific stains and by examining the effects of site-selective antioxidants  on cell survival after fenretinide treatment. Studies of mitochondrial electron transport employed specific inhibitors of individual proteins in the electron transport chain. RESULTS: Knockdown of p75NTR attenuates fenretinide-induced accumulation of mitochondrial superoxide and apoptosis. Overexpression of p75NTR  has the opposite effects. Pretreatment of cells with 2-thenoyltrifluoroacetone or dehydroascorbic acid uniquely prevents mitochondrial superoxide accumulation and  cell death after fenretinide treatment, indicating that mitochondrial complex II  is the likely site of fenretinide-induced superoxide generation and p75NTR-induced potentiation of these phenomena. CONCLUSION: Modification of expression of p75NTR in a particular neuroblastoma cell line modifies its susceptibility to fenretinide. Enhancers of p75NTR expression or signaling could  be potential drugs for use as adjuncts to chemotherapy of neural tumors.

 

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[530]

TÍTULO / TITLE:  - A significant imbalance in mitosis versus apoptosis accelerates the growth rate of sessile serrated adenoma/polyps.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Virchows Arch. 2013 Jan 6.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00428-012-1365-1

AUTORES / AUTHORS:  - Endo A; Koizumi H; Takahashi M; Tamura T; Tatsunami S; Watanabe Y; Takagi M

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, St. Marianna University School of Medicine, Kawasaki, Japan.

RESUMEN / SUMMARY:  - Sessile serrated adenoma/polyps (SSA/Ps) of the colon are thought to be precursors of sporadic carcinomas. Although it is suggested that SSA/P may grow rapidly from the early stage, its cell kinetics remains obscure. To solve this problem, we analyzed the mitotic and apoptotic activity of normal crypts, microvesicular hyperplastic polyps (MVHPs), and tubular adenomas (TAs), using phospho-histone H3 and cleaved caspase 3 immunohistochemistry. The mitotic index  for SSA/Ps (mean, 5.63) and TAs (6.98) was significantly higher than those for normal crypts (2.72) and MVHPs (2.86). Of all tested lesions, the apoptotic index was lowest for SSA/Ps (0.96; normal, 2.71; MVHPs, 2.62; TAs, 6.01) with statistically significant differences. The net growth ratio was close to 1.0 in normal crypts (1.07) while remaining low in MVHPs (1.06) and TAs (1.38), but was  markedly elevated in SSA/Ps (7.32, P < 0.01) due to the large imbalance between mitosis and apoptosis. As to apoptosis regulatory proteins, expression of anti-apoptotic Bcl-2 was significantly reduced or undetectable in MVHPs and SSA/Ps, while TAs showed stronger staining than normal crypts. Expression of pro-apoptotic Bax and its activators, Bim and Bad, was significantly reduced in MVHPs and SSA/Ps. We suggest that other complex mechanisms may act synergistically with Bax, Bim, or Bad deficiency to regulate apoptosis suppression in SSA/Ps.

 

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[531]

TÍTULO / TITLE:  - Combination chemotherapy of serine protease inhibitor nafamostat mesilate with oxaliplatin targeting NF-kappaB activation for pancreatic cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2013 Jan 21. pii: S0304-3835(13)00048-7. doi: 10.1016/j.canlet.2013.01.019.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2013.01.019

AUTORES / AUTHORS:  - Gocho T; Uwagawa T; Furukawa K; Haruki K; Fujiwara Y; Iwase R; Misawa T; Ohashi T; Yanaga K

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan. Electronic address: gocho@jikei.ac.jp.

RESUMEN / SUMMARY:  - In this study, we assessed if nafamostat mesilate may enhance anti-tumor effects  of oxaliplatin on Panc-1 cells and pancreatic cancer mouse model. In combination  treatment with nafamostat mesilate and oxaliplatin, NF-kappaB activation was inhibited by suppressing IkappaBalpha phosphorylation, and caspase-8-mediated apoptosis was more prominent than that treated with oxaliplatin alone, both in vitro and in vivo. Nafamostat mesilate reduced proliferation rate of Panc-1 cells as compared with oxaliplatin alone in vitro and enhanced oxaliplatin-induced tumor growth inhibition in vivo. Combination chemotherapy using nafamostat mesilate and oxaliplatin induces synergistic cytotoxicity in pancreatic cancer and could be a novel strategy for treatment.

 

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[532]

TÍTULO / TITLE:  - Serum spleen tyrosine kinase and vascular endothelial growth factor-C levels predict lymph node metastasis of oesophageal squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Cardiothorac Surg. 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 1093/ejcts/ezs637

AUTORES / AUTHORS:  - Duan L; Ye L; Zhao G; Wu Z; Jin C; Cai X; Li G

INSTITUCIÓN / INSTITUTION:  - Department of Thoracic Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, China.

RESUMEN / SUMMARY:  - OBJECTIVES: Lymph node involvement is a key feature and an independent prognostic factor of oesophageal squamous cell carcinoma. However, an accurate and robust assay to predict the lymphatic spread of oesophageal squamous cell carcinoma is unavailable. The purpose of this study was to determine whether serum vascular endothelial growth factor-C (VEGF-C) and spleen tyrosine kinase levels are potential markers of lymph node metastasis in patients with oesophageal squamous  cell carcinoma. METHODS: In the study, 108 patients with oesophageal squamous cell carcinoma and 24 healthy subjects participated. Serum spleen tyrosine kinase and VEGF-C concentrations were examined by enzyme-linked immunosorbent assays. RESULTS: Patients with oesophageal squamous cell carcinoma had significantly elevated VEGF-C and decreased spleen tyrosine kinase in serum when compared with  normal controls (P < 0.05). Pearson’s correlation analysis revealed that serum spleen tyrosine kinase was negatively correlated with the serum VEGF-C level in oesophageal squamous cell carcinoma patients (r = -0.453, P = 0.000). In addition, surgical resections of the oesophageal tumour profoundly brought both serum spleen tyrosine kinase and VEGF-C closer to the normal range at 2 weeks after operation (P < 0.05). Statistical analysis showed that enhanced serum VEGF-C and reduced spleen tyrosine kinase significantly correlated with the stage of regional lymph node metastasis, tumour size and the status of primary tumour extension, but not with other clinicopathological features of the patients (P < 0.05). CONCLUSIONS: Our data suggest that both serum spleen tyrosine kinase and VEGF-C levels are valuable in the preoperative evaluation of lymph node metastasis in patients with oesophageal squamous cell carcinoma.

 

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[533]

TÍTULO / TITLE:  - Nuclear LEF1/TCF4 correlate with poor prognosis but not with nuclear beta-catenin in cerebral metastasis of lung adenocarcinomas.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Exp Metastasis. 2012 Dec 8.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10585-012-9552-7

AUTORES / AUTHORS:  - Bleckmann A; Siam L; Klemm F; Rietkotter E; Wegner C; Kramer F; Beissbarth T; Binder C; Stadelmann C; Pukrop T

INSTITUCIÓN / INSTITUTION:  - Department of Hematology/Oncology, University Medical Center Gottingen, 37099, Gottingen, Germany.

RESUMEN / SUMMARY:  - An essential function of the transcription factors LEF1/TCF4 in cerebral metastases of lung adenocarcinomas has been described in mouse models, suggesting a WNT/beta-catenin effect as potential mechanism. Their role in humans is still unclear, thus we analyzed LEF1, TCF4, beta-catenin, and early stage prognostic markers in 25 adenocarcinoma brain metastases using immunohistochemistry (IHC). IHC revealed nuclear TCF4 in all adenocarcinoma samples, whereas only 36 % depicted nuclear LEF1 and nuclear beta-catenin signals. Samples with nuclear LEF1 as well as high TCF4 (++++) expression were associated with a shorter survival (p = 0.01, HR = 6.68), while nuclear beta-catenin had no significant impact on prognosis and did not significantly correlate with nuclear LEF1. High proliferation index Ki67 was associated with shorter survival in late-stage disease (p = 0.03, HR 3.27). Additionally, we generated a LEF1/TCF4 as well as an AXIN2 signature, the latter as representative of WNT/beta-catenin activity, following a bioinformatics approach with a gene expression dataset of cerebral metastases in lung adenocarcinoma. To analyze the prognostic relevance in primary lung adenocarcinomas, we applied both signatures to a microarray dataset of 58 primary lung adenocarcinomas. Only the LEF1/TCF4 signature was able to separate clusters with impact on survival (p = 0.01, HR = 0.32). These clusters displayed  diverging enrichment patterns of the cell cycle pathway. In conclusion, our data  show that LEF1/TCF4, but not beta-catenin, have prognostic relevance in primary and cerebrally metastasized human lung adenocarcinomas. In contrast to the previous in vivo findings, these results indicate that LEF1/TCF4 act independently of beta-catenin in this setting.

 

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[534]

TÍTULO / TITLE:  - AEG-1 expression characteristics in human non-small cell lung cancer and its relationship with apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):383. doi: 10.1007/s12032-012-0383-9. Epub 2013 Jan 10.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0383-9

AUTORES / AUTHORS:  - Ke ZF; Mao X; Zeng C; He S; Li S; Wang LT

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Road 58, Guangzhou, 510080, Province Guangdong, People’s Republic of China.

RESUMEN / SUMMARY:  - Expression of astrocyte-elevated gene-1 (AEG-1), a novel oncoprotein, has been shown to promote cell growth and inhibit apoptosis, but the underlying molecular  mechanisms and its functional significance in non-small cell lung cancer (NSCLC)  remain to be elucidated. In the present study, statistical analysis displayed a significant correlation of AEG-1 expression with clinical staging (P = 0.048), differentiation (P = 0.019) and lymph node metastasis (P = 0.032). Simultaneously, the overall survival time in patients with higher AEG-1 expression was obviously shorter than that in patients with lower expression of AEG-1 (P < 0.001). Furthermore, we found that AEG-1 could inhibit apoptotic cell  death in L-78 cells, as assessed by MTT, TUNEL and flow cytometry assay. After treating L-78 cells with AEG-1 siRNA, caspase-3 protein was significantly up-regulated and Bcl-2 protein was markedly decreased in L-78 cells, which was verified by the immunohistochemistry results about AEG-1, caspase-3 and Bcl-2. Furthermore, PI3K p110 protein and phosphorylated Akt were also largely attenuated by the treatment of AEG-1 siRNA. In conclusion, our results indicated  that AEG-1 played a crucial role in the carcinogenesis of NSCLC and could inhibit apoptosis via activating cell survival signaling (enhancing the level of anti-apoptotic protein Bcl-2 and the activation of PI3K/Akt pathway).

 

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[535]

TÍTULO / TITLE:  - Negative regulation of transcription factor FoxM1 by p53 enhances oxaliplatin-induced senescence in hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2012 Dec 20. pii: S0304-3835(12)00725-2. doi: 10.1016/j.canlet.2012.12.008.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2012.12.008

AUTORES / AUTHORS:  - Qu K; Xu X; Liu C; Wu Q; Wei J; Meng F; Zhou L; Wang Z; Lei L; Liu P

INSTITUCIÓN / INSTITUTION:  - Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, 277 West Yanta Road, Xi’an 710061, China.

RESUMEN / SUMMARY:  - Previous studies have demonstrated the involvement of transcriptional factor forkhead box M1 (FoxM1) in cellular senescence of hepatocellular carcinoma (HCC). In the present study, we revealed that oxaliplatin could induce senescence in HCC cells, since advanced HCC patients with lower expression of FoxM1 were more sensitive to oxaliplatin therapy. Our data indicated that due to the repression by p53, FoxM1 played a critical role in oxaliplatin-induced senescence via regulating cycle-related proteins p21, p27, cyclins B1 and D1. Furthermore, inhibition of FoxM1, combined with oxaliplatin treatment, could significantly promote the senescence of HCC cells. Taken together, our findings suggest that FoxM1 may represent a promising therapeutic target for the medication of the chemosensitivity to oxaliplatin in HCC patients.

 

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[536]

TÍTULO / TITLE:  - Prognostic role of clusterin in resected adenocarcinomas of the lung.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Lung Cancer. 2012 Dec 28. pii: S0169-5002(12)00645-9. doi: 10.1016/j.lungcan.2012.11.024.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.lungcan.2012.11.024

AUTORES / AUTHORS:  - Panico F; Casali C; Rossi G; Rizzi F; Morandi U; Bettuzzi S; Davalli P; Corbetta L; Storelli ES; Corti A; Fabbri LM; Astancolle S; Luppi F

INSTITUCIÓN / INSTITUTION:  - Section of Respiratory Diseases, Department of Oncology, Haematology & Pulmonology, University of Modena and Reggio Emilia, Modena, Italy.

RESUMEN / SUMMARY:  - RATIONALE: Clusterin expression may change in various human malignancies, including lung cancer. Patients with resectable non-small cell lung cancer (NSCLC), including adenocarcinoma, have a poor prognosis, with a relapse rate of  30-50% within 5 years. Nuclear factor kB (Nf-kB) is an intracellular protein involved in the initiation and progression of several human cancers, including the lung. OBJECTIVES: We investigate the role of clusterin and Nf-kB expression in predicting the prognosis of patients with early-stage surgically resected adenocarcinoma of the lung. FINDINGS: The level of clusterin gradually decreased  from well-differentiated to poorly differentiated adenocarcinomas. Clusterin expression was significantly higher in patients with low-grade adenocarcinoma, in early-stage disease and in women. Clusterin expression was inversely related to relapse and survival in both univariate and multivariate analyses. Finally, we observed an inverse correlation between Nf-kB and clusterin. CONCLUSIONS: Clusterin expression represents an independent prognostic factor in surgically resected lung adenocarcinoma and was proven to be a useful biomarker for fewer relapses and longer survival in patients in the early stage of disease. The inverse correlation between Nf-kB and clusterin expression confirm the previously reported role of clusterin as potent down regulator of Nf-kB.

 

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[537]

TÍTULO / TITLE:  - Changes in pulmonary function tests predict radiological response to chemotherapy in malignant pleural mesothelioma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Cardiothorac Surg. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1093/ejcts/ezs624

AUTORES / AUTHORS:  - Marulli G; Di Chiara F; Braccioni F; Perissinotto E; Pasello G; Gino Favaretto A; Breda C; Rea F

INSTITUCIÓN / INSTITUTION:  - Department of Cardiothoracic and Vascular Sciences, University of Padua, Padua, Italy.

RESUMEN / SUMMARY:  - OBJECTIVES: Response to chemotherapy in malignant pleural mesothelioma (MPM) is usually evaluated by radiological criteria, but no common agreement exists on their validity, yet. The cytoreductive effect of chemotherapy on pleural thickening may make the lung more expansible, reducing the restrictive ventilatory impairment. The aim of this study was to evaluate the changes in pulmonary function following chemotherapy in patients with MPM and to correlate these findings with radiological changes. METHODS: Between 2004 and 2011, 62 consecutive patients (74% males, median age 63 years) were prospectively investigated. Modified RECIST criteria were used for radiological evaluation of response to chemotherapy. All patients underwent pulmonary function tests before  and after three cycles of platinum-based chemotherapy. Changes between baseline and post-chemotherapy pulmonary function values (Delta) and their differences were assessed by means of Student’s paired and unpaired t-test, respectively. Receiver operating characteristic (ROC) curve analysis was performed on spirometric parameters significantly associated with response. RESULTS: Thirty (48.4%) patients had a radiological stable disease (S), 23 (37.1%) a partial response ® and 9 (14.5%) a progressive disease (P). DeltaFEV1%pred (R: 18.1 +/- 18.5%; S: 0.5 +/- 9.3%; P: -11 +/- 13.5%; P < 0.0001), DeltaFVC%pred (R: 16.1 +/- 11.8%; S: 0.4 +/- 11.2%; P: -9.2 +/- 14.6%; P < 0.0001) and DeltaVC%pred (R: 12.9 +/- 15.7%; S: 1.5 +/- 12.1%; P: -6.1 +/- 13.2%; P = 0.001) were significantly associated with radiological response. A significant correlation was observed between DeltaFEV1%pred (r = 0.46, P = 0.01), DeltaFVC%pred (r = 0.43, P = 0.02) and % change in linear tumour measurement. ROC curve analysis using dichotomized  radiological response (P/S vs R) as classification variables showed AUC = 0.88 (95%CI: 0.77-0.95) for DeltaFEV1%pred (optimal cut-off value: +7%, sensitivity: 83%, specificity: 82%, PPV: 73%, NPV: 89%) and AUC = 0.86 (95%CI: 0.75-0.94) for  DeltaFVC%pred (optimal cut-off value: +6%, sensitivity: 82%, specificity: 74%, PPV: 64%, NPV: 88%). CONCLUSIONS: Dynamic lung volumes and radiological changes after chemotherapy seem directly related. Lung function changes could be an additional tool to better evaluate the response to chemotherapy in MPM.

 

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[538]

TÍTULO / TITLE:  - Aurora-B overexpression is correlated with aneuploidy and poor prognosis in non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Lung Cancer. 2013 Jan 10. pii: S0169-5002(12)00711-8. doi: 10.1016/j.lungcan.2012.12.018.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.lungcan.2012.12.018

AUTORES / AUTHORS:  - Takeshita M; Koga T; Takayama K; Ijichi K; Yano T; Maehara Y; Nakanishi Y; Sueishi K

INSTITUCIÓN / INSTITUTION:  - Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

RESUMEN / SUMMARY:  - Aurora-B is a key regulator of mitosis, and the overexpression has been detected  in a variety of solid tumors. The Aurora-B overexpression has been suggested to correlate with clinical aggressiveness and aneuploidy in vitro, however, the frequency of overexpression of Aurora-B protein, the association with clinicopathologic parameters and aneuploidy remain poorly defined in non-small-cell lung cancer (NSCLC). Using 157 surgical specimens of human NSCLC,  we here show that overexpression of Aurora-B proteins are significantly correlated with aneuploidy and poor outcomes in NSCLC. We examined immunohistochemical protein expression of Aurora-B, and DNA ploidy by laser scanning cytometry in 157 NSCLC cases. Aurora-B overexpression was found in 83 cases (53%) of NSCLC, and was significantly correlated with vascular invasion (p=0.012), poor differentiation (p<0.001), larger tumor size (p=0.010) and lymph  node metastasis (p=0.05) and poor prognosis (p=0.011). Aneuploidy was found in 87 cases (57%), and was significantly correlated with Aurora-B overexpression (p=0.0065). Logistic multivariate analysis revealed overexpression of Aurora-B protein to be significant risk factors for aneuploidy compared with other factors. These results indicate that Aurora-B overexpression may contribute to malignant potential and increased aneuploidy in NSCLC. Thus, Aurora-B may serve as a new therapeutic target in against patients with NSCLC, although further studies will be necessary.

 

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[539]

TÍTULO / TITLE:  - Induction of apoptosis in non-small cell lung cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPA/siRNA complex nanoparticles.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biomaterials. 2013 Jan 24. pii: S0142-9612(13)00007-0. doi: 10.1016/j.biomaterials.2012.12.042.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biomaterials.2012.12.042

AUTORES / AUTHORS:  - Yu H; Zou Y; Jiang L; Yin Q; He X; Chen L; Zhang Z; Gu W; Li Y

INSTITUCIÓN / INSTITUTION:  - Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.

RESUMEN / SUMMARY:  - Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer caused human death. In this work, we selected oncogene mouse double minute 2 (MDM2) as a therapeutic target for NSCLC treatment and proposed that sufficient MDM2 knockdown could inhibit tumor growth via induction of cell cycle arrest and  cancer cell apoptosis. On this regard, a new pH-responsive diblock copolymer of poly(methacryloyloxy ethyl phosphorylcholine)-block-poly(diisopropanolamine ethyl methacrylate) (PMPC-b-PDPA)/siRNA-MDM2 complex nanoparticle with minimized surface charge and suitable particle size was designed and developed for siRNA-MDM2 delivery in vitro and in vivo. The experimental results showed that the nanoparticles were spherical with particle size around 50 nm. MDM2 knockdown  in p53 mutant NSCLC H2009 cells induced significant cell cycle arrest, apoptosis  and growth inhibition through upregulation of p21 and activation of caspase-3. Furthermore, the growth of H2009 xenograft tumor in nude mice was inhibited via repeated injection of PMPC-b-PDPA/siRNA-MDM2 complex nanoparticles. These results suggested that PMPC-b-PDPA/siRNA complex nanoparticles targeting a unique set of  oncogenes could be developed into a new therapeutic approach for NSCLC treatment.

 

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[540]

TÍTULO / TITLE:  - Efficacy of decitabine-loaded nanogels in overcoming cancer drug resistance is mediated via sustained DNA methyltransferase 1 (DNMT1) depletion.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2013 Jan 7. pii: S0304-3835(12)00726-4. doi: 10.1016/j.canlet.2012.12.009.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2012.12.009

AUTORES / AUTHORS:  - Vijayaraghavalu S; Labhasetwar V

INSTITUCIÓN / INSTITUTION:  - Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.

RESUMEN / SUMMARY:  - DNA methyltransferase 1 (DNMT1) promotes DNA methylation to maintain cancer drug  resistance. The epigenetic drug, decitabine (DAC) is a potent hypomethylating agent, but its effect is transient because of its instability. We tested the efficacy of DAC-loaded nanogels in doxorubicin-resistant breast cancer cells, DAC-resistant melanoma cells, and leukemia cells. DAC in nanogel sustained DNMT1  depletion, prolonged cell arrest in the G2/M cell-cycle phase, and significantly  enhanced antiproliferative effect of DAC. The efficacy of DAC-loaded nanogels was more significant in resistant than sensitive cells. Our data suggest that effective delivery of DAC and prolonged DNMT1 depletion are critical to overcoming drug resistance.

 

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[541]

TÍTULO / TITLE:  - Targeting Chk2 improves gastric cancer chemotherapy by impairing DNA damage repair.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Apoptosis. 2012 Dec 28.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10495-012-0794-2

AUTORES / AUTHORS:  - Gutierrez-Gonzalez A; Belda-Iniesta C; Bargiela-Iparraguirre J; Dominguez G; Garcia Alfonso P; Perona R; Sanchez-Perez I

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry, School of Medicine, UAM, Madrid, España.

RESUMEN / SUMMARY:  - Our results demonstrate that the addition of cisplatin after paclitaxel-induced mitotic arrest was more effective than individual treatment on gastric adenocarcinoma cells (MKN45). However, the treatment did not induce benefits in cells derived from lymph node metastasis (ST2957). Time-lapse microscopy revealed that cell death was caused by mitotic catastrophe and apoptosis induction, as the use of the caspase inhibitor z-VAD-fmk decreased cell death. We propose that the  molecular mechanism mediating this cell fate is a slippage suffered by these cells, given that our Western blot (WB) analysis revealed premature cyclin B degradation. This resulted in the cell exiting from mitosis without undergoing DNA damage repair, as demonstrated by the strong phosphorylation of H2AX. A comet assay indicated that DNA repair was impaired, and Western blotting showed that the Chk2 protein was degraded after sequential treatment (paclitaxel-cisplatin).  Based on these results, the modulation of cell death during mitosis may be an effective strategy for gastric cancer therapy.

 

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[542]

TÍTULO / TITLE:  - Defining biomarkers to predict sensitivity to PI3K/Akt/mTOR pathway inhibitors in breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Treat Rev. 2012 Dec 5. pii: S0305-7372(12)00234-4. doi: 10.1016/j.ctrv.2012.11.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ctrv.2012.11.002

AUTORES / AUTHORS:  - Gonzalez-Angulo AM; Blumenschein GR Jr

INSTITUCIÓN / INSTITUTION:  - Department of Breast Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA; Department Systems Biology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA. Electronic address: agonzalez@mdanderson.org.

RESUMEN / SUMMARY:  - BACKGROUND: Identification and validation of biomarkers is increasingly important for the integration of novel targeted agents in the treatment of cancer. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway represents a promising therapeutic target in breast carcinoma, and inhibitors targeting different nodes of the PI3K/Akt/mTOR axis are in development. Identification of biomarkers to help select patients who are most likely to benefit from these treatments is an essential unmet need. DESIGN: MEDLINE and international conference abstracts were searched for evidence of markers of sensitivity to PI3K/Akt/mTOR pathway inhibitors in breast cancer patients and preclinical models. RESULTS: Preclinical evidence suggests that PI3K/Akt/mTOR pathway aberrations, notably in PIK3CA, may identify a subpopulation of patients with breast cancer who preferentially respond to PI3K/Akt/mTOR inhibitors. However, additional markers are needed to identify all  patients with de novo sensitivity to PI3K/Akt/mTOR pathway inhibition. Early clinical studies to validate these biomarkers have as yet been inconclusive. CONCLUSIONS: Prospective, adequately designed and powered clinical trials are needed to test candidate biomarkers of sensitivity to PI3K/Akt/mTOR pathway inhibitors in patients with breast cancer, and to determine whether certain PI3K/Akt/mTOR pathway inhibitors are more appropriate in different subtypes depending on the pattern of molecular alteration.

 

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[543]

TÍTULO / TITLE:  - Blockade of tumor necrosis factor-alpha converting enzyme (TACE) enhances IL-1beta and IFN-gamma via caspase-1 activation: A probable cause for loss of efficacy of TACE inhibitors in humans?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Pharmacol. 2012 Dec 22. pii: S0014-2999(12)01007-2. doi: 10.1016/j.ejphar.2012.12.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejphar.2012.12.002

AUTORES / AUTHORS:  - Sharma M; Mohapatra J; Acharya A; Deshpande SS; Chatterjee A; Jain MR

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacology, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India.

RESUMEN / SUMMARY:  - TNF-alpha converting enzyme (TACE) is a member of the ADAM (a disintegrin and metalloproteinase) family and is known as ADAM17, which processes precursor TNF-alpha in order to release soluble TNF-alpha (sTNF-alpha). Inhibition of TACE  has been effective as a strategy to inhibit arthritis in animal models however; it has been not translated in the clinic due to lack of efficacy or toxicity. We  hypothesized that inhibition of TACE may activate a different pro-inflammatory pathway in human. To investigate this, we studied the effect of TACE inhibitor DPC-333 on cytokine levels in concanavalin A (Con A) activated human peripheral blood mononuclear cells (hPBMC). We have also studied the effects of DPC-333 on Con A induced cytokine levels in mice in vivo or in vitro in whole blood assay. DPC-333 treatment significantly up-regulated IL-1beta and IFN-gamma in Con A activated hPBMC. In contrast, pre-treatment with DPC-333 effectively suppressed IL-1beta and IFN-gamma in mice in vivo or in vitro. Interestingly, DPC-333 was found to up-regulate mRNA expression of caspase-1 in hPBMC in a dose dependent fashion and selective caspase-1 inhibitor completely restored DPC-333 induced IL-1beta and IFN-gamma. Furthermore, selective IL-1beta receptor antagonist (anakinra) prevented DPC-333 induced IFN-gamma. In conclusion, our data demonstrates that blockade of TACE enhances IL-1beta in a caspase-1 dependent manner in vitro in hPBMC and the elevation of IFN-gamma is secondarily mediated via IL-1beta. This novel finding might explain the possible cause behind the loss of efficacy of TACE inhibitors in human.

 

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[544]

TÍTULO / TITLE:  - Adenosine induces cell cycle arrest and apoptosis via cyclinD1/Cdk4 and Bcl-2/Bax pathways in human ovarian cancer cell line OVCAR-3.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Tumour Biol. 2013 Jan 24.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s13277-013-0650-1

AUTORES / AUTHORS:  - Shirali S; Aghaei M; Shabani M; Fathi M; Sohrabi M; Moeinifard M

INSTITUCIÓN / INSTITUTION:  - Department of Laboratory Sciences, Chalous Branch, Islamic Azad University, Chalous, Iran.

RESUMEN / SUMMARY:  - Adenosine is a regulatory molecule with widespread physiological effects in almost every cells and acts as a potent regulator of cell growth. Adenosine has been shown to inhibit cell growth and induce apoptosis in the several cancer cells via caspase activation and Bcl-2/Bax pathway. The present study was designed to understand the mechanism underlying adenosine-induced apoptosis in the OVCAR-3 human ovarian cancer cells. MTT viability, BrdU and cell counting assays were used to study the cell proliferation effect of adenosine in presence  of adenosine deaminase inhibitor and the nucleoside transporter inhibitor. Cell cycle analysis, propidium iodide and annexin V staining, caspase-3 activity assay, cyclinD1, Cdk4, Bcl-2 and Bax protein expressions were assessed to detect  apoptosis. Adenosine significantly inhibited cell proliferation in a concentration-dependent manner in OVCAR-3 cell line. Adenosine induced cell cycle arrest in G0/G1 phase via Cdk4/cyclinD1-mediated pathway. Adenosine induced apoptosis, which was determined by Annexin V-FITC staining and increased sub-G1 population. Moreover, down-regulation of Bcl-2 protein expression, up-regulation  of Bax protein expression and activation of caspase-3 were observed in response to adenosine treatment. The results of this study suggest that extracellular adenosine induced G1 cell cycle arrest and apoptosis in ovarian cancer cells via  cyclinD1/ Cdk4 and Bcl-2/Bax pathways and caspase-3 activation. These data might  suggest that adenosine could be used as an agent for the treatment of ovarian cancer.

 

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[545]

TÍTULO / TITLE:  - The curcumin analog DM-1 induces apoptotic cell death in melanoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Tumour Biol. 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s13277-013-0653-y

AUTORES / AUTHORS:  - Faiao-Flores F; Suarez JA; Maria-Engler SS; Soto-Cerrato V; Perez-Tomas R; Maria DA

INSTITUCIÓN / INSTITUTION:  - Laboratory of Biochemistry and Biophysics, Butantan Institute, 1500 Vital Brasil  Avenue, 05503-900, Sao Paulo, Brazil, fernandafaiao@yahoo.com.br.

RESUMEN / SUMMARY:  - The main difficulty in the successful treatment of metastatic melanoma is that this type of cancer is known to be resistant to chemotherapy. Chemotherapy remains the treatment of choice, and dacarbazine (DTIC) is the best standard treatment. The DM-1 compound is a curcumin analog that possesses several curcumin characteristics, such as antiproliferative, antitumor, and antimetastatic properties. The objective of this study was to evaluate the signaling pathways involved in melanoma cell death after treatment with DM-1 compared to the standard agent for melanoma treatment, DTIC. Cell death was evaluated by flow cytometry for annexin V and iodide propide, cleaved caspase 8, and TNF-R1 expression. Hoechst 33342 staining was evaluated by fluorescent microscopy; lipid peroxidation and cell viability (MTT) were evaluated by colorimetric assays. The  antiproliferative effects of the drugs were evaluated by flow cytometry for cyclin D1 and Ki67 expression. Mice bearing B16F10 melanoma were treated with DTIC, DM-1, or both therapies. DM-1 induced significant apoptosis as indicated by the presence of cleaved caspase 8 and an increase in TNF-R1 expression in melanoma cells. Furthermore, DM-1 had antiproliferative effects in this the same  cell line. DTIC caused cell death primarily by necrosis, and a smaller melanoma cell population underwent apoptosis. DTIC induced oxidative stress and several physiological changes in normal melanocytes, whereas DM-1 did not significantly affect the normal cells. DM-1 antitumor therapy in vivo showed tumor burden decrease with DM-1 monotherapy or in combination with DTIC, besides survival rate increase. Altogether, these data confirm DM-1 as a chemotherapeutic agent with effective tumor control properties and a lower incidence of side effects in normal cells compared to DTIC.

 

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[546]

TÍTULO / TITLE:  - CFL1 and Arp3 are Biomarkers for Metastasis and Poor Prognosis of Squamous Cell/Adenosquamous Carcinomas and Adenocarcinomas of Gallbladder.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Invest. 2013 Feb;31(2):132-9. doi: 10.3109/07357907.2012.756113. Epub 2013 Jan 15.

            ●● Enlace al texto completo (gratuito o de pago) 3109/07357907.2012.756113

AUTORES / AUTHORS:  - Yang ZL; Miao X; Xiong L; Zou Q; Yuan Y; Li J; Liang L; Chen M; Chen S

INSTITUCIÓN / INSTITUTION:  - Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University , Changsha, Hunan , P. R. China,1.

RESUMEN / SUMMARY:  - Cofilin-1 (CFL1) and Arp3 expression in 46 squamous cell and adenosquamous carcinomas (SC/ASCs) and 80 adenocarcinomas (ACs) were measured by using immunohistochemistry. Positive CFL1 and Arp3 expression were significantly associated with large tumor size, high TNM stage, lymph node metastasis, and decreased overall survival in both SC/ASC and AC patients (p < .001). Multivariate Cox regression analysis showed that positive CFL1 and Arp3 expression are independent poor-prognostic factors for both SC/ASC and AC patients. Our study suggested that positive CFL1 and Arp3 expression are closely  related to tumor progression, metastasis, and poor prognosis of gallbladder cancer.

 

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[547]

TÍTULO / TITLE:  - Romidepsin and interferon gamma: A novel combination for refractory cutaneous T-cell lymphoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Am Acad Dermatol. 2013 Jan;68(1):e5-6. doi: 10.1016/j.jaad.2011.06.043.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jaad.2011.06.043

AUTORES / AUTHORS:  - Samimi S; Morrissey K; Anshelevich S; Evans K; Gardner J; Musiek A; Vittorio C; Rook A; Kim E

INSTITUCIÓN / INSTITUTION:  - Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: sara.samimi@uphs.upenn.edu.

 

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[548]

TÍTULO / TITLE:  - Transcriptional regulation of tumour necrosis factor-related apoptosis-inducing ligand.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Mol Life Sci. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00018-013-1264-x

AUTORES / AUTHORS:  - Azahri NS; Kavurma MM

INSTITUCIÓN / INSTITUTION:  - Centre for Vascular Research, University of New South Wales, Sydney, NSW 2052, Australia.

RESUMEN / SUMMARY:  - Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has dual functions mediating both apoptosis and survival of cells. This review focusses on the current regulatory factors that control TRAIL transcription. Here, we also highlight the role of distinct transcription factors that co-operate and regulate TRAIL in different pathological states. A better understanding of the molecular signalling pathways of TRAIL-induced cell death and survival in disease may lead  to more sophisticated technologies for novel therapeutic targets.

 

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[549]

TÍTULO / TITLE:  - Carbonic anhydrase inhibitors: Benzenesulfonamides incorporating cyanoacrylamide  moieties are low nanomolar/subnanomolar inhibitors of the tumor-associated isoforms IX and XII.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Bioorg Med Chem. 2013 Jan 2. pii: S0968-0896(12)00965-0. doi: 10.1016/j.bmc.2012.12.004.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bmc.2012.12.004

AUTORES / AUTHORS:  - Alafeefy AM; Isik S; Abdel-Aziz HA; Ashour AE; Vullo D; Al-Jaber NA; Supuran CT

INSTITUCIÓN / INSTITUTION:  - Department of Pharmaceutical Chemistry, College of Pharmacy, Salman Bin Abdulaziz University, PO Box 173, Alkharj 11942, Saudi Arabia. Electronic address: alafeefy@hotmail.com.

RESUMEN / SUMMARY:  - A series of benzenesulfonamides incorporating cyanoacrylamide moieties (tyrphostine analogues) have been obtained by reaction of sulfanilamide with ethylcyanoacetate followed by condensation with aromatic/heterocyclic aldehydes,  isothiocyanates or diazonium salts. The new compounds have been investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4. 2.1.1), and more specifically against the cytosolic human (h) isoforms hCA I and II, as well as the transmembrane, tumor-associated ones CA IX and XII, which are validated antitumor targets. Most of the new benzenesulfonamides were low nanomolar or subnanomolar CA IX/XII inhibitors whereas they were less effective as inhibitors  of CA I and II. The structure-activity relationship for this class of effective CA inhibitors is also discussed. Generally, electron donating groups in the starting aldehyde reagent favored CA IX and XII inhibition, whereas halogeno, methoxy and dimethylamino moieties led to very potent CA XII inhibitors.

 

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[550]

TÍTULO / TITLE:  - o-Benzenedisulfonimido-sulfonamides are potent inhibitors of the tumor-associated carbonic anhydrase isoforms CA IX and CA XII.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Bioorg Med Chem. 2013 Jan 4. pii: S0968-0896(12)01010-3. doi: 10.1016/j.bmc.2012.12.037.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bmc.2012.12.037

AUTORES / AUTHORS:  - Guzel-Akdemir O; Akdemir A; Isik S; Vullo D; Supuran CT

INSTITUCIÓN / INSTITUTION:  - Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116 Beyazit, Istanbul, Turkey.

RESUMEN / SUMMARY:  - By using phthalimido-substituted aromatic sufonamides as lead molecules, a series of new sulfonamides incorporating ortho-benzenedisulfonimide moieties have been synthesized and tested against the human (h) cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isozymes hCA I and hCA II and the transmembrane, tumor-associated isozymes hCA IX and hCA XII. All these compounds showed K(i) values lower than 100nM and many of them showed better K(i)s than the reference compound acetazolamide, a clinically used sulfonamide. The tumor-associated isozymes were  better inhibited than the cytosolic ones. A molecular docking within the active site of some CA isoforms, such as hCA I, explained these findings, as the benzenedisulfonimide moiety makes favorable interactions (hydrogen bonds) with amino acid residues involved in binding of inhibitors, such as Gln92, His67, and  His64.

 

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[551]

TÍTULO / TITLE:  - Alpha B-crystallin is a new prognostic marker for laryngeal squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Exp Clin Cancer Res. 2012 Dec 12;31:101. doi: 10.1186/1756-9966-31-101.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1756-9966-31-101

AUTORES / AUTHORS:  - Mao Y; Zhang DW; Lin H; Xiong L; Liu Y; Li QD; Ma J; Cao Q; Chen RJ; Zhu J; Feng ZQ

INSTITUCIÓN / INSTITUTION:  - Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Nanjing Medical University, No,121 Jiang jia yuan, Nanjing 210011, China. renjiechenent@yahoo.com.cn.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Alpha B-crystallin (alphaB-crystallin) has been suggested to play an important role in the development of solid tumors. However, the association between alphaB-crystallin expression and clinicopathological characteristics of human laryngeal carcinoma is not well defined. This study aimed to examine the expression of alphaB-crystallin in human laryngeal squamous  cell carcinoma (LSCC) and investigate the relationship between its expression and the prognosis of LSCC. METHODS: Real-time polymerase chain reaction (six LSCC samples, six tumor-adjacent normal samples) and immunohistochemistry by tissue microarrays (109 LSCC samples and 28 tumor-adjacent normal samples) were performed to characterize expression of the alphaB-crystallin gene in LSCC. Kaplan-Meier survival and Cox regression analyses were carried out to evaluate the prognosis of LSCC. RESULTS: Real-time polymerase chain reaction and immunohistochemistry analysis showed that the expression of alphaB-crystallin in  LSCC was significantly higher than that in tumor-adjacent normal tissues. Moreover, the expression level of alphaB-crystallin protein in LSCC was significantly related to alcohol consumption (P = 0.022), tumor differentiation (P = 0.007), pTNM stage (P = 0.041) and 5 years’ survival (P =0.030). COX multi-factor analysis showed that alphaB-crystallin (P = 0.013), as well as pTNM  stage (P =0.027) and lymphatic metastasis (P = 0.015) were independent prognosis  factors for LSCC. CONCLUSIONS: The data suggest that alphaB-crystallin expression is correlated with malignant phenotypes of LSCC and it may serve as a novel prognostic factor for LSCC.

 

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[552]

TÍTULO / TITLE:  - Cytotoxicity of 5-Aza-2’-deoxycytidine against gastric cancer involves DNA damage in an ATM-P53 dependent signaling pathway and demethylation of P16(INK4A).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biomed Pharmacother. 2012 Nov 19. pii: S0753-3322(12)00107-2. doi: 10.1016/j.biopha.2012.10.015.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biopha.2012.10.015

AUTORES / AUTHORS:  - Liu J; Xie YS; Wang FL; Zhang LJ; Zhang Y; Luo HS

INSTITUCIÓN / INSTITUTION:  - Department of Geriatrics, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuchang District, 430060 Wuhan, PR China.

RESUMEN / SUMMARY:  - The DNA methylation inhibitor 5-Aza-2’-deoxycytidine (5-Aza-CdR) has increasingly attracted worldwide attention for its antineoplastic potential. The cytotoxitic mechanisms, however, especially, the relative contribution of silenced genes reactivation by demethylation and enzyme-DNA adduct formation to the efficacy of  5-Aza-CdR is still a crucial unresolved question. In this investigation, we demonstrated that 5-Aza-CdR treatment resulted in growth suppression in a concentration and time-dependent manner and G2 phrase arrest - hallmarks of a DNA damage response in gastric cancer AGS cells. Formation of DNA double-strand breaks, as monitored by comet assay was examined in an ATM (ataxia-telangiectasia mutated)-dependent manner based on the fact that PI3K inhibitor Wortmannin abolished the action of cytotoxicity of 5-Aza-CdR. Upon treatment with 5-Aza-CdR, ATM activation was clearly associated with P53 phosphorylation at Ser(15), which  was directly responsible for 5-Aza-CdR modified P21(Waf1/Cip1) expression. Further exploration revealed that demethylation of P16(INK4A) correlated with the strikingly down-regulated expressions of DNA methyltransferase 3A as well as 3B was, at least in part, attributed to the cytotoxicity of 5-Aza-CdR in AGS cells.  Conclusively, these results greatly enhance our understanding of the mechanisms of cytotoxicity of 5-Aza-CdR and strongly provide the preclinical rationale for an assessment of 5-Aza-CdR to ameliorate patient outcome with gastric cancer.

 

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[553]

TÍTULO / TITLE:  - Tetraarsenic oxide and cisplatin induce apoptotic synergism in cervical cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Jan 18. doi: 10.3892/or.2013.2243.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2243

AUTORES / AUTHORS:  - Byun JM; Jeong DH; Lee DS; Kim JR; Park SG; Kang MS; Kim YN; Lee KB; Sung MS; Kim KT

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, Busan Paik Hospital, Inje University, Busan 614-735, Republic of Korea.

RESUMEN / SUMMARY:  - Tetraarsenic oxide (As4O6, TAO) is a new arsenic compound that inhibits cell growth and induces apoptosis in human cervical cancer cell lines. In the present  study, we report that the growth of tumor cells (CaSki) was inhibited by treatment with TAO alone or in combination with cisplatin or paclitaxel in vitro  and in vivo. Proliferation was assessed by WST-1 assay, and apoptosis was assessed by Annexin-V/PI FACS analysis in the CaSki cell line treated with a single agent or with the combinations of two agents. Expression of apoptosis-related proteins was analyzed by western blot analysis. A mouse xenograft model using CaSki cells was used to determine the in vivo activity of tetraarsenic oxide alone and in combination with cisplatin or paclitaxel by estimation of tumor size. At the end of the experiment, tumor tissue from each mouse was removed and processed for TUNEL analysis for confirmation of apoptotic  cells. TAO was able to inhibit cell proliferation in a time- and dose-dependent manner. A combination of TAO and cisplatin effectively induced apoptosis by activating caspase-3. Using a mouse xenograft model, the sizes of tumors which were treated with a single agent and with a combination of agents decreased in a  time-dependent manner. A combination of TAO and cisplatin resulted in a significantly reduced tumor size (P<0.05). The data for the histochemical staining of TUNEL-positive cells showed that the number of apoptotic cells was significantly increased by the combination of TAO and cisplatin. Thus, TAO is a good candidate for use in a combined regimen with cisplatin for patients with cervical cancer.

 

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[554]

TÍTULO / TITLE:  - Increased efficacy of CDDP in a xenograft model of hepatoblastoma using the apoptosis sensitizer ABT-737.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):646-52. doi: 10.3892/or.2012.2150. Epub 2012 Nov 27.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2150

AUTORES / AUTHORS:  - Lieber J; Dewerth A; Wenz J; Kirchner B; Eicher C; Warmann SW; Fuchs J; Armeanu-Ebinger S

INSTITUCIÓN / INSTITUTION:  - Department of Paediatric Surgery and Paediatric Urology, University Children’s Hospital, 72076 Tubingen, Germany. justus.lieber@med.uni-tuebingen.de

RESUMEN / SUMMARY:  - The response of standard-risk hepatoblastoma (HB) to neoadjuvant cisplatin (CDDP) chemotherapy is excellent; however, in high-risk HB, drug resistance remains a major challenge. Alternative therapeutic strategies may consider combining cytotoxic drugs with apoptosis sensitizers as this has shown additive effects in  various types of malignancies. Analysis of published expression databases have revealed an anti-apoptosis state in HB samples. Herein, we evaluated the synergistic effects of ABT-737 as a modulator of apoptosis in combination with CDDP in HB. To this end, clonogenic assays were performed with HepT1 and HUH6 HB  cells to evaluate the synergistic effects of CDDP and ABT-737. Combination treatment with CDDP and ABT-737 reduced the clonogenicity of HB cells more than 5-fold compared to treatment with CDDP alone. Furthermore, the HUH6 mixed-type HB cells showed higher sensitivity to CDDP and combination treatment compared to the HepT1 embryonal-type cells. Subcutaneous HUH6 tumors in NOD/LtSz-scid IL2Rgammanull mice were treated with CDDP (1.25 and 3 mg/kg body weight, n=6), ABT-737 (100 mg/kg, n=5) and the combination of both agents (n=5). Combined treatment led to a significantly reduced tumor growth compared to CDDP treatment  alone (p<0.02). When using higher doses of CDDP (3 mg/kg) alone or in combination with ABT-737, dose-dependent toxicity was observed in this mouse strain. In conclusion, our results demonstrated the enhancement of chemotherapy efficacy by  using modulators of apoptosis together with cytotoxic agents. Additive effects of ABT-737 may allow reduction in CDDP dosages with maintenance of antitumor activity. Sensitizing HB to apoptosis may also render resistant HB susceptible to established chemotherapy regimens.

 

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[555]

TÍTULO / TITLE:  - Hyaluronan synthesis inhibitor supplements the inhibitory effects of zoledronic acid on bone metastasis of lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Exp Metastasis. 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10585-012-9563-4

AUTORES / AUTHORS:  - Futamura N; Urakawa H; Arai E; Kozawa E; Ishiguro N; Nishida Y

INSTITUCIÓN / INSTITUTION:  - Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65-Tsuruma, Showa, Nagoya, 466-8550, Japan.

RESUMEN / SUMMARY:  - Hyaluronan is known to have pivotal roles in the growth, migration and invasion of malignant tumors. Bone metastases are critical lesions greatly impairing the quality of patients with malignancies. We investigated whether hyaluronan synthesis inhibitor supplements the inhibitory effects of zoledronic acid, which  is a conventional therapeutic agent for bone metastasis. We examined the effects  of methylumbelliferone, an inhibitor of hyaluronan synthesis and/or ZA on the tumorigenicity of one murine lung carcinoma and two human (A549, SK-MES-1) lung cancer cell lines in vitro. The interaction between methylumbelliferone and zoledronic acid was analyzed using Calcucyn software. With a murine bone metastasis model of lung cancer in vivo, we investigated the inhibitory effects and interaction of the two drugs on the progression of metastatic bone lesions. Methylumbelliferone or zoledronic acid treatment individually suppressed proliferation, migration and invasion of 3 cell lines, and combination treatment  showed synergistic effects. Although methylumbelliferone as a single agent did not enhance apoptotic activity, it showed additive effects on apoptotic activity  to those of zoledronic acid. Co-localization of CD44 and ezrin, which might be a  pathway of hyaluronan signaling, was abrogated by methylumbelliferone treatment.  Combination therapy showed additive inhibitory effects on metastatic bone lesions in vivo, which paralleled the inhibition of hyaluronan accumulation by methylumbelliferone, and inhibition of osteoclastogenesis. Although the detailed  mechanisms underlying the synergistic or additive inhibitory effects of these two drugs should be further analyzed, inhibition of hyaluronan synthesis by methylumbelliferone is a promising novel therapeutic candidate for bone metastasis of lung cancer in addition to zoledronic acid.

 

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[556]

TÍTULO / TITLE:  - Effect of ARHI on lung cancer cell proliferation, apoptosis and invasion in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Biol Rep. 2012 Dec 18.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11033-012-2353-x

AUTORES / AUTHORS:  - Wu X; Liang L; Dong L; Yu Z; Fu X

INSTITUCIÓN / INSTITUTION:  - Pulmonary Department, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

RESUMEN / SUMMARY:  - The purposes of this study were to elucidate the effects of ARHI (aplysia ras homolog I) on several biological features of lung cancer cells, including growth, proliferation and invasion, to collect experimental evidence for the future biological treatment of human lung cancer. The eukaryotic expression vector, pcDNA3.1-ARHI, was constructed and transfected into the human lung cancer cell line SK-MES-1. The biological properties of the resulting ARHI-expressing lung cancer cell line were evaluated using methyl thiazolyl tetrazolium assay, flow cytometry, and a Transwell invasion assay. Additionally, the influence of ARHI on the gene expression levels of cyclin D1, p27(KIP1), death-associated protein kinase 1 (DAPK1), and matrix metalloproteinases1/2 (MMP-1/2) was determined. Compared to the non-transfected SK-MES-1 cells and the cells transfected with the empty pcDNA3.1 plasmid, the ARHI-transfected cells displayed significantly reduced growth rates and decreased viability (P < 0.05). The ARHI-transfected cells also displayed a significantly higher percentage of cells in G1 phase (P <  0.05) and a lower percentage of cells in S phase (P < 0.05); a higher percentage  of apoptosis (P < 0.05); and finally, a notable reduction in the basement membrane-penetration rate in the Transwell invasion assay (P < 0.05). Furthermore, it was determined that ARHI is capable of inhibiting the expression  of cyclin D1, MMP-1, and MMP-2; however, ARHI promotes the expression of both p27(KIP1) and DAPK1 in SK-MES-1 cells. In conclusion, overexpression of ARHI gene might be associated with the inhibition of lung cancer cell growth, proliferation and invasion, and the promotion of apoptosis.

 

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[557]

TÍTULO / TITLE:  - KRC-408, a Novel c-Met Inhibitor, Suppresses Cell Proliferation and Angiogenesis  of Gastric Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2013 Jan 21. pii: S0304-3835(13)00044-X. doi: 10.1016/j.canlet.2013.01.015.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2013.01.015

AUTORES / AUTHORS:  - Hong SW; Jung KH; Park BH; Zheng HM; Lee HS; Choi MJ; Yun JI; Kang NS; Lee J; Hong SS

INSTITUCIÓN / INSTITUTION:  - Department of Biomedical Sciences and NCEED, College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea; School of Biology and Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.

RESUMEN / SUMMARY:  - Among many cancer therapeutic targets, c-Met receptor tyrosine kinase has recently given particular attention. This kinase and its ligand, hepatocyte growth factor (HGF), play a central role in cell proliferation and the survival of several human cancers. Thus, we developed KRC-408 as a novel c-Met inhibitor and investigated its anti-cancer effects on human gastric cancer. KRC-408 inhibited the phosphorylation of c-Met and its constitutive downstream effectors  such as phosphatidylinositol 3-kinase (PI3K), Akt, Mek, and Erk. This compound was found to exert anti-cancer effects stronger than those of 5-fluorouracil (5-FU) on gastric cancer cells, especially cell lines that overexpressed c-Met. Interestingly, cytotoxicity of KRC-408 was lower than that of 5-FU in normal gastric cells. Apoptosis induced by KRC-408 was accompanied by increased levels of cleaved caspase-3 and PARP as well as DNA condensation and fragmentation. Flow cytometry analysis showed an accumulation of gastric cancer cells in the G2/M phase with concomitant loss of cells in the S phase following treatment with this drug. In the angiogenesis studies, KRC-408 inhibited tube formation and migration of human umbilical vein endothelial cells (HUVECs), and suppressed microvessel sprouting from rat aortic rings ex vivo along with blood vessel formation in a Matrigel plug assay in mice. Results of an in vivo mouse xenograft experiment showed that the administration of KRC-408 significantly delayed tumor growth in a dose-dependent manner, and suppressed Akt and Erk phosphorylation as well CD34 expression in tumor tissues. These findings indicate that KCR-408 may exert antitumor effects by directly affecting tumor cell growth or survival via the c-Met receptor tyrosine kinase pathway. We therefore suggest that KRC-408 is a novel therapeutic candidate effective against gastric cancers that overexpress c-Met.

 

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[558]

TÍTULO / TITLE:  - Solid tumor penetration by integrin-mediated pegylated poly(trimethylene carbonate) nanoparticles loaded with paclitaxel.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biomaterials. 2013 Feb;34(6):1739-46. doi: 10.1016/j.biomaterials.2012.11.016. Epub 2012 Dec 2.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biomaterials.2012.11.016

AUTORES / AUTHORS:  - Jiang X; Xin H; Gu J; Xu X; Xia W; Chen S; Xie Y; Chen L; Chen Y; Sha X; Fang X

INSTITUCIÓN / INSTITUTION:  - Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai 201203, China.

RESUMEN / SUMMARY:  - Limited penetration of antineoplastic agents is one of the contributing factors for chemotherapy failure of many solid tumors. In order to enhance drug penetration into solid cancer, especially, into the avascular regions inside tumors, we proposed cyclic RGD peptide functionalized PEGylated poly(trimethylene carbonate) nanoparticles (c(RGDyK)-NP). By integrin-mediated transcytosis and enhanced drug permeation, c(RGDyK)-NP could access the neoplastic cells distant from blood vessels, and consequently, avoiding the capability of cancer regeneration from these tumor cells. In the present study, the solid tumor penetration, homing specificity and anticancer efficacy were evaluated both on the ex vivo 3D tumor spheroids and on the subcutaneous xenograft mice model. In comparison with conventional nanoparticles (NP/PTX) and Taxol, c(RGDyK)-NP/PTX showed the strongest penetration and accumulation into 3D tumor spheroids, a marked tumor-homing specificity in vivo and the greatest tumor growth inhibitory  effect in vitro and in vivo. Histochemistry analysis revealed that no obvious histopathological abnormalities or lesions were observed in major organs after intravenous administration with the treatment doses. In conclusion, cyclic RGD peptide-conjugated PEG-PTMC nanoparticle could facilitate drug penetration and accumulation in tumor tissues and may be a promising vehicle for enhancing the chemotherapy of solid cancers.

 

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[559]

TÍTULO / TITLE:  - Erratum to Cost utility of tumour necrosis factor-alpha inhibitors for rheumatoid arthritis: an application of Bayesian methods for evidence synthesis in a Markov  model.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pharmacoeconomics. 2012 Nov;30(11):1096.

            ●● Enlace al texto completo (gratuito o de pago) 2165/11633730-000000000-00000

AUTORES / AUTHORS:  - Nguyen CM; Bounthavong M; Mendes MA; Christopher ML; Tran JN; Kazerooni R; Morreale AP

INSTITUCIÓN / INSTITUTION:  - , .

 

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[560]

TÍTULO / TITLE:  - Identification of Serum MicroRNA-21 as a Biomarker for Chemosensitivity and Prognosis in Human Osteosarcoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Int Med Res. 2012;40(6):2090-7.

AUTORES / AUTHORS:  - Yuan J; Chen L; Chen X; Sun W; Zhou X

INSTITUCIÓN / INSTITUTION:  - Department of Orthopaedics, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China.

RESUMEN / SUMMARY:  - OBJECTIVE: The aim of this study was to investigate the serum level of microRNA (miR)-21 in patients with osteosarcoma and its correlation with chemosensitivity  and prognosis. METHODS: miR-21 levels in sera from 65 patients with osteosarcoma  and 30 healthy controls were measured by real-time reverse transcription-polymerase chain reaction. Correlations between serum miR-21 and clinicopathological features in patients with osteosarcoma were determined. The prognostic significance of serum miR-21 was assessed using a Cox proportional hazards model. RESULTS: The serum level of miR-21 was significantly higher in patients with osteosarcoma than in control subjects. High serum miR-21 was significantly correlated with advanced Enneking stage and chemotherapeutic resistance. Univariate and multivariate analyses for overall survival showed that upregulation of serum miR-21 was an independent, unfavourable prognostic factor for patients with osteosarcoma (hazard ratio, 2.325). CONCLUSIONS: miR-21 might be a good candidate for a therapeutic target, and a potential biomarker for the prediction of chemotherapeutic sensitivity and prognosis in patients with osteosarcoma.

 

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[561]

TÍTULO / TITLE:  - Oridonin induces apoptosis in gastric cancer through Apaf-1, cytochrome c and caspase-3 signaling pathway.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Gastroenterol. 2012 Dec 28;18(48):7166-74. doi: 10.3748/wjg.v18.i48.7166.

            ●● Enlace al texto completo (gratuito o de pago) 3748/wjg.v18.i48.7166

AUTORES / AUTHORS:  - Sun KW; Ma YY; Guan TP; Xia YJ; Shao CM; Chen LG; Ren YJ; Yao HB; Yang Q; He XJ

INSTITUCIÓN / INSTITUTION:  - Ke-Wang Sun, Qiong Yang, Department of Thyroid and Breast Surgery, Zhejiang Provincial People’s Hospital, Hangzhou 310014, Zhejiang Province, China.

RESUMEN / SUMMARY:  - AIM: To investigate the effect and mechanism of oridonin on the gastric cancer cell line HGC-27 in vitro. METHODS: The inhibitory effect of oridonin on HGC-27 cells was detected using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. After treatment with 10 mug/mL oridonin for 24 h and 48 h, the cells were stained with acridine orange/ethidium bromide. The morphologic changes were observed under an inverted fluorescence microscope. DNA  fragmentation (a hallmark of apoptosis) and lactate dehydrogenase activity were examined using DNA ladder assay and lactate dehydrogenase-release assay. After treated with oridonin (0, 1.25, 2.5, 5 and 10 mug/mL), HGC-27 cells were collected for anexin V-phycoerythrin and 7-amino-actinomycin D double staining and tested by flow cytometric analysis, and oridonin- induced apoptosis in HGC-27 cells was detected. After treatment with oridonin for 24 h, the effects of oridonin on expression of Apaf-1, Bcl-2, Bax, caspase-3 and cytochrome c were also analyzed using reverse-transcript polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: Oridonin significantly inhibited the proliferation of  HGC-27 cells in a dose- and time-dependent manner. The inhibition rates of HGC-27 treated with four different concentrations of oridonin for 24 h (1.25, 2.5, 5 and 10 mug/mL) were 1.78% +/- 0.36%, 4.96% +/- 1.59%, 10.35% +/- 2.76% and 41.6% +/-  4.29%, respectively, which showed a significant difference (P < 0.05). The inhibition rates of HGC-27 treated with oridonin at the four concentrations for 48 h were 14.77% +/- 4.21%, 21.57% +/- 3.75%, 30.31% +/- 4.91% and 61.19% +/- 5.81%, with a significant difference (P < 0.05). The inhibition rates of HGC-27 treated with oridonin for 72 h at the four concentrations were 25.77% +/- 4.85%,  31.86% +/- 3.86%, 48.30% +/- 4.16% and 81.80% +/- 6.72%, with a significant difference (P < 0.05). Cells treated with oridonin showed typical apoptotic features with acridine orange/ethidium bromide staining. After treatment with oridonin, the cells became round, shrank, and developed small buds around the nuclear membrane while forming apoptotic bodies. Lactate dehydrogenase (LDH) release assay showed that after treated with 1.25 mug/mL and 20 mug/mL oridonin for 24 h, LDH release of HGC-27 caused by apoptosis increased from 22.94% +/- 3.8% to 52.68% +/- 2.4% (P < 0.001). However, the change in the release of LDH caused by necrosis was insignificant, suggesting that the major cause of oridonin-induced HGC-27 cell death was apoptosis. Flow cytometric analysis also revealed that oridonin induced significant apoptosis compared with the controls (P < 0.05). And the apoptosis rates of HGC-27 induced by the four different concentrations of oridonin were 5.3% +/- 1.02%, 12.8% +/- 2.53%, 28.5% +/- 4.23%  and 49.6% +/- 3.76%, which were in a dose-dependent manner (P < 0.05). After treatment for 24 h, DNA ladder showed that oridonin induced a significant increase in DNA fragmentation in a dose-dependent manner. RT-PCR revealed that mRNA expression levels were up-regulated compared with the controls in caspase-3  (0.917 +/- 0.103 vs 0.357 +/- 0.019, P < 0.05), cytochrome c (1.429 +/- 0.111 vs  1.002 +/- 0.014, P < 0.05), Apaf-1 (0.688 +/- 0.101 vs 0.242 +/- 0.037, P < 0.05) and Bax (0.856 +/- 0.101 vs 0.278 +/- 0.027, P < 0.05) (P < 0.05), whereas down-regulated in Bcl-2 (0.085 +/- 0.012 vs 0.175 +/- 0.030, P < 0.05). Western blotting analysis also confirmed this result. CONCLUSION: Apoptosis of HGC-27 induced by oridonin may be associated with differential expression of Apaf-1, caspase-3 and cytochrome c, which are highly dependent upon the mitochondrial pathway.

 

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[562]

TÍTULO / TITLE:  - Thrombospondin-1 and pigment epithelium-derived factor enhance responsiveness of  KM12 colon tumor to metronomic cyclophosphamide but have disparate effects on tumor metastasis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2012 Dec 8. pii: S0304-3835(12)00717-3. doi: 10.1016/j.canlet.2012.11.055.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2012.11.055

AUTORES / AUTHORS:  - Jia L; Waxman DJ

INSTITUCIÓN / INSTITUTION:  - Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, United States.

RESUMEN / SUMMARY:  - The anti-tumor activity, metronomic chemotherapy sensitization potential and metastatic effects of the endogenous angiogenesis inhibitors thrombospondin-1 and PEDF were investigated in KM12 colon adenocarcinoma xenografts. Thrombospondin-1  and PEDF decreased KM12 tumor microvessel density, increased macrophage infiltration, and improved responsiveness to metronomic cyclophosphamide (CPA) treatment, but did not activate the anti-tumor innate immunity that metronomic CPA induces in other tumor models. Moreover, thrombospondin-1, but not PEDF, significantly increased KM12 metastasis to the lung, while PEDF augmented the anti-metastatic activity of metronomic CPA. Thus, while thrombospondin-1 and PEDF both increase the KM12 tumor responsiveness to metronomic CPA, they have disparate effects on tumor metastasis.

 

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[563]

TÍTULO / TITLE:  - Prognostic value of interleukin-6 and interleukin-8 in laryngeal squamous cell cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):333. doi: 10.1007/s12032-012-0333-6. Epub 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0333-6

AUTORES / AUTHORS:  - Hao W; Zhu Y; Zhou H

INSTITUCIÓN / INSTITUTION:  - Department of Otolaryngological, Tianjin Medical University General Hospital, Tianjin, 300052, People’s Republic of China.

RESUMEN / SUMMARY:  - The aim of this study was to evaluate serum levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) as prognostic variables in patients with laryngeal squamous  cell cancer. A total of 92 patients with primary diagnosis of laryngeal squamous  cell cancer (LSCC), treated between 2003 and 2005, were included in this evaluation. Preoperative serum levels of IL-6 and IL-8 were measured by enzyme-linked immunosorbent assay methods. Results were compared according to clinical and pathological date criteria. Serum IL-6 and IL-8 levels were significantly higher in patients with LSCC compared to healthy controls (P < 0.0001). Serum IL-6 level was associated with lymph node metastasis (P < 0.001),  T classification (P < 0.001) and clinical stage (P = 0.001). Multivariate analysis indicated that serum IL-6 was an independent predictor of LSCC-specific  progression-free survival (P = 0.049) and overall survival (P = 0.040). Higher serum IL-6 level (IL-6 > 9.7 pg/ml) was associated with a shortened overall survival and progression-free survival (P < 0.05). Our data indicate that serum IL-6 is associated with the development and progression of LSCC. Serum IL-6 may serve as an independent prognostic marker for LSCC patients.

 

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[564]

TÍTULO / TITLE:  - Pharmacokinetics, pharmacodynamics and tolerability of opicapone, a novel catechol-o-methyltransferase inhibitor, in healthy subjects : prediction of slow  enzyme-inhibitor complex dissociation of a short-living and very long-acting inhibitor.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Pharmacokinet. 2013 Feb;52(2):139-51. doi: 10.1007/s40262-012-0024-7.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s40262-012-0024-7

AUTORES / AUTHORS:  - Almeida L; Rocha JF; Falcao A; Nuno Palma P; Loureiro AI; Pinto R; Bonifacio MJ; Wright LC; Nunes T; Soares-da-Silva P

INSTITUCIÓN / INSTITUTION:  - Health Sciences Department, University of Aveiro, Aveiro, Portugal.

RESUMEN / SUMMARY:  - BACKGROUND AND OBJECTIVES: Opicapone is a novel catechol-O-methyltransferase (COMT) inhibitor. The purpose of this study was to evaluate the tolerability, pharmacokinetics (including the effect of food) and pharmacodynamics (effect on COMT activity) following single oral doses of opicapone in young healthy male volunteers. METHODS: Single rising oral doses of opicapone (10, 25, 50, 100, 200, 400, 800 and 1,200 mg) were administered to eight groups of eight subjects per group (two subjects randomized to placebo and six subjects to opicapone), under a double-blind, randomized, placebo-controlled design. In an additional group of 12 subjects, a 50 mg single dose of opicapone was administered on two occasions, once having fasted overnight and once with a high-fat high-calorie meal. RESULTS: Opicapone was well tolerated at all doses tested. The extent of systemic exposure (area under the plasma concentration-time curve and maximum plasma concentration) to opicapone and metabolites increased in an approximately dose-proportional manner and showed a decrease following concomitant ingestion of a high-fat high-calorie meal. The apparent terminal elimination half-life of opicapone was 0.8-3.2 h. Sulphation appeared to be the main metabolic pathway for opicapone, and both opicapone and the main sulphated metabolite are likely excreted by the biliary route. Maximum COMT inhibition by opicapone was dose dependent, ranged from 36.1 % (10 mg) to 100 % (200 mg and above), and reached statistical significance at all doses tested. The long duration of COMT inhibition by opicapone, however, tended to be independent from the dose taken. The observed half-life of opicapone-induced COMT inhibition in human erythrocytes was 61.6 h (standard deviation [SD] = 37.6 h), which reflects an underlying dissociative process with a kinetic rate constant of 3.1 x 10(-6) s(-1) (SD = 1.9 x 10(-6) s(-1)). Such a process compares well to the estimated dissociation rate constant  (k(off)) of the COMT-opicapone molecular complex (k(off) = 1.9 x 10(-6) s(-1)). CONCLUSIONS: Opicapone was well-tolerated and presented dose-proportional kinetics. Opicapone demonstrated marked and sustained inhibition of erythrocyte soluble COMT activity. Based on the observation that the half-life of COMT inhibition is independent of the dose and that it reflects an underlying kinetic  process that is consistent with the k(off) value of the COMT-opicapone complex, we propose that the sustained COMT inhibition, far beyond the observable point of clearance of circulating drug, is due to the long residence time of the reversible complex formed between COMT and opicapone. Globally, these promising results provide a basis for further clinical development of opicapone.

 

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[565]

TÍTULO / TITLE:  - Curcumin and docosahexaenoic acid block insulin-induced colon carcinoma cell proliferation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Prostaglandins Leukot Essent Fatty Acids. 2012 Dec 21. pii: S0952-3278(12)00194-9. doi: 10.1016/j.plefa.2012.11.010.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.plefa.2012.11.010

AUTORES / AUTHORS:  - Fenton JI; McCaskey SJ

INSTITUCIÓN / INSTITUTION:  - Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States; College of Osteopathic Medicine; Michigan State University, East Lansing, MI, United States. Electronic address: imigjeni@msu.edu.

RESUMEN / SUMMARY:  - Diets high in fish and curcumin are associated with a decreased risk of CRC. Insulin resistance and obesity are associated with increased CRC risk and higher  reoccurrence rates. We utilized cell culture to determine if dietary compounds could reduce insulin-induced cell proliferation comparing the response in normal  and metastatic colon epithelial cells. We treated model normal murine colon epithelial cells (YAMC) and adenocarcinoma cells (MC38) with docosahexaenoic acid (DHA) or curcumin alone and then co-treatments of the diet-derived compound and insulin were combined. Cell proliferation was stimulated with insulin (1ug/mL) to model insulin resistance in obesity. Despite the presence of insulin, proliferation was reduced in the MC38 cells treated with 10muM curcumin (p<0.001) and 50muM DHA (p<0.001). Insulin stimulated MAPK and MEK phosphorylation was inhibited by DHA and curcumin in MC38 cancer cells. Here we show that curcumin and DHA can block insulin-induced colon cancer cell proliferation in vitro via a  MEK mediated mechanism.

 

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[566]

TÍTULO / TITLE:  - Erratum to: Inhibition of cancer growth and induction of apoptosis by BGP-13 and  BGP-15, new calcipotriene-derived vitamin D(3) analogs, in-vitro and in-vivo studies.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Invest New Drugs. 2013 Jan 16.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10637-013-9924-0

AUTORES / AUTHORS:  - Berkovich L; Sintov AC; Ben-Shabat S

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacology, Faculty of Health Sciences, Ben-Gurion University of  the Negev, PO Box 653, Beer-Sheva, 84105, Israel.

 

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[567]

TÍTULO / TITLE:  - Inflammation and cancer revisited: An hypothesis on the oncogenic potential of the apoptotic tumor cell.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Autoimmunity. 2013 Jan 16.

            ●● Enlace al texto completo (gratuito o de pago) 3109/08916934.2012.755961

AUTORES / AUTHORS:  - Gregory CD

INSTITUCIÓN / INSTITUTION:  - MRC Centre for Inflammation Research, University of Edinburgh, Queens Medical Research Institute , Edinburgh, EH16 4TJ , UK.

RESUMEN / SUMMARY:  - It is well known that an important property of apoptosis is the prevention of cancer. However, it is becoming increasingly clear that apoptotic cells have the  capacity to activate reparative and regenerative responses, which have the potential to make significant impact on pathological processes underlying autoimmune disease and cancer. Those properties of apoptotic cells that influence their immediate microenvironment are reviewed here in the context of cancer progression and treatment.

 

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[568]

TÍTULO / TITLE:  - Lymphangiogenesis and Prognostic Significance of Vascular Endothelial Growth Factor C in Gastro-oesophageal Junction Adenocarcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Exp Pathol. 2013 Feb;94(1):39-46. doi: 10.1111/iep.12005.

            ●● Enlace al texto completo (gratuito o de pago) 1111/iep.12005

AUTORES / AUTHORS:  - Xie LX; Zhai TT; Yang LP; Yang E; Zhang XH; Chen JY; Zhang H

INSTITUCIÓN / INSTITUTION:  - Cancer Hospital of Medical College, Shantou University, Shantou, Guangdong Province, China.

RESUMEN / SUMMARY:  - Vascular endothelial growth factor C (VEGF-C) is a crucial regulator of the development of lymphatic vessels and is involved in the lymph node metastasis of  cancer. The levels of VEGF-C expression and lymphatic vessel density (LVD) in 128 gastro-oesophageal junction adenocarcinoma (GEJA) tissues were examined by immunohistochemistry and analysed for their association with clinicopathological  features and disease-free survival. We found that 75.0% of tumour samples displayed strong immunoreactivity to VEGF-C. The levels of VEGF-C expression in the tumour tissues were associated with the stages of the clinical tumours and the lymph node metastasis status, but not with the age, gender and the size and type of tumours in the cohort. Similarly, LVD, as evaluated by anti-D2-40 staining, was also associated with the clinical stages of GEJA. The values of LVD were positively correlated with the levels of VEGF-C expression in these samples  (r = 0.3760, P = 0.0001). High levels of VEGF-C expression and high values of LVD were associated with shorter periods of disease-free survival (DFS) in patients with GEJA (P < 0.001). In addition, GEJA at N1 and N2 stages, at T4 stage, chemotherapy after surgery, high levels of VEGF-C expression and lower marginal resection were independent factors for the prognosis of DFS in patients with GEJA. Our data indicate that VEGF-C may promote the lymphangiogenesis and lymphatic metastasis of GEJA and that VEGF-C may be a valuable biomarker for the  diagnosis of lymphatic metastasis and a prognostic factor of the survival of patients with GEJA.

 

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[569]

TÍTULO / TITLE:  - Cytotoxic and Apoptosis-Inducing Activities of 12-O-Acetylazedarachin B from the  Fruits of Melia azedarach in Human Cancer Cell Lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biol Pharm Bull. 2013;36(1):135-9.

AUTORES / AUTHORS:  - Kikuchi T; Pan X; Ishii K; Nakamura Y; Ogihara E; Koike K; Tanaka R; Akihisa T

INSTITUCIÓN / INSTITUTION:  - College of Science and Technology, Nihon University.

RESUMEN / SUMMARY:  - 12-O-Acetylazedarachin B (1), isolated from the fruit extract of Melia azedarach, exhibited potent cytotoxicity against leukemia (HL-60) (IC(50) 0.016 microM) and  stomach (AZ521) (IC(50) 0.035 microM) cancer cell lines. Upon assessing the apoptosis-inducing activity in HL-60 cells, compound 1 exhibited induction of apoptosis detected by the observation of membrane phospholipid exposure and DNA fragmentation in flow cytometry. Western blot analysis showed that 1 markedly reduced the levels of procaspases-3, 8, and 9, while being increased the levels of cleaved caspases-3, 8, and 9. In addition, compound 1 increased significantly  Bax/Bcl-2 ratio. These results suggested that 1 induced apoptotic cell death in HL-60 via both mitochondrial and death receptor-mediated pathways. Therefore, compound 1 may be promising lead compound for developing an effective drug for treatment of leukemia. Flow cytometric analysis suggested that the cytotoxicity of 1 against AZ521 is due to inducing apoptosis as well as necrosis with the latter predominated.

 

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[570]

TÍTULO / TITLE:  - Antitumor and anti-angiogenesis effects of thymoquinone on osteosarcoma through the NF-kappaB pathway.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):571-8. doi: 10.3892/or.2012.2165. Epub 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2165

AUTORES / AUTHORS:  - Peng L; Liu A; Shen Y; Xu HZ; Yang SZ; Ying XZ; Liao W; Liu HX; Lin ZQ; Chen QY; Cheng SW; Shen WD

INSTITUCIÓN / INSTITUTION:  - Department of Orthopaedic Surgery, The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang 325000, PR China.

RESUMEN / SUMMARY:  - Thymoquinone (TQ), the predominant bioactive constituent derived from the medicinal spice Nigella sativa (also known as black cumin), has been applied for  medical purposes for more than 2,000 years. Recent studies reported that thymoquinone exhibited inhibitory effects on the cell proliferation of several cancer cell lines. This study was performed to investigate the antitumor and anti-angiogenic effects of thymoquinone on osteosarcoma in vitro and in vivo. Our results showed that thymoquinone induced a higher percentage of growth inhibition and apoptosis in the human osteosarcoma cell line SaOS-2 compared to that of control, and thymoquinone significantly blocked human umbilical vein endothelial  cell (HUVEC) tube formation in a dose-dependent manner. To investigate the possible mechanisms involved in these events, we performed electrophoretic mobility shift assay (EMSA) and western blot analysis, and found that thymoquinone significantly downregulated NF-kappaB DNA-binding activity, XIAP, survivin and VEGF in SaOS-2 cells. Moreover, the expression of cleaved caspase-3  and Smac were upregulated in SaOS-2 cells after treatment with thymoquinone. In addition to these in vitro results, we also found that thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing NF-kappaB and its regulated molecules. Collectively, our results demonstrate that thymoquinone effectively inhibits tumor growth and angiogenesis both in vitro and in vivo. Moreover, inhibition of NF-kappaB and downstream effector molecules is a possible underlying mechanism of the antitumor and anti-angiogenic activity of thymoquinone in osteosarcoma.

 

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[571]

TÍTULO / TITLE:  - Pathological implication and function of Bcl2-inhibitor of transcription in ovarian serous papillary adenocarcinomas.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Neoplasma. 2013;60(2):143-50.

AUTORES / AUTHORS:  - Hua W; Miao S; Zou W; Yang H; Chen BL

RESUMEN / SUMMARY:  - The Bit-1 protein appears to be apart of the integrin-specific signaling pathway  involved into anoikis. When Bit1 is released from the mitochondria into the cytoplasm it can elicit caspase-independent apoptosis. The expression of Bit1 in  78 serous papillary adenocarcinomas and 78 normal epithelial ovarian tissue specimens was analyzed by immunohistochemistry. We also investigate Bit1 function by transfection. Bit1 was expressed in 100% and 33.3% of ovarian cancers and normal epithelial tissues, respectively, and its expression was significantly correlated with histologic grade and overall survival. However, Bit1 expression was not associated with age. We also confirmed that Bit1 overexpression in cytosol of Caov-3 cells induced apoptosis. Bit1 may be auseful pathological marker and aprognostic marker for serous papillary adenocarcinomas outcome. Its pro-apoptotic property also makes it apotential gene medicine for ovarian cancers therapy. Keywords: Bit1 (Bcl2-inhibitor of transcription), serous papillary adenocarcinomas, Apoptosis, Anoikis.

 

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[572]

TÍTULO / TITLE:  - Antitumour effect of sesquiterpene (+)-chabranol on four human cancer cell lines  by inducing apoptosis and autophagy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Int Med Res. 2012;40(5):1644-53.

AUTORES / AUTHORS:  - Liu XY; Lv TH; Xie XD; Li J; Su G; Wu H

INSTITUCIÓN / INSTITUTION:  - School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province, China.

RESUMEN / SUMMARY:  - OBJECTIVE: To investigate the effects and mechanisms of sesquiterpene (+)-chabranol on proliferation of a panel of four human tumour cell lines (BGC-823, SGC-7901, SSMC-7721 and HepG2). METHODS: Cell viability was assessed using a standard methyltetrazolium assay; cell-cycle analysis of BGC-823 cells was performed by flow cytometry. Transmission electron microscopy (TEM) was used  to examine the ultrastructure of BGC-823 cells exposed to (+)-chabranol. Apoptosis was investigated by evaluating DNA laddering, using gel electrophoresis. RESULTS: (+)-Chabranol had a marked time- and concentration-dependent inhibitory effect on BGC-823 cell proliferation. The effect was less marked in SGC-7901, SSMC-7721 and HepG2 cells. Exposure of BGC-823 cells to (+)-chabranol arrested the cell cycle at G(1). Evidence of apoptosis and autophagy was observed by TEM; DNA laddering in BGC-823 cells supported the presence of apoptosis. CONCLUSIONS: This study suggested that (+)-chabranol has antitumour activity against BGC-823 cells, and may exert its action by inhibition of proliferation and induction of apoptosis and autophagy. With further development, (+)-chabranol may represent a potential novel treatment for poorly differentiated gastric cancer.

 

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[573]

TÍTULO / TITLE:  - Melatonin is involved in the apoptosis and necrosis of pancreatic cancer cell line SW-1990 via modulating of Bcl-2/Bax balance.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biomed Pharmacother. 2012 Nov 15. pii: S0753-3322(12)00097-2. doi: 10.1016/j.biopha.2012.10.005.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biopha.2012.10.005

AUTORES / AUTHORS:  - Xu C; Wu A; Zhu H; Fang H; Xu L; Ye J; Shen J

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Canglang District, Suzhou 215006, Jiangsu Province, PR China.

RESUMEN / SUMMARY:  - Melatonin influences a number of physiological processes and is believed to play  an antitumoral role in several types of cancers, but its impact on pancreatic cancer is not fully clarified. The growth inhibitory effect of melatonin on pancreatic cancer cell line SW-1990 was detected in vitro and in vivo. Annexin V/PI assay was applied to detect apoptosis and necrosis in SW-1990 cells. Changes of Bcl-2 and Bax expression were investigated by RT-PCR and Western blot. An obvious growth inhibition was found in SW-1990 after melatonin or combined treatment with melatonin and gemicitabine through both apoptosis and necrosis in  vitro, and also found in transplanted tumors in nude mice. RT-PCR and Western blot showed that Bcl-2 expression was downregulated, while Bax expression was upregulated, after melatonin treatment. Melatonin may be a pro-apoptotic and pro-necrotic agent for pancreatic cancer cells via its modulation of Bcl-2/Bax balance.

 

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[574]

TÍTULO / TITLE:  - The Prevalence and Importance of Crypt Apoptosis, Focal Active Cryptitis, and Neutrophilic Infiltrate of the Lamina Propria in Colorectal Adenomas.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Surg Pathol. 2013 Jan 27.

            ●● Enlace al texto completo (gratuito o de pago) 1177/1066896912474339

AUTORES / AUTHORS:  - Abdullgaffar B; Hotait H; Gopal P; Al-Awadhi S; Bamakhrama K; Elfaki B

RESUMEN / SUMMARY:  - Even though apoptotic bodies (ABs) are frequent in colorectal adenomas, their relevance has been covered only in a few studies. Focal active cryptitis (FAC) is a well-known manifestation of several etiologies; however, its prevalence and significance in colonic adenomas were not scrutinized. Likewise, whether the neutrophilic infiltrate of the lamina propria (LP) in colonic adenomas has a clinical or pathologic significance was not previously studied. We attempted to investigate the prevalence and importance of ABs in the cryptal epithelium and of neutrophils in the form of FAC and in the form of LP infiltrates in conventional  colorectal adenomas. We conducted a retrospective review study over a 6-year period. We collected 223 conventional adenomas from 156 patients. We studied the  interrelationship between these 3 histologic parameters and their potential association with other clinical and pathologic variables. Comparison controls included normal colonic mucosa, hyperplastic polyps, serrated adenomas, and flat  adenomas. We found 91 (41%) adenomas to have crypt apoptosis, 40 (18%) to have FAC, and 69 (31%) to have neutrophilic infiltrate of the LP. We found ABs to be more frequent in high-grade adenomas. LP neutrophilic infiltrate was significantly associated with high-grade adenomas and in high-grade adenomas with invasive foci. In contrast, FAC was not associated with high-grade adenomas and was secondary to bowel preparations and drugs. Crypt apoptosis and LP neutrophils might have a potential prognostic value in predicting the biologic behavior of colonic adenomas. FAC in adenomas is a nonspecific finding of no prognostic significance and is related to external stimuli.

 

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[575]

TÍTULO / TITLE:  - MicroRNA-99a/100 promotes apoptosis by targeting mTOR in human esophageal squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):411. doi: 10.1007/s12032-012-0411-9. Epub 2013 Jan 5.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0411-9

AUTORES / AUTHORS:  - Sun J; Chen Z; Tan X; Zhou F; Tan F; Gao Y; Sun N; Xu X; Shao K; He J

INSTITUCIÓN / INSTITUTION:  - Department of Thoracic Surgery, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing, 100021, People’s Republic of China.

RESUMEN / SUMMARY:  - Recently, microRNA-99 family members, such as miR-99a/b and miR-100, have been reported to exhibit abnormal expression in various malignant tumors, but their functions in carcinomas are controversial. In this study, we focused on miR-99a and miR-100, which were determined to be universally downregulated in esophageal  squamous cell carcinoma, and investigated their functions and potential mechanisms of action. The downregulation of miR-99a/100 was validated by qRT-PCR  in 101 ESCC surgical tissue samples and in 3 ESCC cell lines. The overexpression  of miR-99a and miR-100 via the transient transfection of the corresponding precursor molecules inhibited cell proliferation by inducing apoptosis in the ESCC cell lines. To investigate the molecular mechanism of miR-99a/100-induced apoptosis, luciferase reporter assays and Western blots were performed to demonstrate that the overexpression of miR-99a/100 suppressed the expression of mTOR by directly targeting its 3’UTR in a post-transcriptional manner. Clinically, the decreased expression of miR-99a/100 was associated with worse overall survival in ESCC patients. In conclusion, these results indicated that miR-99a and miR-100 inhibited cell proliferation by suppressing mTOR in ESCC cell lines, and therefore, the miR-99a/100-mTOR signaling pathway is a potential therapeutic target for inducing apoptosis to combat ESCC.

 

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[576]

TÍTULO / TITLE:  - Protective effects of ADAM8 against cisplatin-mediated apoptosis in non-small-cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Biol Int. 2013 Jan;37(1):47-53. doi: 10.1002/cbin.10011. Epub 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cbin.10011

AUTORES / AUTHORS:  - Zhang W; Wan M; Ma L; Liu X; He J

INSTITUCIÓN / INSTITUTION:  - Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangzhou  Medical College, State Key Laboratory of Respiratory Disease, Guangzhou 510120, China.

RESUMEN / SUMMARY:  - A disintegrin, metalloproteinase 8 (ADAM8), is overexpressed in the vast majority of lung cancers and can be a diagnostic marker of lung cancer. We have investigated the effect of ADAM8 on the cisplatin resistance in non-small-cell lung cancer (NSCLC) cell lines. Stable cell lines overexpressing ADAM8 in A549 and H460 cells were generated, both of which have low endogenous ADAM8. Ectopic expression of ADAM8 rendered cells more resistant to cisplatin-induced toxicity,  increasing the half maximal inhibitory concentration (IC(50) ) values by 1.85-fold in A549 cells and 3.91-fold in H460 cells relative to mock-transfected  cells. Moreover, silencing of ADAM8 in H647 cells with high endogenous level of ADAM8 sensitised them to cisplatin-induced toxicity, with a lower IC(50) value of 11.2 microM relative to an IC(50) of 25.3 microM in mock-transfected cells. Moreover, knockdown of ADAM8 caused a significant increase in cisplatin-induced apoptosis assessed by annexin-V/propidium iodide double staining, accompanying with enhanced cleavage of caspase-3 and poly(ADP-ribose) polymerase. Western blot analysis showed that a greater amount of phosphorylated signal transducer and activator of transcription 3 (STAT3) in ADAM8-overexpressing A549 cells compared  to parental or mock-transfected cells. STAT3 silencing increased the susceptibility of ADAM8-overexpressing A549 cells to cisplatin. Both Bcl-2 and Mcl-1 in ADAM8-overexpressing A549 cells were profoundly diminished by STAT3 knockdown. Thus, ADAM8 is implicated in cisplatin resistance of NSCLC cells through activation of the STAT3 signalling pathway, and thus represents a potential therapeutic target in this malignancy.

 

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[577]

TÍTULO / TITLE:  - Targeting RET to induce medullary thyroid cancer cell apoptosis: an antagonistic  interplay between PI3K/Akt and p38MAPK/caspase-8 pathways.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Apoptosis. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10495-013-0803-0

AUTORES / AUTHORS:  - Mazumdar M; Adhikary A; Chakraborty S; Mukherjee S; Manna A; Saha S; Mohanty S; Dutta A; Bhattacharjee P; Ray P; Chattopadhyay S; Banerjee S; Chakraborty J; Ray AK; Sa G; Das T

INSTITUCIÓN / INSTITUTION:  - Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Road, Scheme VII M, Kolkata, West Bengal, 700 054, India.

RESUMEN / SUMMARY:  - Mutations in REarranged during Transfection (RET) receptor tyrosine, followed by  the oncogenic activation of RET kinase is responsible for the development of medullary thyroid carcinoma (MTC) that responds poorly to conventional chemotherapy. Targeting RET, therefore, might be useful in tailoring surveillance of MTC patients. Here we showed that theaflavins, the bioactive components of black tea, successfully induced apoptosis in human MTC cell line, TT, by inversely modulating two molecular pathways: (i) stalling PI3K/Akt/Bad pathway that resulted in mitochondrial transmembrane potential (MTP) loss, cytochrome-c release and activation of the executioner caspases-9 and -3, and (ii) upholding p38MAPK/caspase-8/caspase-3 pathway via inhibition of Ras/Raf/ERK. Over-expression of either constitutively active myristoylated-Akt-cDNA (Myr-Akt-cDNA) or dominant-negative-caspase-8-cDNA (Dn-caspase-8-cDNA) partially  blocked theaflavin-induced apoptosis, while co-transfection of Myr-Akt-cDNA and Dn-caspase-8-cDNA completely eradicated the effect of theaflavins thereby negating the possibility of existence of other pathways. A search for the upstream signaling revealed that theaflavin-induced disruption of lipid raft caused interference in anchorage of RET in lipid raft that in turn stalled phosphorylation of Ras and PI3Kinase. In such anti-survival cellular micro-environment, pro-apoptotic signals were triggered to culminate into programmed death of MTC cell. These findings not only unveil a hitherto unexplained mechanism underlying theaflavin-induced MTC death, but also validate  RET as a promising and potential target for MTC therapy.

 

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[578]

TÍTULO / TITLE:  - IL28B GENOTYPE IS NOT USEFUL FOR PREDICTING TREATMENT OUTCOME IN ASIAN CHRONIC HEPATITIS B PATIENTS TREATED WITH PEGYLATED-INTERFERON-alpha

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Gastroenterol Hepatol. 2013 Jan 9. doi: 10.1111/jgh.12110.

            ●● Enlace al texto completo (gratuito o de pago) 1111/jgh.12110

AUTORES / AUTHORS:  - Holmes JA; Nguyen T; Ratnam D; Heerasing NM; Tehan JV; Bonanzinga S; Dev A; Bell S; Pianko S; Chen R; Visvanathan K; Hammond R; Iser D; Rusli F; Sievert W; Desmond PV; Bowden DS; Thompson AJ

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology, St Vincent’s Hospital; University of Melbourne, Melbourne, Australia.

RESUMEN / SUMMARY:  - BACKGROUND AND AIM: IL28B genotype predicts response to pegylated-interferon (peg-IFN)-based therapy in chronic hepatitis C. However, the utility of IL28B genotyping in chronic hepatitis B (CHB) cohorts treated with peg-IFN is unclear.  We investigated whether IL28B genotype is associated with peg-IFN treatment outcomes in a predominantly Asian CHB cohort. METHODS: This was a retrospective analysis of CHB patients treated with 48-weeks of peg-IFN monotherapy. IL28B genotype (rs12979860) was determined (TaqMan allelic discrimination kit). Baseline HBV DNA, ALT, and liver histology were available. The primary endpoints  were HBeAg seroconversion with HBV DNA <2,000 IU/mL 24-weeks post-therapy (HBeAg-positive patients), and HBV DNA <2,000 IU/mL 24-weeks after peg-IFN (HBeAg-negative patients). We analysed the association between IL28B genotype and peg-IFN outcomes. RESULTS: IL28B genotype was determined for 96 patients. 88% were Asian, 62% were HBeAg-positive and 13% were METAVIR stage F3-4. Median follow-up time was 39.3 months. The majority of patients carried the CC IL28B genotype (84%). IL28B genotype did not differ according to HBeAg status. The primary endpoints were achieved in 27% of HBeAg-positive and 61% of HBeAg-negative patients. There was no association between IL28B genotype and the  primary endpoint in either group. Furthermore, there was no difference in HBeAg loss alone, HBsAg loss, ALT normalisation or on-treatment HBV DNA levels according to IL28B genotype. CONCLUSIONS: In the context of a small possible effect size, and high frequency in Asian populations, IL28B genotyping is likely  to have, at best, limited clinical utility for predicting peg-IFN treatment outcome for CHB patients in the Asian-Pacific region.

 

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[579]

TÍTULO / TITLE:  - Characteristics of sequential targeting of brain glioma for transferrin-modified  cisplatin liposome.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Pharm. 2013 Jan 21. pii: S0378-5173(13)00052-5. doi: 10.1016/j.ijpharm.2013.01.025.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ijpharm.2013.01.025

AUTORES / AUTHORS:  - Lv Q; Li LM; Han M; Tang XJ; Yao JN; Ying XY; Li FZ; Gao JQ

INSTITUCIÓN / INSTITUTION:  - Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, P.R.China; College of Pharmaceutical Science, Zhejiang Chinese Medical University, China.

RESUMEN / SUMMARY:  - Methods on how to improve the sequential targeting of glioma subsequent to passing of drug through the blood-brain barrier (BBB) have been occasionally reported. However, the characteristics involved are poorly understood. In the present study, cisplatin (Cis) liposome (lipo) was modified with transferrin(Tf)  to investigate the characteristics of potential sequential targeting to glioma. In bEnd3/C6 co-culture BBB models, higher transport efficiency across the BBB and cytotoxicity in basal C6 cells induced by Cis-lipo(Tf) than Cis-lipo and Cis-solution, suggest its sequential targeting effect. Interestingly, similar liposomal morphology as that of donor compartment was first demonstrated in the receptor solution of BBB models. Meanwhile, a greater acquisition in the lysosome of bEnd3, distribution sequentially into the nucleus of C6 cells were found for the Cis-lipo(Tf). Pre-incubation of chlorpromazine and Tf inhibited this process, indicating that a clathrin-dependent endocytosis is involved in the transport of  Cis-lipo(Tf) across the BBB (Graphical Abstract Fig. 8).

 

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[580]

TÍTULO / TITLE:  - Degarelix versus Goserelin (+ Antiandrogen Flare Protection) in the Relief of Lower Urinary Tract Symptoms Secondary to Prostate Cancer: Results from a Phase IIIb Study (NCT00831233).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Urol Int. 2012 Dec 15.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000345423

AUTORES / AUTHORS:  - Anderson J; Al-Ali G; Wirth M; Gual JB; Gomez Veiga F; Colli E; van der Meulen E; Persson BE

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Royal Hallamshire Hospital, Sheffield, UK.

RESUMEN / SUMMARY:  - Introduction: No studies to date have assessed the efficacy/tolerability of degarelix in the relief of lower urinary tract symptoms (LUTS) secondary to prostate cancer (PrCa). Methods: Patients were randomised to degarelix 240/80 mg  or goserelin 3.6 mg + bicalutamide flare protection (G+B); both treatments were administered for 3 months. The primary endpoint was change in International Prostate Symptom Score (IPSS) at week 12 compared with baseline. Results: This study was stopped early due to recruitment difficulties. 40 patients received treatment (degarelix n = 27; G+B n = 13); most had locally advanced disease and were highly symptomatic. Degarelix was non-inferior to G+B in reducing IPSS at week 12 in the full analysis set (p = 0.20); the significantly larger IPSS reduction in the per-protocol analysis (p = 0.04) was suggestive of superior reductions with degarelix. Significantly more degarelix patients had improved quality of life (IPSS question) at week 12 (85 vs. 46%; p = 0.01). Mean prostate  size reductions at week 12 were 42 versus 25% for patients receiving degarelix versus G+B, respectively (p = 0.04; post hoc analysis). Most adverse events were  mild/moderate; more degarelix patients experienced injection site reactions whereas more G+B patients had urinary tract infections/cystitis. Conclusion: In 40 men with predominantly locally advanced PrCa and highly symptomatic LUTS, degarelix was at least non-inferior to G+B in reducing IPSS at week 12.

 

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[581]

TÍTULO / TITLE:  - Targeting the apoptosis pathway in prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer J. 2013 Jan;19(1):79-89. doi: 10.1097/PPO.0b013e3182801cf7.

            ●● Enlace al texto completo (gratuito o de pago) 1097/PPO.0b013e3182801cf7

AUTORES / AUTHORS:  - Zielinski RR; Eigl BJ; Chi KN

INSTITUCIÓN / INSTITUTION:  - From the BC Cancer Agency, Vancouver, British Columbia, Canada.

RESUMEN / SUMMARY:  - ABSTRACT: Important inroads have been made in the understanding and treatment of  metastatic prostate cancer in recent years. However, the need for agents targeting novel pathways remains ever present. One such area with promise is through apoptosis or programmed cell death. Many perturbations within the apoptotic process have been associated with treatment resistance and progression  in castration-resistant prostate cancer; thus, therapeutic potential exists with  agents that can restore an effective apoptotic response to cellular stressors. This article focuses on agents in clinical development targeting apoptosis through the intrinsic and extrinsic pathways. We review the current status of agents that intervene at the Bcl2 checkpoints, humanized antibodies to death receptors, agents that target the inhibitors of apoptosis proteins, mimetics of small mitochondria-derived activator of caspases, and antisense therapies targeting cytoprotective chaperones. Although single-agent activity has been demonstrated with some of these agents, the clinical development path forward will see them coupled with standard hormonal therapy and chemotherapy. OGX-011 (custirsen), which inhibits expression of the cytoprotective chaperone protein clusterin, is the most mature of these agents and is being tested in combination  with chemotherapy in phase III clinical trials for castration-resistant prostate  cancer, and results are eagerly awaited.

 

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[582]

TÍTULO / TITLE:  - Crucial Role of CD4+CD 25+ FOXP3+ T Regulatory Cell, Interferon-gamma and Interleukin-16 in Malignant and Tuberculous Pleural Effusions.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Immunol Invest. 2013;42(2):122-36. doi: 10.3109/08820139.2012.736116. Epub 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 3109/08820139.2012.736116

AUTORES / AUTHORS:  - Ibrahim L; Salah M; Rahman AA; Zeidan A; Ragb M

INSTITUCIÓN / INSTITUTION:  - Mansoura Faculty of Medicine, Clinical Pathology , Mansoura , Egypt.

RESUMEN / SUMMARY:  - The differential diagnosis between malignant and tuberculous exudative pleural effusions is an important clinical problem. The aim of current study is to evaluate the frequencies of T-regulatory cells (Treg) on the basis of distinct phenotypes in the differential diagnosis between malignant and tuberculous pleural effusion. In addition, to evaluate Interferon-gamma (IFN- gamma) and interleukin-16 (IL-16) levels and their correlation to Treg cells in malignant and tuberculous pleural effusions. Sixty patients with pleural effusion (26 tuberculous and 34 malignant) and 20 healthy controls were included in the study. Pleural fluid and peripheral blood were assessed for frequencies of T regs, IL-16, and IFN-gamma. Pleural effusions from both tuberculous and malignant groups represented significantly higher levels (more in TB) for the following cell populations than peripheral blood: total lymphocytes, CD3+lymphocyte, CD4+CD25+lymphocyte and Treg (CD4+ CD25+FoxP3+). Levels of IL-16 and IFN-gamma in tuberculous group were significantly higher than that in malignant group. Regulatory T cells, INF-gamma and IL-16 are new important tools for differentiation between tuberculous and malignant pleural effusion.

 

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[583]

TÍTULO / TITLE:  - Erratum to: The role of pharmacogenomics in metastatic renal cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Metastasis Rev. 2012 Dec 9.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10555-012-9416-2

AUTORES / AUTHORS:  - Castellano D; Virizuela JA; Cruz J; Sepulveda JM; Saez MI; Paz-Ares L

INSTITUCIÓN / INSTITUTION:  - Hospital Universitario 12 de Octubre, Madrid, España.

 

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[584]

TÍTULO / TITLE:  - Effects of HSP27 Chaperone on THP-1 Tumor Cell Apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Bull Exp Biol Med. 2012 Oct;154(1):77-9.

AUTORES / AUTHORS:  - Kaigorodova EV; Ryazantseva NV; Novitskii VV; Maroshkina AN; Belkina MV

INSTITUCIÓN / INSTITUTION:  - Department of Fundamental Clinical Medicine, Research and Educational Center of Molecular Medicine, Department of Pathophysiology, Siberian State Medical University, the Ministry of Health and Social Development of the Russian Federation, Tomsk, Russia. zlobinae@mail.ru.

RESUMEN / SUMMARY:  - The role of Hsp27 (heat shock protein 27) chaperone in regulation of THP-1 tumor  cell apoptosis was studied. Realization of tumor cell apoptosis under conditions  of in vitro culturing with Hsp27 specific inhibitor (KRIBB3) was evaluated by fluorescent microscopy with FITC-labeled annexin V and propidium iodide. Measurements of Bcl-2 family proteins (Bcl-2, Bax, Bad) in tumor cells incubated  with Hsp27 inhibitor were carried out by Western blotting. Chaperone Hsp27 acted  as apoptosis inhibitor in THP-1 tumor cells modulating the proportion of antiapoptotic (Bcl-2) and proapoptotic (Bax and Bad) proteins.

 

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[585]

TÍTULO / TITLE:  - New developments in biomarkers for melanoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Opin Oncol. 2013 Jan 17.

            ●● Enlace al texto completo (gratuito o de pago) 1097/CCO.0b013e32835dafdf

AUTORES / AUTHORS:  - Griewank KG; Ugurel S; Schadendorf D; Paschen A

INSTITUCIÓN / INSTITUTION:  - aDepartment of Dermatology, University Hospital Essen, Essen bDepartment of Dermatology, Julius-Maximilian-University Wurzburg, Wurzburg, Germany.

RESUMEN / SUMMARY:  - PURPOSE OF REVIEW: Therapy of malignant melanoma recently experienced remarkable  advances with the introduction of two treatment regimens, gene mutation-based therapies with signaling pathway inhibitors (kinase inhibitors) and treatments with immune modulators. Both strategies prolong patients’ survival but still have specific limitations, demanding the identification of additional genetic and immunological biomarkers as predictors of treatment response and prognosis. New developments in that field are summarized in this review. RECENT FINDINGS: Activating oncogene mutations are important melanoma biomarkers. They predict responsiveness to kinase inhibitor therapies and have therapy independent prognostic relevance. Epigenetic alterations (DNA methylation, chromatin remodeling, and noncoding RNA) in melanoma are emerging as potentially valuable biomarkers. With the successful introduction of immunotherapies for melanoma, interest in immunological biomarkers has grown. Tumor-reactive cytotoxic T cells  from patients’ peripheral blood were recently proposed to predict prognosis and response to immunotherapy. A superior immune profile assessment could be achieved by combining a detailed characterization of a tumor’s immune cell infiltrate with its (immune) gene signature. SUMMARY: Genetic melanoma markers have already become clinically relevant. We expect both their role and that of immunological biomarkers to increase significantly in the next few years, enabling personalized therapy with optimal treatment selection for individual tumors.

 

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[586]

TÍTULO / TITLE:  - Neoadjuvant Androgen Deprivation Therapy for Prostate Volume Reduction, Lower Urinary Tract Symptom Relief and Quality of Life Improvement in Men with Intermediate- to High-risk Prostate Cancer: A Randomised Non-inferiority Trial of Degarelix versus Goserelin plus Bicalutamide.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Oncol (R Coll Radiol). 2012 Dec 17. pii: S0936-6555(12)00342-1. doi: 10.1016/j.clon.2012.09.010.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clon.2012.09.010

AUTORES / AUTHORS:  - Mason M; Maldonado Pijoan X; Steidle C; Guerif S; Wiegel T; van der Meulen E; Bergqvist PB; Khoo V

INSTITUCIÓN / INSTITUTION:  - Cardiff University, Section of Oncology & Palliative Medicine, Velindre Hospital, Cardiff, UK. Electronic address: MasonMD@cf.ac.uk.

RESUMEN / SUMMARY:  - AIMS: The treatment of intermediate- to high-risk prostate cancer with radical radiotherapy is usually in combination with neoadjuvant androgen deprivation therapy. The aim of the present trial was to investigate whether degarelix achieves comparable efficacy with that of goserelin plus bicalutamide as neoadjuvant therapy before radiotherapy. MATERIALS AND METHODS: The study was a randomised, parallel-arm, active-controlled, open-label trial in 244 men with a UICC prostate cancer TNM category T2b-T4, N0, M0, Gleason score >/=7, or prostate-specific antigen >/=10 ng/ml and a total prostate volume >30 ml, who were scheduled to undergo radical radiotherapy and in whom neoadjuvant androgen deprivation therapy was indicated. Eligible patients received treatment with either monthly degarelix (240/80 mg) or goserelin (3.6 mg) for 12 weeks, the latter patients also receiving bicalutamide (50 mg) for 17 days initially. The primary efficacy measure was the mean percentage reduction in total prostate volume from baseline at week 12 measured by transrectal ultrasound. The severity  and relief of lower urinary tract symptoms were assessed by the International Prostate Symptom Score questionnaire. Quality of life was assessed by the eighth  question of the International Prostate Symptom Score. About 50% of the patients had moderate to severe lower urinary tract symptoms at baseline. RESULTS: The total prostate volume decreased significantly from baseline to week 12 in both treatment groups, reaching -36.0 +/- 14.5% in degarelix-treated patients and -35.3 +/- 16.7% in goserelin-treated patients (adjusted difference: -0.3%; 95% confidence interval: -4.74; 4.14%). At the end of the therapy, more degarelix- than goserelin-treated patients reported International Prostate Symptom Score decreases of >/=3 points (37% versus 27%, P = 0.21). In addition, in patients with a baseline International Prostate Symptom Score of >/=13, the magnitude of the decrease was larger in degarelix- (n = 53) versus goserelin-treated patients  (n = 17) (6.04 versus 3.41, P = 0.06). CONCLUSIONS: The efficacy of degarelix in  terms of prostate shrinkage is non-inferior to that of goserelin plus bicalutamide. The added benefits of degarelix in terms of more pronounced lower urinary tract symptom relief in symptomatic patients could be the reflection of differences in the direct effects on extra-pituitary receptors in the lower urinary tract [Clinicaltrials.gov ID: NCT00833248].

 

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[587]

TÍTULO / TITLE:  - Are Tyrosine Kinase Inhibitors Still Active in Patients With Metastatic Renal Cell Carcinoma Previously Treated With a Tyrosine Kinase Inhibitor and Everolimus? Experience of 36 Patients Treated in France in the RECORD-1 Trial.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Genitourin Cancer. 2013 Jan 16. pii: S1558-7673(12)00240-6. doi: 10.1016/j.clgc.2012.12.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clgc.2012.12.001

AUTORES / AUTHORS:  - Blesius A; Beuselinck B; Chevreau C; Ravaud A; Rolland F; Oudard S; Escudier B

INSTITUCIÓN / INSTITUTION:  - Department of Medicine, Institut Gustave Roussy, Villejuif, France.

RESUMEN / SUMMARY:  - BACKGROUND: Because the response to treatment is limited, patients with metastatic renal cell carcinoma (mRCC) typically receive multiple treatments. Guidelines recommend everolimus for patients previously treated with tyrosine kinase inhibitors (TKI) sunitinib or sorafenib. This study evaluated the efficacy of TKI re-treatment in patients with disease progression after a TKI-everolimus sequence. PATIENTS AND METHODS: Data were reviewed for patients enrolled in RECORD-1 (Renal Cell Cancer Treatment With Oral RAD001 Given Daily) at French sites. Response, progression-free survival (PFS), and overall survival were evaluated in patients treated with a TKI-everolimus-TKI sequence. RESULTS: Thirty-six patients received a TKI after everolimus: sunitinib in 17 patients, sorafenib in 15, and dovitinib (TKI258) in 4. The response rate with TKI re-treatment was 8%, and the disease-control rate (response plus stable disease)  was 75%. The median PFS with each component of the TKI-everolimus-TKI sequence was 10.7 months (95% CI, 1.8-28.5 months), 8.9 months (95% CI, 1.7-34.6 months),  and 8.2 months (95% CI, 5.2-11.9 months), respectively. The median overall survival from the start of everolimus was 29.1 months (95% CI 21.1 to not reached months), which suggests a benefit in using TKI in this setting. CONCLUSIONS: Administration of a TKI-everolimus-TKI sequence may be associated with clinical benefit and should be prospectively investigated.

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[588]

TÍTULO / TITLE:  - Quinacrine-mediated autophagy and apoptosis in colon cancer cells is through a p53- and p21-dependent mechanism.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Res. 2012;20(2-3):81-91.

AUTORES / AUTHORS:  - Mohapatra P; Preet R; Das D; Satapathy SR; Choudhuri T; Wyatt MD; Kundu CN

INSTITUCIÓN / INSTITUTION:  - KIIT School of Biotechnology, KIIT University, Orissa, India.

RESUMEN / SUMMARY:  - We previously showed that quinacrine (QC), a small molecule antimalarial agent, also presented anticancer activity in breast cancer cells through activation of p53, p21, and inhibition of topoisomerase activity. Here we have systematically studied the detailed cell death mechanism of this drug using three colon cancer cell lines (HCT-116 parental, isogenic HCT-116 p53-/-, and HCT-116 p21-/- sublines). QC caused a dose-dependent reduction in cell viability in all three cell lines. However, the parental cells were more susceptible to QC-mediated cell death, suggesting that p53- and p21-dependent processes were involved. QC-mediated cell death was measured with the following endpoints: the Bax/Bcl-xL  ratio, cleaved PARP, apoptotic nuclei visualized by DAPI staining, and COMET formation. In addition, markers of autophagy were measured. Acridine orange staining revealed increased accumulation of autophagic vacuoles (AVs) after QC treatment in a dose-dependent manner in parental cells, and decreased staining in isogenic HCT-116 p53-/- and HCT-116 p21-/- cells. Immunofluorescence of LC3B was  significantly lowered in QC-treated cells lacking p53 or p21, compared to the parental cells. Interestingly, the expression of the autophagy marker LC3B-II after exposure to QC was decreased in either p53 or p21 null cells compared to parental cells. After deletion of p21 in HCT-116 p53-/- cells, no change in LC3B-II expression was noted following QC treatment. Collectively, the results suggest that QC-mediated autophagy and apoptosis dependent on p53 and p21.

 

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[589]

TÍTULO / TITLE:  - PTEN enhances the sensitivity of human hepatocellular carcinoma cells to sorafenib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Res. 2012;20(2-3):113-21.

AUTORES / AUTHORS:  - Ruan ZP; Xu R; Lv Y; Tian T; Wang WJ; Guo H; Nan KJ

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, First Affiliated Hospital, Medical College of Xi’an Jiaotong University, Xi’an, P.R. China.

RESUMEN / SUMMARY:  - Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several  genomic alterations and ranks as the third highest cause of cancer-related death  globally. The unresectable or metastatic HCC has very poor prognosis. Although multikinase inhibitor sorafenib can increase the survival of patients with advanced HCC, it is becoming apparent that combination therapies are critical to  overcome the complex genomic aberrations in HCC. PTEN, as one of the most commonly inactivated genes in HCC, exerts a wide range of antitumor effects. In this study, we found that PTEN was downregulated in HCC tissues, especially in those tissues with extrahepatic metastasis. And negative PTEN expression cases showed increased proliferation activity. Overexpression of PTEN significantly reduced the proliferation of tumor cells HepG2. In addition, HepG2 cells transfected with PTEN were more sensitive to sorafenib in terms of its ability to inhibit proliferation and to induce apoptosis. Moreover, overexpression of PTEN decreased phosphorylation of MEK, a key downstream effector of RAF/MEK/ERK cascade, and levels of cyclin D1, antiapoptotic Bcl-2, and VEGF. These observations indicated that combination therapies with sorafenib and PTEN overexpression have potential to further improve therapeutic options for HCC.

 

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[590]

TÍTULO / TITLE:  - Phase I/II trial of clofarabine and cytarabine in children with relapsed/refractory acute lymphoblastic leukemia (AAML0523): A report from the Children’s Oncology Group.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pediatr Blood Cancer. 2013 Jan 17. doi: 10.1002/pbc.24398.

            ●● Enlace al texto completo (gratuito o de pago) 1002/pbc.24398

AUTORES / AUTHORS:  - Cooper TM; Razzouk BI; Gerbing R; Alonzo TA; Adlard K; Raetz E; Gamis AS; Perentesis J; Whitlock JA

INSTITUCIÓN / INSTITUTION:  - Aflac Cancer and Blood Disorders Center/Children’s Healthcare of Atlanta/Emory University, Atlanta, Georgia. todd.cooper@choa.org.

RESUMEN / SUMMARY:  - BACKGROUND: The discovery of effective re-induction regimens for children with more than one relapse of acute lymphoblastic leukemia (ALL) remains elusive. The  novel nucleoside analog clofarabine exhibits modest single agent efficacy in relapsed ALL, though optimal combinations of this agent with other active chemotherapy drugs have not yet been defined. Herein we report the response rates of relapsed ALL patients treated on Children’s Oncology Group study AAML0523, a Phase I/II study of the combination of clofarabine and cytarabine. PROCEDURE: AAML0523 enrolled 21 children with ALL in second or third relapse, or those refractory to re-induction therapy. The study consisted of two phases: a dose finding phase and an efficacy phase. The dose finding portion consisted of a single dose escalation/de-escalation of clofarabine for 5 days in combination with a fixed dose of cytarabine (1 g/m(2) /day for 5 days). Eight patients received clofarabine at 40 mg/m(2) /day and 13 patients at 52 mg/m(2) /day. RESULTS: Toxicities observed at all doses of clofarabine were typical of intensive chemotherapy regimens for leukemia, with infection being the most common. We did not observe significant hepatotoxicity as reported in other clofarabine combination regimens. The recommended pediatric Phase II dose of clofarabine in combination with cytarabine for the efficacy portion of AAML0523 was 52 mg/m(2) . Of 21 patients with ALL, 3 (14%) achieved a complete response (CR). Based on the two-stage design definition of first-stage inactivity, the therapy was deemed ineffective. CONCLUSION: The combination of clofarabine and cytarabine in relapsed/refractory childhood ALL does not warrant further clinical investigation. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.

 

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[591]

TÍTULO / TITLE:  - Efficacy and toxicity differences in lung cancer populations in the era of clinical trials globalization: the ‘common arm’ approach.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Expert Rev Anticancer Ther. 2012 Dec;12(12):1591-6. doi: 10.1586/era.12.135.

            ●● Enlace al texto completo (gratuito o de pago) 1586/era.12.135

AUTORES / AUTHORS:  - Mack PC; Gandara DR; Lara PN Jr

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, USA.

RESUMEN / SUMMARY:  - Historically, notable variability has been observed in clinical trial outcomes between different regions and populations worldwide, even when employing the same cytotoxic regimen in lung cancer. These divergent results underscore the inherent challenges in interpreting trials conducted abroad and raise questions regarding  the general applicability of transnational clinical trials. Various reasons have  been postulated to account for these differences in efficacy and toxicity, including trial design, eligibility criteria, patient demographics and, perhaps most intriguingly, population-related pharmacogenomics. However, without methodology to control for such variables, these hypotheses remain largely untested. The authors previously developed the ‘common arm’ approach in order to  directly compare efficacy and toxicity results of trials simultaneously performed in different countries. By standardizing clinical trial-associated variables such as treatment regimens (dose, schedule, and so on), eligibility, staging, response and toxicity criteria, this approach has the potential to determine the underlying reasons for divergences in trial outcomes across countries, and whether population-associated polymorphisms contribute to these differences. In the past decade, Japanese and US investigators have applied the common arm analytic method to trials in both extensive-stage small-cell lung cancer (SCLC) and advanced nonSCLC. In the SCLC analysis, a comparison of the cisplatin/irinotecan arms from both trials revealed significant differences in response rates and overall survival. Significant differences were also observed in the distribution of gender and performance status. The common arm analysis in  nonSCLC included two trials from Japan and one from the USA, each containing a ‘common’ carboplatin/paclitaxel arm. Clinical results were similar in the two Japanese trials, but were significantly different from the US trial with regard to survival, neutropenia, febrile neutropenia and anemia. The underlying basis for these divergent outcomes is discussed. The common arm methodology provides a  template for identifying and interpreting patient outcome differences across populations, and is an instructive lesson in the burgeoning era of clinical trials globalization.

 

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[592]

TÍTULO / TITLE:  - Hypoxia-related molecules HIF-1alpha, CA9, and osteopontin : Predictors of survival in patients with high-grade glioma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Strahlenther Onkol. 2013 Feb;189(2):147-154. Epub 2012 Dec 22.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00066-012-0262-5

AUTORES / AUTHORS:  - Erpolat OP; Gocun PU; Akmansu M; Ozgun G; Akyol G

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, Medical School of Gazi University, Ahmet Taner  Kislali Mah, Konutkent 2 sitesi, A8 Blok, No: 62 Cayyolu, Ankara, Turkey, petektater@yahoo.com.

RESUMEN / SUMMARY:  - PURPOSE: A high expression of hypoxia-inducible factor-1 alpha (HIF)-1alpha, carbonic anhydrase 9 (CA9), and osteopontin appears to be a strong prognostic indicator in many malignancies; however, their role is unclear in high-grade gliomas. PATIENTS AND METHODS: HIF-1alpha, CA9, and osteopontin levels in tissue  specimens of 92 patients with high-grade glioma were evaluated by immunohistochemistry. RESULTS: Patients with a high expression of cytoplasmic and nuclear HIF-1alpha, CA9, and osteopontin had significantly shorter overall survival. The expression results of these markers were combined to form a hypoxic profile, and high hypoxic scores (expression of two or three markers) were significantly correlated to poorer overall survival. In multivariate analysis, high hypoxic score-1 (cytoplasmic HIF-1alpha, CA9, and osteopontin) was the only  independent negative prognostic factor for survival (p = 0.028). CONCLUSION: Our  results showed that a combination of hypoxic markers is more robust than a single marker for predicting survival in high-grade glioma. It may be necessary to utilize the hypoxic score in selecting patients for targeted therapy in the future.

 

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[593]

TÍTULO / TITLE:  - Amplification of the telomerase RNA component gene as a new genetic marker for disease progression and prognosis in esophageal squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Dis Esophagus. 2013 Jan 14. doi: 10.1111/dote.12021.

            ●● Enlace al texto completo (gratuito o de pago) 1111/dote.12021

AUTORES / AUTHORS:  - Wang JD; Ma J; Wang FY; Peng LB; Wang X; Shi SS; Ma HH; Lu ZF; Lu GM; Zhou XJ

INSTITUCIÓN / INSTITUTION:  - Departments of Pathology, Clinical School of Medical College of Nanjing University, Nanjing, China; Digestive Diseases, Clinical School of Medical College of Nanjing University, Nanjing, China.

RESUMEN / SUMMARY:  - Amplification of the human telomerase RNA component (TERC) gene was found in esophageal squamous cell carcinoma (ESCC). However, its roles in the progression  and prognosis of ESCC have not been well understood. The amplification of TERC in normal mucosa, low-grade and high-grade intraepithelial neoplasia, and invasive ESCC samples were evaluated using a fluorescence in situ hybridization assay. The amplification of TERC invariably occurred in high-grade intraepithelial neoplasia and invasive ESCC, partially occurred in low-grade intraepithelial neoplasia specimens, and seldom occurred in normal mucosa. The average signal ratio of TERC to chromosome 3 centromere-specific probe (TERC/CSP3) was 1.00 +/- 0.01 (average  +/- standard deviation) in normal mucosas, 1.01 +/- 0.08 in low-grade intraepithelial neoplasias, 1.39 +/- 0.26 in high-grade intraepithelial neoplasias, and 1.56 +/- 0.41 in invasive ESCC. High TERC/CSP3 ratio was positively associated with lymph node metastasis (P = 0.005) and advanced tumor stage (P = 0.045). Patients with high amplification of TERC had poor survival (P  = 0.01). The amplification of TERC could be used as a new genomic marker for disease progression and prognosis of ESCC. The amplified TERC gene may be a potential therapeutic target for ESCC.

 

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[594]

TÍTULO / TITLE:  - The Role of Immunohistochemistry in Breast Cancer Patients Treated With Neoadjuvant Chemotherapy: An Old Tool With an Enduring Prognostic Value.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Breast Cancer. 2013 Jan 10. pii: S1526-8209(12)00265-0. doi: 10.1016/j.clbc.2012.11.006.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clbc.2012.11.006

AUTORES / AUTHORS:  - Sanchez-Munoz A; Plata-Fernandez YM; Fernandez M; Jaen-Morago A; Fernandez-Navarro M; de la Torre-Cabrera C; Ramirez-Tortosa C; Lomas-Garrido M; Llacer C; Navarro-Perez V; Alba-Conejo E; Sanchez-Rovira P

INSTITUCIÓN / INSTITUTION:  - Medical Oncology Service, Hospital Universitario Virgen de la Victoria de Malaga, Malaga, España. Electronic address: asmoncomed@yahoo.es.

RESUMEN / SUMMARY:  - BACKGROUND: To assess the molecular subtypes determined by hormonal receptors (HR) and human epidermal growth factor receptor 2 (HER2) status and the role of proliferation measured by the Ki-67 marker as predictive and prognostic factors in breast cancer patients treated with neoadjuvant chemotherapy. METHODS: A total of 127 breast cancer patients were treated with neoadjuvant chemotherapy every 2  weeks as part of 2 studies. Study A consisted of the administration of Adriamycin (40 mg/m(2)) on day 1 plus paclitaxel (150 mg/m(2)) and gemcitabine 2000 mg/m(2)) on day 2 for 6 cycles (n = 54). Study B consisted of the administration of epirubicin (90 mg/m(2)), cyclophosphamide (600 mg/m(2)) on day 1 for 3 cycles, followed by the administration of paclitaxel (150 mg/m(2)) and gemcitabine 2500 (mg/m(2)) on day 1 with or without trastuzumab according to HER2 status (n = 73). In study A, patients did not receive trastuzumab regardless of HER2 status. The molecular subtypes of the patients with breast cancer were classified as 49% HR(+)/HER2(-), 17.5% HR(+)/HER2(+), 13.5% HR(-)/HER2(+), and 20% HR(-)/HER2(-). RESULTS: Pathologic complete response (pCR), defined as the absence of invasive cells in the breast and the lymph nodes, was achieved in 35 (28%) patients. The pCR rate was significantly different between the molecular subtypes of breast cancer, with 9% in HR(+)/HER2(-), 23% in HR(+)/HER2(+), 50% in HR(-)/HER2(+), and 56% in HR(-)/HER2(-) tumors (P < .001). The pCR rate was significantly higher in  tumors that had high Ki-67 (>/=20%) expression and were HR(-). HER2(+) was associated with a higher trend of pCR but did not reach statistical significance. The median follow-up was 81 months (r = 15-150 months). Patients who achieved a pCR had a significantly lower recurrence (P = .01) and higher overall survival (P = .02) compared with those who did not achieve pCR. A multivariate analysis revealed that pCR (hazard ratio 0.24 [95% CI, 0.07-0.7]; P = .019), the molecular subtype (hazard ratio 0.3 [95% CI, 0.1-0.8]; P = .02), and the Ki-67 index (hazard ratio 3.2 [95% CI, 1.4-7.1]; P = .004) were significant independent predictors of disease-free survival. Similar results were obtained for overall survival, in which the pCR rate (hazard ratio 0.119 [95% CI, 0.028-0.5]; P = .004), the molecular subtype (hazard ratio 0.17 [95% CI, 0.03-0.86]; P = .02), and the Ki-67 index (hazard ratio 3.6 [95% CI, 1.3-9.7]; P = .01) also displayed  a significant influence on survival. CONCLUSIONS: Molecular subtypes and Ki-67 index were independent prognostic factors for disease-free survival and overall survival in breast cancer patients treated with neoadjuvant chemotherapy. A high  rate of Ki-67 and HR(-) expression were predictors of pCR.

 

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[595]

TÍTULO / TITLE:  - Erlotinib and Gefitinib, Epidermal Growth Factor Receptor Kinase Inhibitors, May  Treat Non-Cancer-Related Tumor Necrosis Factor-alpha Mediated Inflammatory Diseases.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncologist. 2013;18(1):e3-5. doi: 10.1634/theoncologist.2012-0219.

            ●● Enlace al texto completo (gratuito o de pago) 1634/theoncologist.2012-0219

AUTORES / AUTHORS:  - Brooks MB

INSTITUCIÓN / INSTITUTION:  - M.H.A., 2150 Silverado Circle, Palm Springs, CA 92264, USA. SBrooksPSP@aol.com.

 

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[596]

TÍTULO / TITLE:  - Growth inhibition of pancreatic cancer by experimental treatment with 4-phenylbutyrate is associated with increased expression of Connexin 43.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Res. 2012;20(2-3):103-11.

AUTORES / AUTHORS:  - Dovzhanskiy DI; Hartwig W; Lazar NG; Schmidt A; Felix K; Straub BK; Hackert T; Krysko DV; Werner J

INSTITUCIÓN / INSTITUTION:  - Department of General Surgery, University of Heidelberg, Heidelberg, Germany.

RESUMEN / SUMMARY:  - Histone deacetylase inhibitors are a new and promising drug family with a strong  anticancer activity and potent modulation of connexin expression. The restoration of connexins in cancer cells has been suggested as a possible mechanism to control tumor progression. The aim of this study was to investigate the effects of 4-phenylbutyrate (4-PB) on the growth of human pancreatic cell lines in vitro  and in vivo with a focus on connexin modulation. The proliferation of tumor cells was determined using an MTT assay, and the effect of 4-PB in vivo was studied in  a chimeric mouse model. The expression and localization of connexin 43 (Cx43) were assessed by Western blot, immunofluorescence microscopy, and immunohistochemistry. Antitumoral activity was assessed by immunohistochemistry for Ki-67 and histone H4. Treatment with 4-PB resulted in the significant in vitro and in vivo growth inhibition of pancreatic tumor cells. The reduction of the xenograft tumor volume was associated with the inhibition of histone deacetylation and decrease in cell proliferation. Treatment with 4-PB caused a significant increase in the Cx43 expression in T3M4 cells (up to 2.8-fold). The newly synthesized Cx43 was localized in the cytoplasm but not on the cell membrane. Treatment with 4-PB inhibited the proliferation of human pancreatic tumor cells in vitro and in vivo and increased the expression of Cx43. Therefore, 4-PB might be useful in the therapy of pancreatic cancer.

 

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[597]

TÍTULO / TITLE:  - Impacts and predictors of cytotoxic anticancer agents in different breast cancer  subtypes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Res. 2012;20(2-3):71-9.

AUTORES / AUTHORS:  - Ishikawa T; Shimizu D; Yamada A; Sasaki T; Morita S; Tanabe M; Kawachi K; Nozawa A; Chishima T; Kimura M; Ichikawa Y; Endo I

INSTITUCIÓN / INSTITUTION:  - Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama, Japan. tishik@urahp.yokohama-cu.ac.jp

RESUMEN / SUMMARY:  - Breast cancer is not a single entity. This study therefore aimed to identify differences in the impacts of anticancer agents and predictive factors between different breast cancer subtypes. A total of 234 patients with luminal (n = 109), luminal-HER2 (L-H, n = 29), HER-2 (n = 35), or triple negative (TN, n = 61) breast cancer subtypes were treated with standard neoadjuvant chemotherapy consisting of an anthracycline and/or taxane. Pathological response and prognosis were examined in each subtype. Expression levels of estrogen and progesterone receptors, HER-2, nuclear grade, MIB-1, p53, topoisomerase IIalpha (topoIIalpha), cytokeratin (CK) 5/6, and epidermal growth factor receptor (EGFR) were examined in association with quasipathological complete response (QpCR). QpCR rates were 9.1% (10/109) in luminal, 45% (13/29) in L-H, 37% (13/35) in HER2, and 54.1% (33/61) in TN. Non-QpCR patients showed significantly poorer 3-year disease-free  survival than QpCR patients in TN, but not in patients with other subtypes. No factors were associated with QpCR in luminal patients. Patients with higher nuclear grade were more likely to achieve QpCR in L-H. The proliferative markers  MIB-1 and topoIlalpha had opposite impacts on pathological response in HER-2 and  TN. The QpCR rate was significantly higher in TN lacking CK5/6 and/or EGFR expression, defined as nonbasal subtype, compared with basal subtype (p = 0.049). Cytotoxic anticancer agents were associated with different responses in different breast cancer subtypes. Identifying basal-type cancer and further subdivision of  nonbasal types is important for treating TN patients.

 

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[598]

TÍTULO / TITLE:  - Development and Clinical Validation of a Real-Time PCR Assay for PITX2 DNA Methylation to Predict Prostate-Specific Antigen Recurrence in Prostate Cancer Patients Following Radical Prostatectomy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Mol Diagn. 2012 Dec 21. pii: S1525-1578(12)00306-6. doi: 10.1016/j.jmoldx.2012.11.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jmoldx.2012.11.002

AUTORES / AUTHORS:  - Dietrich D; Hasinger O; Banez LL; Sun L; van Leenders GJ; Wheeler TM; Bangma CH; Wernert N; Perner S; Freedland SJ; Corman JM; Ittmann MM; Lark AL; Madden JF; Hartmann A; Schatz P; Kristiansen G

INSTITUCIÓN / INSTITUTION:  - Institute of Pathology, University Hospital Bonn, Bonn, Germany. Electronic address: dimo.dietrich@gmail.com.

RESUMEN / SUMMARY:  - Prostate cancer is the most common cancer among men. The prospective discrimination of aggressive and clinically insignificant tumors still poses a significant and, as yet, unsolved problem. PITX2 DNA methylation is a strong prognostic biomarker in prostate cancer. Recently, a diagnostic microarray for prostate cancer prognosis based on PITX2 methylation has been developed and validated. Because this microarray requires nonstandard laboratory equipment, its use in a diagnostic setting is limited. This study aimed to develop and validate  an alternative quantitative real-time PCR assay for measuring PITX2 methylation that can easily be established in clinical laboratories, thereby facilitating the implementation of this biomarker in clinical practice. A methylation cut-off for  patient stratification was established in a training cohort (n = 157) and validated in an independent test set (n = 523) of men treated with radical prostatectomy. In univariate Cox proportional hazards analysis, PITX2 hypermethylation was a significant predictor for biochemical recurrence (P < 0.001, hazard ratio = 2.614). Moreover, PITX2 hypermethylation added significant  prognostic information (P = 0.003, hazard ratio = 1.814) to the Gleason score, pathological T stage, prostate-specific antigen, and surgical margins in a multivariate analysis. The clinical performance was particularly high in patients at intermediate risk (Gleason score of 7) and in samples containing high tumor cell content. This assay might aid in risk stratification and support the decision-making process when determining whether a patient might benefit from adjuvant treatment after radical prostatectomy.

 

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[599]

TÍTULO / TITLE:  - Serum angiopoietin-2 level as a predictor of tumor invasiveness in patients with  hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Scand J Gastroenterol. 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 3109/00365521.2012.746391

AUTORES / AUTHORS:  - Diaz-Sanchez A; Matilla A; Nunez O; Lorente R; Fernandez A; Rincon D; Campos R; Banares R; Clemente G

INSTITUCIÓN / INSTITUTION:  - Gastroenterology Unit, Hospital Universitario del Sureste , Arganda del Rey, Madrid , España.

RESUMEN / SUMMARY:  - Abstract Background. Because hepatocellular carcinoma (HCC) has important angiogenic activity, the expression of angiopoietin-2 (Ang-2) may have a pathogenic role. The information about the influence of serum Ang-2 (sAng-2) in patients with HCC is scarce. Aims. The aim was to assess the association between  sAng-2 levels and characteristics of tumor and liver disease in patients with HCC. Methods. sAng-2 concentrations in peripheral (sAng-2-P) and hepatic (sAng-2-H) veins were analyzed by ELISA in 33 patients with chronic liver disease who underwent a splanchnic hemodynamic study. Thirty-two patients received treatment for HCC. Results. The median age was 61 years and 79% were male. Hepatitis C infection (70%) was the main etiology. Most patients were Child-Pugh  grade A (72.7%). sAng-2-P and sAng-2-H were well correlated (r = 0.95; p < 0.0001). A significant association was found between sAng-2-H and lobar tumor extension, vascular thrombosis, BCLC staging, infiltrating pattern, abnormal alpha-fetoprotein level, fulfillment of the Milan criteria, and performance of nonsystemic treatment. sAng-2-H also showed a significant correlation with the MELD score (r = 0.49; p = 0.007), albumin (r = -0.63; p < 0.001), and HVPG (r = 0.44; p = 0.02). Eleven patients received treatment with radiofrequency ablation  and eight with transarterial chemoembolization. HCC treatment did not influence the sAng-2 concentration while the necrosis response to treatment was not influenced by previous sAng-2 levels. Conclusions. Ang-2 seems to play an important role in the angiogenic processes of HCC and its serum levels are associated with tumor characteristics and invasive behavior. Our results suggest  that Ang-2 is not related with treatment response and its level is not modified by treatment.

 

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[600]

TÍTULO / TITLE:  - Genomic Variation by Whole-Genome SNP Mapping Arrays Predicts Time-to-Event Outcome in Patients with Chronic Lymphocytic Leukemia: A Comparison of CLL and HapMap Genotypes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Mol Diagn. 2012 Dec 26. pii: S1525-1578(12)00311-X. doi: 10.1016/j.jmoldx.2012.09.006.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jmoldx.2012.09.006

AUTORES / AUTHORS:  - Schweighofer CD; Coombes KR; Majewski T; Barron LL; Lerner S; Sargent RL; O’Brien S; Ferrajoli A; Wierda WG; Czerniak BA; Medeiros LJ; Keating MJ; Abruzzo LV

INSTITUCIÓN / INSTITUTION:  - Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

RESUMEN / SUMMARY:  - Genomic abnormalities, such as deletions in 11q22 or 17p13, are associated with poorer prognosis in patients with chronic lymphocytic leukemia (CLL). We hypothesized that unknown regions of copy number variation (CNV) affect clinical  outcome and can be detected by array-based single-nucleotide polymorphism (SNP) genotyping. We compared SNP genotypes from 168 untreated patients with CLL with genotypes from 73 white HapMap controls. We identified 322 regions of recurrent CNV, 82 of which occurred significantly more often in CLL than in HapMap (CLL-specific CNV), including regions typically aberrant in CLL: deletions in 6q21, 11q22, 13q14, and 17p13 and trisomy 12. In univariate analyses, 35 of total and 11 of CLL-specific CNVs were associated with unfavorable time-to-event outcomes, including gains or losses in chromosomes 2p, 4p, 4q, 6p, 6q, 7q, 11p, 11q, and 17p. In multivariate analyses, six CNVs (ie, CLL-specific variations in  11p15.1 to 15.4 or 6q27) predicted time to treatment or overall survival independently of established markers of prognosis. Moreover, genotypic complexity (ie, the number of independent CNVs per patient) significantly predicted prognosis, with a median time to treatment of 64 months versus 23 months in patients with zero to one versus two or more CNVs, respectively (P = 3.3 x 10(-8)). In summary, a comparison of SNP genotypes from patients with CLL with HapMap controls allowed us to identify known and unknown recurrent CNV and to determine regions and rates of CNV that predict poorer prognosis in patients with CLL.

 

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[601]

TÍTULO / TITLE:  - A Multigene Prognostic Assay for Selection of Adjuvant Chemotherapy in Patients with T3, Stage II Colon Cancer: Impact on Quality-Adjusted Life Expectancy and Costs.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Value Health. 2012 Dec;15(8):1014-21. doi: 10.1016/j.jval.2012.07.012. Epub 2012  Nov 7.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jval.2012.07.012

AUTORES / AUTHORS:  - Hornberger J; Lyman GH; Chien R; Meropol NJ

INSTITUCIÓN / INSTITUTION:  - Stanford University School of Medicine, Stanford, CA, USA; Cedar Associates LLC,  Menlo Park, CA, USA. Electronic address: ujch@stanford.edu.

RESUMEN / SUMMARY:  - OBJECTIVES: Uncertainty exists regarding appropriate and affordable use of adjuvant chemotherapy in stage II colon cancer (T3, proficient DNA mismatch repair). This study aimed to estimate the effectiveness and costs from a US societal perspective of a multigene recurrence score (RS) assay for patients recently diagnosed with stage II colon cancer (T3, proficient DNA mismatch repair) eligible for adjuvant chemotherapy. METHODS: RS was compared with guideline-recommended clinicopathological factors (tumor stage, lymph nodes examined, tumor grade, and lymphovascular invasion) by using a state-transition (Markov) lifetime model. Data were obtained from published literature, a randomized controlled trial (QUick And Simple And Reliable) of adjuvant chemotherapy, and rates of chemotherapy use from the National Cooperative Cancer  Network Colon/Rectum Cancer Outcomes study. Life-years, quality-adjusted life expectancy, and lifetime costs were examined. RESULTS: The RS is projected to reduce adjuvant chemotherapy use by 17% compared with current treatment patterns  and to increase quality-adjusted life expectancy by an average of 0.035 years. Direct medical costs are expected to decrease by an average of $2971 per patient. The assay was cost saving for all subgroups of patients stratified by clinicopathologic factors. The most influential variables affecting treatment decisions were projected years of life remaining, recurrence score, and patients’ disutilities associated with adjuvant chemotherapy. CONCLUSIONS: Use of the multigene RS to assess recurrence risk after surgery in stage II colon cancer (T3, proficient DNA mismatch repair) may reduce the use of adjuvant chemotherapy  without decreasing quality-adjusted life expectancy and be cost saving from a societal perspective. These findings need to be validated in additional cohorts,  including studies of clinical practice as assay use diffuses into nonacademic settings.

 

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[602]

TÍTULO / TITLE:  - Additional prognostic value of the 70-gene signature (MammaPrint(®)) among breast cancer patients with 4-9 positive lymph nodes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast. 2013 Jan 21. pii: S0960-9776(12)00246-9. doi: 10.1016/j.breast.2012.12.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.breast.2012.12.002

AUTORES / AUTHORS:  - Saghatchian M; Mook S; Pruneri G; Viale G; Glas AM; Guerin S; Cardoso F; Piccart M; Tursz T; Delaloge S; Van’t Veer L

INSTITUCIÓN / INSTITUTION:  - Institut Gustave Roussy, Villejuif, France; Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: saghatchian@igr.fr.

RESUMEN / SUMMARY:  - BACKGROUND: The 70 gene-signature (MammaPrint(®)) is a prognostic profile of distant recurrence and survival of primary breast cancer (BC). BC patients with 4-9 positive nodes (LN 4-9) are considered clinically at high-risk. Herein we examined MammaPrint(®) added prognostic value in this group. PATIENTS AND METHODS: MammaPrint(®) profiles were generated from frozen tumours of patients  operated from primary BC. Samples were classified as genomic Low Risk (GLR) or genomic High Risk (GHR). RESULTS: Among the 173 samples, 70 (40%) were classified as GLR and 103 (60%) as GHR. Tumours in the GHR group were significantly more often ductal carcinomas (93%), grade 3 (60%), oestrogen and progesterone-negative, Her2 positive (25%). In the GLR category, the 5-year overall survival was 97% vs. 76% for in the GHR group (p < 0.01); Distant Metastasis Free Survival (DMFS) at 5 years was 87% for GLR patients and 63% for GHR patients (p < 0.01). In the Luminal A subgroup, the genomic profile was the only independent risk factor for DM and BC specific death. CONCLUSION: In the Luminal A subgroup, MammaPrint(®) is an independent prognostic marker in BC patients with LN 4-9 and may be integrated in a selection strategy of patients candidate for more aggressive therapeutic approaches.

 

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[603]

TÍTULO / TITLE:  - Role of immunoglobulin G fragment C receptor polymorphism-mediated antibody-dependant cellular cytotoxicity in colorectal cancer treated with cetuximab therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pharmacogenomics J. 2013 Jan 8. doi: 10.1038/tpj.2012.54.

            ●● Enlace al texto completo (gratuito o de pago) 1038/tpj.2012.54

AUTORES / AUTHORS:  - Negri FV; Musolino A; Naldi N; Bortesi B; Missale G; Laccabue D; Zerbini A; Camisa R; Chernyschova N; Bisagni G; Loupakis F; Ruzzo A; Neri TM; Ardizzoni A

INSTITUCIÓN / INSTITUTION:  - Medical Oncology Unit and Medical Genetics Unit, University Hospital of Parma, Parma, Italy.

RESUMEN / SUMMARY:  - Antibody-dependent cellular cytotoxicity (ADCC), which is activated by effector cells via immunoglobulin G (IgG) fragment C receptors (FcRs), was proposed as a mechanism of cetuximab efficacy. Peripheral blood mononuclear cells (PBMCs) from  23 healthy donors and 13 patients with metastatic colorectal cancer (mCRC) treated with cetuximab were tested for FcgammaR polymorphisms and cetuximab-mediated ADCC. ADCC was measured by chromium-51 release on a epidermal  growth factor receptor (EGFR)-positive human colon cancer cell line. Overall, 86  mCRC patients were genotyped for study purposes. PBMCs harbouring the FcgammaRIIIa 158 V/V genotype had a significantly higher cetuximab-mediated ADCC. No correlation was found between FcgammaR polymorphisms and response rate or time to progression after cetuximab-based therapy. Despite the in vitro analysis showing that the FcgammaRIIIa 158 V/V genotype is associated with higher ADCC, clinical data do not support a predictive role of FcgammaRIIIa polymorphisms in mCRC treated with cetuximab.The Pharmacogenomics Journal advance online publication, 8 January 2013; doi:10.1038/tpj.2012.54.

 

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[604]

TÍTULO / TITLE:  - A trial with 3’-azido-2’, 3’-dideoxythymidin and human interferon-alpha in cats naturally infected with feline leukaemia virus.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Feline Med Surg. 2013 Jan 15.

            ●● Enlace al texto completo (gratuito o de pago) 1177/1098612X12473468

AUTORES / AUTHORS:  - Stuetzer B; Brunner K; Lutz H; Hartmann K

INSTITUCIÓN / INSTITUTION:  - 1Clinic of Small Animal Medicine, LMU University of Munich, Germany.

RESUMEN / SUMMARY:  - Feline leukaemia virus (FeLV) infection is still one of the leading causes of infection-related deaths in domestic cats. Treatment with various drugs has been  attempted, but none has resulted in cure or complete virus elimination. Human interferon-alpha2a (huIFN-alpha2a) and 3’-azido-2’,3’-dideoxythymidin (AZT) have  been proven to decrease antigenaemia in cats infected experimentally with FeLV. The purpose of this study was to assess the efficacy of huIFN-alpha2a, AZT and a  combination of both drugs in cats infected naturally with FeLV in a placebo-controlled double-blinded trial. Fourty-four FeLV-infected cats in which  free FeLV p27 antigen was detected in serum by enzyme-linked immunosorbent assay  were included in the study. Cats were assigned to one of four treatment groups that received either high dose huIFN-alpha2a (10(5) IU/kg q24h; 12 cats), AZT (5  mg/kg q12h; 10 cats, both of these treatments (12 cats) or placebo (10 cats). All cats were treated for 6 weeks. Clinical variables, including stomatitis, and laboratory parameters, such as CD4(+) and CD8(+) counts and serum FeLV p 27 antigen concentration, were recorded throughout the treatment period. No significant difference among the groups was observed during the treatment period  for any of the parameters. Aside from anaemia in one cat treated with AZT, no adverse effects were observed. It was not possible to demonstrate efficacy of huIFN-alpha2a or AZT alone or together in cats infected naturally with FeLV when  given according to this regimen for 6 weeks; however, no notable side effects were detected.

 

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[605]

TÍTULO / TITLE:  - Expression of the Bcl-2 apoptotic marker in cats diagnosed with inflammatory bowel disease and gastrointestinal lymphoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Feline Med Surg. 2013 Feb;15(2):167. doi: 10.1177/1098612X12470324.

            ●● Enlace al texto completo (gratuito o de pago) 1177/1098612X12470324

RESUMEN / SUMMARY:  - Christine M Swanson, Rebecca C Smedley, Paulo Vilar Saavedra, Matti Kiupel and Barbara E Kitchell J Feline Med Surg 2012; 14: 741-745, DOI: 10.1177/1098612X12451404.

 

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[606]

TÍTULO / TITLE:  - Five Most Common Prognostically Important Fusion Oncogenes are Detected in the Majority of Pakistani Pediatric Acute Lymphoblastic Leukemia Patients and are Strongly Associated with Disease Biology and Treatment Outcome.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian Pac J Cancer Prev. 2012;13(11):5469-5475.

AUTORES / AUTHORS:  - Awan T; Iqbal Z; Aleem A; Sabir N; Absar M; Rasool M; Tahir AH; Basit S; Khalid AM; Sabar MF; Asad S; Ali AS; Mahmood A; Akram12 M; Saeed T; Saleem A; Mohsin D; Shah IH; Khalid M; Asif M; Haq R; Iqbal M; Akhtar T

INSTITUCIÓN / INSTITUTION:  - Hematology, Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences Laboratories, Faculty of Biological Sciences, Department of Zoology, University of the Punjab, Pakistan E-mail : mianzafaram@yahoo.com.

RESUMEN / SUMMARY:  - Background and Objectives: Acute lymphoblastic leukemia (ALL) is a complex genetic disease involving many fusion oncogenes (FO) having prognostic significance. The frequency of various FO can vary in different ethnic groups, with important implications for prognosis, drug selection and treatment outcome.  Method: We studied fusion oncogenes in 101 pediatric ALL patients using interphase FISH and RT-PCR, and their associations with clinical features and treatment outcome. Results: Five most common fusion genes i.e. BCR-ABL t (22; 9), TCF3-PBX1 (t 1; 19), ETV6-RUNX1 (t 12; 21), MLL-AF4 (t 4; 11) and SIL-TAL1 (del 1p32) were found in 89/101 (88.1%) patients. Frequency of BCR-ABL was 44.5% (45/101). BCR-ABL positive patients had a significantly lower survival (43.7+/-4.24 weeks) and higher white cell count as compared to others, except patients with MLL-AF4. The highest relapse-free survival was documented with ETV6-RUNX1 (14.2 months) followed closely by those cases in which no gene was detected (13.100). RFS with BCR-ABL, MLL-AF4, TCF3-PBX1 and SIL-TAL1 was less than 10 months (8.0, 3.6, 5.5 and 8.1 months, respectively). Conclusions: This is the first study from Pakistan correlating molecular markers with disease biology  and treatment outcome in pediatric ALL. It revealed the highest reported frequency of BCR-ABL FO in pediatric ALL, associated with poor overall survival.  Our data indicate an immediate need for incorporation of tyrosine kinase inhibitors in the treatment of BCR-ABL+ pediatric ALL in this population and the  development of facilities for stem cell transplantation.

 

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[607]

TÍTULO / TITLE:  - Epigenetic silencing of BLU through interfering apoptosis results in chemo-resistance and poor prognosis of ovarian serous carcinoma patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Endocr Relat Cancer. 2013 Jan 17.

            ●● Enlace al texto completo (gratuito o de pago) 1530/ERC-12-0117

AUTORES / AUTHORS:  - Chiang YC; Chang MC; Chen PJ; Wu MM; Hsieh CY; Chen CA; Cheng WF

INSTITUCIÓN / INSTITUTION:  - Y Chiang, Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, United Kingdom.

RESUMEN / SUMMARY:  - Epithelial ovarian carcinoma is usually present at the advanced stage, during which the patients generally have poor prognosis. Our study aimed to evaluate the correlation of gene methylation and the clinical outcome of patients with advanced stage high grade ovarian serous carcinoma. The methylation status of eight candidate genes was first evaluated by methylation-specific polymerase chain reaction and capillary electrophoresis to select three potential genes including DAPk, E-cadherin, and BLU from the exercise group of 40 patients. The methylation status of these three genes was further investigated in the validation group consisting of 136 patients. Patients with methylated BLU had significantly shorter progression free survival (PFS) (HR: 1.48, 95% C.I.: 1.01-2.56, p=0.013) and overall survival (OS) (HR: 1.83, 95% C.I.: 1.07-3.11, p=0.027) in multivariate analysis. Methylation of BLU was also an independent risk factor of those 58 patients undergoing optimal debulking surgery for PFS (HR: 2.37, 95% C.I.: 1.03-5.42, p=0.043) and OS (HR: 3.96, 95% C.I.: 1.45-10.81,  p=0.007) in multivariate analysis. The possible mechanism of BLU in chemo-resistance was investigated in ovarian cancer cell line by in vitro apoptotic assays. In vitro studies showed that BLU could up-regulate the expression of Bax and enhance the effect of paclitaxel-induced apoptosis in ovarian cancer cells. Our study suggested that methylation of BLU could be a potential prognostic biomarker for advanced ovarian serous carcinoma.

 

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[608]

TÍTULO / TITLE:  - MGMT promoter methylation status and MGMT and CD133 immunohistochemical expression as prognostic markers in glioblastoma patients treated with temozolomide plus radiotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Transl Med. 2012 Dec 17;10:250. doi: 10.1186/1479-5876-10-250.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1479-5876-10-250

AUTORES / AUTHORS:  - Melguizo C; Prados J; Gonzalez B; Ortiz R; Concha A; Alvarez PJ; Madeddu R; Perazzoli G; Oliver JA; Lopez R; Rodriguez-Serrano F; Aranega A

INSTITUCIÓN / INSTITUTION:  - Institute of Biopathology and Regenerative Medicine (IBIMER), Granada 18100, España. jcprados@ugr.es.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: The CD133 antigen is a marker of radio- and chemo-resistant stem cell populations in glioblastoma (GBM). The O6-methylguanine DNA methyltransferase (MGMT) enzyme is related with temozolomide (TMZ) resistance. Our propose is to analyze the prognostic significance of the CD133 antigen and promoter methylation and protein expression of MGMT in a homogenous group of GBM  patients uniformly treated with radiotherapy and TMZ. The possible connection between these GBM markers was also investigated. METHODS: Seventy-eight patients  with GBM treated with radiotherapy combined with concomitant and adjuvant TMZ were analyzed for MGMT and CD133. MGMT gene promoter methylation was determined by methylation-specific polymerase chain reaction after bisulfite treatment. MGMT and CD133 expression was assessed immunohistochemically using an automatic quantification system. Overall and progression-free survival was calculated according to the Kaplan-Meier method. RESULTS: The MGMT gene promoter was found to be methylated in 34 patients (44.7%) and unmethylated in 42 patients (55.3%).  A significant correlation was observed between MGMT promoter methylation and patients’ survival. Among the unmethylated tumors, 52.4% showed low expression of MGMT and 47.6% showed high-expression. Among methylated tumors, 58.8% showed low-expression of MGMT and 41.2% showed high-expression. No correlation was found between MGMT promoter methylation and MGMT expression, or MGMT expression and survival. In contrast with recent results, CD133 expression was not a predictive  marker in GBM patients. Analyses of possible correlation between CD133 expression and MGMT protein expression or MGMT promoter methylation were negative. CONCLUSIONS: Our results support the hypothesis that MGMT promoter methylation status but not MGMT expression may be a predictive biomarker in the treatment of  patients with GBM. In addition, CD133 should not be used for prognostic evaluation of these patients. Future studies will be necessary to determine its clinical utility.

 

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[609]

TÍTULO / TITLE:  - Upregulation of DLX2 confers a poor prognosis in glioblastoma patients by inducing a proliferative phenotype.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Mol Med. 2013 Jan 15.

AUTORES / AUTHORS:  - Yan ZH; Bao ZS; Yan W; Liu YW; Zhang CB; Wang HJ; Feng Y; Wang YZ; Zhang W; You G; Zhang QG; Jiang T

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Beijing Tiantan Hospital, No. 6 Tiantan Xili, Dongcheng District, Beijing 100050, China. taojiang1964@yahoo.com.cn.

RESUMEN / SUMMARY:  - The human Distal-less Homeobox (DLX) gene family encodes homeobox transcription factors involved in the control of morphogenesis and tissue homeostasis, which is primarily expressed in embryonic development. Recently, DLX gene family was reported to have essential roles in carcinogenesis. We have profiled whole genome expressed genes in 83 glioblastoma multiforme (GBM) patients from the Chinese Glioma Genome Atlas (CGGA) Group. Two major groups of samples were identified in  mRNA expression profiles (referred to as Group 1 (G1) and Group 2 (G2)). We identified 7 out of the top 10 Gene Ontology terms in the G1 group were associated with differentiation and development of neuronal cell. The most significant prognostic gene was DLX2 (P<0.001, OR=1.744); overexpression of DLX2  indicated poor survival in the 83 GBM patients (low DLX2 vs. high DLX2, 77.6 vs.  44.7 weeks, P<0.001). Annotation of mRNA profiling data on GBM from The Cancer Genome Atlas and MD Anderson Cancer Center showed the proneural and neural subtypes highly correlated with low and high DLX2 expression, respectively. Knocking down of DLX2 in GBM cell line-LN229 results in decreased cyclin D1 expression and cell proliferation. Collectively, these data identified high expression of DLX2 as a poor prognostic marker to GBM patients.

 

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[610]

TÍTULO / TITLE:  - Pretreatment Levels of Vascular Endothelial Growth Factor in Plasma Predict a Complete Remission Rate and Time to Relapse or Progression in Patients with Diffuse Large B-Cell Lymphoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Arch Immunol Ther Exp (Warsz). 2013 Jan 3.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00005-012-0215-9

AUTORES / AUTHORS:  - Lech-Maranda E; Bienvenu J; Broussais-Guillaumot F; Michallet AS; Warzocha K; Bilinski P; Boyle P; Coiffier B; Salles G

INSTITUCIÓN / INSTITUTION:  - Equipe d’Accueil “Pathologie des Cellules Lymphoides”, Universite Claude Bernard, Lyon, France, ewamaranda@wp.pl.

RESUMEN / SUMMARY:  - The aim of this study was to verify whether pretreatment plasma levels of vascular endothelial growth factor (VEGF) correlate with prognosis and survival of patients with diffuse large B-cell lymphoma (DLBCL). Plasma VEGF levels were assessed at the time of diagnosis in 157 DLBCL patients treated with anthracycline-based chemotherapy. Plasma VEGF levels greater than or equal to the highest quartile (high VEGF levels) were associated with lower probability of a complete remission achievement (odds ratio 0.3; 95 % confidence interval [CI]: 0.1-0.6; p = 0.002) in univariate as well as in multivariate analysis (p = 0.04). The estimated 3-year progression-free survival (PFS) rate of patients with high VEGF levels was 31.7 % (95 % CI 17-51) compared to the 62.5 % 3-year PFS rate (95 % CI 53-71; p = 0.0004) in the patients with lower values. The former group of patients demonstrated an estimated 3-year overall survival (OS) rate of 47.1 % (95 % CI 30-65) in contrast to the 3-year OS rate of 64.3 % (95 % CI 54-73; p = 0.02) in the latter. In multivariate analysis, the high VEGF level retained its independent impact on shorter PFS (p = 0.02). Our results suggest that VEGF plays an important role in the clinical course of DLBCL. VEGF may be a useful marker for selecting the patients for whom new treatment approaches, especially those based on VEGF inhibitors, could be recommended.

 

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[611]

TÍTULO / TITLE:  - A dry extract of Phyllanthus niruri protects normal cells and induces apoptosis in human liver carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Exp Biol Med (Maywood). 2012 Nov 1;237(11):1281-8. doi: 10.1258/ebm.2012.012130.

            ●● Enlace al texto completo (gratuito o de pago) 1258/ebm.2012.012130

AUTORES / AUTHORS:  - de Araujo Junior RF; de Souza TP; Pires JG; Soares LA; de Araujo AA; Petrovick PR; Macedo HD; de Sa Leitao Oliveira AL; Guerra GC

INSTITUCIÓN / INSTITUTION:  - Department of Morphology, Federal University of Rio Grande do Norte, Natal.

RESUMEN / SUMMARY:  - The ability to induce apoptosis is an important marker for cytotoxic antitumor agents. Some natural compounds have been shown to modulate apoptosis pathways that are frequently blocked in human cancers, and therefore, these compounds provide novel opportunities for cancer drug development. Phyllanthus, a plant genus of the family Euphorbiaceae, exhibits multiple pharmacological actions. Of  these, Phyllanthus niruri extracts exhibit significant antitumor activity, which  is consistent with the traditional medicinal use of this plant. To examine the apoptotic effects of a spray-dried extract of P. niruri (SDEPN), human hepatocellular carcinoma cells (HepG2, Huh-7), colorectal carcinoma cells (Ht29)  and keratinocytes (HaCaT) were exposed to the extract for 4, 8 and 24 h. Flow cytometry and caspase-3 immunostaining were used to detect apoptosis, while analysis of variance was applied to identify significant differences between groups (P < 0.05). At all timepoints, the SDEPN induced significantly different cytotoxic effects for HepG2 and Huh-7 cells compared with control cells (P < 0.001). In contrast, the SDEPN had a protective effect on HaCaT cells compared with control cells at all timepoints (P < 0.001). In caspase-3 assays, activation was detected after cell death was induced in Huh-7 and HepG2 cancer cells by the  SDEPN. In combination, these results indicate that the SDEPN is selectively toxic towards cancer cell lines, yet is protective towards normal cells.

 

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[612]

TÍTULO / TITLE:  - Reactive oxygen species H(2)O(2) and OH, but not O(2)(-) promote oridonin-induced phagocytosis of apoptotic cells by human histocytic lymphoma U937 cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int Immunopharmacol. 2013 Jan 22. pii: S1567-5769(13)00018-0. doi: 10.1016/j.intimp.2013.01.004.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.intimp.2013.01.004

AUTORES / AUTHORS:  - Zang L; He H; Xu Q; Yu Y; Zheng N; Liu W; Hayashi T; Tashiro SI; Onodera S; Ikejima T

INSTITUCIÓN / INSTITUTION:  - China-Japan Research Institute of Medical Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.

RESUMEN / SUMMARY:  - We reported previously that phagocytosis of apoptotic cells by U937 cells was enhanced by the treatment with oridonin that showed high activity to induce the generation of reactive oxygen species (ROS) in many cells. ROS, important signaling molecules, are involved in the immune defenses, cell repair and proliferation. In this study, oridonin caused modest amount of ROS generation in  U937 cells, with hydrogen peroxide (H(2)O(2)) and hydroxyl free radical (OH) as the major types. Meanwhile, H(2)O(2) and OH were positive regulators involved in  oridonin-enhanced engulfment of apoptotic cells through down-regulating mitochondrial membrane potential (MMP) and inducing autophagy. The ROS-mediated phagocytosis was independent of cellular adenosine triphosphate (ATP) levels. H(2)O(2) and OH generation also activated phosphatidylinositol 3-kinases-Akt (PI3K-Akt) and phospholipase C gamma-protein kinase C(PLC gamma)-Ras-Raf-ERK signaling pathways, which were essential for oridonin-induced engulfment of apoptotic cells. Phagocytosis, the loss of MMP, autophagy and the activated signaling pathways were all suppressed by ROS scavenger N-acetyl-l-cysteine (NAC), H(2)O(2)scavenger catalase or OH scavenger glutathione (GSH). However, superoxide anion (O(2)-) and its scavenger superoxide dismutase (SOD) did not significantly affect these oridonin-induced biological processes.

 

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[613]

TÍTULO / TITLE:  - The translocator protein (TSPO) ligand PK11195 induces apoptosis and cell cycle arrest and sensitizes to chemotherapy treatment in pre- and post-relapse neuroblastoma cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Biol Ther. 2013 Jan 28;14(4).

AUTORES / AUTHORS:  - Mendonca-Torres MC; Roberts SS

INSTITUCIÓN / INSTITUTION:  - Department of Pediatrics; Division of Hematology/Oncology; Uniformed Services University of the Health Sciences; Bethesda, MD USA.

RESUMEN / SUMMARY:  - High-risk neuroblastoma (NB) has a poor prognosis. Even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal, and new treatments are needed. Translocator protein 18kDa (TSPO) ligands have been studied as potential new therapeutic agents in many cancers, but not in NB. We studied the effects of TSPO ligands on cell proliferation, cell cycle progression and apoptosis using paired cell lines derived from the same patient at the time of initial surgery and again after development of progressive disease or relapse  post-chemotherapy. We found that TSPO expression was significantly increased 2- to 10-fold in post-relapse cell lines compared with pre-treatment lines derived from the same individual. Subsequently, these cell lines were treated with the specific TSPO ligand 1-(2-chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide  (PK11195) (0-160microM) as a single agent, with cytotoxic chemotherapy agents alone (carboplatin, etoposide or melphalan), or with combinations of PK11195 and  chemotherapy drugs. We found that PK11195 inhibited proliferation in a dose-dependent manner, induced apoptosis and caused G 1/S cell cycle arrest in all tested NB cell lines at micromolar concentrations. In addition, PK11195 significantly decreased mRNA expression of the chemotherapy resistance efflux pumps ABCA3, ABCB1 and ABCC1 in two post-relapse NB cell lines. We also found that pre-treatment with PK11195 sensitized these cell lines to treatment with cytotoxic chemotherapy agents. These results suggest that PK11195 alone or in combination with standard chemotherapeutic drugs warrants further study for the treatment of neuroblastoma.

 

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[614]

TÍTULO / TITLE:  - Calcium, cancer and killing: The role of calcium in killing cancer cells by cytotoxic T lymphocytes and natural killer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochim Biophys Acta. 2012 Dec 3. pii: S0167-4889(12)00348-5. doi: 10.1016/j.bbamcr.2012.11.016.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbamcr.2012.11.016

AUTORES / AUTHORS:  - Schwarz EC; Qu B; Hoth M

INSTITUCIÓN / INSTITUTION:  - Department of Biophysics, Saarland University, Homburg, Germany.

RESUMEN / SUMMARY:  - Killing cancer cells by cytotoxic T lymphocytes (CTL) and by natural killer (NK)  cells is of vital importance. Cancer cell proliferation and apoptosis depend on the intracellular Ca(2+) concentration, and the expression of numerous ion channels with the ability to control intracellular Ca(2+) concentrations has been correlated with cancer. A rise of intracellular Ca(2+) concentrations is also required for efficient CTL and NK cell function and thus for killing their targets, in this case cancer cells. Here, we review the data on Ca(2+)-dependent  killing of cancer cells by CTL and NK cells. In addition, we discuss emerging ideas and present a model how Ca(2+) may be used by CTL and NK cells to optimize  their cancer cell killing efficiency. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.

 

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[615]

TÍTULO / TITLE:  - Glioblastoma Tumor Initiating Cells: Therapeutic Strategies Targeting Apoptosis and MicroRNA Pathways.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Mol Med. 2013 Jan 15.

AUTORES / AUTHORS:  - Liu J; Albrecht AM; Ni X; Yang J; Li M

INSTITUCIÓN / INSTITUTION:  - The Vivian L. Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, Texas 77030, USA. Min.Li@uth.tmc.edu.

RESUMEN / SUMMARY:  - Glioblastoma (GBM) is a highly malignant primary brain tumor known for its invasiveness and aggressive resistance to standard treatment. It is currently the most common primary brain tumor which is associated with a high mortality rate. Tumor initiating cells (TICs) are a subpopulation of GBM stem cells which are capable of self-renewal and apoptotic resistance, and are thought to account for  GBMs aggressive nature. Recent efforts have focused on therapies which target key intracellular apoptotic pathways which may confer tumor resistance, such as Akt,  p53, Bcl-2 family proteins, caspase family proteases, and more recently microRNAs. Research into microRNA’s role in GBM has shown that microRNAs play a key regulatory role in the GBM apoptotic pathway, making it a potential therapeutic target. In this review we summarized the molecular mechanisms involved in the signaling pathways of human GBM TIC apoptosis and microRNAs, the  contemporary treatments involving different members of the signaling cascade, and the future direction of GBM treatment strategies.

 

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[616]

TÍTULO / TITLE:  - Side effects associated with ultrarapid cytochrome P450 2D6 genotype among women  with early stage breast cancer treated with tamoxifen.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Lab. 2012;58(11-12):1211-8.

AUTORES / AUTHORS:  - Rolla R; Vidali M; Meola S; Pollarolo P; Fanello MR; Nicolotti C; Saggia C; Forti L; Agostino FD; Rossi V; Borra G; Stratica F; Alabiso O; Bellomo G

INSTITUCIÓN / INSTITUTION:  - Departmentt of Medical Sciences, University “Amedeo Avogadro” of East Piedmont, Novara, Italy. roberta.rolla@med.unipmn.it

RESUMEN / SUMMARY:  - BACKGROUND: The side effects of tamoxifen, a drug widely used for the treatment and the prevention of recurrence in patients with estrogen receptor positive breast cancers (ER+), have been reported in clinical trials, but to date no information is available on their possible association with an increased enzymatic activity of CYP2D6 (ultra-metabolizers, UMs). The aim of this study was therefore to evaluate the association between the presence of multiple functional CYP2D6 alleles and the occurrence of side effects. METHODS: 61 women with ER+ breast cancer receiving tamoxifen monotherapy were investigated in order to assess the relationships between CYP2D6 UM phenotype and side effects. Genotyping of 16 CYP2D6 polymorphisms was performed using a new DNA microarray technology. RESULTS: A highly significant difference was detected (41.2% of difference, 95% CI 6 - 61%, Fisher’s exact test, p = 0.030) between the numbers of Ultrarapid Metabolizer patients (UM; high activity) with two or more adverse drug reactions  to tamoxifen (7/9; 77.8%), compared to the number of Extensive Metabolizers (EM;  normal activity), Intermediate Metabolizers (IM; reduced activity), and Poor Metabolizers (PM; no activity) with at least two side effects (19/52, 36.5%). A similar difference was also observed comparing the two groups (UM vs EM-IM-PM) for the number of side effects (median and inter quartile range, IQR: AM/EM/IM 1, IQR 0-2 vs. ULTRA 2, IQR 2-4; Mann-Whitney p = 0.005). CONCLUSIONS: Our results suggest a new association between CYP2D6 gene duplication and side effects to tamoxifen, indicating a possible role of CYP2D6 in their occurrence.

 

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[617]

TÍTULO / TITLE:  - Apoptotic effect of dibenzylideneacetone on oral cancer cells via modulation of specificity protein 1 and Bax.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oral Dis. 2012 Dec 28. doi: 10.1111/odi.12062.

            ●● Enlace al texto completo (gratuito o de pago) 1111/odi.12062

AUTORES / AUTHORS:  - Yu HJ; Shin JA; Nam JS; Kang BS; Cho SD

INSTITUCIÓN / INSTITUTION:  - Department of Oral Pathology, School of Dentistry, Institute of Oral Bioscience,  Chonbuk National University, Jeonju, Korea.

RESUMEN / SUMMARY:  - OBJECTIVE: Dibenzylideneacetone (DBA), an analogue of curcumin, has been shown to have potential anticancer effects against several cancers. However, the molecular mechanism underlying anticancer activity of DBA has not been well established yet. In this study, we investigated the function and molecular mechanism of DBA in human oral cancer cells. MATERIALS AND METHODS: The growth-inhibitory and apoptotic effects and related signaling pathways of DBA were evaluated using trypan blue exclusion assay, 4’-6-diamidino-2-phenylindole staining, Western blot analysis, siRNA, and reverse transcription-polymerase chain reaction. RESULTS: DBA inhibited cell growth and induced apoptosis, as evidenced by PARP cleavage, activation of caspase-3, and nuclear condensation. DBA also decreased specificity protein 1 (Sp1) expression through facilitating protein degradation. In addition, DBA enhanced the induction of pro-apoptotic protein Bax, resulting in their conformational change, translocation into mitochondrial outer membrane, and its oligomerization. The down-regulation of Sp1 by siRNA targeting Sp1 and mithramycin A increasingly activated Bax to trigger apoptosis. Moreover, DBA-induced growth inhibition and apoptosis in various human oral cancer cell lines were associated with Sp1 down-regulation and induction of Bax. CONCLUSION:  These findings suggest that DBA may be a potential anticancer drug candidate to induce apoptosis through down-regulation of Sp1 in human oral cancer.

 

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[618]

TÍTULO / TITLE:  - Triptolide inhibits MDM2 and induces apoptosis in acute lymphoblastic leukemia cells through a p53-independent pathway.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Cancer Ther. 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1535-7163.MCT-12-0425

AUTORES / AUTHORS:  - Huang M; Zhang H; Liu T; Tian D; Gu L; Zhou M

INSTITUCIÓN / INSTITUTION:  - 1Pediatric Hematology/Oncology, Emory University.

RESUMEN / SUMMARY:  - Triptolide, a natural product derived from the Chinese plant Tripterygium wilfordii, is reported to exhibit antitumor effects in a broad range of cancers.  The antitumor activity of triptolide is associated with its biological activities, as it inhibits various pro-proliferative or anti-apoptotic factors that are dominantly expressed in given types of cancer cells. Herein, we demonstrate that triptolide induced apoptosis in a subgroup of acute lymphoblastic leukemia (ALL) cells overexpressing the MDM2 oncoprotein, by inhibiting MDM2 expression. More specifically, we found that triptolide inhibited MDM2 at the transcriptional level by suppressing its mRNA synthesis. This MDM2 inhibition led in turn to increased levels of p53 protein; however, p53 functionality was not activated, due to the fact that triptolide-treated cells lacked induction of p21 and PUMA as well as in G1 cell-cycle arrest. Triptolide-mediated downregulation of MDM2 increased inhibition of XIAP, its translational target, in a manner distinct from reactions to cellular stress and  DNA-damaging agent ionizing radiation (IR) that induce XIAP due to p53-activated  MDM2. These results suggest that increased inhibition of XIAP due to downregulation of MDM2 may play a critical role in triptolide-induced apoptosis in MDM2-overexpressing cancers.

 

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[619]

TÍTULO / TITLE:  - Role of tumor necrosis factor inhibitor in granulomatous interstitial nephritis secondary to Crohn’s disease.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int Urol Nephrol. 2012 Dec 30.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11255-012-0362-2

AUTORES / AUTHORS:  - Saha MK; Tarek H; Sagar V; Abraham P

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Institution of Regions Hospital, Saint Paul, MN, 55129, USA, drmks1@gmail.com.

RESUMEN / SUMMARY:  - A 17-year-old male with attention deficit hyperactivity disorder was admitted to  the hospital with generalized weakness. Vital signs and physical examination were normal. Laboratory data were notable for a creatinine of 4.5 mg/dL (baseline 0.6  mg/dL), estimated glomerular filtration rate of 18 ml/min/1.73 m(2) and hemoglobin 10 g/dL. Urinalysis revealed only 30 mg/dL protein. Serology for autoimmune workup was negative. Renal ultrasound was normal. Kidney biopsy showed noncaseating granulomas and acute on chronic tubulointerstitial nephritis (TIN) with lymphocytes, macrophages, plasma cells and no eosinophils. Acid fast bacilli and Grocott’s methenamine silver stains were negative. Granulomatous interstitial nephritis (GIN) was diagnosed. Prednisone at 60 mg/day was started and tapered. He was then noted to have diarrhea. Colonoscopy showed active enteritis with granulomatous inflammation consistent with Crohn’s disease (CD). Azathioprine was started but due to worsening renal function and diarrhea, it was discontinued. He did not tolerate continued higher doses of prednisone because of mood swings and  cushingoid features. Infliximab was initiated with improvement in renal function. There was rapid worsening of renal function when infliximab therapy was interrupted but improved when both prednisone and inflixamb were reinitiated.

 

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[620]

TÍTULO / TITLE:  - Aromatase inhibitors in the treatment of elderly women with metastatic breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast. 2013 Jan 12. pii: S0960-9776(12)00259-7. doi: 10.1016/j.breast.2012.12.015.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.breast.2012.12.015

AUTORES / AUTHORS:  - Gluck S; von Minckwitz G; Untch M

INSTITUCIÓN / INSTITUTION:  - Department of Medicine, Division of Hematology/Oncology, Sylvester Comprehensive  Cancer Center, University of Miami, Leonard M. Miller School of Medicine, 1475 NW 12th Ave, Miami, FL 33136, USA. Electronic address: sgluck@med.miami.edu.

RESUMEN / SUMMARY:  - The proportion of elderly women in the population is rising, and in tandem, the incidence of breast cancer rises with age. Because of health and tolerability concerns, as well as life expectancy, physicians may be reluctant to advise a standard treatment regimen for elderly patients with metastatic breast cancer. To elucidate this issue, we performed a literature review of clinical studies that included women with metastatic breast cancer who were over the age of 65. Our results show that although little clinical evidence exists, what is available suggests that standard treatment is tolerated and beneficial for patients meeting certain criteria. A geriatric assessment may identify specific patient groups (independent, dependent, or frail) and thereby guide treatment. Treatment recommendations for elderly patients with metastatic breast cancer are sparse, although first-line endocrine treatment, usually aromatase inhibitors or tamoxifen, is recommended for hormone-sensitive disease. In general, the evidence from clinical studies suggests that aromatase inhibitors are more effective than  either tamoxifen or megestrol acetate as first- or second-line treatment in postmenopausal women with metastatic breast cancer. Ultimately, quality of life,  treatment effects, and comorbidities are important aspects in this population and may guide treatment choice. To provide evidence-based treatment guidance, future  clinical trials should include more patients over the age of 65 years.

 

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[621]

TÍTULO / TITLE:  - The DNA repair protein ALKBH2 mediates temozolomide resistance in human glioblastoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Neuro Oncol. 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1093/neuonc/nos301

AUTORES / AUTHORS:  - Johannessen TC; Prestegarden L; Grudic A; Hegi ME; Tysnes BB; Bjerkvig R

INSTITUCIÓN / INSTITUTION:  - NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway (T.-C.A.J., L.P., A.G., B.B.T., R.B.); Department of Dermatology, Haukeland University Hospital, Bergen, Norway (L.P.); Department of Clinical Neurosciences, Lausanne University Hospital, Lausanne, Switzerland (M.E.H.); NorLux Neuro-Oncology, Oncology Department, Centre de Recherche Public de la Sante, Luxembourg, Luxembourg (R.B.).

RESUMEN / SUMMARY:  - IntroductionGlioblastoma multiforme (GBM; World Health Organization astrocytoma grade IV) is the most frequent and most malignant primary brain tumor in adults.  Despite multimodal therapy, all such tumors practically recur during the course of therapy, causing a median survival of only 14.6 months in patients with newly  diagnosed GBM. The present study was aimed at examining the expression of the DNA repair protein AlkB homolog 2 (ALKBH2) in human GBM and determining whether it could promote resistance to temozolomide chemotherapy.MethodsALKBH2 expression in GBM cell lines and in human GBM was determined by quantitative real-time PCR (qRT-PCR) and gene expression analysis, respectively. Drug sensitivity was assessed in GBM cells overexpressing ALKBH2 and in cells in which ALKBH2 expression was silenced by small-interfering (si)RNA. ALKBH2 expression following activation of the p53 pathway was examined by western blotting and qRT-PCR.ResultsALKBH2 was abundantly expressed in established GBM cell lines and  human GBM, and temozolomide exposure increased cellular ALKBH2 expression levels. Overexpression of ALKBH2 in the U87 and U251 GBM cell lines enhanced resistance to the methylating agents temozolomide and methyl methanesulfonate but not to the nonmethylating agent doxorubicin. Conversely, siRNA-mediated knockdown of ALKBH2  increased sensitivity of GBM cells to temozolomide and methyl methanesulfonate but not to doxorubicin or cisplatin. Nongenotoxic activation of the p53 pathway by the selective murine double minute 2 antagonist nutlin-3 caused a significant  decrease in cellular ALKBH2 transcription levels.ConclusionOur findings identify  ALKBH2 as a novel mediator of temozolomide resistance in human GBM cells. Furthermore, we place ALKBH2 into a new cellular context by showing its regulation by the p53 pathway.

 

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[622]

TÍTULO / TITLE:  - Sustained EKR inhibition by EGFR targeting therapies is a predictive factor for synergistic cytotoxicity with PDT as neoadjuvant therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochim Biophys Acta. 2012 Nov 28. pii: S0304-4165(12)00330-3. doi: 10.1016/j.bbagen.2012.11.010.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbagen.2012.11.010

AUTORES / AUTHORS:  - Weyergang A; Selbo PK; Berg K

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway. Electronic address: anette.weyergang@rr-research.no.

RESUMEN / SUMMARY:  - BACKGROUND: Tyrosin kinase inhibitors (TKIs) and monoclonal antibodies aimed to target epidermal growth factor receptor (EGFR) have shown limited effect as monotherapies and drug resistance is a major limitation for therapeutic success.  Adjuvant therapies to EGFR targeting therapeutics are therefore of high clinical  relevance. METHODS: Three EGFR targeting drugs, Cetuximab, Erlotinib and Tyrphostin AG1478 were used in combination with photodynamic therapy (PDT) in two EGFR positive cell lines, A-431 epidermoid skin carcinoma and WiDr colorectal adenocarcinoma cells. The amphiphilic meso-tetraphenylporphine with 2 sulphonate  groups on adjacent phenyl rings (TPPS(2a)) was utilized as a photosensitizer for  PDT. The cytotoxic outcome of the combined treatments was evaluated by cell counting and MTT. Cellular signalling was explored by Western blotting. RESULTS:  PDT as neoadjuvant to Tyrphostin in A-431 cells as well as to Tyrphostin or Erlotinib in WiDr cells revealed synergistic cytotoxicity. In contrast, Erlotinib or Cetuximab combined with neoadjuvant PDT induced an antagonistic effect on cell survival of A-431 cells. Neoadjuvant PDT and EGFR targeting therapies induced a synergistic inhibition of ERK as well as synergistic cytotoxicity only when the EGFR targeting monotherapies caused a prolonged ERK inhibition. There were no correlation between EGFR inhibition by the EGFR targeting monotherapies or the combined therapies and the cytotoxic outcome combination-therapies. CONCLUSIONS:  The results suggest that sustained ERK inhibition by EGFR targeting monotherapies is a predictive factor for synergistic cytotoxicity when combined with neoadjuvant PDT. GENERAL SIGNIFICANCE: The present study provides a rationale for selecting anticancer drugs which may benefit from PDT as adjuvant therapy.

 

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[623]

TÍTULO / TITLE:  - Bortezomib Sensitizes Human Acute Myeloid Leukemia Cells to All-Trans-Retinoic Acid-induced Differentiation by modifying the RARalpha/STAT1 axis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Cancer Ther. 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1535-7163.MCT-12-0433

AUTORES / AUTHORS:  - Ying M; Zhou X; Zhong L; Ling N; Jing H; Luo P; Yang X; Song H; Yang B; He Q

INSTITUCIÓN / INSTITUTION:  - 1College of Pharmaceutical Sciences, Zhejiang University.

RESUMEN / SUMMARY:  - All-Trans-Retinoic Acid (ATRA) has held great promise for differentiation-based therapy, but reportedly down-regulates retinoic acid receptor alpha (RARalpha) in a proteasome-dependent manner, which leads to decreased AML cell differentiation  efficiency. Therefore, research strategies that seek to further sensitize cells to retinoids and extend the range of retinoid-affected myeloid malignancies beyond APL are key investigative avenues. Here, we demonstrate that bortezomib, the first proteasome inhibitor approved for newly diagnosed and relapsed multiple myeloma, exhibited strong synergism with ATRA to promote HL60 and NB4 AML cell differentiation. We observed that bortezomib sensitized AML cells to ATRA-induced morphologic, biochemical, and functional changes indicative of myeloid differentiation, without cell death. Additionally, treatment of human leukemia HL60 xenografts with bortezomib and ATRA together did not increase bortezomib-induced progressive weight loss but resulted in significant tumor growth inhibition in addition to increased differentiation (p<0.05). These enhanced differentiation effects were accompanied by RARalpha stabilization and STAT1 activation. Taken together, our study was the first to evaluate bortezomib  and ATRA synergy in AML cell differentiation and to assess new opportunities for  bortezomib and ATRA combination as a promising approach for future differentiation therapy.

 

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[624]

TÍTULO / TITLE:  - EGF receptor tyrosine kinase inhibitors in the treatment of brain metastases from non-small-cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Expert Rev Anticancer Ther. 2012 Nov;12(11):1429-35. doi: 10.1586/era.12.121.

            ●● Enlace al texto completo (gratuito o de pago) 1586/era.12.121

AUTORES / AUTHORS:  - Bartolotti M; Franceschi E; Brandes AA

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Azienda Unita Sanitaria Locale, Bologna, Italy.

RESUMEN / SUMMARY:  - The incidence of brain metastasis (BM) is high in patients with non-small-cell lung cancer. Available standard therapeutic options, such as whole-brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. Novel agents, such as EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs), have now been included in standard non-small-cell lung cancer treatments. In a small subset of patients harboring EGFR-activating mutations, erlotinib and gefitinib administration was followed by a response rate of 70-80%, and a longer progression-free and overall  survival than those obtained with standard chemotherapeutic regimens. However, since most of the larger studies on these agents have excluded BM patients from their series, few prospective data are available on the efficacy of these agents  in this setting. In recent years, however, several authors have reported a growing number of cases of partial and complete response in BM patients treated with EGFR TKIs. Data from retrospective series and Phase II studies also suggest  that a response can be obtained using EGFR TKI treatment for patients with BM, especially those harboring EGFR mutations.

 

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[625]

TÍTULO / TITLE:  - Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Neuro Oncol. 2013 Jan 17.

            ●● Enlace al texto completo (gratuito o de pago) 1093/neuonc/nos308

AUTORES / AUTHORS:  - Lalezari S; Chou AP; Tran A; Solis OE; Khanlou N; Chen W; Li S; Carrillo JA; Chowdhury R; Selfridge J; Sanchez DE; Wilson RW; Zurayk M; Lalezari J; Lou JJ; Ormiston L; Ancheta K; Hanna R; Miller P; Piccioni D; Ellingson BM; Buchanan C; Mischel PS; Nghiemphu PL; Green R; Wang HJ; Pope WB; Liau LM; Elashoff RM; Cloughesy TF; Yong WH; Lai A

INSTITUCIÓN / INSTITUTION:  - Department of Neurology (S.L., A.T., W.C., S.L., R.C., J.S., M.Z., J.L., J.J.L.,  L.O., K.A., R.H., P.M., D.P., P.L.N., T.F.C., A.L.), Department of Neurosurgery (A.P.C., C.B., L.M.L.), and Department of Pathology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California (O.E.S., N.K., D.E.S., R.W.W. P.S.M. W.H.Y.); Department of Neurology, UC Irvine School of Medicine, University of California, Irvine, California (J.A.C.); Department of Radiological Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California (B.M.E., W.B.P.); Kaiser Permanente Southern  California (R.G.); and Department of Biomathematics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California (H.-J.W., R.M.E.).

RESUMEN / SUMMARY:  - BackgroundPromoter methylation of the DNA repair gene, O-6-methylguanine-DNA methyltransferase (MGMT), is associated with improved treatment outcome for newly diagnosed glioblastoma (GBM) treated with standard chemoradiation. To determine the prognostic significance of MGMT protein expression as assessed by immunohistochemistry (IHC) and its relationship with methylation, we analyzed MGMT expression and promoter methylation with survival in a retrospective patient cohort.MethodsWe identified 418 patients with newly diagnosed GBM at University of California Los Angeles Kaiser Permanente Los Angeles, nearly all of whom received chemoradiation, and determined MGMT expression by IHC, and MGMT promoter methylation by methylation-specific PCR (MSP) and bisulfite sequencing (BiSEQ) of 24 neighboring CpG sites.ResultsWith use of the median percentage of cells staining by IHC as the threshold, patients with <30% staining had progression-free survival (PFS) of 10.9 months and overall survival (OS) of 20.5  months, compared with PFS of 7.8 months (P < .0001) and OS of 16.7 months (P < .0001) among patients with >/=30% staining. Inter- and intrareader correlation of IHC staining was high. Promoter methylation status by MSP was correlated with IHC staining. However, low IHC staining was frequently observed in the absence of promoter methylation. Increased methylation density determined by BiSEQ correlated with both decreased IHC staining and increased survival, providing a practical semiquantitative alternative to MSP. On the basis of multivariate analysis validated by bootstrap analysis, patients with tandem promoter methylation and low expression demonstrated improved OS and PFS, compared with the other combinations.ConclusionsOptimal assessment of MGMT status as a prognostic biomarker for patients with newly diagnosed GBM treated with chemoradiation requires determination of both promoter methylation and IHC protein expression.

 

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[626]

TÍTULO / TITLE:  - Development of peptide inhibitor as a therapeutic agent against head and neck squamous cell carcinoma (HNSCC) targeting p38alpha MAP kinase.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochim Biophys Acta. 2012 Dec 11;1830(3):2763-2769. doi: 10.1016/j.bbagen.2012.12.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbagen.2012.12.001

AUTORES / AUTHORS:  - Gill K; Singh AK; Kapoor V; Nigam L; Kumar R; Holla P; Das SN; Yadav S; Subbarao N; Mohanti BK; Dey S

INSTITUCIÓN / INSTITUTION:  - Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India.

RESUMEN / SUMMARY:  - BACKGROUND: The p38alpha MAP kinase pathway is involved in inflammation, cell differentiation, growth, apoptosis and production of pro-inflammatory cytokines TNF-alpha and IL-1beta. The overproduction of these cytokines plays an important  role in cancer. The aim of this work was to design a peptide inhibitor on the basis of structural information of the active site of p38alpha. METHODS: A tetrapeptide, VWCS as p38alpha inhibitor was designed on the basis of structural  information of the ATP binding site by molecular modeling. The inhibition study of peptide with p38alpha was performed by ELISA, binding study by Surface Plasmon Resonance and anti-proliferative assays by MTT and flow cytometry. RESULTS: The percentage inhibition of designed VWCS against pure p38alpha protein and serum of HNSCC patients was 70.30 and 71.5%, respectively. The biochemical assay demonstrated the K(D) and IC(50) of the selective peptide as 7.22x10(-9)M and 20.08nM, respectively. The VWCS as inhibitor significantly reduced viability of oral cancer KB cell line with an IC(50) value of 10muM and induced apoptosis by activating Caspase 3 and 7. CONCLUSIONS: VWCS efficiently interacted at the ATP binding pocket of p38alpha with high potency and can be used as a potent inhibitor in case of HNSCC. GENERAL SIGNIFICANCE: VWCS can act as an anticancer agent as it potentially inhibits the cell growth and induces apoptosis in oral cancer cell-line in a dose as well as time dependent manner. Hence, p38alpha MAP  kinase inhibitor can be a potential therapeutic agent for human oral cancer.

 

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[627]

TÍTULO / TITLE:  - The radio-sensitizing effect of xanthohumol is mediated by STAT3 and EGFR suppression in doxorubicin-resistant MCF-7 human breast cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochim Biophys Acta. 2012 Dec 16;1830(3):2638-2648. doi: 10.1016/j.bbagen.2012.12.005.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbagen.2012.12.005

AUTORES / AUTHORS:  - Kang Y; Park MA; Heo SW; Park SY; Kang KW; Park PH; Kim JA

INSTITUCIÓN / INSTITUTION:  - College of Pharmacy, Yeungnam University, Gyeongsan 712-749, South Korea.

RESUMEN / SUMMARY:  - BACKGROUND: Chemotherapeutic drug resistance remains a clinical obstacle in cancer management. Drug-resistant cancer cells usually exhibit cross-resistance to ionizing radiation, which has devastating consequences for patients. With a better understanding of the molecular mechanisms, it will be possible to develop  strategies to overcome this cross-resistance and to increase therapeutic sensitivity. METHODS: Natural and synthetic flavonoid compounds including xanthohumol, the principal flavonoid in hops, were investigated for its radio-sensitizing activity on human breast cancer MCF-7 and adriamycin-resistant  MCF-7 (MCF-7/ADR) cells. Chemo-sensitizing or radio-sensitizing effect was analyzed by tetrazolium-based colorimetric assay and flow cytometry. Western blot analysis, confocal microscopy, gene silencing with siRNA transfection and luciferase reporter gene assay were performed to examine signaling molecule activation. RESULTS: Among the tested flavonoid compounds, pretreatment of the cells with xanthohumol significantly sensitized MCF-7/ADR cells to the radiation  treatment by inducing apoptosis. In MCF-7/ADR cells, treatment with xanthohumol alone or with gamma-rays significantly decreased levels of anti-apoptotic proteins. Multi-drug resistance 1 (MDR1), epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3) expression levels  in MCF-7/ADR cells were suppressed by xanthohumol treatment. In addition, xanthohumol treatment increased death receptor (DR)-4 and DR5 expression. The xanthohumol-induced changes of these resistance-related molecules in MCF-7/ADR cells were synergistically increased by gamma-ray treatment. CONCLUSIONS: Xanthohumol restored sensitivity of MCF-7/ADR cells to doxorubicin and radiation  therapies. GENERAL SIGNIFICANCE: Our results suggest that xanthohumol may be a potent chemo- and radio-sensitizer, and its actions are mediated through STAT3 and EGFR inhibition.

 

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[628]

TÍTULO / TITLE:  - Decreased Expression and Prognostic Role of Mitogen-Activated Protein Kinase Phosphatase 4 in Hepatocellular Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Gastrointest Surg. 2013 Jan 17.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11605-013-2138-0

AUTORES / AUTHORS:  - Liu J; Ni W; Xiao M; Jiang F; Ni R

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology, Affiliated Hospital of Nantong University, 20# Xisi Road, Nantong, 226001, Jiangsu, China.

RESUMEN / SUMMARY:  - PURPOSE: This study aimed to investigate the potential role and prognostic significance of mitogen-activated protein kinase phosphatase 4 (MKP-4) in the pathology of hepatocellular carcinoma (HCC). METHODS: Western blot analysis and quantitative real-time polymerase chain reaction were performed to detect MKP-4 expression in HCC tissues, pericarcinomatous liver (PCL) tissues, and proliferating HCC cells. The detailed role of MKP-4 was further explored by MKP-4 downregulation in HepG2 cells using small interfering RNA (siRNA). Specimens of 134 HCC patients who had undergone hepatic resection were immunohistochemically evaluated for MKP-4 expression. RESULTS: MKP-4 protein and mRNA levels were significantly lower in HCC tissues than in PCL tissues. In vitro, its expression  was gradually reduced following release of HepG2 cells from serum starvation. The cell counting kit-8 assay and Annexin-V-Fluos staining indicated that MKP-4 knockdown by siRNA in HCC cells enhanced cell survival and inhibited apoptosis. Univariate and multivariate analyses revealed that MKP-4 was a significant predictor for overall survival (OS) and time to recurrence (TTR). High MKP-4 expression was well correlated with prognosis independent of Edmondson grade and  microvascular invasion (P < 0.001). CONCLUSIONS: MKP-4 expression was downregulated in HCC tissues and proliferating HCC cells and correlated with OS and TTR, which suggested that MKP-4 is a candidate prognostic marker for HCC.

 

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[629]

TÍTULO / TITLE:  - The miR-183/96/182 Cluster Regulates Oxidative Apoptosis and Sensitizes Cells to  Chemotherapy in Gliomas.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Cancer Drug Targets. 2012 Dec 13.

AUTORES / AUTHORS:  - Tang H; Bian Y; Tu C; Wang Z; Yu Z; Liu Q; Xu G; Wu M; Li G

INSTITUCIÓN / INSTITUTION:  - Cancer Research Institute, Central South University, Changsha, Hunan, China.

RESUMEN / SUMMARY:  - Many microRNAs reside in clusters in the genome, are generally similar in sequence, are transcribed in the same direction, and usually function synergistically. The miR-183/96/182 cluster is composed of 3 miRNA genes, and increased expression of miR-183, 96 and 182 are implicated in glioma carcinogenesis. Knockdown of individual components or of the entire miR-183/96/182 cluster inhibits the survival of glioma cells by regulating the ROS-induced apoptosis pathway. Furthermore, inhibition of the miR-183/96/182 cluster induced ROS-mediated AKT/survival independent of three target genes FGF9, CPEB1, and FOXO1, and inhibition of the miRNA cluster induced p53/apoptosis signaling, which was dependent on these same genes. In addition, knockdown of the miR-183/96/182 cluster enhanced the anticancer effect of Temozolomide on glioma cells by the ROS-mediated apoptosis pathway. Therefore, the miR-183/96/182 cluster may be a pleiotropic target for glioma therapy.

 

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[630]

TÍTULO / TITLE:  - Effect of Response to Interferon-alpha Therapy on the Occurrence of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Dig Dis. 2012;30(6):568-73. doi: 10.1159/000343068. Epub 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000343068

AUTORES / AUTHORS:  - Lee D; Chung YH; Lee SH; Kim SE; Lee YS; Kim KM; Lim YS; Lee HC; Lee YS; Yu E

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

RESUMEN / SUMMARY:  - Objectives: The aim of this study was to examine whether interferon-alpha (IFN-alpha) therapy may reduce the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) and to determine its effect based on responsiveness  to IFN-alpha therapy. Methods: A total of 641 biopsy-proven CHB patients were treated with IFN-alpha2b. They were followed by biochemistry and/or imaging studies at 3- to 6-month intervals for a median period of 113 months (range 6-222). Results: HCC was detected in 22 patients and 5- and 10-year cumulative occurrence rates were 0.4 and 3.2%, respectively. In univariate analysis, age (p  < 0.001), serum AFP levels (p < 0.001), and serum HBV-DNA levels (p = 0.002) at baseline were associated with HCC development. HCC occurred less frequently in biochemical responders at the end of treatment than in non-responders (p = 0.001). However, virologic response was not associated with HCC development. Multivariate analysis showed that poor biochemical response (p = 0.007) as well as older age (p = 0.018) and a higher serum AFP level (p < 0.001) remained independent predisposing factors of HCC development in CHB patients treated with  IFN-alpha. Conclusion: The results suggest that the biochemical but not virologic response to IFN-alpha therapy reduces independently the occurrence of HCC in patients with CHB.

 

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[631]

TÍTULO / TITLE:  - Role of Conventional Chemosensitivity Test and Tissue Biomarker Expression in Predicting Response to Treatment of Peritoneal Carcinomatosis From Colon Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Colorectal Cancer. 2013 Jan 15. pii: S1533-0028(12)00147-8. doi: 10.1016/j.clcc.2012.11.006.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clcc.2012.11.006

AUTORES / AUTHORS:  - Arienti C; Tesei A; Verdecchia GM; Framarini M; Virzi S; Grassi A; Scarpi E; Turci L; Silvestrini R; Amadori D; Zoli W

INSTITUCIÓN / INSTITUTION:  - Biosciences Laboratory, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy.

RESUMEN / SUMMARY:  - BACKGROUND: 5-Fluorouracil- or oxaliplatin-based regimens are the treatments of choice in patients with PC from colon cancer. There are currently no useful preclinical evaluations to guide the decision-making process for tailored therapy. The aim of the present study was to compare the advantages and limits of a conventional in vitro chemosensitivity test with those of a panel of biomolecular markers in predicting clinical response to different drugs used to treat colon cancer-derived PC. PATIENTS AND METHODS: Fresh surgical biopsy specimens were obtained from 28 patients with peritoneal carcinomatosis from colon cancer. TS, TP, DPD, MDR1, MRP-1, MGMT, BRCA1, ERCC1, GSTP1, and XPD gene expression levels were determined by real-time reverse transcription polymerase chain reaction. An in vitro chemosensitivity test was used to define a sensitivity or resistance profile to the drugs used to treat each patient. RESULTS: Expression levels of the genes analyzed were generally poorly related to each other. TS and ERCC1 expression was inversely related to response to 5-FU-and/or oxaliplatin-containing regimens. Significant predictivity in terms of sensitivity but poor predictivity of resistance (56.2%) (P = .037) were observed  for ERCC1 expression (90%), and high predictivity of resistance (100%) but very low predictivity of sensitivity (40%) (P = .014) were registered for TS. The best overall and significant predictivity was observed for chemosensitivity test results (62.5% sensitivity and 89% resistance; P = .005). CONCLUSIONS: Sensitivity and resistance to drugs used in vivo was better defined by the chemosensitivity test than by biomarker expression.

 

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[632]

TÍTULO / TITLE:  - Salinomycin induces apoptosis and senescence in breast cancer: Upregulation of p21, downregulation of survivin and histone H3 and H4 hyperacetylation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochim Biophys Acta. 2013 Jan 22. pii: S0304-4165(13)00014-7. doi: 10.1016/j.bbagen.2013.01.010.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbagen.2013.01.010

AUTORES / AUTHORS:  - Dhaheri YA; Attoub S; Arafat K; Abuqamar S; Eid A; Faresi NA; Iratni R

INSTITUCIÓN / INSTITUTION:  - Department of Biology, College of Science, UAE University, P.O. Box: 17551, United Arab Emirates University, Al-Ain, P.O. Box 17551, United Arab Emirates.

RESUMEN / SUMMARY:  - In the present study, we investigated the effect of Salinomycin on the survival of three human breast cancer cell lines MCF-7, T47D and MDA-MB-231 grown in adherent culture conditions. Salinomycin was able to inhibit the growth of the three cell lines in time- and concentration-dependent manners. We showed that depending on the concentrations used, Salinomycin elicits different effects on the MDA-MB-231 cells. High concentrations of Salinomycin induced a G2 arrest, downregulation of survivin and triggered apoptosis. Interestingly, treatment with low concentrations of Salinomycin induced a transient G1 arrest at earlier time point and G2 arrest at later point and senescence associated with enlarged cell morphology, upregulation of p21 protein, increase in histone H3 and H4 hyperacetylation and expression of SA-beta-Gal activity. Furthermore, we found that Salinomycin was able to potentiate the killing of the MCF-7 and MDA-MB-231 cells, by the chemotherapeutic agents, 4-Hydroxytamoxifen and frondoside A, respectively. Our data are the first to link senescence and histone modifications to Salinomycin. This study provides a new insight to better understand the mechanism of action of Salinomycin, at least in breast cancer cells.

 

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[633]

TÍTULO / TITLE:  - Set9, NF-kappaB, and microRNA-21 mediate berberine-induced apoptosis of human multiple myeloma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Acta Pharmacol Sin. 2013 Jan;34(1):157-66. doi: 10.1038/aps.2012.161. Epub 2012 Dec 17.

            ●● Enlace al texto completo (gratuito o de pago) 1038/aps.2012.161

AUTORES / AUTHORS:  - Hu HY; Li KP; Wang XJ; Liu Y; Lu ZG; Dong RH; Guo HB; Zhang MX

INSTITUCIÓN / INSTITUTION:  - Oncology Department of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China.

RESUMEN / SUMMARY:  - Aim:To investigate the mechanisms by which berberine suppressed the proliferation of human multiple myeloma cells.Methods:Human U266 multiple myeloma cell line was tested. Cell proliferation, apoptosis, ultramicrostructure and secretion function were examined using Cell Counting Kit-8 (CCK8), flow cytometry (FCM), electron and fluorescence microscopy, as well as ELISA assay. The microRNAs (miRs) and transcription factors in U266 cells were detected using arrays and verified by qRT-PCR. EMSA and luciferase assays were used to verify the p65-dependent transactivation of miR-21 gene.Results:Treatment of U266 cells with berberine (40-160 mumol/L) suppressed cell proliferation and IL-6 secretion in dose- and time-dependent manners. Meanwhile, berberine dose-dependently induced ROS generation, G(2)/M phase arrest and apoptosis in U266 cells, and decreased the levels of miR-21 and Bcl-2. Overexpression of miR-21 counteracted berberine-induced suppression of cell proliferation and IL-6 secretion. In U266 cells treated with berberine (80 mumol/L), the activity of NF-kappaB was decreased by approximately 50%, followed by significant reduction of miR-21 level. berberine (80-160 mumol/L) increased the level of Set9 (lysine methyltransferase) by more than 2-fold, caused methylation of the RelA subunit, which inhibited NF-kappaB nuclear translocation and miR-21 transcription. In U266 cells treated with berberine (80 mumol/L), knockdown of Set9 with siRNAs significantly increased NF-kappaB protein level accompanying with a partial recovery of proliferation.Conclusion:In U266 cells, berberine suppresses NF-kappaB nuclear translocation via Set9-mediated lysine methylation, leads to decrease in the levels miR21 and Bcl-2, which induces ROS generation and apoptosis.

 

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[634]

TÍTULO / TITLE:  - Apoptosis drives cancer cells proliferate and metastasize.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Cell Mol Med. 2013 Jan;17(1):205-11. doi: 10.1111/j.1582-4934.2012.01663.x. Epub 2013 Jan 11.

            ●● Enlace al texto completo (gratuito o de pago) 1111/j.1582-4934.2012.01663.x

AUTORES / AUTHORS:  - Wang RA; Li QL; Li ZS; Zheng PJ; Zhang HZ; Huang XF; Chi SM; Yang AG; Cui R

INSTITUCIÓN / INSTITUTION:  - State Key Lab of Tumor Biology, The Fourth Military Medical University, Xi’an, China; Department of Pathology of Xijing Hospital, The Fourth Military Medical University, Xi’an, China; Department of Pathology and Pathophysiology, The Fourth Military Medical University, Xi’an, China.

RESUMEN / SUMMARY:  - Cancer has been considered to be the result of accumulated gene mutations, which  result in uncontrolled cell proliferations for a long time. Cancers are also regarded to be capable of immune evasion. Furthermore, resistance to apoptosis was recognized as an important trait of cancer in the last score of years. However, there are numerous paradoxical issues in this whole set of theory. For example, there is no known set of genes of which mutations are responsible for human cancers. As for the trait of ‘resistance to apoptosis’, the fact is that cancer has increased frequency of apoptosis. The more malignant the tumour is, the more apoptosis shows. In this study, we propose a new theory that apoptosis plays a key role in the malignant progression and metastasis of cancer. The growth of tumour is the difference between tumour cell proliferation and attrition plus the hyperplastic growth of stroma. Increased and unpreventable death caused by innate or environmental factors such as ischaemia and inflammation drives the tumour cells to proliferate relentlessly, move to new lands to establish colonies. In short, increased cell death is the origin of malignancy.

 

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[635]

TÍTULO / TITLE:  - Synthesis of spirolactone-type diterpenoid derivatives from kaurene-type oridonin with improved antiproliferative effects and their apoptosis-inducing activity in  human hepatoma Bel-7402 cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Med Chem. 2013 Jan;59:322-8. doi: 10.1016/j.ejmech.2012.11.002. Epub 2012 Nov 21.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejmech.2012.11.002

AUTORES / AUTHORS:  - Li D; Cai H; Jiang B; Liu G; Wang Y; Wang L; Yao H; Wu X; Sun Y; Xu J

INSTITUCIÓN / INSTITUTION:  - Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.

RESUMEN / SUMMARY:  - A series of novel spirolactone-type diterpenoid derivatives of oridonin (12a-j) were designed and synthesized. All the target compounds showed improved anti-proliferative activity against a panel of human cancer cell lines and the most effective compound 12j was more potent than positive control Taxol in K562 and Bel-7402 cells with IC(50) values of 0.39 muM and 1.39 muM, respectively. The cellular mechanisms showed that compound 12j induced apoptosis at low micromolar  concentrations in human hepatoma Bel-7402 cells. These results demonstrate that the spirolactone-type diterpenoid derivatives of oridonin have optimized growth inhibitory activity against cancer cells and interesting apoptosis-inducing ability.

 

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[636]

TÍTULO / TITLE:  - Gene delivery of cyclin-dependent kinase inhibitors p21 ( Waf1 ) and p27 ( Kip1 ) suppresses proliferation of MCF-7 breast cancer cells in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer. 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12282-012-0438-y

AUTORES / AUTHORS:  - Jiang D; Wang X; Liu X; Li F

INSTITUCIÓN / INSTITUTION:  - Breast Surgery, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, 266003, Shandong, China.

RESUMEN / SUMMARY:  - BACKGROUND: Because tumorigenesis depends on a variety of oncogenes, symphyseal study of combined genes may lead to more significant knowledge about tumorigenesis and progression. Combined deficiency of p21 and p27 proteins in mice is linked to more aggressive spontaneous tumorigenesis. We investigated the  effect of the transfected p21 ( Waf1 )-p27 ( Kip1 ) gene on centrosome duplication, cell proliferation, and apoptosis of MCF-7, a breast cancer cell line. METHODS: The pIRES-p21 ( Waf1 ), pIRES-p27 ( Kip1 ), and pIRES-p21 ( Waf1 )-p27 ( Kip1 ) genes were transfected into MCF-7 cells by lipofection. The effect on proliferation was evaluated by MTT assay and clone-formation assay. Cell cycle and apoptosis were analyzed by flow cytometry. Apoptosis was tested by flow cytometry and TUNEL assay. Centrosome duplication was detected by use of indirect immunofluorescence microscopy. RESULTS: The results showed that the pIRES-p21 ( Waf1 ), pIRES-p27 ( Kip1 ), and pIRES-p21 ( Waf1 )-p27 ( Kip1 ) significantly inhibited proliferation of MCF-7 cells, followed by accumulation of MCF-7 cells in cycle G(1), induced apoptosis, and a decrease in the proportion of MCF-7 cells which contained abnormal centrosomes. Compared with p21 ( Waf1 ) or p27 ( Kip1 )  alone, combination of p21 ( Waf1 ) and p27 ( Kip1 ) had a much more significant effect (P < 0.05). CONCLUSION: Altogether, these results indicate that the p21 (  Waf1 )-p27 ( Kip1 ) gene combination has a more obvious antitumor effect than p21 ( Waf1 ) or p27 ( Kip1 ) alone. This study provides preclinical evidence that combination of p21 ( Waf1 ) and p27 ( Kip1 ) could be a novel and promising therapeutic approach to treatment of breast cancer with suppressed p21 ( Waf1 ) and p27 ( Kip1 ) expression.

 

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[637]

TÍTULO / TITLE:  - VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Cancer Ther. 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1535-7163.MCT-12-0466

AUTORES / AUTHORS:  - Hart S; Novotny-Diermayr V; Goh KC; Williams M; Tan YC; Ong LC; Cheong A; Ng BK; Amalini C; Madan B; Nagaraj H; Jayaraman R; Pasha KM; Ethirajulu K; Chng WJ; Mustafa N; Goh BC; Benes CH; McDermott U; Garnett MJ; Dymock B; Wood JM

INSTITUCIÓN / INSTITUTION:  - 1Biology, S*BIO Pte Ltd.

RESUMEN / SUMMARY:  - Dysregulation of the PI3K/mTOR pathway either through amplifications, deletions or as a direct result of mutations, has been closely linked to the development and progression of a wide range of cancers. Moreover, this pathway activation is  a poor prognostic marker for many tumor types and confers resistance to various cancer therapies. Here we describe VS-5584, a novel, low molecular-weight compound with equivalent potent activity against mTOR (IC50 = 37 nM) and all class I PI3K isoforms IC50: PI3Kalpha = 16 nM; PI3Kbeta = 68 nM; PI3Kgamma= 25 nM; PI3Kdelta= 42 nM), without relevant activity on 400 lipid and protein kinases. VS-5584 shows robust modulation of cellular PI3K/mTOR pathways, inhibiting phosphorylation of substrates downstream of PI3K and mTORC1/2. A large human cancer cell line panel screen (436 lines) revealed broad anti-proliferative sensitivity and that cells harboring mutations in PI3KCA are generally more sensitive towards VS-5584 treatment. VS-5584 exhibits favorable pharmacokinetic properties after oral dosing in mice and is well tolerated. VS-5584 induces long-lasting and dose-dependent inhibition of PI3K/mTOR signaling in tumor tissue, leading to tumor growth inhibition in various rapalogue-sensitive and -resistant human xenograft models. Furthermore, VS-5584 is synergistic with an EGFRi in a gastric tumor model. The unique selectivity profile and favorable pharmacological and pharmaceutical properties of VS-5584 and its efficacy in a wide range of human tumor models supports further investigations of VS-5584 in clinical trials.

 

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[638]

TÍTULO / TITLE:  - Profilin1 potentiates apoptosis induced by staurosporine in cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Mol Med. 2013 Jan 15.

AUTORES / AUTHORS:  - Yao W; Cai X; Liu C; Qin Y; Cheng H; Ji S; Xu W; Wu C; Chen T; Xu J; Long J; Fang Z; Qu B; Hoth M; Ni Q; Zha X; Yu X

INSTITUCIÓN / INSTITUTION:  - Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China, 270 Dong An Road, Shanghai, 200032, P.R. China. yuxianjun88@hotmail.com.

RESUMEN / SUMMARY:  - The correlation between the loss of Profilin1 (Pfn1) with tumor progression indicated that Pfn1 is a tumor suppressor in human carcinoma. The molecular mechanisms underlying Pfn1 tumor suppression has yet to be elucidated. In this study, we showed that Pfn1 overexpression sensitizes cancer cells to apoptosis through the typical intrinsic apoptotic pathway. Mechanistically, the increased Pfn1 expression mediated the upregulation of p53R273H, one of the most common tumor-associated hotspot mutations of p53, with trans-activation deletion in tumorigenesis and increased localization of p53R273H in cytoplasm. Further studies showed that mutant p53R273H was involved in apoptosis induced by Staurosporine (STS) via transcription-independent mitochondrial functions. We observed (i) the increased cytosolic localization of p53R273H, (ii) the activation of phosphorylation at Ser15, (iii) its mitochondrial localization; Pfn1 acted as a positive regulator of these processes. We also found that Pfn1 interacted with p53R273H and thus facilitated its exertion over the transcription-independent activity in the cytoplasm during drug action. Our results define a new function and mechanism of Pfn1 demonstrating that the combined effect with apoptotic agents led to a synergistic increase in apoptosis. In addition, p53R273H abrogating DNA binding was found to play a major role in the Pfn1-sensitized apoptosis through a transactivation-independent and cytosolic activity.

 

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[639]

TÍTULO / TITLE:  - Gambogic acid promotes apoptosis and resistance to metastatic potential in MDA-MB-231 human breast carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Cell Biol. 2012 Dec;90(6):718-30. doi: 10.1139/o2012-030. Epub 2012 Oct 30.

            ●● Enlace al texto completo (gratuito o de pago) 1139/o2012-030

AUTORES / AUTHORS:  - Li C; Qi Q; Lu N; Dai Q; Li F; Wang X; You Q; Guo Q

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.

RESUMEN / SUMMARY:  - Gambogic acid (GA) is considered a potent anti-tumor agent for its multiple effects on cancer cells in vitro and in vivo. Low concentrations of GA (0.3-1.2 micromol/L) can suppress invasion of human breast carcinoma cells without affecting cell viability. To get a whole profile of the inhibition on breast cancers, higher concentrations of GA and spontaneous metastatic animal models were employed. Treatment with GA (3 and 6 micromol/L) induced apoptosis in MDA-MB-231 cells and the accumulation of reactive oxygen species (ROS). Furthermore, GA induced PARP cleavage, activation of caspase-3, caspase-8, and caspase-9, as well as an increased ratio of Bax/Bcl-2. Moreover, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c  (Cyt c) from mitochondria were observed, indicating that GA induced apoptosis through accumulation of ROS and mitochondrial apoptotic pathway. GA also inhibited cell survival via blocking Akt/mTOR signaling. In vivo, GA significantly inhibited the xenograft tumor growth and lung metastases in athymic BALB/c nude mice bearing MDA-MB-231 cells. Collectively, these data provide further support for the multiple effects of GA on human breast cancer cells, as well as for its potential application to inhibit tumor growth and prevent metastasis in human cancers.

 

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[640]

TÍTULO / TITLE:  - Polysaccharide-K (PSK) increases p21(WAF/Cip1) and promotes apoptosis in pancreatic cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pancreatology. 2012 Nov-Dec;12(6):467-74. doi: 10.1016/j.pan.2012.09.004. Epub 2012 Sep 23.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.pan.2012.09.004

AUTORES / AUTHORS:  - Rosendahl AH; Sun C; Wu D; Andersson R

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Clinical Sciences, Lund University, SE-221 84 Lund, Sweden.

RESUMEN / SUMMARY:  - BACKGROUND: Polysaccharide-K (PSK, Krestin(®)) is a natural remedy and one of the most commonly used medicinal mushroom extracts. It has been used as oral adjuvant treatment in cancer therapy in Japan and other Asian countries for more  than 40 years. PSK is thought to be an immune modulator, however, its antitumor actions remain undefined. The aim of the present study was to investigate underlying mechanisms by which PSK exerts its antitumor effects on malignant epithelial cells. METHODS: Antitumor activities of PSK were evaluated on multiple human pancreatic adenocarcinoma cells in vitro. Cell viability, apoptotic pathways, cytokine expression and involvement of TLR2 and TLR4 were monitored by  MTT, flow cytometry, Western blotting and protein arrays. RESULTS: We demonstrate that PSK acts as a growth inhibitor for pancreatic cancer cells, known otherwise  to be highly resistant to conventional chemotherapies. Pancreatic cancer cells can be protected against PSK-mediated growth inhibition by neutralizing antibodies against TLR2 and TLR4. The antiproliferative actions were associated with upregulated cell cycle regulatory p21(WAF/Cip1) and pro-apoptotic protein Bax levels, resulting in cell cycle arrest and induction of apoptosis. In addition, a significant growth inhibition and additive effect was observed with PSK and gemcitabine administered as combined treatment. CONCLUSION: While previous studies have emphasized the potential importance of PSK in immune activation, the present results uncover additional mechanisms on epithelial cells that may contribute to the antitumor effects provided by PSK as suggested by clinical observations.

 

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[641]

TÍTULO / TITLE:  - Ursolic acid sensitizes prostate cancer cells to TRAIL-mediated apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochim Biophys Acta. 2013 Mar;1833(3):723-30. doi: 10.1016/j.bbamcr.2012.12.005. Epub 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbamcr.2012.12.005

AUTORES / AUTHORS:  - Shin SW; Park JW

INSTITUCIÓN / INSTITUTION:  - School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Taegu 702-701, Korea.

RESUMEN / SUMMARY:  - Prostate cancer is one of the most commonly occurring malignancies in men, and because existing treatments are not able to manage this neoplasm adequately, novel approaches are needed. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has strong antitumor activity via the induction of apoptotic cell death in a wide range of tumor cell types and has negligible toxicity to most normal cells, some prostate carcinoma cells are resistant to the apoptotic effects of TRAIL. Therefore, combinatorial approaches with TRAIL and different chemotherapeutic agents have been developed to overcome the resistance  of cancer cells to TRAIL. Here, we investigated the sensitizing effects of ursolic acid (UA), a pentacyclic triterpenoid found in many plants, on TRAIL-induced prostate cancer cell apoptosis. We found TRAIL-induced prostate cancer cells apoptosis was significantly enhanced by UA, and that UA induced CHOP-dependent DR5 up-regulation. This study shows the use of UA as a sensitizer  for TRAIL-induced apoptotic cell death offers a promising means of enhancing the  efficacy of TRAIL-based prostate cancer treatments.

 

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[642]

TÍTULO / TITLE:  - MiR-218 sensitizes glioma cells to apoptosis and inhibits tumorigenicity by regulating ECOP-mediated suppression of NF-kappaB activity.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Neuro Oncol. 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 1093/neuonc/nos296

AUTORES / AUTHORS:  - Xia H; Yan Y; Hu M; Wang Y; Wang Y; Dai Y; Chen J; Di G; Chen X; Jiang X

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Yijishan Hospital, Wannan Medical College, Wuhu, China (H.X., M.H., Y.D., J.C., G.D., X.J.); Department of Neurology, Huzhou Central Hospital, Huzhou, China (Y.Y., Y.W.); Department of Respiratory Medicine, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China (Y.W.); Henan Cancer Hospital, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China (X.C.).

RESUMEN / SUMMARY:  - IntroductionMalignant gliomas are the most common and deadly primary brain tumors in adults. Increasing evidence has indicated that microRNAs (miRNAs) have an influence on the regulation of apoptotic cell signaling. Downregulation of miRNA  218 (miR-218) has been indicated in human glioma specimens. Here, we investigate  the function of miR-218 in apoptosis and tumor growth of glioma cells.MethodsThe  expression of miR-218 was detected by real-time quantitative reverse transcriptase PCR. The effects of miR-218 on glioma cell proliferation and tumorigenicity were investigated by in vitro clonogenicity and in vivo xenograft  assay. Apoptosis was evaluated by flow cytometric analysis and assay by terminal  deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling. The downstream targets of miR-218 were identified by bioinformatics analysis and further validated by Western blot and luciferase reporter assay.ResultsOverexpression of miR-218 induces glioma cell apoptosis and inhibits glioma cell viability, proliferation, and tumorigenicity. Epidermal growth factor receptor-coamplified and overexpressed protein (ECOP) was identified as a functional downstream target of miR-218, which can regulate transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and associated with apoptotic response. Ectopic expression of ECOP rescued the glioma cells from miR-218-induced apoptosis and increased NF-kappaB activity.ConclusionThese results suggest that miR-218 sensitizes glioma cells to  apoptosis by regulating ECOP-mediated suppression of NF-kappaB activity, which may provide novel opportunities for glioma therapy.

 

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[643]

TÍTULO / TITLE:  - COX-2 and PPAR-gamma Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Cancer Ther. 2013 Jan;12(1):69-82. doi: 10.1158/1535-7163.MCT-12-0335. Epub 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1535-7163.MCT-12-0335

AUTORES / AUTHORS:  - Ramer R; Heinemann K; Merkord J; Rohde H; Salamon A; Linnebacher M; Hinz B

INSTITUCIÓN / INSTITUTION:  - Corresponding Author: Burkhard Hinz, Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany. burkhard.hinz@med.uni-rostock.de.

RESUMEN / SUMMARY:  - The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-gamma in cannabidiol’s proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by  NS-398 (COX-2 inhibitor), GW9662 (PPAR-gamma antagonist), and siRNA targeting COX-2 and PPAR-gamma. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-gamma mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-gamma mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PG) among which PGD(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) caused a translocation of PPAR-gamma to the nucleus and induced a PPAR-gamma-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-gamma in tumor tissue and tumor regression that was reversible  by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol  involving initial upregulation of COX-2 and PPAR-gamma and a subsequent nuclear translocation of PPAR-gamma by COX-2-dependent PGs. Mol Cancer Ther; 12(1); 69-82. ©2012 AACR.

 

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[644]

TÍTULO / TITLE:  - Identification of 5-hydroxy-3,6,7,8,3 ,4 -hexamethoxyflavone from Hizikia fusiforme involved in the induction of the apoptosis mediators in human AGS carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Microbiol Biotechnol. 2012 Dec;22(12):1665-72.

AUTORES / AUTHORS:  - Kim MJ; Lee HH; Seo MJ; Kang BW; Park JU; Kim KS; Kim GY; Joo WH; Choi YH; Cho YS; Jeong YK

INSTITUCIÓN / INSTITUTION:  - Department of Biotechnology, Dong-A University, Busan, Korea.

RESUMEN / SUMMARY:  - An 80% ethanol extract of Hizikia fusiforme was obtained and followed by successive fractionation using the organic solvents n-hexane, ethyl acetate, and  n-butanol to identify the antioxidative substance. The aqueous part of the nbutanol fractionation step, showing high antioxidative activity, was subjected to reverse-phase liquid chromatography. As a result, a substance purified from a  BB-2 fraction showed high antioxidative activity. The m/z 419 [M+H] molecular ion peak in the fraction was observed by the analysis of the ESI-LC/MS spectrum. By the analysis of 1H NMR (500 MHz, DMSO-d6) and 13C NMR (125 MHz, DMSO-d6) spectra, a unique compound of the fraction was biochemically identified as a 5-hydroxy-3,6,7,8,3 ,4 - hexamethoxyflavone (5HHMF). We also investigated the effect of 5HHMF on human gastric AGS carcinoma cells. Western blot analysis suggested that the flavone substantially increased the levels of the death receptor-associated apoptosis mediators Fas, Fas L, FADD, TRADD, and DR4 in a concentration-dependent manner. The levels of Fas, Fas L, TRADD, and DR4 in the cells treated with 5HHMF (5 microgram/ml) were approximately 26.4-, 12.8-, 6.7-,  and 9.8- times higher than those of non-treated cells, respectively. Of note, the level of FADD protein in the cells exposed to 5HHMF (1 microgram/ml) increased approximately 9.6-times. In addition, the cleavage of caspase-3, -8, and -9 in cultured AGS cells treated with 5HHMF was significantly confirmed. Therefore, our results suggest that 5HHMF from H. fusiforme is involved in the induction of death receptor-associated apoptosis mediators in human gastric AGS carcinoma cells.

 

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[645]

TÍTULO / TITLE:  - Suppression of Autophagy Enhanced Growth Inhibition and Apoptosis of Interferon-beta in Human Glioma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Neurobiol. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12035-013-8403-0

AUTORES / AUTHORS:  - Li Y; Zhu H; Zeng X; Fan J; Qian X; Wang S; Wang Z; Sun Y; Wang X; Wang W; Ju D

INSTITUCIÓN / INSTITUTION:  - Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai, 201203, China.

RESUMEN / SUMMARY:  - Interferon-beta (IFN-beta) is a cytokine with anti-viral, anti-proliferative, and immunomodulatory effects. In this study, we investigated the effects of IFN-beta  on the induction of autophagy and the relationships among autophagy, growth inhibition, and apoptosis induced by IFN-beta in human glioma cells. We found that IFN-beta induced autophagosome formation and conversion of microtubule associated protein 1 light chain 3 (LC3) protein, whereas it inhibited cell growth through caspase-dependent cell apoptosis. The Akt/mTOR signaling pathway was involved in autophagy induced by IFN-beta. A dose- and time-dependent increase of p-ERK ½ expression was also observed in human glioma cells treated  with IFN-beta. Autophagy induced by IFN-beta was suppressed when p-ERK1/2 was impaired by treatment with U0126. We also demonstrated that suppression of autophagy significantly enhanced growth inhibition and cell apoptosis induced by  IFN-beta, whereas inhibition of caspase-dependent cell apoptosis impaired autophagy induced by IFN-beta. Collectively, these findings indicated that autophagy induced by IFN-beta was associated with the Akt/mTOR and ERK ½ signaling pathways, and inhibition of autophagy could enhance the growth inhibitory effects of IFN-beta and increase apoptosis in human glioma cells. Together, these findings support the possibility that autophagy inhibitors may improve IFN-beta therapy for gliomas.

 

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[646]

TÍTULO / TITLE:  - Clinical significance of overexpressed cyclin-dependent kinase subunits 1 and 2 in esophageal carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Dis Esophagus. 2013 Jan 10. doi: 10.1111/dote.12013.

            ●● Enlace al texto completo (gratuito o de pago) 1111/dote.12013

AUTORES / AUTHORS:  - Wang JJ; Fang ZX; Ye HM; You P; Cai MJ; Duan HB; Wang F; Zhang ZY

INSTITUCIÓN / INSTITUTION:  - Center for Clinical Laboratory, Zhongshan Hospital, Xiamen University, Xiamen, China.

RESUMEN / SUMMARY:  - The mammalian cyclin-dependent kinase subunit (Cks) family has two members, Cks1  and Cks2. Overexpression of Cks1 and Cks2 has been reported to be associated with high aggressiveness and poor prognosis in several malignancies, including prostate and hepatocellular carcinomas. However, whether Cks1 and Cks2 are overexpressed in esophageal carcinoma remains uncharacterized. To investigate whether overexpression of the Cks family is clinically relevant in esophageal carcinoma, and whether expression patterns of Cks1 and Cks2 can serve as biomarkers for esophageal carcinoma. Real-time quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and Western blot analyses were applied to detect the expression of Cks1 and Cks2 at the mRNA and protein levels, respectively. The associations between Cks1 or Cks2 expressions and clinical features and p27(kip1) expressions in esophageal carcinoma were analyzed. Comparing with the adjacent noncancerous tissues, esophageal carcinoma exhibited  elevated expression of Cks1 in 58% cases at the mRNA level and 54% cases at the protein level, and elevated expression of Cks2 in 65% cases at the mRNA level and 61% cases at the protein level, respectively. The expressions of both Cks1 and Cks2 were negatively associated with the p27(kip1) protein level in the tumor tissues. Furthermore, overexpression of Cks1 and Cks2 in esophageal carcinoma was closely associated with poor pathological features of esophageal carcinoma, including higher histologic grade of tumor, regional lymph nodes invasion, and neoplastic embolus. Overexpression of Cks1 and Cks2 is associated with the aggressive tumor behaviors of esophageal carcinoma. Further efforts are needed to determine whether overexpression of Cks1 and Cks2 can serve as novel biomarkers for esophageal carcinoma.

 

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[647]

TÍTULO / TITLE:  - High Expression of Class III beta-Tubulin Predicts Good Response to Neoadjuvant Taxane and Doxorubicin/Cyclophosphamide-Based Chemotherapy in Estrogen Receptor-Negative Breast Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Breast Cancer. 2012 Dec 5. pii: S1526-8209(12)00259-5. doi: 10.1016/j.clbc.2012.11.003.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clbc.2012.11.003

AUTORES / AUTHORS:  - Wang Y; Sparano JA; Fineberg S; Stead L; Sunkara J; Horwitz SB; McDaid HM

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY. Electronic address: yw232687@gmail.com.

RESUMEN / SUMMARY:  - BACKGROUND: Expression of class III beta-tubulin (betaIotaIotaIota-tubulin) correlates with tumor progression and resistance to taxane-based therapies for several human malignancies including breast cancer. However its predictive value  in a neoadjuvant setting in breast cancer remains unexplored. The objective of this explorative study was to determine whether betaIotaIotaIota-tubulin expression in breast cancer correlated with pathologic characteristics and whether its expression was predictive of response to neoadjuvant chemotherapy. PATIENTS AND METHODS: We determined betaIotaIotaIota-tubulin expression in 85 breast cancers, including 41 localized breast cancers treated with primary surgery and 44 treated with neoadjuvant chemotherapy before surgery. betaIotaIotaIota-tubulin expression was evaluated by immunohistochemical methods  and was correlated with pathologic characteristics and response to neoadjuvant chemotherapy using residual cancer burden (RCB) score. RESULTS: High betaIotaIotaIota-tubulin expression was significantly associated with poorly differentiated high-grade breast cancers (P = .003) but not with tumor size, estrogen receptor (ER) status, or human epidermal growth factor receptor 2 (HER2)/neu overexpression. In ER(-) tumors treated with neoadjuvant chemotherapy, high betaIotaIotaIota-tubulin expression was associated with a significantly greater likelihood of achieving a good pathologic response to chemotherapy as reflected by lower RCB scores (P = .021). CONCLUSION: This study reveals differential betaIotaIotaIota-tubulin expression in breast cancers of different histologic grades, hormone receptors, and HER2/neu status. It also suggests a potential role for betaIotaIotaIota-tubulin as a predictive biomarker for response in neoadjuvant chemotherapy for ER(-) breast cancer, which has not been  previously reported. These data provide a strong rationale for considering betaIotaIotaIota-tubulin status and further validation of this marker in a large  study.

 

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[648]

TÍTULO / TITLE:  - Quantification of plasma cell-free DNA in predicting therapeutic efficacy of sorafenib on metastatic clear cell renal cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Dis Markers. 2013 Jan 2.

            ●● Enlace al texto completo (gratuito o de pago) 3233/DMA-120950

AUTORES / AUTHORS:  - Feng G; Ye X; Fang F; Pu C; Huang H; Li G

INSTITUCIÓN / INSTITUTION:  - Clinical Genetics Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu,  Anhui, China.

RESUMEN / SUMMARY:  - PURPOSE: The objective of this study is to determine whether or not plasma cfDNA  levels can predict efficacy of sorafenib in patient with metastatic cRCC. MATERIALS AND METHODS: Plasma cfDNA levels were quantified by quantitative real-time PCR at six different time-points (before treatment, 4 weeks, 8 weeks, 12 weeks, 16 weeks, and 24 weeks) in 18 metastatic cRCC patients receiving sorafenib, as assessed by CT examination according to RECIST 1.1. RESULTS: A significantly lower plasma cfDNA level, measured from 8 weeks to 24 weeks, was found in patients with remission or stable disease than in those with progression. Higher levels in plasma cfDNA levels during the course of treatment  indicated poor outcome. For predicting progression, a sensitivity of 66.7% was achieved at 100% specificity using cfDNA levels at 8 weeks. CONCLUSIONS: Monitoring of plasma cfDNA levels during the course of sorafenib therapy could identify metastatic cRCC patients who are likely to exhibit a poor response at an early stage.

 

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[649]

TÍTULO / TITLE:  - Long non-coding RNA HOTAIR is an independent prognostic marker for nasopharyngeal carcinoma progression and survival.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Sci. 2013 Jan 3. doi: 10.1111/cas.12092.

            ●● Enlace al texto completo (gratuito o de pago) 1111/cas.12092

AUTORES / AUTHORS:  - Nie Y; Liu X; Qu S; Song E; Zou H; Gong C

INSTITUCIÓN / INSTITUTION:  - Breast Tumor Center, Guangzhou, China; Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Guangzhou, China.

RESUMEN / SUMMARY:  - Identification of new nasopharyngeal carcinoma (NPC) biomarkers is of great clinical value for the diagnosis and treatment of NPC. HOTAIR, a cancer-related long non-coding RNA, was tested and its prognostic value for NPC was evaluated. As determined using in situ hybridization (ISH), 91 of 160 (56.87%) paraffin-embedded NPC biopsies showed high expression levels of HOTAIR (staining  index score >/= 6). HOTAIR was upregulated in tumors with a large size (P = 0.021), more advanced clinical stage (P = 0.012) and increased lymph node tumor burden (P = 0.005). Quantified using real-time PCR, HOTAIR expression levels in fresh tissue and paraffin-embedded samples were 5.2 ~ 48.4-fold higher compared with non-cancer tissue samples. Moreover, HOTAIR expression levels increased with clinical stage progression, which was consistent with ISH findings in the paraffin-embedded tissue. Most importantly, NPC patients with higher HOTAIR levels had a poor prognosis for overall survival using univariate and multivariate analysis. In addition, HOTAIR mediated the migration, invasion and proliferation of NPC cells in vitro. HOTAIR is a potential biomarker for the prognosis of NPC, and dysregulation of HOTAIR might play an important role in NPC progression.

 

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[650]

TÍTULO / TITLE:  - The tyrosine kinase inhibitor E-3810 combined with paclitaxel inhibits the growth of advanced- stage triple-negative breast cancer xenografts.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Cancer Ther. 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1535-7163.MCT-12-0275-T

AUTORES / AUTHORS:  - Bello E; Taraboletti G; Colella G; Zucchetti M; Forestieri D; Licandro SA; Berndt A; Richter P; D’Incalci M; Cavalletti E; Giavazzi R; Camboni G; Damia G

INSTITUCIÓN / INSTITUTION:  - 1Oncology, Istituto Mario Negri.

RESUMEN / SUMMARY:  - E-3810 is a novel small molecule that inhibits VEGFR-1, -2 and -3 and FGFR-1 tyrosine kinases at nM concentrations currently in Phase clinical II. In preclinical studies it had a broad spectrum of antitumor activity when used as monotherapy in a variety of human xenografts. We here investigated the activity of E-3810 combined with different cytotoxic agents in a MDA-MB-231 triple-negative breast cancer xenograft model. The molecule could be safely administered with 5-fluorouracil, cisplatin and paclitaxel. The E-3810-paclitaxel combination showed a striking activity with complete, lasting tumor regressions;  the antitumor activity of the combination was also confirmed in another triple negative breast xenograft, MX-1. The activity was superior to that of the combinations paclitaxel+brivanib and paclitaxel+sunitinib. Pharmacokinetics studies suggest that the extra antitumor activity of the combination is not due to higher paclitaxel tumor levels, which in fact were lower in mice pre-treated with all three kinase inhibitors and the paclitaxel plasma levels excluded reduced drug availability. Pharmacodynamic studies showed that E-3810, brivanib and sunitinib given as single agents or in combination with paclitaxel reduced the number of vessels, but did not modify vessel maturation. Reduced tumor collagen IV and increased plasma collagen IV, associated with increased matrix metalloproteinases, particularly host MMP-9, indicate a proteolytic remodeling of the extracellular matrix caused by E-3810 that in conjunction with the cytotoxic  effect of paclitaxel on the tumor cells (caspase 3/7 activity) might contribute to the striking activity of their combination. These data support the therapeutic potential of combining E-3810 with conventional chemotherapy.

 

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[651]

TÍTULO / TITLE:  - Prognostic Factors Associated With Disease Progression and Overall Survival in Patients With Myelodysplastic Syndromes Treated With Decitabine.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Lymphoma Myeloma Leuk. 2012 Dec 20. pii: S2152-2650(12)00244-3. doi: 10.1016/j.clml.2012.11.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clml.2012.11.001

AUTORES / AUTHORS:  - Jabbour E; Garcia-Manero G; Ravandi F; Faderl S; O’Brien S; Fullmer A; Cortes JE; Wierda W; Kantarjian H

INSTITUCIÓN / INSTITUTION:  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: ejabbour@mdanderson.org.

RESUMEN / SUMMARY:  - BACKGROUND: Myelodysplastic syndromes (MDS) progress to acute myeloid leukemia (AML) in approximately 30% of patients. Identification of risk factors for progression to AML and overall survival (OS) would help guide treatment decisions. PATIENTS AND METHODS: We investigated prognostic factors for progression to AML and survival in 163 patients with MDS treated with decitabine  15 mg/m(2) over 3 hours every 8 hours for 3 days every 6 weeks (n = 74) or 20 mg/m(2) over 1 hour daily for 5 days every 4 weeks (n = 89). RESULTS: Multivariate analysis of pooled baseline data revealed that only study effect was associated with progression to AML. A hemoglobin value at least 10 g/dL, platelet count at least 50 x 10(3)/muL, and lack of chromosome 5 or 7 abnormalities were associated with longer OS. CONCLUSIONS: Patients with certain prognostic factors  should be considered for other interventions in addition to decitabine treatment.

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[652]

TÍTULO / TITLE:  - Interconnections between apoptotic, autophagic and necrotic pathways: implications for cancer therapy development.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Cell Mol Med. 2013 Jan;17(1):12-29. doi: 10.1111/jcmm.12001. Epub 2013 Jan 10.

            ●● Enlace al texto completo (gratuito o de pago) 1111/jcmm.12001

AUTORES / AUTHORS:  - Jain MV; Paczulla AM; Klonisch T; Dimgba FN; Rao SB; Roberg K; Schweizer F; Lengerke C; Davoodpour P; Palicharla VR; Maddika S; Los M

INSTITUCIÓN / INSTITUTION:  - Department of Clinical & Experimental Medicine, Division of Cell Biology, Integrative Regenerative Med. Center (IGEN), Linkoping University, Linkoping, Sweden.

RESUMEN / SUMMARY:  - The rapid accumulation of knowledge on apoptosis regulation in the 1990s was followed by the development of several experimental anticancer- and anti-ischaemia (stroke or myocardial infarction) drugs. Activation of apoptotic pathways or the removal of cellular apoptotic inhibitors has been suggested to aid cancer therapy and the inhibition of apoptosis was thought to limit ischaemia-induced damage. However, initial clinical studies on apoptosis-modulating drugs led to unexpected results in different clinical conditions and this may have been due to co-effects on non-apoptotic interconnected cell death mechanisms and the ‘yin-yang’ role of autophagy in survival versus cell death. In this review, we extend the analysis of cell death  beyond apoptosis. Upon introduction of molecular pathways governing autophagy and necrosis (also called necroptosis or programmed necrosis), we focus on the interconnected character of cell death signals and on the shared cell death processes involving mitochondria (e.g. mitophagy and mitoptosis) and molecular signals playing prominent roles in multiple pathways (e.g. Bcl2-family members and p53). We also briefly highlight stress-induced cell senescence that plays a role not only in organismal ageing but also offers the development of novel anticancer strategies. Finally, we briefly illustrate the interconnected character of cell death forms in clinical settings while discussing irradiation-induced mitotic catastrophe. The signalling pathways are discussed in their relation to cancer biology and treatment approaches.

 

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[653]

TÍTULO / TITLE:  - Valproic acid enhances cisplatin cytotoxicity in melanoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Acta Pol Pharm. 2012 Nov-Dec;69(6):1298-302.

AUTORES / AUTHORS:  - Chodurek E; Orchel A; Gruchlik A; Aleksander E; Golabek K; Dzierzewicz Z

INSTITUCIÓN / INSTITUTION:  - Department of Biopharmacy, Medical University of Silesia, Sosnowiec, Poland. echodurek@sum.edu.pl

RESUMEN / SUMMARY:  - In recent years, there has been a growing interest in anticancer potential of valproic acid (VPA) resulting from inhibition of histone deacetylase activity. The aim of our study was to evaluate the influence of valproic acid and cisplatin (CPT) on the growth rate of human melanoma cell lines: A375 (melanotic) and C32 (amelanotic). Both tested drugs decreased cell proliferation in a dose-dependent  manner. VPA used alone significantly inhibited the growth of both cell lines at concentrations of 3 and 10 mM. Cisplatin significantly decreased cell proliferation at concentration = 0.3 microM. However, VPA enhanced the cytostatic action of CPT since simultaneous exposure of cells to 1 mM VPA and 0.1 microM CPT resulted in a significant reduction of cell growth. It can be concluded that VPA  increases the sensitivity of melanoma cells to chemotherapeutic agent—cisplatin.

 

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[654]

TÍTULO / TITLE:  - Prognostic impact of Fas-associated death domain, a key component in death receptor signaling, is dependent on the presence of lymph node metastasis in head and neck squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Biol Ther. 2013 Jan 28;14(4).

AUTORES / AUTHORS:  - Fan S; Muller S; Chen ZG; Pan L; Tighiouart M; Shin DM; Khuri FR; Sun SY

INSTITUCIÓN / INSTITUTION:  - Department of Hematology and Medical Oncology; Emory University School of Medicine and Winship Cancer Institute; Atlanta, GA USA; Department of Pathology;  The Second Xiang-Ya Hospital; Central South University; Changsha, China.

RESUMEN / SUMMARY:  - FAS-associated death domain (FADD) is a key adaptor protein that bridges a death  receptor (e.g., death receptor 5; DR5) to caspase-8 to form the death-inducing signaling complex during apoptosis. The expression and prognostic impact of FADD  in head and neck squamous cell carcinoma (HNSCC) have not been well studied. This study focuses on detecting FADD expression and analyzing its prognostic impact in primary and metastatic HNSCCs. We found a significant increase in FADD expression in primary tumors with lymph node metastasis (LNM) in comparison with primary tumors with no LNM. This increase was significantly less in the matched LNM tissues. Both univariate and multivariable analyses indicated that lower FADD expression was significantly associated with better disease-free survival and overall survival in HNSCC patients with LNM although FADD expression did not significantly affect survival of HNSCC patients without LNM . When combined with  DR5 or caspase-8 expression, patients with LNM expressing both low FADD and DR5 or both low FADD and caspase-8 had significantly better prognosis than those expressing both high FADD and DR5 or both high FADD and caspase-8. However, the expression of both low FADD and caspase-8 was significantly linked to worse overall survival compared with both high FADD and caspase-8 expression in HNSCC patients without LNM. Hence, we suggest that FADD alone or together with DR5 and  caspase-8 participates in metastatic process of HNSCC.

 

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[655]

TÍTULO / TITLE:  - Angiogenesis Inhibitors in the Treatment of Epithelial Ovarian Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Treat Options Oncol. 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11864-012-0220-6

AUTORES / AUTHORS:  - Han ES; Wakabayashi M; Leong L

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Division of Gynecologic Oncology, City of Hope, 1500 E. Duarte Road, Duarte, CA, 91010, USA, ehan@coh.org.

RESUMEN / SUMMARY:  - OPINION STATEMENT: Treatment of epithelial ovarian cancer involves surgical management with staging or debulking surgery and chemotherapy with a platinum and taxane-containing regimen. Despite achieving a 70-80 % complete remission, patients often will recur. Novel therapies are needed to improve the treatment of ovarian cancers. Tumor angiogenesis is a critical process involved in the growth  and metastasis of ovarian cancer. Numerous phase II trials with angiogenesis inhibitors have been reported and have led to the development and completion of several recent phase III trials in both upfront and recurrent ovarian cancers. Future studies will need to focus on how and when to incorporate angiogenesis inhibitors in the treatment armamentarium for ovarian cancers.

 

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[656]

TÍTULO / TITLE:  - Making Capecitabine Targeted Therapy for Breast Cancer: Which is the Role of Thymidine Phosphorylase?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Breast Cancer. 2012 Dec 4. pii: S1526-8209(12)00262-5. doi: 10.1016/j.clbc.2012.10.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clbc.2012.10.002

AUTORES / AUTHORS:  - Bonotto M; Bozza C; Di Loreto C; Osa EO; Poletto E; Puglisi F

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, University Hospital of Udine, Udine, Italy.

RESUMEN / SUMMARY:  - Thymidine phosphorylase (TP) expression has been found to be elevated in various  solid tumors where it is likely involved in mechanisms that regulate cell proliferation, apoptosis, and angiogenesis. Based on these properties, it is tempting to hypothesize a potential prognostic role of TP, suggesting that a high TP expression could predict a poor outcome. On the other hand, TP expression has  been studied for its role in predicting benefit from treatment with fluoropyrimidine-containing chemotherapy. Several studies have been conducted on  breast cancer. The current evidence on the value of TP is not mature enough to allow its translation into clinical practice. However, several findings support the potentially predictive role of TP. In this light, TP appears to be a promising marker that can give helpful information to predict the benefit from capecitabine-based chemotherapy in patients with breast cancer.

 

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[657]

TÍTULO / TITLE:  - Irinotecan combined with 5-fluorouracil and leucovorin third-line chemotherapy after failure of fluoropyrimidine, platinum, and taxane in gastric cancer: treatment outcomes and a prognostic model to predict survival.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Gastric Cancer. 2012 Dec 25.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10120-012-0227-5

AUTORES / AUTHORS:  - Kang EJ; Im SA; Oh DY; Han SW; Kim JS; Choi IS; Kim JW; Kim YJ; Kim JH; Kim TY; Lee JS; Bang YJ; Lee KW

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Republic of Korea.

RESUMEN / SUMMARY:  - BACKGROUND: The aim of this study was to evaluate the activity and safety of the  combination chemotherapy of 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI regimen) after failure of fluoropyrimidine, platinum, and taxane in gastric cancer (GC) and to evaluate the prognostic factors for survival. METHODS: Patients received biweekly FOLFIRI chemotherapy as third-line treatment. The FOLFIRI-1 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (200 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 600 mg/m(2) in a 22-h continuous infusion) on days 1 and 2. FOLFIRI-2 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (400 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 2400 mg/m(2) in a 46-h continuous infusion) on day 1. RESULTS: A total of 158 patients were included. The overall response rate was 9.6 % in patients with measurable lesions. The median progression-free survival (PFS) and  overall survival (OS) were 2.1 months [95 % confidence interval (CI), 1.7-2.5] and 5.6 months (95 % CI, 4.7-6.5), respectively. The major grade ¾ toxicity was myelosuppression (36.7 %). Good performance status (PS), fewer metastatic sites,  and longer duration from the first-line to third-line chemotherapy were independent prognostic factors affecting both PFS and OS. CONCLUSIONS: The FOLFIRI regimen showed antitumor activity and tolerable toxicity profiles against advanced GC in the third-line setting. Patients with good PS, fewer metastatic sites and longer previous treatment duration might have the maximal benefit from  third-line chemotherapy.

 

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[658]

TÍTULO / TITLE:  - Increased anaerobic metabolism is a distinctive signature in a colorectal cancer  cellular model of resistance to antiepidermal growth factor receptor antibody.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Proteomics. 2012 Dec 26. doi: 10.1002/pmic.201200303.

            ●● Enlace al texto completo (gratuito o de pago) 1002/pmic.201200303

AUTORES / AUTHORS:  - Monteleone F; Rosa R; Vitale M; D’Ambrosio C; Succoio M; Formisano L; Nappi L; Romano MF; Scaloni A; Tortora G; Bianco R; Zambrano N

INSTITUCIÓN / INSTITUTION:  - CEINGE Biotecnologie Avanzate, Napoli, Italy.

RESUMEN / SUMMARY:  - Cetuximab is a chimeric antibody approved for the treatment of metastatic colorectal cancer that selectively targets epidermal growth factor receptor (EGFR) signaling. Treatment efficacy with this drug is often impaired by acquired resistance and poor information has been accumulated on the mechanisms underlying such a phenomenon. By taking advantage of a syngenic cellular system of sensitivity and acquired resistance to anti-EGFR therapy in the colorectal carcinoma GEO cell line, we profiled protein expression differences between Cetuximab-sensitive and -resistant cells. Combined 2D DIGE and MS analyses revealed a main proteomic signature resulting from selective deregulation of various metabolic enzymes, including glucose-6-phosphate dehydrogenase, transketolase, lactate dehydrogenase B, and pyruvate dehydrogenase E1, which was  also confirmed by Western blotting experiments. Lactate dehydrogenase B downregulation has been already related to an increased anaerobic utilization of  glucose by tumor cells; accordingly, we verified that Cetuximab-resistant cells have a significantly higher production of lactate. Resistant cells also showed decreased nicotinamide adenine dinucleotide phosphate (NADPH) levels. Observed protein deregulations were not related to functional alterations of the hypoxia-inducible factor 1-associated pathways. Our data demonstrate that increased anaerobic metabolism is a prominent feature observed in the GEO syngenic model of acquired resistance to anti-EGFR therapy in colorectal cancer.

 

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[659]

TÍTULO / TITLE:  - Genome-wide transcriptomic variations of human lymphoblastoid cell lines: insights from pairwise gene-expression correlations.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pharmacogenomics. 2012 Dec;13(16):1893-904. doi: 10.2217/pgs.12.179.

            ●● Enlace al texto completo (gratuito o de pago) 2217/pgs.12.179

AUTORES / AUTHORS:  - Vincent M; Oved K; Morag A; Pasmanik-Chor M; Oron-Karni V; Shomron N; Gurwitz D

INSTITUCIÓN / INSTITUTION:  - Universite Paris Descartes, INSERM UMRS775, Paris, France.

RESUMEN / SUMMARY:  - AIMS: Human lymphoblastoid cell lines (LCLs) are a rich resource of information on human interindividual genomic, transcriptomic, proteomic and phenomic variations, and are therefore gaining popularity for pharmacogenomic studies. In  the present study we demonstrate that genome-wide transcriptomic data from a small LCL panel from unrelated individuals is sufficient for detecting pairs of genes that exhibit highly correlated expression levels and may thus convey insights about coregulated genes. MatERIALS & METHODS: RNA samples were prepared  from LCLs representing 12 unrelated healthy adult female Caucasian donors. Transcript levels were determined with the Affymetrix Human Gene arrays. Expression-level correlations were searched using Partek(®) Genomics Suite and  the R environment. Sequences of detected correlated gene pairs were compared for  shared conserved 3 -UTR miRNA binding. RESULTS: Most of the approximately 33,000  transcripts covered by the Affymetrix arrays showed closely similar expression levels in LCLs from unrelated donors. However, the expression levels of some transcripts showed large inter-individual variations. When comparing the expression levels of each of the top 1000 genes showing the largest interindividual expression variations against the others, two sets containing 156 and 4438 correlated gene pairs with false-discovery rates of 0.01 and 0.05 were detected, respectively. Similar analysis of another gene-expression data set from LCLs (GSE11582) indicated that 61 and 39% of identified pairs matched the pairs detected from our transcriptomic data, respectively. Shared conserved 3 -UTR miRNA binding sites were noted for 14-17% of the top 100 gene pairs, suggesting that regulation by miRNA may contribute to their coordinated expression. CONCLUSION: Probing genome-wide transcriptomic data sets of LCLs from unrelated individuals may detect coregulated genes, adding insights on cellular regulation  by miRNAs.

 

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[660]

TÍTULO / TITLE:  - Elafin, an inhibitor of elastase, is a prognostic indicator in breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res. 2013 Jan 15;15(1):R3.

            ●● Enlace al texto completo (gratuito o de pago) 1186/bcr3374

AUTORES / AUTHORS:  - Hunt KK; Wingate H; Yokota T; Liu Y; Mills GB; Zhang F; Fang B; Su CH; Zhang M; Yi M; Keyomarsi K

RESUMEN / SUMMARY:  - ABSTRACT: INTRODUCTION: Elafin is an elastase-specific inhibitor with increased transcription in normal mammary epithelial cells compared to mammary carcinoma cells. In this report, we test the hypothesis that inhibition of elastase, through induction of elafin leads to inhibition of human breast cancer cell viability and therefore predicts survival in breast cancer patients. METHODS: Panels of normal and immortalized breast epithelial cells, along with breast carcinoma cells, were used to examine the impact of adenoviral-mediated elafin expression or shRNA-mediated inhibition of elastase on the growth of cells and xenografts in nude mice. To determine the prognostic significance of decreased elafin in patients with invasive breast cancer, previously published gene array datasets were interrogated. RESULTS: Elafin expression had no effect on non-tumorigenic cells but resulted in marked inhibition of cell growth in breast  cancer cell lines. Control-treated xenografts generated a tumor burden that necessitated sacrifice within 1 month of initial treatment, whereas xenograft-bearing mice treated with Ad-Elafin were alive at 8 months with marked  reduction in tumor growth. Elastase inhibition mimicked these results, showing decreased tumor cell growth in vitro and in vivo. Low expression of elafin gene correlated with significantly reduced time to relapse, and when combined with high expression of elastase gene was associated with decreased survival in breast cancer patients. CONCLUSION: Our data suggest that elafin plays a direct role in  the suppression of tumors through inhibition of elastase and thus serves as a prognostic indicator for breast cancer patients.

 

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[661]

TÍTULO / TITLE:  - Chemokine CXCL14 is associated with prognosis in patients with colorectal carcinoma after curative resection.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Transl Med. 2013 Jan 7;11:6. doi: 10.1186/1479-5876-11-6.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1479-5876-11-6

AUTORES / AUTHORS:  - Zeng J; Yang X; Cheng L; Liu R; Lei Y; Dong D; Li F; Lau QC; Deng L; Nice EC; Xie K; Huang C

INSTITUCIÓN / INSTITUTION:  - The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University,  Chengdu, 610041, P, R, China. mei97@sina.com.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: The chemokine CXCL14 has been reported to play an important role in the progression of many malignancies such as breast cancer and papillary  thyroid carcinoma, but the role of CXCL14 in colorectal carcinoma (CRC) remains to be established. The purpose of this study was to investigate the expression pattern and significance of CXCL14 in CRC progression. METHOD: 265 colorectal carcinoma specimens and 129 matched adjacent normal colorectal mucosa specimens were collected. Expression of CXCL14 in clinical samples was examined by immunostaining. The effect of CXCL14 on colorectal carcinoma cell proliferation was measured by MTT assay, BrdU incorporation assay and colony formation assay. The impact of CXCL14 on migration and invasion of colorectal carcinoma cells was  determined by transwell assay and Matrigel invasion assay, respectively. RESULTS: CXCL14 expression was significantly up-regulated in tumor tissues compared with adjacent nontumorous mucosa tissues (P < 0.001). Tumoral CXCL14 expression levels were significantly correlated with TNM (Tumor-node-metastasis) stage, histodifferentiation, and tumor size. In multivariate Cox regression analysis, high CXCL14 expression in tumor specimens (n = 91) from stage I/II patients was associated with increased risk for disease recurrence (risk ratio, 2.92; 95% CI,  1.15-7.40; P = 0.024). Elevated CXCL14 expression in tumor specimens (n = 135) from stage III/IV patients correlated with worse overall survival (risk ratio, 3.087; 95% CI, 1.866-5.107; P < 0.001). Functional studies demonstrated that enforced expression of CXCL14 in SW620 colorectal carcinoma cells resulted in more aggressive phenotypes. In contrast, knockdown of CXCL14 expression could mitigate the proliferative, migratory and invasive potential of HCT116 colorectal carcinoma cells. CONCLUSION: Taken together, CXCL14 might be a potential novel prognostic factor to predict the disease recurrence and overall survival and could be a potential target of postoperative adjuvant therapy in CRC patients.

 

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[662]

TÍTULO / TITLE:  - Prognostic implications of volume-based measurements on FDG PET/CT in stage III non-small-cell lung cancer after induction chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Nucl Med Mol Imaging. 2013 Jan 11.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00259-012-2321-7

AUTORES / AUTHORS:  - Soussan M; Chouahnia K; Maisonobe JA; Boubaya M; Eder V; Morere JF; Buvat I

INSTITUCIÓN / INSTITUTION:  - University Paris 13, Sorbonne Paris Cite, Bobigny, France, michael.soussan@avc.aphp.fr.

RESUMEN / SUMMARY:  - PURPOSE: We sought to determine whether metabolic volume-based measurements on FDG PET/CT scans could provide additional information for predicting outcome in patients with stage III non-small-cell lung cancer (NSCLC) treated with induction chemotherapy. METHODS: Included in the study were 32 patients with stage III NSCLC who were treated with induction platinum-based chemotherapy followed in 21  by surgery. All patients had an FDG PET/CT scan before and after the induction chemotherapy. Tumours were delineated using adaptive threshold methods. The SUVmax, SUVpeak, SUVmean, tumour volume (TV), total lesion glycolysis (TLG), and  volume and largest diameter on the CT images (CTV and CTD, respectively) were calculated. Index ratios of the primary tumour were calculated by dividing the follow-up measurements by the baseline measurements. The prognostic value of each parameter for event-free survival (EFS) was determined using Cox regression models. RESULTS: The median follow-up time was 19 months (range 6-43 months). Baseline PET and CT parameters were not significant prognostic factors. After induction therapy, only SUVmax, SUVpeak, SUVmean, TV, TLG and CTV were prognostic factors for EFS, in contrast to CTD. Of the index ratios, only TV and TLG ratios  were prognostic factors for EFS. Patients with a TLG ratio <0.48 had a longer EFS than those with a TLG ratio >0.48 (13.9 vs. 9.2 months, p = 0.04). After adjustment for the effect of surgical treatment, all the parameters significantly correlated with EFS remained significant. CONCLUSION: SUV, metabolic volume-based indices, and CTV after induction chemotherapy give independent prognostic information in stage III NSCLC. However, changes in metabolic TV and TLG under induction treatment provide more accurate prognostic information than SUV alone,  and CTD and CTV.

 

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[663]

TÍTULO / TITLE:  - Up-regulation of miR-182 by beta-catenin in breast cancer increases tumorigenicity and invasiveness by targeting the matrix metalloproteinase inhibitor RECK.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochim Biophys Acta. 2013 Jan 16. pii: S0304-4165(13)00013-5. doi: 10.1016/j.bbagen.2013.01.009.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbagen.2013.01.009

AUTORES / AUTHORS:  - Chiang CH; Hou MF; Hung WC

INSTITUCIÓN / INSTITUTION:  - Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.

RESUMEN / SUMMARY:  - BACKGROUND: MiR-182 is a member of the miR-183 cluster located at human chromosome 7q32 region and is up-regulated in human cancers. We study the regulation of miR-182 expression and its oncogenic role. METHODS: MiR-182 level was investigated by real-time reverse transcription-PCR. Chromatin immunoprecipitation assay was used to confirm promoter binding of transcription factors. The correlation between miR-182 and RECK was analyzed by Western blotting, real-time RT-PCR and 3(‘)-untranslated region reporter assay. Zymography, matrix metalloproteinase activity, invasion and colony formation were used to study the tumorigenic activity. RESULTS: MiR-182 is over-expressed in human breast tumor tissues and cell lines. Inhibition or knockdown of beta-catenin reduced miR-182 level in MDA-MB-231 cells. ChIP assay confirmed the  binding of beta-catenin on miR-182 promoter. Anti-miR-182 increased the MMP inhibitor RECK protein in MDA-MB-231 cells while pre-miR-182 reduced RECK protein but not mRNA in normal mammary epithelial H184B5F5/M10 cells. Restoration of RECK protein by anti-miR-182 attenuated MMP-9 activity, cell invasion and colony formation. Ectopic expression of miR-182 inhibited restoration of RECK protein by beta-catenin inhibitor indicating miR-182 is important for beta-catenin-induced down-regulation of RECK. An inverse association between miR-182 and RECK was demonstrated in breast tumor tissues. CONCLUSIONS: We provide evidence that miR-182 is up-regulated by beta-catenin signaling pathway in breast cancer and its up-regulation increases tumorigenicity and invasiveness by repressing RECK. GENERAL SIGNIFICANCE: Our data demonstrate for the first time that miR-182 expression is controlled by beta-catenin. In addition, we identify a new miR-182  target RECK which is important for miR-182-induced tumorigenesis.

 

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[664]

TÍTULO / TITLE:  - Low cyclin F expression in hepatocellular carcinoma associates with poor differentiation and unfavorable prognosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Sci. 2013 Jan 10. doi: 10.1111/cas.12100.

            ●● Enlace al texto completo (gratuito o de pago) 1111/cas.12100

AUTORES / AUTHORS:  - Fu J; Qiu H; Cai M; Pan Y; Cao Y; Liu L; Yun J; Zhang CZ

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Pathology, Sun Yat-sen University Cancer  Center, Guangzhou, China.

RESUMEN / SUMMARY:  - Cyclin F, capable of forming SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complex, is implicated in controlling centrosome duplication and preventing genome instability. Cyclin F oscillates during cell cycle with a similar pattern  of cyclin A. However, its expression and the relevant significance in cancer remain totally obscure. In this study, we showed that cyclin F was noticeably decreased in 16 pairs of tissue samples of hepatocellular carcinoma (HCC), compared to paracarcinoma tissues, at both mRNA and protein levels. Immunohistochemical staining data revealed that in 71.8% (176/245) of HCC cases,  cyclin F expression in tumor tissue was much lower than that in nontumorous tissue. Low cyclin F expression, defined by receiver operating characteristic curve (ROC) analysis, was present in 69.0% of HCC patients. Low expression of cyclin F significantly correlated with tumor size, clinical stage, serum AFP level and tumor multiplicity. Further study showed that cyclin F expression was reversely associated with tumor differentiation in HCC. Kaplan-Meier analysis indicated that low cyclin F expression was related to poor overall survival and recurrence-free survival. The prognostic impact of cyclin F was further confirmed by stratified survival analysis. Importantly, multivariate analysis revealed that low cyclin F expression was an independent poor prognostic marker for overall survival. Collectively, we conclude that cyclin F is downregulated in HCC and could be served as a promising prognostic marker for patients suffering from this deadly disease.

 

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[665]

TÍTULO / TITLE:  - Anti-angiogenic and anti-tumor effects of TAK-593, a potent and selective inhibitor of VEGF and PDGF receptor tyrosine kinase.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Sci. 2013 Jan 10. doi: 10.1111/cas.12101.

            ●● Enlace al texto completo (gratuito o de pago) 1111/cas.12101

AUTORES / AUTHORS:  - Awazu Y; Mizutani A; Nagase Y; Tsuchiya S; Nakamura K; Kakoi Y; Kitahara O; Takeuchi T; Yamasaki S; Miyamoto N; Iwata H; Miki H; Imamura SI; Hori A

INSTITUCIÓN / INSTITUTION:  - Inflammation Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.

RESUMEN / SUMMARY:  - We recently reported that TAK-593, a novel imidazo[1,2-b]pyridazine derivative, is a highly potent and selective inhibitor of the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptor tyrosine kinase  families. Moreover, TAK-593 exhibits a uniquely long-acting inhibitory profile towards VEGF receptor 2 (VEGFR2) and PDGF receptor beta (PDGFRbeta). In this study, we demonstrated that TAK-593 potently inhibits VEGF- and PDGF-stimulated cellular phosphorylation and proliferation of human umbilical vein endothelial cells and human coronary artery smooth muscle cells. TAK-593 also potently inhibits VEGF-induced tube formation of endothelial cells co-cultured with fibroblasts. Oral administration of TAK-593 exhibited strong anti-tumor effects against various human cancer xenografts along with good tolerability despite low  level of plasma exposure. Even after the blood and tissue concentrations of TAK-593 decreased below the detectable limit, a pharmacodynamic marker (phospho VEGFR2) was almost completely suppressed, indicating that its long duration of enzyme inhibition might contribute to the potent activity of TAK-593. Immunohistochemical staining indicated that TAK-593 showed anti-proliferative and pro-apoptotic effects on tumors along with a decrease of vessel density and inhibition of pericyte recruitment to microvessels in vivo. Furthermore, dynamic  contrast-enhanced magnetic resonance imaging revealed that TAK-593 reduced tumor  vessel permeability prior to the onset of anti-tumor activity. In conclusion, TAK-593 is an extremely potent VEGFR/PDGFR kinase inhibitor whose potent anti-angiogenic activity suggests therapeutic potential for the treatment of solid tumors.

 

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[666]

TÍTULO / TITLE:  - Combination of guanine arabinoside and Bcl-2 inhibitor YC137 overcomes the cytarabine resistance in HL-60 leukemia cell line.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Sci. 2013 Jan 15. doi: 10.1111/cas.12103.

            ●● Enlace al texto completo (gratuito o de pago) 1111/cas.12103

AUTORES / AUTHORS:  - Nishi R; Yamauchi T; Negoro E; Takemura H; Ueda T

INSTITUCIÓN / INSTITUTION:  - Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki Matsuoka, Eiheiji, Fukui, 910-1193, Japan.

RESUMEN / SUMMARY:  - Cytarabine (ara-C) is the key agent for treating acute myeloid leukemia. After being transported into leukemic cells, ara-C is phosphorylated, by several enzymes including deoxycytidine kinase (dCK), to ara-C triphosphate (ara-CTP), an active metabolite, and then incorporated into DNA, thereby inhibiting DNA synthesis. Therefore, the cytotoxicity of ara-C depends on the production of ara-CTP and the induction of apoptosis. Here, we established a new ara-C-resistant acute myeloid leukemia cell line (HL-60/ara-C60) with dual resistance characteristics of the anti-antimetabolic character of decreased ara-CTP production and an increase in the antiapoptotic factors Bcl-2 and Bcl-XL. We further attempted to overcome resistance by augmenting ara-CTP production and  stimulating apoptosis. A relatively new nucleoside analog, 9-beta-D-arabinofuranosylguanine (ara-G), and the small molecule Bcl-2 antagonist YC137 were used for this purpose. HL-60/ara-C60 was 60-fold more ara-C-resistant  than the parental HL-60 cells. HL-60/ara-C60 cells exhibited low dCK protein expression, which resulted in decreased ara-CTP production. HL-60/ara-C60 cells were also refractory to ara-C-induced apoptosis due to overexpression of Bcl-2 and Bcl-XL. Combination treatment of ara-C with ara-G augmented the dCK protein level, thereby increasing ara-CTP production and subsequent cytotoxicity. Moreover, the combination of ara-C with YC137 produced the greater amount of apoptosis than ara-C alone. Importantly, the three-drug combination of ara-C, ara-G and YC137 provided the greater cytotoxicity than ara-C+ara-G or ara-C+YC137. These findings suggest possible combination strategies for overcoming ara-C resistance by augmenting ara-CTP production and reversing refractoriness against the induction of apoptosis in ara-C resistant leukemic cells.

 

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[667]

TÍTULO / TITLE:  - Expression and Prognostic Significance of Livin, Caspase-3, and Ki-67 in the Progression of Human Ampullary Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Appl Immunohistochem Mol Morphol. 2013 Jan 21.

            ●● Enlace al texto completo (gratuito o de pago) 1097/PAI.0b013e31827da412

AUTORES / AUTHORS:  - Xue D; Zuo K; Li X; Zhang T; Chen H; Cheng Y; Chen Y

INSTITUCIÓN / INSTITUTION:  - *Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Ji’nan  Departments of daggerInfectious Diseases double daggerPathology section signHepatobiliary Surgery, The People’s Hospital of Binzhou, Binzhou, China.

RESUMEN / SUMMARY:  - Livin is a new member of the inhibitor of apoptosis proteins family of proteins that interacts with downstream caspases, such as caspase-3, caspase-7, and caspase-9, however, its role in human ampullary carcinoma has not been clearly defined. Immunohistochemistry was used to evaluate tissue samples from patients with ampullary carcinomas (n=71) using antibodies against livin, Ki-67 (a proliferation marker), and caspase-3. Livin was detected in 33/71 cases (in the cytoplasm of all and in the nucleus of only 2 cases). High livin expression correlated with cell differentiation, tumor-node-metastasis stage, and lymph node metastasis (P=0.001, P<0.001, and P=0.028, respectively). Caspase-3 and Ki-67 expression were significantly associated with differentiation (P<0.001, P=0.008,  respectively). There was a significant negative correlation between livin and caspase-3 (r=-0.575, P<0.001), and a positive correlation between livin and Ki-67 (r=0.308, P=0.009). Survival of patients with high livin expression was shorter compared with that of patients with low livin expression (P=0.001). Expression of caspase-3 was not associated with overall survival in this cohort (P=0.335). Livin expression was an independent prognostic factor (hazard ratio 2.693, P=0.017), as was lymph node metastasis (hazard ratio 4.959; P<0.001). In this study livin expression significantly correlated with the proliferation marker Ki-67, but was negatively correlated with caspase-3 expression. These data suggest that livin may be a valuable prognostic factor for human ampullary carcinoma.

 

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[668]

TÍTULO / TITLE:  - DNA methylation profiling of medulloblastoma allows robust subclassification and  improved outcome prediction using formalin-fixed biopsies.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Acta Neuropathol. 2013 Jan 5.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00401-012-1077-2

AUTORES / AUTHORS:  - Schwalbe EC; Williamson D; Lindsey JC; Hamilton D; Ryan SL; Megahed H; Garami M; Hauser P; Dembowska-Baginska B; Perek D; Northcott PA; Taylor MD; Taylor RE; Ellison DW; Bailey S; Clifford SC

INSTITUCIÓN / INSTITUTION:  - Northern Institute for Cancer Research, Newcastle University, Sir James Spence Institute Level 5, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK.

RESUMEN / SUMMARY:  - Molecular subclassification is rapidly informing the clinical management of medulloblastoma. However, the disease remains associated with poor outcomes and therapy-associated late effects, and the majority of patients are not characterized by a validated prognostic biomarker. Here, we investigated the potential of epigenetic DNA methylation for disease subclassification, particularly in formalin-fixed biopsies, and to identify biomarkers for improved  therapeutic individualization. Tumor DNA methylation profiles were assessed, alongside molecular and clinical disease features, in 230 patients primarily from the SIOP-UKCCSG PNET3 clinical trial. We demonstrate by cross-validation in frozen training and formalin-fixed test sets that medulloblastoma comprises four  robust DNA methylation subgroups (termed WNT, SHH, G3 and G4), highly related to  their transcriptomic counterparts, and which display distinct molecular, clinical and pathological disease characteristics. WNT patients displayed an expected favorable prognosis, while outcomes for SHH, G3 and G4 were equivalent in our cohort. MXI1 and IL8 methylation were identified as novel independent high-risk biomarkers in cross-validated survival models of non-WNT patients, and were validated using non-array methods. Incorporation of MXI1 and IL8 into current survival models significantly improved the assignment of disease risk; 46 % of patients could be classified as ‘favorable risk’ (>90 % survival) compared to 13  % using current models, while the high-risk group was reduced from 30 to 16 %. DNA methylation profiling enables the robust subclassification of four disease subgroups in frozen and routinely collected/archival formalin-fixed biopsy material, and the incorporation of DNA methylation biomarkers can significantly improve disease-risk stratification. These findings have important implications for future risk-adapted clinical disease management.

 

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[669]

TÍTULO / TITLE:  - Trastuzumab emtansine for advanced HER2-positive breast cancer and beyond: genome landscape-based targets.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Expert Rev Anticancer Ther. 2013 Jan;13(1):5-8. doi: 10.1586/era.12.152.

            ●● Enlace al texto completo (gratuito o de pago) 1586/era.12.152

AUTORES / AUTHORS:  - Cho WC; Roukos DH

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China.

 

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[670]

TÍTULO / TITLE:  - Pyruvate kinase M2 is highly correlated with the differentiation and the prognosis of esophageal squamous cell cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Dis Esophagus. 2013 Jan 14. doi: 10.1111/dote.12023.

            ●● Enlace al texto completo (gratuito o de pago) 1111/dote.12023

AUTORES / AUTHORS:  - Zhan C; Shi Y; Lu C; Wang Q

INSTITUCIÓN / INSTITUTION:  - Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.

RESUMEN / SUMMARY:  - It’s frequently stated that the pyruvate kinase M2 (PKM2) and Warburg effect are  important for cancer development by accumulating more raw materials for macromolecule biosynthesis. However, the correlation between PKM2 and cancer is poorly reported. Here, we investigated the PKM2 expression in esophageal squamous cell cancer (ESCC). We observed that the expression of PKM2 was much higher in ESCC than in control normal tissue, and it is highly associated with many clinical features and prognosis. Specially, we found that the expression of PKM2  was closely related to the differentiation state of ESCC, and we further confirmed this discovery in vitro. As a result, out data indicated that PKM2 might be a useful indicator for determining the survival of patients with ESCC. Considering previous researches on the link among PKM2, Warburg effect, and differentiation, our study inferred the direct roles of PKM2 and Warburg effect in the differentiation of cancer cells rather than only providing synthetic intermediates for the promotion of cancer’s progression.

 

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[671]

TÍTULO / TITLE:  - Diagnostic and Prognostic Role of HBME-1, Galectin-3, and beta-Catenin in Poorly  Differentiated and Anaplastic Thyroid Carcinomas.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Appl Immunohistochem Mol Morphol. 2012 Dec 11.

            ●● Enlace al texto completo (gratuito o de pago) 1097/PAI.0b013e3182688d0f

AUTORES / AUTHORS:  - Rossi ED; Straccia P; Palumbo M; Stigliano E; Revelli L; Lombardi CP; Santeusanio G; Pontecorvi A; Fadda G

INSTITUCIÓN / INSTITUTION:  - *Division of Anatomic Pathology and Histology daggerDivision of Endocrinology double daggerDivision of Endocrine Surgery, Universita Cattolica del Sacro Cuore, “Agostino Gemelli” School of Medicine and Hospital section signDepartment of Pathology and Imaging, University “Tor Vergata”, Rome, Italy.

RESUMEN / SUMMARY:  - AIM:: Thyroid cancer represents the first endocrine malignant neoplasm, accounting for 1% of human malignancy. The majority of which are well-differentiated cancer representing up to 90% of thyroid cancer and pursuing  a favorable clinical course. The groups of poorly differentiated thyroid cancer (PDC) and anaplastic thyroid cancer (ATC) have a poor outcome and need a strict clinical surveillance. MATERIALS AND METHODS:: Thirty-four cases including 23 PDC/insular cancer and 9 ATC were examined for the expression of an immunohistochemical panel made up by HBME-1, galectin-3, and beta-catenin and correlated either with histologic prognostic parameters or the overall surveillance. RESULTS:: HBME-1 and galectin-3 were expressed in 100% of the PDC/insular cases and in none of the ATC cases. The data for beta-catenin pointed out an 80% expression (12/15) in the PDCs and only a focal and nonspecific positivity in the ATCs. A beta-catenin-positive expression was found in all patients with a worse outcome/death and in the presence of vascular invasion and  metastatic disease. All 3 PDC patients with beta-catenin negativity are alive, whereas only 41% (5/12) are alive in the beta-catenin-positive group. CONCLUSIONS:: Our data set up the idea that PDC represents an intermediate step in the biological process of dedifferentiation of thyroid tumors toward ATC. This shift is underlined by the beta-catenin expression, which seems to be related to  a worse prognostic behavior. HBME-1 and galectin-3 show a similar pattern in PDC  compared with well-differentiated carcinoma, whereas they are not expressed, as well as beta-catenin, in anaplastic carcinomas.

 

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[672]

TÍTULO / TITLE:  - PKI 166 induced redox signalling and apoptosis through activation of p53, MAP kinase and caspase pathway in epidermoid carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Exp Ther Oncol. 2012;10(2):139-53.

AUTORES / AUTHORS:  - Das S; Dey KK; Bharti R; MaitiChoudhury S; Maiti S; Mandal M

INSTITUCIÓN / INSTITUTION:  - School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Midnapore, West Bengal, India.

RESUMEN / SUMMARY:  - Cellular redox changes have emerged as a pivotal and proximal event in cancer. PKI 166 is used to determine the effects of redox sensitive inhibition of EGFR, metastasis and apoptosis in epidermoid carcinoma. Cytotoxicity study of PKI 166 (IC50 1.0 microM) treated A431 cells were performed by MTT assay for 48 and 72 hrs. Morphological analysis of PKI 166 treated A431 cells for 48 hrs. revealed the cell shrinkage, loss of filopodia and lamellipodia by phase contrast and SEM  images in dose dependent manner. It has cytotoxic effects through inhibiting cellular proliferation, leads to the induction of apoptosis, as increased fraction of sub-G1 phase of the cell cycle, chromatin condensation and DNA ladder. It inhibited cyclin-D1 and cyclin-E expression and induced p53, p21 expression in dose dependent manner. Consequently, an imbalance of Bax/Bcl-2 ratio triggered caspase cascade and subsequent cleavage of PARP, thereby shifting the balance in favour of apoptosis. PKI 166 treatment actively stimulated reactive oxygen species (ROS) and mitochondrial membrane depolarization. It inhibited some metastatic properties of A431 cells supressing colony formation by soft agar assay and inhibition of MMP 9 activity by gelatin zymography and western blot analysis. PKI 166 inhibited growth factor induced phosphorylation of EGFR, Akt, MAPK, JNK and colony formation in A431 cells. Thus the inhibition of proliferation was associated with redox regulation of the caspase cascade, EGFR,  Akt/PI3K, MAPK/ ERK and JNK pathway. On the other hand, increased antioxidant activity leads to decreased ROS generation inhibit the anti-proliferative and apoptotic properties of PKI 166 in A431 cells. These observations indicated PKI 166 induced redox signalling dependent inhibition of cell proliferation, metastatic properties and induction of apoptotic potential in epidermoid carcinoma.

 

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[673]

TÍTULO / TITLE:  - MicroRNA Expression Profiling of Peripheral Blood Samples Predicts Resistance to  First-line Sunitinib in Advanced Renal Cell Carcinoma Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Neoplasia. 2012 Dec;14(12):1144-52.

AUTORES / AUTHORS:  - Gamez-Pozo A; Anton-Aparicio LM; Bayona C; Borrega P; Gallegos Sancho MI; Garcia-Dominguez R; de Portugal T; Ramos-Vazquez M; Perez-Carrion R; Bolos MV; Madero R; Sanchez-Navarro I; Fresno Vara JA; Arranz EE

INSTITUCIÓN / INSTITUTION:  - Laboratory of Molecular Oncology and Pathology, Instituto de Genetica Medica y Molecular (INGEMM), Instituto de Investigacion Sanitaria del Hospital Universitario La Paz (IdiPAZ), Madrid, España.

RESUMEN / SUMMARY:  - Anti-angiogenic therapy benefits many patients with advanced renal cell carcinoma (RCC), but there is still a need for predictive markers that help in selecting the best therapy for individual patients. MicroRNAs (miRNAs) regulate cancer cell behavior and may be attractive biomarkers for prognosis and prediction of response. Forty-four patients with RCC were recruited into this observational prospective study conducted in nine Spanish institutions. Peripheral blood samples were taken before initiation of therapy and 14 days later in patients receiving first-line therapy with sunitinib for advanced RCC. miRNA expression in peripheral blood was assessed using microarrays and L2 boosting was applied to filtered miRNA expression data. Several models predicting poor and prolonged response to sunitinib were constructed and evaluated by binary logistic regression. Blood samples from 38 patients and 287 miRNAs were evaluated. Twenty-eight miRNAs of the 287 were related to poor response and 23 of the 287 were related to prolonged response to sunitinib treatment. Predictive models identified populations with differences in the established end points. In the poor response group, median time to progression was 3.5 months and the overall survival was 8.5, whereas in the prolonged response group these values were 24 and 29.5 months, respectively. Ontology analyses pointed out to cancer-related pathways, such angiogenesis and apoptosis. miRNA expression signatures, measured  in peripheral blood, may stratify patients with advanced RCC according to their response to first-line therapy with sunitinib, improving diagnostic accuracy. After proper validation, these signatures could be used to tailor therapy in this setting.

 

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[674]

TÍTULO / TITLE:  - Biomarker-driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Med. 2012 Oct;1(2):207-17. doi: 10.1002/cam4.27. Epub 2012 Aug 16.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cam4.27

AUTORES / AUTHORS:  - Arcaroli J; Quackenbush K; Dasari A; Powell R; McManus M; Tan AC; Foster NR; Picus J; Wright J; Nallapareddy S; Erlichman C; Hidalgo M; Messersmith WA

INSTITUCIÓN / INSTITUTION:  - University of Colorado Cancer Center Denver, Colorado.

RESUMEN / SUMMARY:  - Src tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP-sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6-month survival. A Simon MinMax two-stage phase II design was used.  Saracatinib (175 mg/day) was administered orally continuously in 28-day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6-month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker-driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin-like growth factor-binding protein 2 [IGFBP2] “top scoring pairs” polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker-positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3’  untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6-month survival endpoint. As the frequency of biomarker-positive patients was very low (<3%), the study was closed. Although we were unable to conclude whether enriching for a subset of second/third line pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6-month survival, we demonstrate that testing pancreatic tumor samples for a biomarker-driven, multicenter study in metastatic pancreas cancer is feasible.

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[675]

TÍTULO / TITLE:  - Clinical implications of arrest-defective protein 1 expression in hepatocellular  carcinoma: a novel predictor of microvascular invasion.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Dig Dis. 2012;30(6):603-8. doi: 10.1159/000343090. Epub 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000343090

AUTORES / AUTHORS:  - Shim JH; Chung YH; Kim JA; Lee D; Kim KM; Lim YS; Lee HC; Lee YS; Yu E; Lee YJ

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.

RESUMEN / SUMMARY:  - Objective: The associations between arrest-defective protein 1 (ARD1) gene expression and the clinicopathological characteristics and clinical outcomes of 94 patients undergoing hepatectomy for hepatocellular carcinoma (HCC) were investigated. Methods: ARD1 mRNA levels in HCC and corresponding non-cancerous tissues were quantified by real-time PCR. The gene expression of the tumor relative to that in the non-tumor tissues was calculated using the 2(-)(DeltaDelta)(CT) method. The subjects were classified into high expression (2(-)(DeltaDelta)(CT) > 1, n = 38) and low expression (2(-)(DeltaDelta)(CT) </= 1, n = 56) groups. Results: The HCCs did not differ from matched liver tissues in terms of ARD1 mRNA levels. The high expression group had more often microvascular invasion than the low expression group (32 vs. 14%; p = 0.045). The two groups did not differ significantly in terms of other patient or tumor variables. The median follow-up period was 92.1 months. The 5-year recurrence-free and overall survival rates were 34 and 76% for the high expression group, respectively, which were similar to the rates of the low expression group (46 vs. 73%, p = 0.98 and p = 0.52, respectively). Conclusions: Intratumoral ARD1 mRNA overexpression was involved in the microvascular invasion process in patients with HCC, although it  did not associate strongly with postresectional outcomes.

 

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[676]

TÍTULO / TITLE:  - Molecular markers of response and resistance to EGFR inhibitors in head and neck  cancers .

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Front Biosci. 2013 Jan 1;18:520-42.

AUTORES / AUTHORS:  - Box C; Zimmermann M; Eccles S

INSTITUCIÓN / INSTITUTION:  - Tumour Biology and Metastasis Team, CR-UK Cancer Therapeutics Unit, McElwain Laboratories, The Institute of Cancer Research, Cotswold Road, Belmont, Sutton, Surrey, SM2 5NG, UK.

RESUMEN / SUMMARY:  - Receptor tyrosine kinases (RTK) are key targets for novel cancer therapeutics since they activate multiple oncogenic signalling pathways. Also, they are inherently ‘druggable’ due to their small ATP-dependent kinase domains (inhibitable by small molecules) and cell surface location which renders them accessible to monoclonal antibody-based therapies. The epidermal growth factor receptor (EGFR) is overexpressed in the majority of SCCHN cases and this review focuses primarily on the progress made in targeting the EGFR for the therapy of SCCHN by both small molecules and antibody-based therapies. We then discuss the overlapping and distinct molecular markers of response, innate or acquired resistance to each modality, and how these may be overcome. We also consider other RTKs overexpressed in this disease that may impact on responses and/or provide additional targets for combination therapy.

 

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[677]

TÍTULO / TITLE:  - MDM2 is a useful prognostic biomarker for resectable gastric cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Sci. 2013 Jan 24. doi: 10.1111/cas.12111.

            ●● Enlace al texto completo (gratuito o de pago) 1111/cas.12111

AUTORES / AUTHORS:  - Ye Y; Li X; Yang J; Miao S; Wang S; Chen Y; Xia X; Wu X; Zhang J; Zhou Y; He S; Tan Y; Qiang F; Li G; Roe OD; Zhou J

INSTITUCIÓN / INSTITUTION:  - Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, 210029, China.

RESUMEN / SUMMARY:  - MDM2 protein expression appears to be increased in malignancy and correlated to prognosis of tumors, but its role in gastric cancer remains controversial. Our recent investigations indicated that JWA was a novel candidate biomarker for gastric cancer. To evaluate the impact of MDM2 protein expression alone and combined with JWA on the prognostic and predictive of patients with resectable gastric cancer, expression of MDM2 and JWA were examined by immunohistochemistry  in three large patient cohorts (total n=1131) of gastric cancer. We found that MDM2 protein levels were significantly upregulated in gastric cancer (70.4%, 57 of 81) compared with adjacent non-cancerous tissues. High tumoral MDM2 expression significantly correlated with clinicopathologic characteristics, as well as with  shorter overall survival (OS) (P < 0.001 for all cohorts) in patients without adjuvant treatment. The effect of that adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) improved OS compared with surgery alone was evident only in the high MDM2 group (HR = 0.57; 95% CI = 0.37-0.89; P = 0.013). Furthermore, knockdown of MDM2 and overexpression of JWA has synergetic effect on suppression of gastric cancer cell proliferation and migration. Patients with low MDM2 and high JWA expression had a better outcome of survival compared with the other groups (P < 0.001 for all cohorts). For the first time, our data suggest that MDM2 is a potent prognostic and predictive factor for benefit from adjuvant FLO chemotherapy in resectable gastric cancer. And MDM2 expression combined with JWA may serve as a more effective candidate prognostic biomarker for gastric cancer.

 

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[678]

TÍTULO / TITLE:  - Overexpression of Histone Deacetylase 2 Predicts Unfavorable Prognosis in Human Gallbladder Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pathol Oncol Res. 2012 Dec 16.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12253-012-9592-y

AUTORES / AUTHORS:  - Du X; Zhao H; Zang L; Song N; Yang T; Dong R; Yin J; Wang C; Lu J

INSTITUCIÓN / INSTITUTION:  - Department of general surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, People’s Republic of China, du.xilintd@gmail.com.

RESUMEN / SUMMARY:  - As important regulators of chromatin, histone deacetylases (HDACs) are involved in silencing tumor suppressor genes. HDAC2, a member of HDACs, has been demonstrated to be implicated in the development and progression of various human malignancies; however, its expression and role in human primary gallbladder carcinoma (PGC) are not fully understood. Therefore, we conducted this study to address this problem. The subjects were 136 patients underwent resection for PGC. Immunostainings for HDAC2 were performed on these archival tissues. The correlation of HDAC2 expression with clinicopathological characteristics including survival was analyzed. HDAC2 was positively expressed in the nucleus of tumor cells in 86.0 % (117/136) of PGC but not in the normal epithelium of the gallbladder. Additionally, there was a significant difference in the incidence of positive nodal metastasis between high and low HDAC2 expression groups (P = 0.001). The incidences of advanced clinical stage (P = 0.005) and pathologic T stage (P < 0.001), and higher histologic grade (P < 0.001) were respectively higher in the high HDAC2 expression group than in the low group. Moreover, univariate and multivariate analyses revealed the high HDAC2 expression to be an  independent prognostic factor for both overall and disease-free survival of patients with PGC. High HDAC2 expression was correlated with a high incidence of  lymph node metastasis and aggressive tumor progression of PGC. It also was an independent prognostic factor for poorer overall and disease-free survival in patients. Therefore, detection of HDAC2 expression may help us screen patients at increased risk of malignant behavior for PGC.

 

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[679]

TÍTULO / TITLE:  - A model for the design and construction of a resource for the validation of prognostic prostate cancer biomarkers: the Canary Prostate Cancer Tissue Microarray.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Adv Anat Pathol. 2013 Jan;20(1):39-44. doi: 10.1097/PAP.0b013e31827b665b.

            ●● Enlace al texto completo (gratuito o de pago) 1097/PAP.0b013e31827b665b

AUTORES / AUTHORS:  - Hawley S; Fazli L; McKenney JK; Simko J; Troyer D; Nicolas M; Newcomb LF; Cowan JE; Crouch L; Ferrari M; Hernandez J; Hurtado-Coll A; Kuchinsky K; Liew J; Mendez-Meza R; Smith E; Tenggara I; Zhang X; Carroll PR; Chan JM; Gleave M; Lance R; Lin DW; Nelson PS; Thompson IM; Feng Z; True LD; Brooks JD

INSTITUCIÓN / INSTITUTION:  - Canary Foundation, Palo Alto, CA 94304, USA. sarah@canaryfoundation.org

RESUMEN / SUMMARY:  - Tissue microarrays (TMAs) provide unique resources for rapid evaluation and validation of tissue biomarkers. The Canary Foundation Retrospective Prostate Tissue Microarray Resource used a rigorous statistical design, quota sampling, a  variation of the case-cohort study, to select patients for inclusion in a multicenter, retrospective prostate cancer TMA cohort. The study is designed to definitively validate tissue biomarkers of prostate cancer recurrence after radical prostatectomy. Tissue samples from over 1000 participants treated for prostate cancer with radical prostatectomy between 1995 and 2004 were selected at 6 participating institutions in the United States and Canada. This design captured the heterogeneity of screening and clinical practices in the contemporary North American population. Standardized clinical data were collected in a centralized database. The project has been informative in several respects.  The scale and complexity of assembling TMAs with over 200 cases at each of 6 sites involved unanticipated levels of effort and time. Our statistical design promises to provide a model for outcome-based studies where tissue localization methods are applied to high-density TMAs.

 

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[680]

TÍTULO / TITLE:  - The prognostic significance and value of cyclin D1, CDK4 and p16 in human breast  cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res. 2013 Jan 21;15(1):R5.

            ●● Enlace al texto completo (gratuito o de pago) 1186/bcr3376

AUTORES / AUTHORS:  - Peurala E; Koivunen P; Haapasaari KM; Bloigu R; Jukkola-Vuorinen A

RESUMEN / SUMMARY:  - ABSTRACT: INTRODUCTION: Loss of the retinoblastoma protein tumor suppressor gene  (RB) coding for a nuclear phosphoprotein that regulates the cell cycle is found in many human cancers and probably leads to disruption of the p16-cyclin D1-CDK4/6-RB pathway. Cyclin D1 is known to activate CDK4, which then phosphorylates the RB protein, leading to cell cycle progression. p16 inhibits CDK4, keeping RB hypophosphorylated and preventing cell cycle progression. The significance of these three markers, cyclin D1, CDK4 and p16, for breast cancer and carcinogenesis is nevertheless still controversial. METHODS: The material consisted of 102 formalin-fixed human breast cancer samples, in which cyclin D1,  CDK4 and p16 expression was evaluated immunohistochemically. The amounts of cyclin D1 mRNA present were analyzed by quantitative real time PCR. RESULTS: High cyclin D1 expression statistically significantly correlated with lower tumor grade, estrogen and progesterone receptor positivity and lower proliferation activity in breast tumors and increased breast cancer-specific survival and overall survival. Tumors with high cyclin D1 protein had 1.8 times higher expression of cyclin D1 mRNA. CDK4 expression did not correlate with cyclin D1 expression or the survival data. p16 expression was associated with HER2 negativity and increased breast cancer-specific survival and disease-free survival. No statistical correlations between cyclin D1, CDK4 and p16 were found. CONCLUSIONS: Cyclin D1 was associated with a good breast cancer prognosis but functioned independently of CDK4. High cyclin D1 expression may be partially due  to increased CCND1 transcription. p16 correlated with a better prognosis and may  function without CDK4. In conclusion, it appears that cyclin D1, CDK4 and p16 function independently in human breast cancer.

 

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[681]

TÍTULO / TITLE:  - Low Expression of NQO1 Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Breast Cancer Patients Treated with TAC Regimen.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Folia Biol (Praha). 2012;58(5):185-92.

AUTORES / AUTHORS:  - Grim J; Jandik P; Slanska I; Dolezalova-Brcakova E; Fuksa L; Ryska A; Knizek J; Petera J; Micuda S; Hornychova H

INSTITUCIÓN / INSTITUTION:  - Department of Oncology and Radiotherapy, Charles University in Prague, Faculty of Medicine and University Teaching Hospital in Hradec Kralove, Czech Republic.

RESUMEN / SUMMARY:  - The aim of this study was to evaluate preoperative tumour expression of NAD(P)H:quinone oxidoreductase 1 (NQO1) along with other biological markers as potential predictors of pathological complete response (pCR) to neoadjuvant docetaxel, doxorubicin, and cyclophosphamide-containing (TAC) chemotherapy in patients with primary breast cancer. Sixty-one patients who received neoadjuvant  chemotherapy (NCT) with TAC regimen were enrolled in this prospective study. The  pre- and post- NCT expression of oestrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor 1 and 2 (EGFR and HER2), NQO1, Ki-67 proliferation index, multidrug resistance protein 1 (MDR1), p53 and BCL2 were evaluated by immunohistochemistry. The pCR was reached in 14 patients (23 % of the study group). Multivariate analysis demonstrated that patients with ER-, PR-, NQO1- negative, and Ki-67-positive tumours had a significantly higher chance to achieve pCR. Within the biological subtypes, the highest pCR rate (50 %) was seen in triple-negative (i.e. ER-, PR-, HER2-) tumours. Post-operative evaluation showed that in comparison to pre-operative tissue samples, NQO1 expression was significantly increased, while Ki-67 and HER2 decreased, in the residual tissue after NCT. In conclusion, the present data suggests that NQO1 expression may be a novel diagnostic biomarker for the prediction of positive response to NCT in patients with breast cancer.

 

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[682]

TÍTULO / TITLE:  - Use of molecular biomarkers to quantify the spatial distribution of effects of anticancer drugs in solid tumors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Cancer Ther. 2013 Jan 24.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1535-7163.MCT-12-0967

AUTORES / AUTHORS:  - Saggar JK; Fung AS; Patel KJ; Tannock IF

INSTITUCIÓN / INSTITUTION:  - 1MEDICAL BIOPHYSICS, UNIVERSITY OF TORONTO.

RESUMEN / SUMMARY:  - Poor distribution of anticancer drugs within solid tumors may limit their effectiveness. Here we characterize the distribution within solid tumors of biomarkers of drug effect. gammaH2aX, cleaved-caspase -3 or -6 and Ki-67 were quantified in tumor sections in relation to blood vessels (recognized by CD31) using monoclonal antibodies and immunohistochemistry. To validate their use we compared their time-dependent distribution with that of (i) fluorescent doxorubicin and (ii) a monoclonal antibody that detects melphalan-induced DNA adducts. The biomarkers were then used to quantify the distribution of docetaxel  in relation to tumor blood vessels. Activation of gammaH2aX was evaluated following in vitro exposure of tumor cells to multiple drugs. Distributions of doxorubicin in MDA-MB-231 and MCF-7 xenografts and of melphalan-induced DNA adducts in MCF-7 & EMT-6 tumors decreased with distance from blood vessels, similar to the distributions of (i) gammaH2aX at 10 minutes, (ii) cleaved caspase-3 or -6 and (iii) change in Ki-67 at 24 hours following treatment. The distribution of these biomarkers following treatment with docetaxel also decreased with increasing distance from tumor blood vessels. Activation of gammaH2aX occurred within 1 hour after exposure to several drugs in culture. Multiple anticancer drugs show a decrease in activity with increasing distance from tumor blood vessels; poor drug distribution is an important cause of drug resistance. The above biomarkers may be employed in designing strategies to overcome therapeutic resistance by modifying or complementing the limited spatial distribution of drug activity in solid tumors.

 

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[683]

TÍTULO / TITLE:  - Gain(1)(q21) is an Unfavorable Genetic Prognostic Factor for Patients With Relapsed Multiple Myeloma Treated With Thalidomide but Not for Those Treated With Bortezomib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Lymphoma Myeloma Leuk. 2013 Jan 4. pii: S2152-2650(12)00257-1. doi: 10.1016/j.clml.2012.11.012.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clml.2012.11.012

AUTORES / AUTHORS:  - Smetana J; Berankova K; Zaoralova R; Nemec P; Greslikova H; Kupska R; Mikulasova A; Frohlich J; Sevcikova S; Zahradova L; Krejci M; Sandecka V; Almasi M; Kaisarova P; Melicharova H; Adam Z; Penka M; Jarkovsky J; Jurczyszyn A; Hajek R; Kuglik P

INSTITUCIÓN / INSTITUTION:  - Babak Myeloma Group, Department of Pathological Physiology, Faculty of Medicine,  Masaryk University, Brno, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.

RESUMEN / SUMMARY:  - BACKGROUND: Prognostic impact of specific chromosomal aberrations in patients with relapsed multiple myeloma (MM) treated with the novel agents is briefly described. PATIENTS AND METHODS: We analyzed the prognostic value of an extended  panel of chromosomal aberrations [del(13)(q14), del(17)(p13), t(4;14)(p16;q32), gain(1)(q21), and hyperdiploidy] by using the technique of interphase fluorescence in situ hybridization in a cohort of 102 patients with relapsed MM treated with thalidomide- or bortezomib-based protocols. RESULTS: The gain(1)(q21) had a negative impact on overall survival for patients with MM treated with thalidomide (15.7 vs. 41.3 months; P = .004). Moreover, we confirmed the negative impact of the cumulative effect of 2 or more cytogenetic changes that occur simultaneously on the overall survival in the thalidomide group (20.3  months vs. not yet reached; P = .039). We did not find any significant impact of  the aberrations studied on overall survival in the bortezomib cohort of patients. CONCLUSION: We conclude that bortezomib-based protocols are able to partially overcome the negative prognostic impact of the tested chromosomal abnormalities in patients with relapsed MM.

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[684]

TÍTULO / TITLE:  - Autophagy, apoptosis, mitoptosis and necrosis: interdependence between those pathways and effects on cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Arch Immunol Ther Exp (Warsz). 2013 Feb;61(1):43-58. doi: 10.1007/s00005-012-0205-y. Epub 2012 Dec 11.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00005-012-0205-y

AUTORES / AUTHORS:  - Chaabane W; User SD; El-Gazzah M; Jaksik R; Sajjadi E; Rzeszowska-Wolny J; Los MJ

INSTITUCIÓN / INSTITUTION:  - Division of Cell Biology, Department Clinical and Experimental Medicine (IKE), and Integrative Regenerative Medicine Center (IGEN), Linkoping University, Cell Biology Building, Level 10, 581 85, Linkoping, Sweden.

RESUMEN / SUMMARY:  - Cell death is a fundamental ingredient of life. Thus, not surprisingly more than  one form of cell death exists. Several excellent reviews on various forms of cell death have already been published but manuscripts describing interconnection and  interdependence between such processes are uncommon. Here, what follows is a brief introduction on all three classical forms of cell death, followed by a more detailed insight into the role of p53, the master regulator of apoptosis, and other forms of cell death. While discussing p53 and also the role of caspases in  cell death forms, we offer insight into the interplay between autophagy and apoptosis, or necrosis, where autophagy may initially serve pro-survival functions. The review moves further to present some details about less researched forms of programmed cell death, namely necroptosis, necrosis and mitoptosis. These “mixed” forms of cell death allow us to highlight the interconnected nature of cell death forms, particularly apoptosis and necrosis. The interdependence between apoptosis, autophagy and necrosis, and their significance for cancer development and treatment are also analyzed in further parts of the review. In the concluding parts, the afore-mentioned issues will be put in perspective for the development of novel anti-cancer therapies.

 

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[685]

TÍTULO / TITLE:  - Strychnos nux-vomica Root Extract Induces Apoptosis in the Human Multiple Myeloma Cell Line-U266B1.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Biochem Biophys. 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12013-012-9492-5

AUTORES / AUTHORS:  - Rao PS; Prasad MN

INSTITUCIÓN / INSTITUTION:  - Laboratory of Environmental Biotechnology, Department of Plant Sciences, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India, sraopasupuleti@yahoo.com.

RESUMEN / SUMMARY:  - Multiple myeloma (MM) is an incurable B cell neoplasm causing significant morbidity and mortality. Despite recent advances in the MM-treatment, the disease still remains incurable; necessitating a search for new therapeutic agents. Therefore, Strychnos nux-vomica L. root extract (SN) was screened using the human MM-cell line, U266B1. SN-extract demonstrated anti-proliferative effect in a time- and dose-dependent manner. Morphological studies, cell cycle analysis by FACS indicate apoptosis. Furthermore, assessment of signaling molecules like IL-6 (interleukin-6) and CD-138 (Sydencan-1) confirmed apoptosis. The anti-proliferative activity of SN-extract is associated with apoptosis, which is  likely due to the presence of alkaloids, strychnine and brucine, which have been  identified by MALDI-TOF-MS and RP-HPLC analysis.

 

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[686]

TÍTULO / TITLE:  - Histone deacetylase inhibitor induction of epithelial-mesenchymal transitions via up-regulation of Snail facilitates cancer progression.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochim Biophys Acta. 2013 Mar;1833(3):663-71. doi: 10.1016/j.bbamcr.2012.12.002. Epub 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbamcr.2012.12.002

AUTORES / AUTHORS:  - Jiang GM; Wang HS; Zhang F; Zhang KS; Liu ZC; Fang R; Wang H; Cai SH; Du J

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Laboratory, The First Affiliated Hospital of University of South China, Hengyang, 421001, PR China; Department of Microbial and Biochemical  Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China.

RESUMEN / SUMMARY:  - Histone deacetylase inhibitors (HDACIs) are now emerging as a new class of anticancer drugs. Some of them have been used in clinical treatment for tumors, most impressively in the hematological tumors. But their single-agent activities  in epithelial-derived tumors are limited. The mechanisms of these actions of HDACIs are not yet well understood. In this study, it was found for the first time that HDACIs were able to induce epithelial-mesenchymal transitions (EMT) which is believed to trigger tumor cell invasion and metastasis. We show that HDACIs induce fibroblast-like morphology, up-regulate Snail and Vimentin and down-regulate E-cadherin in epithelial cell-derived tumor cell lines. It demonstrates that HDACI treatment enhances further Snail acetylation and reduces  its ubiquitylation, and induces Snail transcription as well as Snail nuclear translocation in CNE2 cells. Snail knockdown by siRNAs prevents the change in cell morphology and Vimentin up-regulation in response to HDACIs. The results suggested that Snail plays an important role in the HDACI-induced EMT. It is very crucial for a better understanding of clinical therapeutical failure of HDACIs in the patients with epithelial cell-derived cancers. Therefore, our results indicate that more attention should be paid to the cancer treatment using HDACIs  due to the fact that it will enhance the spread risks of cancer cells to facilitate cancer progression and it is very important to select appropriate drugs for different tumors.

 

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[687]

TÍTULO / TITLE:  - Combined use of anti-ErbB monoclonal antibodies and erlotinib enhances antibody-dependent cellular cytotoxicity of wild-type erlotinib-sensitive NSCLC cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Cancer. 2012 Dec 12;11(1):91.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1476-4598-11-91

AUTORES / AUTHORS:  - Cavazzoni A; Alfieri RR; Cretella D; Saccani F; Ampollini L; Galetti M; Quaini F; Graiani G; Madeddu D; Mozzoni P; Galvani E; La Monica S; Bonelli M; Fumarola C; Mutti A; Carbognani P; Tiseo M; Barocelli E; Petronini PG; Ardizzoni A

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: The epidermal growth factor receptor (EGFR) is an established target for anti-cancer treatment in different tumour types. Two different strategies have been explored to inhibit this pivotal molecule in epithelial cancer development: small molecules TKIs and monoclonal antibodies. ErbB/HER-targeting by monoclonal antibodies such as cetuximab and trastuzumab or  tyrosine-kinase inhibitors as gefitinib or erlotinib has been proven effective in the treatment of advanced NSCLC. RESULTS: In this study we explored the potential of combining either erlotinib with cetuximab or trastuzumab to improve the efficacy of EGFR targeted therapy in EGFR wild-type NSCLC cell lines. Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the drug inducing protein stabilization. The combined treatment had marginal effect on cell proliferation but markedly increased antibody-dependent, NK mediated, cytotoxicity in vitro. Moreover, in the Calu-3 xenograft model, the combination significantly inhibited  tumour growth when compared with erlotinib and cetuximab alone. CONCLUSION: Our results indicate that erlotinib increases surface expression of EGFR and/or HER2  only in EGFR-TKI sensitive NSCLC cell lines and, in turns, leads to increased susceptibility to ADCC both in vitro and in a xenograft models. The combination of erlotinib with monoclonal antibodies represents a potential strategy to improve the treatment of wild-type EGFR NSCLC patients sensitive to erlotinib.

 

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[688]

TÍTULO / TITLE:  - 12th Annual meeting of the Society of Urologic Oncology (SUO) bladder cancer sessions I and II summary report.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Urol Oncol. 2012 Nov-Dec;30(6):944-7. doi: 10.1016/j.urolonc.2012.07.006.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.urolonc.2012.07.006

AUTORES / AUTHORS:  - Chang SS; Dinney CP; Donat SM; Dahm P; Gore JL; Lotan Y; Parekh DJ; Solit DB; O’Donnell PH; Feng FY; Hansel D; Milowsky MI

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA.

RESUMEN / SUMMARY:  - Health care reform with the Affordable Care Act aims to control health care costs, in part, through the use of comparative effectiveness research and quality of care measures. Bladder cancer is one of the most expensive malignancies to manage as related to the need for continuous monitoring and the treatment of recurrence. The use of clinical practice guidelines relying on evidence based medicine in the management of patients with bladder cancer will help to ensure quality of care and cost containment. The goal of session I was to provide a thorough discussion of the quality of care and cost issues related to bladder cancer including an examination of levels of evidence, implementation and compliance with clinical practice guidelines, the use of standardized reporting methodologies, and comparative effectiveness research. Bladder cancer is a common malignancy with a variable biology and natural history. Although the majority of  patients are diagnosed with non-invasive disease, approximately 20-40% of patients either present with or develop more advanced disease. The 5-year survival for patients with lymph node involvement at the time of surgery is 20-30% and patients with metastatic disease treated with chemotherapy have a median survival of only 15 months. Novel approaches for the management of patients with bladder cancer are desperately needed. The goal of session II was to review the current state of translational research in bladder cancer as related to both early and late stage disease including a discussion of novel molecular targets and targeted therapeutics, pharmacogenomics to predict response to therapy, and exploring the role for agents targeting angiogenesis.

 

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[689]

TÍTULO / TITLE:  - Emerging VEGF-receptor inhibitors for colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Expert Opin Emerg Drugs. 2012 Dec 6.

            ●● Enlace al texto completo (gratuito o de pago) 1517/14728214.2013.749856

AUTORES / AUTHORS:  - Martinelli E; Troiani T; Morgillo F; Orditura M; De Vita F; Belli G; Ciardiello F

INSTITUCIÓN / INSTITUTION:  - Oncologia Medica and Immunologia Clinica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale F. Magrassi e A. Lanzara, Seconda Universita  degli Studi di Napoli , Via S. Pansini 5, 80131 Napoli , Italia +39 081 5666745;  +39 081 5666725 ; +39 0815666732 ; fortunato.ciardiello@unina2.it , fortunatociardiello@yahoo.com ; erikamartinelli75@yahoo.it.

RESUMEN / SUMMARY:  - Introduction: Targeted agents have dramatically improved and enriched the therapeutical choices for patients with metastatic colorectal cancer (mCRC). By better understanding the role of the angiogenic pathway in colorectal cancer (CRC), new therapies have been developed. Bevacizumab, the first anti-angiogenetic agent approved for the treatment of mCRC provide a proof of concept since it has improved the progression-free survival and overall survival  when combined with cytotoxic chemotherapy. Areas covered: This review is focused  on the most recent findings on the VEGF signaling pathway and new therapeutic drugs explored in clinical trials. Expert opinion: Despite the advantage offered  by bevacizumab, the median overall survival of mCRC patient exceeds 21 months; thus, investigational efforts are needed. Several antiangiogenic agents for the treatment of mCRC are being tested in preclinical and clinical Phase I/II trials. Unfortunately a discrete number of Phase III trials produced negative results. Recently aflibercept and regorafenib, two new antiangiogenic drugs, have been approved as the new-targeted agents for the treatment of mCRC, according to the positive findings from the VELOUR and the CORRECT studies. In order to maximize clinical impact it will be important to validate predictive biomarkers and best combination treatments to offer for mCRC patients; further research and intense investigation is still required.

 

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[690]

TÍTULO / TITLE:  - The anticancer mechanism of caffeic acid phenethyl ester (CAPE): review of melanomas, lung and prostate cancers.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur Rev Med Pharmacol Sci. 2012 Dec;16(15):2064-8.

AUTORES / AUTHORS:  - Ozturk G; Ginis Z; Akyol S; Erden G; Gurel A; Akyol O

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Biochemistry, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey. oakyol@hacettepe.edu.tr

RESUMEN / SUMMARY:  - <strong> BACKGROUND: </strong> Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, specifically inhibits NF-kappaB. It exhibits antioxidant, antiinflammatory, antiproliferative, cytostatic, and most improtantly, antineoplastic properties. <strong> AIM: </strong> The aim of the present mini-review is to summarize and evaluate the anticancer mechanism of CAPE with examples of several cancer types. <strong> RESULTS: </strong> In view of the mechanisms and findings in our laboratory and those of others in literature, we suggest that CAPE possess anticancer and apoptosis inducing activities. <strong>  CONCLUSIONS: </strong> Further researches are needed regarding the anticancer basis of CAPE in all disciplines of medicine. Also, clinical potential toxicities of CAPE should be revealed if it is going to be used as an anticancer agent.

 

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[691]

TÍTULO / TITLE:  - Automated Quantitative RNA in Situ Hybridization for Resolution of Equivocal and  Heterogeneous ERBB2 (HER2) Status in Invasive Breast Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Mol Diagn. 2013 Jan 8. pii: S1525-1578(12)00315-7. doi: 10.1016/j.jmoldx.2012.10.003.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jmoldx.2012.10.003

AUTORES / AUTHORS:  - Wang Z; Portier BP; Gruver AM; Bui S; Wang H; Su N; Vo HT; Ma XJ; Luo Y; Budd GT; Tubbs RR

INSTITUCIÓN / INSTITUTION:  - Department of Molecular Pathology, Cleveland Clinic, Cleveland, Ohio.

RESUMEN / SUMMARY:  - Patient management based on HER2 status in breast carcinoma is an archetypical example of personalized medicine but remains hampered by equivocal testing and intratumoral heterogeneity. We developed a fully automated, quantitative, bright-field in situ hybridization technique (RNAscope), applied it to quantify single-cell HER2 mRNA levels in 132 invasive breast carcinomas, and compared the  results with those by real-time quantitative PCR (qPCR) and Food and Drug Administration-approved methods, including fluorescence in situ hybridization (FISH), IHC, chromogenic in situ hybridization, and dual in situ hybridization. Both RNAscope and qPCR were 97.3% concordant with FISH in cases in which FISH results were unequivocal. RNAscope was superior to qPCR in cases with intratumoral heterogeneity or equivocal FISH results. This novel assay may enable ultimate HER2 status resolution as a reflex test for current testing algorithms.  Quantitative in situ RNA measurement at the single-cell level may be broadly applicable in companion diagnostic applications.

 

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[692]

TÍTULO / TITLE:  - The globular heads of the C1q receptor regulate apoptosis in human cervical squamous carcinoma cells via a p53-dependent pathway.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Transl Med. 2012 Dec 26;10(1):255.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1479-5876-10-255

AUTORES / AUTHORS:  - Chen ZL; Gu PQ; Liu K; Su YJ; Gao LJ

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: The globular heads of the human C1q receptor (gC1qR) localize predominantly to the mitochondrial matrix. gC1qR mediates many biological responses, including growth perturbation, morphological abnormalities  and the initiation of apoptosis. The purpose of this study was to investigate the relationship between mitochondrial dysfunction, p53 status and gC1qR expression and the regulation of apoptosis in human cervical squamous carcinoma cells (C33a  and SiHa). METHODS: Here, gC1qR expression was examined in human cervical tissues using real-time PCR and Western blot analysis. Apoptotic death of C33a and SiHa cells was assessed by flow cytometric analysis that detected the subG1 population. Mitochondrial function was assessed via ROS generation, the content of cytosolic Ca2+, and the change in mitochondrial membrane potential (Deltapsim). The viability and migration of C33a and SiHa cells were detected via the water-soluble tetrazolium salt (WST-1) assay and the transwell assay, respectively. RESULTS: gC1qR expression was decreased in cervical squamous cell carcinoma tissues compared with normal tissues. C33a and SiHa cells transfected with a vector encoding gC1qR displayed mitochondrial dysfunction and apoptosis, which was abrogated by the addition of a mutant form of p53 or p53 small interference RNA (siRNA). Furthermore, upon overexpression of gC1qR, cell viability and migration were significantly enhanced, and the apoptosis of C33a and SiHa cells were decreased when cells were treated with mutant p53 or p53 siRNA. CONCLUSIONS: These data support a mechanism whereby gC1qR induces apoptosis through the mitochondrial and p53-dependent pathways in cervical squamous cell carcinoma.

 

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[693]

TÍTULO / TITLE:  - Secretory clusterin contributes to oxaliplatin resistance by activating Akt pathway in hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Sci. 2012 Dec 20. doi: 10.1111/cas.12088.

            ●● Enlace al texto completo (gratuito o de pago) 1111/cas.12088

AUTORES / AUTHORS:  - Xiu P; Dong X; Dong X; Xu Z; Zhu H; Liu F; Wei Z; Zhai B; Kanwar JR; Jiang H; Li J; Sun X

INSTITUCIÓN / INSTITUTION:  - Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, China.

RESUMEN / SUMMARY:  - Secretory clusterin (sCLU) is expressed in numerous cancers and is associated with the resistance to chemotherapy. However, the role of sCLU in the resistance  of hepatocellular carcinoma (HCC) to oxaliplatin (OXA), a recently used third-generation platinum agent, remains unclear. The stable transfectants that are depleted of or overexpress sCLU and OXA-resistant cells were generated using  human HCC cells. Overexpression of sCLU abrogated OXA-induced inhibition of cell  growth and cell apoptosis, but depletion of sCLU synergized with OXA to inhibit cell growth and enhance cell apoptosis, by regulating proteins involved in mitochondrial apoptosis pathways, such as Bcl-2, Bax, Bcl-xL and caspase-9, and affecting phosphorylation of Akt and GSK-3beta. Overexpression of sCLU in either  OXA-resistant cells or stable transfectants that overexpress sCLU significantly increased phosphorylated Akt. However, specific inhibition of Akt enhanced sensitivity of sCLU-overexpressing cells to OXA, but had no effect on sCLU expression, suggesting that the regulatory effects between sCLU and pAkt may be in a one-way manner in HCC cells. The expression levels of sCLU affected the therapeutic efficacy of OXA to treat HCC tumors established in immunodeficiency mice. The results have demonstrated that sCLU contributes to OXA resistance by activating Akt pathway, indicating that sCLU may be a novel molecular target for  overcoming OXA resistance in HCC.

 

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[694]

TÍTULO / TITLE:  - Ubiquitin C-terminal Hydrolase 37, a novel predictor for hepatocellular carcinoma recurrence, promotes cell migration and invasion via interacting and deubiquitinating PRP19.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochim Biophys Acta. 2013 Mar;1833(3):559-72. doi: 10.1016/j.bbamcr.2012.11.020. Epub 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbamcr.2012.11.020

AUTORES / AUTHORS:  - Fang Y; Fu D; Tang W; Cai Y; Ma D; Wang H; Xue R; Liu T; Huang X; Dong L; Wu H; Shen X

INSTITUCIÓN / INSTITUTION:  - The Department of Gastroenterology of Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China.

RESUMEN / SUMMARY:  - Ubiquitin C-terminal hydrolase 37 (UCH37) plays a crucial role in numerous biological processes and is also involved in oncogenesis. In this study, clinicopathologic data showed that UCH37 was over-expressed in hepatocellular carcinoma (HCC) cancerous tissues and was a significant predictor for time to recurrence (TTR). In vitro, we discovered that UCH37 could promote cell migration and invasion. Subsequently, we utilized Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) to identify differentially expressed proteins in UCH37 over-expressing cells compared with the control cells, and found that PRP19, an essential RNA splicing factor, was up-regulated. The relationship between UCH37,  PRP19 and the capability of cell migration and invasion was further confirmed. Collectively, this study demonstrated that UCH37 could promote cell migration and invasion in HCC cell lines through interacting and deubiquitinating PRP19, and suggested that UCH37 could be a novel predictor for HCC recurrence after curative resection.

 

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[695]

TÍTULO / TITLE:  - Structure-based design, synthesis and evaluation of novel anthra[1,2-d]imidazole-6,11-dione derivatives as telomerase inhibitors and potential for cancer polypharmacology.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Med Chem. 2012 Nov 29;60C:29-41. doi: 10.1016/j.ejmech.2012.11.032.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejmech.2012.11.032

AUTORES / AUTHORS:  - Chen CL; Chang DM; Chen TC; Lee CC; Hsieh HH; Huang FC; Huang KF; Guh JH; Lin JJ; Huang HS

INSTITUCIÓN / INSTITUTION:  - Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan.

RESUMEN / SUMMARY:  - A series of anthra[1,2-d]imidazole-6,11-dione derivatives were synthesized and evaluated for telomerase inhibition, hTERT expression and suppression of cancer cell growth in vitro. All of the compounds tested, except for compounds 4, 7, 16, 24, 27 and 28 were selected by the NCI screening system. Among them, compounds 16, 39, and 40 repressed hTERT expression without greatly affecting cell growth,  suggesting for the selectivity toward hTERT expression. Taken together, our findings indicated that the analysis of cytotoxicity and telomerase inhibition might provide information applicable for further developing potential telomerase  and polypharmacological targeting strategy.

 

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[696]

TÍTULO / TITLE:  - Tumor Necrosis Factor Inhibitor-Induced Serositis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Ther. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MJT.0b013e31826fc4d1

AUTORES / AUTHORS:  - Annapureddy N; Agarwal SK; Ammakkanavar N; Kanakadandi V; Sabharwal MS; Sanjani HP; Simoes P; Nadkarni GN

INSTITUCIÓN / INSTITUTION:  - 1Department of Rheumatology, The Orthopedic Building at Rush University Medical Center, Rush University Medical Center, Chicago, IL 2Department of Medicine, St.  Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY 3Department of Hematology/Oncology, Indiana University, Indianapolis, IN 4Department of Gastroenterology, Kansas City VA Medical Center,  Kansas City, MO 5Department of Cardiology, Albert Einstein College of Medicine, Bronx, NY 6Osmania Medical College, Hyderabad, India 7Department of Nephrology, The Mount Sinai School of Medicine, New York, NY.

RESUMEN / SUMMARY:  - A 46-year-old man with a history of asthma and psoriatic arthritis on adalimumab  presented with fever, tachycardia, and hypoxia. He was diagnosed with pleural effusion and started on antibiotics, as it was noted to be an exudative effusion. Patient failed to improve on multiple courses of antibiotics, and his blood and pleural fluid cultures were negative. He was then started on prednisone 1 mg/kg and showed remarkable recovery. He was diagnosed with adalimumab-induced serositis.

 

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[697]

TÍTULO / TITLE:  - Custirsen (OGX-011): Clusterin Inhibitor in Metastatic Prostate Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Oncol Rep. 2012 Dec 25.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11912-012-0285-1

AUTORES / AUTHORS:  - Al-Asaaed S; Winquist E

INSTITUCIÓN / INSTITUTION:  - Division of Medical Oncology, Department of Oncology, Western University, London, ON, Canada.

RESUMEN / SUMMARY:  - Adenocarcinoma of the prostate is the most common cancer in men in the Western Hemisphere. This diagnosis includes a clinicopathologically diverse collection of disease entities, encompassing a spectrum from early localized disease to advanced-stage castration-sensitive and ultimately metastatic, castration-resistant states. Although early-stage disease is treatable and potentially curable, treatment options for castration-resistant prostate cancer,  the common pathway to prostate cancer death, remain limited and palliative in nature. Therapeutic resistance to androgen blockade, cytotoxic chemotherapy, and  radiotherapy is underpinned by a number of cellular mechanisms. The upregulation  of protective, antiapoptotic chaperone proteins is one of these mechanisms, and is exemplified by the protein clusterin in castration-resistant prostate cancer.  Antisense oligonucleotide technology provides the potential to inhibit specific genes in cancer cells and with this the possibility of a vast impact in oncology, but no antisense drugs have been approved for use in cancer patients to date. Custirsen (OGX-011) is a novel antisense oligonucleotide drug which targets clusterin expression, and its application in prostate cancer is reviewed in this  article.

 

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[698]

TÍTULO / TITLE:  - Tasquinimod: A Novel Angiogenesis Inhibitor-Development in Prostate Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Oncol Rep. 2013 Jan 20.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11912-013-0295-7

AUTORES / AUTHORS:  - George S; Pili R

INSTITUCIÓN / INSTITUTION:  - Genitorurinary Program, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA, Saby.George@RoswellPark.org.

RESUMEN / SUMMARY:  - Castration resistant prostate cancer (CRPC) treatment has been revolutionized over the past few years by the approval of novel therapies including cabazitaxel, sipuleucel-T, abiraterone and enzalutamide. Though androgen deprivation and chemotherapy remain the main therapeutic approaches for this disease, a series of targeted agents is also in development for the treatment of CRPC. Tasquinimod is  a quinolone-3-carboxamide with antiangiogenic and antitumor activity in preclinical models of prostate cancer. A recent Phase II trial with this agent has demonstrated a significant clinical activity in asymptomatic or minimally symptomatic, chemotherapy-naive, CRPC patients. A confirmatory Phase III trial of tasquinimod in prostate cancer is underway. Because of its antiangiogenic and immunomodulatory properties tasquinimod represents a novel targeted therapy with  a unique mechanism of action.

 

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[699]

TÍTULO / TITLE:  - New targets for the antitumor activity of gambogic acid in hematologic malignancies.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Acta Pharmacol Sin. 2012 Dec 31. doi: 10.1038/aps.2012.163.

            ●● Enlace al texto completo (gratuito o de pago) 1038/aps.2012.163

AUTORES / AUTHORS:  - Yang LJ; Chen Y

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

RESUMEN / SUMMARY:  - Gambogic acid (GA) is the main active ingredient of gamboge, a brownish to orange dry resin secreted from Garcinia hanburyi, a plant that is widely distributed in  nature. Recent in vitro and in vivo studies have demonstrated that GA exerts potent antitumor effects against solid tumors of various derivations, and its antitumor mechanisms have been thoroughly investigated. On the other hand, normal cells remain relatively resistant to GA, indicating a therapeutic window. GA is currently in clinical trials in China. Over the last decade, our laboratory demonstrates that GA exhibits potent anticancer activities against hematological  malignancies. This review focuses on the new mechanisms through which GA inhibits proliferation and induces apoptosis in malignant hematological cells. These include the regulation of expression and intracellular positioning of nucleoporin and nucleophosmin; downregulation of steroid receptor coactivator-3 (SRC-3) and its downstream proteins; upregulation of death inducer-obliterator (DIO-1); downregulation of HERG potassium channel; as well as induction of reactive oxygen species (ROS) accumulation.

 

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[700]

TÍTULO / TITLE:  - Regorafenib (BAY 73-4506): Stromal and Oncogenic Multikinase Inhibitor with Potential Activity in Renal Cell Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Oncol Rep. 2013 Jan 20.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11912-013-0292-x

AUTORES / AUTHORS:  - Zaki K; Aslam S; Eisen T

INSTITUCIÓN / INSTITUTION:  - Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK, Kamarul.Zaki@addenbrookes.nhs.uk.

RESUMEN / SUMMARY:  - The introduction of targeted therapies, specifically those that target the VEGF receptor (VEGFR), PDGF receptor (PDGFR) and the mTOR pathways, has significantly  changed the approach to patients with unresectable renal cell cancer (RCC). However, drug resistance develops through bypassing of targeted pathways. Regorafenib (BAY 73-4506) is a novel bi-aryl urea compound that has potential anti-tumour activity in RCC, as along with targeting VEGF and PDGF receptors, it  targets additional kinases associated with alternative pathways of angiogenesis and resistance to VEGF-targeted drugs. Based on a phase II clinical trial, the efficacy outcome of regorafenib in the first-line setting of unresectable RCC appears comparable that of other targeted first-line drugs. However, testing regorafenib in standard phase III trials seems inappropriate in view of its toxic effects. Further assessment of regorafenib should exploit the drug’s ability to inhibit mechanisms of escape from anti-angiogenic treatment through biomarker-driven clinical trials.

 

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[701]

TÍTULO / TITLE:  - Early Response to Bortezomib Combined Chemotherapy Can Help Predict Survival in Patients with Multiple Myeloma Who Are Ineligible for Stem Cell Transplantation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Korean Med Sci. 2013 Jan;28(1):80-86. Epub 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 3346/jkms.2013.28.1.80

AUTORES / AUTHORS:  - Lee HS; Kim YS; Kim K; Kim JS; Kim HJ; Min CK; Suh C; Eom HS; Yoon SS; Lee JH; Kim MK; Kim SH; Bae SH; Mun YC; Jo DY; Chung JS

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea.

RESUMEN / SUMMARY:  - Novel agents to treat multiple myeloma (MM) have increased complete respone (CR)  rates compared with conventional chemotherapy, and the quality of the response to treatment has been correlated with survival. The purpose of our study was to show how of early response to bortezomib combined chemotherapy influences survival in  patients with newly diagnosed MM who are ineligible for stem cell transplantation. We assessed patient responses to at least four cycles of bortezomib using the International Myeloma Working Group response criteria. The endpoints were comparisons of progression free survival (PFS) and overall survival (OS) between early good response group (A group) and poor response group (B group). We retrospectively analyzed data from 129 patients registered by the Korean Multiple Myeloma Working Party, a nationwide registration of MM patients.  The 3 yr PFS for the A and B groups was 55.6% and 18.4%, respectively (P < 0.001). The 3 yr OS for the A and B groups was 65.3% and 52.9%, respectively (P = 0.078). The early response to at least four cycle of bortezomib before next chemotherapy may help predict PFS in patients with MM who are ineligible stem cell transplantation.

 

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[702]

TÍTULO / TITLE:  - Towards Mechanism Classifiers: Expression-anchored Gene Ontology Signature Predicts Clinical Outcome in Lung Adenocarcinoma Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - AMIA Annu Symp Proc. 2012;2012:1040-9. Epub 2012 Nov 3.

AUTORES / AUTHORS:  - Yang X; Li H; Regan K; Li J; Huang Y; Lussier YA

INSTITUCIÓN / INSTITUTION:  - Center for Biomedical Informatics, Dept. of Medicine, Section of Hematology/Oncology, Department of Pediatrics; The University of Chicago, Chicago, IL 60637;

RESUMEN / SUMMARY:  - We aim to provide clinically applicable, reproducible, mechanistic interpretations of gene expression changes that lack in gene overlap among predictive gene-signatures. Using a method we recently developed, Functional Analysis of Individual Microarray Expression (FAIME), we provide evidence that Gene Ontology-anchored signatures (GO-signatures) show reliable prognosis in lung cancer. In order to demonstrate the biological congruence and reproducibility of  FAIME-derived mechanism classifiers, we chose a disease where gene expression classifiers signatures alone had failed to significantly stratify a larger collection of samples and that exhibited poor or no genetic overlap. For each patient in the two lung adenocarcinoma studies, personalized FAIME-profiles of GO biological processes are generated from genome-wide expression profiles. For both training studies, GO-signatures significantly associated to patient mortality were identified (Prediction Analysis for Microarrays; three-fold cross-validation). These two GO-signatures could effectively stratify patients from an independent validation cohort into sub-groups that show significant differences in disease-free survival (log-rank test P=0.019; P=0.001). Importantly, significant mechanism overlaps assessed by information-theory similarity were detected between the two GO-signatures (Fischer Exact Test p=0.001). Hence, together with machine learning technologies, FAIME could be utilized to develop an ontology-driven and expression-anchored prognostic signature that is personalized for an individual patient.

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[703]

TÍTULO / TITLE:  - The risk allele of SNP rs3803662 and the mRNA level of its closest genes TOX3 and LOC643714 predict adverse outcome for breast cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Cancer. 2012 Dec 27;12:621. doi: 10.1186/1471-2407-12-621.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2407-12-621

AUTORES / AUTHORS:  - Gudmundsdottir ET; Barkardottir RB; Arason A; Gunnarsson H; Amundadottir LT; Agnarsson BA; Johannsson OT; Reynisdottir I

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Landspitali-University Hospital, Hringbraut, 101, Reykjavik, Iceland. ingar@landspitali.is.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: The minor allele of SNP rs3803662 has been shown to correlate with increased breast cancer risk and with lower expression of TOX3. The SNP is closely located to TOX3 residing within an uncharacterised gene LOC643714. The aim of the study was to examine the association of the risk allele with expression of TOX3 and LOC643714, and of mRNA levels and genotype with clinical and pathological characteristics. METHODS: The SNP was genotyped in DNA  isolated from blood and normal tissue from 160 breast cancer patients and mRNA levels were measured by microarrays and quantitative real-time (qRT)-PCR in breast tumours. Association with clinical and pathological characteristics was analysed by parametric tests. RESULTS: An association of the risk allele of rs3803662 with lower TOX3 expression was confirmed in oestrogen receptor (ER) positive tumours. It was more often observed in lobular tumours (p = 0.04), and carriers of the risk allele who had been diagnosed with luminal A tumours had shorter overall survival (OS) than carriers of the non-risk allele (p = 0.01). Positive correlation between the mRNA levels of TOX3 and LOC643714 was observed (r = 0.44 and p < 0.001). Association analysis with tumour pathology showed that  low TOX3 and LOC643714 expression correlated with high Ki67 levels (p = 0.026 and p = 0.002) and the basal subtype (p < 0.001 and p < 0.001), whereas high expression correlated with ER (p = 0.004 and p < 0.001) and progesterone receptor (PgR) (p = 0.005 and p < 0.001) expression. Furthermore, high TOX3 and LOC643714  correlated with positive lymph nodes (p < 0.001 and p = 0.01). Patients with ER positive tumours and high levels of TOX3 mRNA had shorter overall- and distant metastasis free-survival (p = 0.017 and p = 0.021), an effect mostly attributable to patients with luminal B tumours. CONCLUSIONS: The results suggest that the effect of the risk allele of rs3803662 is strongest in luminal A tumours and that the expression levels of TOX3 and/or LOC643714 affect the progression of breast cancer. The effect may vary depending on the subtype and developmental stage of the tumour.

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[704]

TÍTULO / TITLE:  - Heterogeneous Expression of CT10, CT45 and GAGE7 Antigens and their Prognostic Significance in Human Breast Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Jpn J Clin Oncol. 2013 Jan 11.

            ●● Enlace al texto completo (gratuito o de pago) 1093/jjco/hys236

AUTORES / AUTHORS:  - Zhou X; Yang F; Zhang T; Zhuang R; Sun Y; Fang L; Zhang C; Ma Y; Huang G; Ma F; Song C; Jin B

INSTITUCIÓN / INSTITUTION:  - 1Department of Immunology.

RESUMEN / SUMMARY:  - OBJECTIVE: The goal of this study was to detect the intertumoral heterogeneity of CT10, CT45 and GAGE7 expression and further to analyze their prognostic value. METHODS: The intertumoral heterogeneity of three cancer/testis antigens was examined by immunohistochemistry using 120 samples from patients with infiltrating ductal breast carcinoma. The expression patterns were classified and correlated with the clinicopathologic variables and outcome of the patients. RESULTS: CT10 showed punctate, focal and diffuse expression patterns according to the characteristic of its distribution. CT45 showed cytoplasmic, nuclear or combined cytoplasmic and nuclear expression patterns according to its subcellular location. GAGE7 exhibited nuclear, cytoplasmic and nucleolar expression patterns. Three cancer/testis antigens were also observed coordinately expressed in infiltrating ductal breast carcinoma. Patients with tumors with CT10 expression was significantly correlated with nodal metastases (P < 0.001) and advanced clinical stages (P = 0.001). Patients with tumors with cytoplasmic GAGE7 and with the expression of two or more cancer/testis antigens were significantly correlated with advanced clinical stages (P = 0.001 and P = 0.030). No signi fi cant difference was identi fi ed between the different expression patterns of CT45 and clinicopathologic variables. In addition, Kaplan-Meier analysis revealed that diffuse CT10 expression and coexpression of three cancer/testis antigens were related to the poor prognosis of patients with infiltrating ductal breast carcinoma. CONCLUSIONS: Diffuse CT10 expression and the coexpression of three cancer/testis antigens can be used as a biomarker to distinguish patients with a  poorer outcome of the breast carcinoma. Our finding may provide useful data for evaluating the prognosis of this disease and improving the effectiveness of therapeutic application based on the three cancer/testis antigens.

 

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[705]

TÍTULO / TITLE:  - Predictive role of GSTs on the prognosis of breast cancer patients with neoadjuvant chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian Pac J Cancer Prev. 2012;13(10):5019-22.

AUTORES / AUTHORS:  - Bai YL; Zhou B; Jing XY; Zhang B; Huo XQ; Ma C; He JM

INSTITUCIÓN / INSTITUTION:  - Department of Ultrasound, First Affiliated Hospital, Xinxiang Medical College, Xinxiang, China.

RESUMEN / SUMMARY:  - OBJECTIVE: To evaluate the predictive value of GST gene polymorphisms with regard to prognosis of breast cancer patients receiving neoadjuvant chemotherapy. METHODS: A total of 159 patients were included in our study between January 2005  and January 2007. All the patients were followed up until January 2012. Genotyping was based upon the duplex polymerase-chain-reaction with the PCR-CTPP  method. RESULTS: Patients with null GSTM1 and GSTP1 Val/Val genotypes had significantly had better response rates to chemotherapy when compared with non-null GSTM1 and GSTP1 Ile/ Ile genotypes (OR=1.96 and OR=2.14, respectively).  Patients with the GSTM1 null genotype had a longer average survival time and significantly lower risk of death than did those with non-null genotypes (HR=0.66). Similarly, those carrying the GSTP1 Val/Val genotype had 0.54- fold the risk of death of those with GSTP1 Ile/ Ile (HR=0.54). CONCLUSION: A significant association was found between GSTM1 and GSTP1 gene polymorphisms and  clinical outcomes in breast cancer cases.

 

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[706]

TÍTULO / TITLE:  - Epithelial-mesenchymal transition expression profiles as a prognostic factor for  disease-free survival in hepatocellular carcinoma: Clinical significance of transforming growth factor-beta signaling.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2013 Jan;5(1):149-154. Epub 2012 Oct 5.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.954

AUTORES / AUTHORS:  - Mima K; Hayashi H; Kuroki H; Nakagawa S; Okabe H; Chikamoto A; Watanabe M; Beppu T; Baba H

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

RESUMEN / SUMMARY:  - Epithelial-mesenchymal transition (EMT) plays a pivotal role in cancer invasion and metastasis, and transforming growth factor (TGF)-beta signaling is a potent inducer of EMT. However, the clinical significance of the correlation between EMT marker expression and TGF-beta signaling in hepatocellular carcinoma (HCC) patients remains unknown. In this study, immunohistochemistry was used to analyze the expression of EMT markers and phospho-Smad2 nuclear positivity, and their association with clinicopathological features in 150 HCC patients. E-cadherin(high)/vimentin(low) and E-cadherin(low)/vimentin(high) expression profiles were determined in 55 (36.7%) and 21 (14.0%) patients, respectively. The E-cadherin(low)/vimentin(high) expression profile was significantly correlated with poor tumor differentiation (P<0.001), vascular invasion (P=0.007) and extrahepatic recurrence following curative surgery (P=0.026). Furthermore, the E-cadherin(low)/vimentin(high) expression profile was significantly correlated with shorter disease-free survival compared to E-cadherin(high)/vimentin(low) (P=0.002). Forty-one patients (27.3%) were demonstrated to have high phospho-Smad2 nuclear positivity, which was significantly correlated with the E-cadherin(low)/vimentin(high) expression profile (P<0.001). In conclusion, this  study suggests that EMT expression profiles are useful prognostic markers for disease-free survival in HCC patients, and that the E-cadherin(low)/vimentin(high) expression profile is closely associated with high-grade malignant behavior such as tumoral vascular invasion and metastasis in HCC. Additionally, TGF-beta-mediated EMT may play an important role in the aggressiveness of HCC.

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[707]

TÍTULO / TITLE:  - Persistent elevated C-reactive protein after treatment is an independent marker of a poor prognosis in patients with hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Transl Oncol. 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12094-012-0976-y

AUTORES / AUTHORS:  - Imai N; Kinoshita A; Onoda H; Iwaku A; Oishi M; Tanaka K; Fushiya N; Koike K; Nishino H; Tajiri H

INSTITUCIÓN / INSTITUTION:  - Division of Gastroenterology and Hepatology, The Jikei University Daisan Hospital, 4-11-1 Izumihon-cho, Komae, Tokyo, 201-8601, Japan.

RESUMEN / SUMMARY:  - PURPOSE: The pretreatment C-reactive protein (CRP) level is reported to be a prognostic indicator in patients with hepatocellular carcinoma (HCC). METHODS: We investigated the prognostic implications of the changes in the CRP level after initial treatment in patients with HCC. We prospectively evaluated a cohort of 150 patients with newly diagnosed HCC. The patients were categorized into three groups: group 1 (n = 120) with pre- and post-treatment CRP <1.0 mg/dl, group 2 (n = 5) with pre-treatment CRP >/=1.0 mg/dl and post-treatment CRP <1.0 mg/dl, and group 3 (n = 25) with pre- and post-treatment CRP >/=1.0 mg/dl. RESULTS: The 1- and 3-year overall survival rates were 92.3 and 82.9 % for group 1, 80.0 and 53.3 % for group 2, and 58.8 and 4.2 % for group 3. The overall survival rate for group 3 was significantly lower than that for group 1 (P < 0.0001), or group 2 (P = 0.003). No significant difference was found between groups 1 and 2 (P = 0.627). A multi-variate analysis showed that albumin level (P = 0.049), the CRP group (P  < 0.0001), and the Cancer of the Liver Italian Program (CLIP) score (P < 0.0001)  were independently associated with the overall survival. CONCLUSIONS: A persistently elevated CRP level after initial treatment is an independent marker  of a poor prognosis, and normalization of the CRP level after initial treatment is associated with a better outcome in patients with HCC.

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[708]

TÍTULO / TITLE:  - Nimotuzumab promotes radiosensitivity of EGFR-overexpression esophageal squamous  cell carcinoma cells by upregulating IGFBP-3.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Transl Med. 2012 Dec 11;10:249. doi: 10.1186/1479-5876-10-249.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1479-5876-10-249

AUTORES / AUTHORS:  - Zhao L; He LR; Xi M; Cai MY; Shen JX; Li QQ; Liao YJ; Qian D; Feng ZZ; Zeng YX; Xie D; Liu MZ

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, No 651 Dongfeng Road East, Guangzhou 510060, China. xiedan@sysucc.org.cn.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Epidermal growth factor receptor (EGFR) is suggested to predict the radiosensitivity and/or prognosis of human esophageal squamous cell carcinoma (ESCC). The objective of this study was to investigate the efficacy of  Nimotuzumab (an anti-EGFR monoclonal antibody) on ESCC radiotherapy (RT) and underlying mechanisms. METHODS: Nimotuzumab was administrated to 2 ESCC cell lines KYSE30 and TE-1 treated with RT. Cell growth, colony formation and apoptosis were used to measure anti-proliferation effects. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3) in ESCC cells radiosensitivity treated with Nimotuzumab. In vivo effect of Nimotuzumab on ESCC radiotherapy was done using a  mouse xenograft model. RESULTS: Nimotuzumab enhanced radiation response of KYSE30 cells (with high EGFR expression) in vitro, as evidenced by increased radiation-inhibited cell growth and colony formation and radiation-mediated apoptosis. Mechanism study revealed that Nimotuzumab inhibited phosphorylated EGFR (p-EGFR) induced by EGF in KYSE30 cells. In addition, knockdown of IGFBP-3 by short hairpin RNA significantly reduced KYSE30 cells radiosensitivity (P<0.05), and even after the administration of Nimotuzumab, the RT response of IGFBP-3 silenced KYSE30 cells was not enhanced (P>0.05). In KYSE30 cell xenografts, Nimotuzumab combined with radiation led to significant tumor growth delay, compared with that of radiation alone (P=0.029), and also with IGFBP-3 up-regulation in tumor tissue. CONCLUSIONS: Nimotuzumab could enhance the RT effect of ESCC cells with a functional active EGFR pathway. In particular, the increased ESCC radiosensitivity by Nimotuzumab might be dependent on the up-regulation of IGFBP-3 through EGFR-dependent pathway.

 

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[709]

TÍTULO / TITLE:  - Multidrug resistance protein 2 genetic polymorphism and colorectal cancer recurrence in patients receiving adjuvant FOLFOX-4 chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Med Report. 2013 Feb;7(2):613-7. doi: 10.3892/mmr.2012.1226. Epub 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 3892/mmr.2012.1226

AUTORES / AUTHORS:  - Mirakhorli M; Rahman SA; Abdullah S; Vakili M; Rozafzon R; Khoshzaban A

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Selangor 43400, Malaysia.

RESUMEN / SUMMARY:  - Multidrug resistance protein 2 (MRP2), encoded by the ATP-binding cassette C2 (ABCC2) gene, is an efflux pump located on the apical membrane of many polarized  cells, which transports conjugate compounds by an ATP-dependent mecha-nism. The correlation of G1249A ABCC2 polymorphism with the development of colorectal cancer (CRC) and poor prognosis was evaluated in patients who were treated with fluorouracil/-leucovorin (FL) plus oxaliplatin (FOLFOX-4). A total of 50 paraffinembedded tissue samples collected from CRC patients were analyzed to identify the polymorphism. Patients were in stage II/III and received postoperative FOLFOX-4 chemotherapy. As a control group, an equal number of unrelated healthy subjects were enrolled in the study. The polymorphism was genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, and results were compared with clinicopathological markers, early relapse and survival rates. During the 12 months of follow-up, local and distant recurrences were observed in 15 (30%) patients. No significant difference in the distribution of wild-type and polymorphic genotypes was observed between the patient and control groups and between the patients who experienced recurrence within 1 year and those who did not (all P>0.05). In conclusion, the G1249A polymorphism is not associated with CRC risk and early recurrence. However, signifi-cant correlation was observed between G1249A polymorphism and the overall survival and disease-free survival of the patients.

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[710]

TÍTULO / TITLE:  - Gene expression profile of peripheral blood lymphocytes from renal cell carcinoma patients treated with IL-2, interferon-alpha and dendritic cell vaccine.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e50221. doi: 10.1371/journal.pone.0050221. Epub 2012 Dec 3.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0050221

AUTORES / AUTHORS:  - Wolf B; Schwarzer A; Cote AL; Hampton TH; Schwaab T; Huarte E; Tomlinson CR; Gui J; Fisher JL; Fadul CE; Hamilton JW; Ernstoff MS

INSTITUCIÓN / INSTITUTION:  - Medical Oncology Immunotherapy Group, Section of Hematology/Oncology, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, United States of America.

RESUMEN / SUMMARY:  - Lymphocytes are a key component of the immune system and their differentiation and function are directly influenced by cancer. We examined peripheral blood lymphocyte (PBL) gene expression as a biomarker of illness and treatment effect using the Affymetrix Human Gene ST1 platform in patients with metastatic renal cell carcinoma (mRCC) who received combined treatment with IL-2, interferon-?-2a  and dendritic cell vaccine. We examined gene expression, cytokine levels in patient serum and lymphocyte subsets as determined by flow cytometry (FCM). Pre-treatment PBLs from patients with mRCC exhibit a gene expression profile and  serum cytokine profile consistent with inflammation and proliferation not found in healthy donors (HD). PBL gene expression from patients with mRCC showed increased mRNA of genes involved with T-cell and T(REG)-cell activation pathways, which was also reflected in lymphocyte subset distribution. Overall, PBL gene expression post-treatment (POST) was not significantly different than pre-treatment (PRE). Nevertheless, treatment related changes in gene expression (post-treatment minus pre-treatment) revealed an increased expression of T-cell and B-cell receptor signaling pathways in responding ® patients compared to non-responding (NR) patients. In addition, we observed down-regulation of T(REG)-cell pathways post-treatment in R vs. NR patients. While exploratory in nature, this study supports the hypothesis that enhanced inflammatory cytotoxic pathways coupled with blunting of the regulatory pathways is necessary for effective anti-cancer activity associated with immune therapy. This type of analysis can potentially identify additional immune therapeutic targets in patients with mRCC.

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[711]

TÍTULO / TITLE:  - The relationship between tyrosine kinase inhibitor therapy and overall survival in patients with non-small cell lung cancer carrying EGFR mutations.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Cancer. 2012 Dec 7. doi: 10.5732/cjc.012.10160.

            ●● Enlace al texto completo (gratuito o de pago) 5732/cjc.012.10160

AUTORES / AUTHORS:  - Suzuki H; Hirashima T; Okamoto N; Yamadori T; Tamiya M; Morishita N; Shiroyama T; Otsuka T; Kitai K; Kawase I

INSTITUCIÓN / INSTITUTION:  - Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, 3-7-1 Habikino Habikino-shi Osaka, 583-8588 Japan. suzukih@ra.opho.jp.

RESUMEN / SUMMARY:  - For patients with epidermal growth factor receptor (EGFR) mutation-positive lung  cancer, the relationship between the dose or duration of treatment with tyrosine  kinase inhibitor (TKI) and overall survival remains unclear. Here, we retrospectively analyzed clinical data for 39 patients who were diagnosed with EGFR mutation-positive non-small cell lung cancer and treated with TKI, but subsequently died. Several parameters were measured in this study: overall survival; first, second, and overall TKI therapy durations; first TKI intensity (actual dose/normal dose); and TKI rate (overall TKI therapy duration/overall survival). The response rate to TKI therapy was 50%, and the median survival was  553 days. After TKI therapy failed, 38.5% patients were re-challenged with TKI. We observed a moderate relationship [r = 0.534, 95% confidential interval (CI) =  0.263- 0.727, P < 0.001] between overall TKI therapy duration and overall survival. However, we found no relationship between overall survival and first TKI intensity (r = 0.073, 95% CI = -0.380 to 0.247, P = 0.657) or TKI rate (r = 0.0345, 95% CI = -0.284 to 0.346, P = 0.835). Non-small cell lung cancer patients with mutation-positive tumors remained on TKI therapy for, on average, 33% of the overall survival time. These findings suggest that patients with EGFR mutation-positive tumors should not stick to using TKIs.

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[712]

TÍTULO / TITLE:  - XRCC1 and ADPRT polymorphisms associated with survival in breast cancer cases treated with chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian Pac J Cancer Prev. 2012;13(10):4923-6.

AUTORES / AUTHORS:  - Ye S; Rong J; Huang SH; Zheng ZS; Yun M; Wang SM

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

RESUMEN / SUMMARY:  - AIM: To investigate whether XRCC1 and ADPRT polymorphisms might be associated with outcomes of breast cancer. METHODS: A prospective study was conducted with a total of 335 breast cancer patients undergoing chemotherapy consecutively collected from Jan. 2005 to Jan. 2008. Genotyping of XRCC1 and ADPRT polymorphisms was conducted by PCR-RFLP assay. RESULTS: All 335 patients were followed up until death or the end of Jan. 2012, with a median follow-up period of 38.8 (2-64) months. It was shown that the variant genotype of XRCC1 399Gln/Gln was strongly significantly associated with a decreased risk of death from breast  cancer, with an HR (95% CI) of 0.52 (0.28-0.91). Similarly, individuals carrying  the ADPRT 762Ala/Ala demonstrated longer survival compared to ADPRT 762 Val/ Val, with an HR (95% CI) of 0.58 (0.31-0.97). Individuals with combination genotypes of XRCC1 399Gln allele and ADPRT 762Ala/Ala presented with a longer survival, the HR (95% CI) being 0.56 (0.32-0.97). CONCLUSION: We found a significant association between XRCC1399Gln/ Gln and ADPRT 762Ala/Ala polymorphisms and clinical outcomes. These two genotypes could be used as a surrogate markers of clinical outcome in glioma cases receiving chemotherapy.

 

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[713]

TÍTULO / TITLE:  - Lenalidomide-based combined therapy induced alterations in serum proteins of multiple myeloma patient: a follow-up case report and overview of the literature.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Exp Oncol. 2012 Dec;34(4):373-6.

AUTORES / AUTHORS:  - Senthilkumar CS; Ganesh N

INSTITUCIÓN / INSTITUTION:  - Clinical Cytogenetic Laboratory, Department of Research, Jawaharlal Nehru Cancer  Hospital &amp; Research Centre (JNCHRC), Bhopal - 462 001 Madhya Pradesh, India.

RESUMEN / SUMMARY:  - Aim: Multiple myeloma (MM) is a malignant neoplasm of plasma cells (PC) derived from the bone marrow (BM) origin. The present case report was aimed to monitor the efficiency of lenalidomide-based combined therapy (LBCT) induced alterations  in serum proteins of 42-year-old female MM patient. Besides, in the context of case report we also present an overview of the literature describing LBCT. Study  design: Serum protein electrophoresis (SPEP) was performed in three visits (V1-V3) to monitor the disease status of the patient and her treatment response to LBCT. Level of monoclonal protein (M-protein) was measured through cellulose acetate zone electrophoresis and quantified by densitometer in follow-up investigations after therapy intervals. Results: A significant reduction of M-protein in gamma-globulin region was observed (P < 0.007) after receiving LBCT. However, the condition depicted hyper gamma-globulinemia. beta-globulin (P < 0.002) and alpha2-globulin(P < 0.047) was suppressed from the initial visit and subsequent follow-up also indicated the status of hypoglobulinaemia. Although, serum albumin level was found to be increased after therapy (P < 0.016), hypoalbuminaemia was also noticed before and after LBCT. Conclusion: On the basis of this case report and pertinent literature, we conclude that LBCT is more efficient in the treatment of MM and has significant role in serum protein alterations especially in the reduction of M-protein in the MM patients.

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[714]

TÍTULO / TITLE:  - DAB2IP Regulates Autophagy in Prostate Cancer in Response to Combined Treatment of Radiation and a DNA-PKcs Inhibitor.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Neoplasia. 2012 Dec;14(12):1203-12.

AUTORES / AUTHORS:  - Yu L; Tumati V; Tseng SF; Hsu FM; Kim DN; Hong D; Hsieh JT; Jacobs C; Kapur P; Saha D

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX.

RESUMEN / SUMMARY:  - Radiation therapy (RT) is an effective strategy for the treatment of localized prostate cancer (PCa) as well as local invasion. However, some locally advanced cancers develop radiation resistance and recur after therapy; therefore, the development of radiation-sensitizing compounds is essential for treatment of these tumors. DOC-2/DAB2 interactive protein (DAB2IP), which is a novel member of the Ras-GTPase activating protein family and a regulator of phosphatidylinositol  3-kinase-Akt activity, is often downregulated in aggressive PCa. Our previous studies have shown that loss of DAB2IP results in radioresistance in PCa cells primarily because of accelerated DNA double-strand break (DSB) repair kinetics, robust G(2)/M checkpoint control, and evasion of apoptosis. A novel DNA-PKcs inhibitor NU7441 can significantly enhance the effect of radiation in DAB2IP-deficient PCa cells. This enhanced radiation sensitivity after NU7441 treatment is primarily due to delayed DNA DSB repair. More significantly, we found that DAB2IP-deficient PCa cells show dramatic induction of autophagy after  treatment with radiation and NU7441. However, restoring DAB2IP expression in PCa  cells resulted in decreased autophagy-associated proteins, such as LC3B and Beclin 1, as well as decreased phosphorylation of S6K and mammalian target of rapamycin (mTOR). Furthermore, the presence of DAB2IP in PCa cells can lead to more apoptosis in response to combined treatment of NU7441 and ionizing radiation. Taken together, NU7441 is a potent radiosensitizer in aggressive PCa cells and DAB2IP plays a critical role in enhancing PCa cell death after combined treatment with NU7441 and radiation.

 

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[715]

TÍTULO / TITLE:  - Proteomic approaches to the discovery of cancer biomarkers for early detection and personalized medicine.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Jpn J Clin Oncol. 2013 Feb;43(2):103-9. doi: 10.1093/jjco/hys200. Epub 2012 Dec 16.

            ●● Enlace al texto completo (gratuito o de pago) 1093/jjco/hys200

AUTORES / AUTHORS:  - Honda K; Ono M; Shitashige M; Masuda M; Kamita M; Miura N; Yamada T

INSTITUCIÓN / INSTITUTION:  - *Department of Chemotherapy and Clinical Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. khonda@ncc.go.jp.

RESUMEN / SUMMARY:  - Cancer biomarkers for the early detection of malignancies and selection of therapeutic strategies have been requested in the clinical field. Accurate and informative cancer biomarkers hold significant promise for improvements in the early detection of disease and in the selection of the most effective therapeutic strategies. Recently, significant progress in the comprehensive analysis of the human genome, epigenome, transcriptome, proteome and metabolome has led to revolutionary changes in the discovery of cancer biomarkers. The Human Proteome Organization has launched a global Human Proteome Project to map the entire human protein set. The Human Proteome Project research group has focused on three working proteomic pillars-mass spectrometry-based, antibody-based and knowledge-based proteomics-and each of these technologies is advancing rapidly. In this review, we introduce the proteomic platforms that are currently being used for cancer biomarker discovery, and describe examples of novel cancer biomarkers that were identified with each proteomic technology.

 

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[716]

TÍTULO / TITLE:  - Predictive values of urinary bladder tumor markers survivin and soluble-Fas comparison with cystoscopy and bladder tumor antigen.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Minerva Urol Nefrol. 2012 Dec;64(4):279-85.

AUTORES / AUTHORS:  - Ganas V; Kalaitzis C; Sountoulides P; Giannakopoulos S; Touloupidis S

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Elpis Hospital, Athens, Greece - chkalaitzis@hotmail.com.

RESUMEN / SUMMARY:  - AIM: The aim of the study was to evaluate the predictive values of two novel urinary markers for bladder cancer: survivin and soluble-Fas (s-Fas). METHODS: The study included 84 individuals divided in two groups. The first group contained 47 patients, who underwent transurethral bladder tumor resection and the second, control, group 20 patients with non-malignant conditions, who underwent cystoscopy and 17 health volunteers. Fresh, second morning voided urine was collected for measurement of s-Fas, survivin, BTA and for cytology. Sensitivity, specificity, positive and negative predictive values and accuracy were calculated. RESULTS: Bladder tumor patients had significantly higher survivin urine levels in comparison to the controls. Survivin correlated also with the tumor stage. Combination of survivin with BTA had a sensitivity of 86.4% but still lower than that of cystoscopy (97.8%). Only the specificity of the combination between survivin and BTA was higher than that of cystoscopy (86.4% and 75.6%, respectively). CONCLUSION: Survivin was a better marker for tumor detection than s-Fas and was better enough to discriminate cancer stage. Combination of survivin and BTA had a specificity of 86.4% to exclude bladder malignancy and the combination of s-Fas with survivin and BTA had a sensitivity of 93.6% to detect bladder cancer.

 

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[717]

TÍTULO / TITLE:  - Variability in UDP-glucuronosyltransferase genes and morphine metabolism: observations from a cross-sectional multicenter study in advanced cancer patients with pain.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pharmacogenet Genomics. 2013 Mar;23(3):117-126.

            ●● Enlace al texto completo (gratuito o de pago) 1097/FPC.0b013e32835ce485

AUTORES / AUTHORS:  - Fladvad T; Klepstad P; Langaas M; Dale O; Kaasa S; Caraceni A; Skorpen F

INSTITUCIÓN / INSTITUTION:  - aDepartment of Cancer Research and Molecular Medicine, European Palliative Care Research Center (PRC) bDepartment of Laboratory Medicine, Children’s and Women’s  Health, Faculty of Medicine cDepartment of Mathematical Sciences, Faculty of Information Technology, Mathematics and Electrical Engineering, Norwegian University of Science and Technology (NTNU) Departments of dAnaesthesiology and Emergency Medicine eOncology, St Olavs University Hospital, Trondheim, Norway fPalliative Care, Pain Therapy and Rehabilitation Department, IRCCS Foundation National Cancer Institute, Milan, Italy.

RESUMEN / SUMMARY:  - OBJECTIVE: The objective of the present study was to determine whether genetic variability in UDP-glucuronosyltransferase (UGT) genes, together with clinical factors, contribute to variability in morphine glucuronide (M6G and M3G) to morphine serum concentration ratios in patients with advanced cancer receiving chronic morphine therapy. MATERIALS AND METHODS: A total of 41 polymorphisms and  predicted haplotypes in the UGT2B7, UGT1A1, and UGT1A8 genes were analyzed in 759 patients who were recruited from the European Pharmacogenetic Opioid Study and received chronic morphine therapy by the oral route (n=635) or parenterally (n=124). The administration groups were analyzed separately by multiple linear regression analyses. RESULTS: Two haplotypes in UGT1A1/UGT1A8 were weak predictors of reduced M6G/morphine and M3G/morphine serum ratios after oral administration (false discovery rate-corrected P-values<0.1). No effect of genotype was seen in the parenteral group. Of the clinical variables (age, sex, BMI, renal function, Karnofsky performance status, and presence of liver metastases), renal function was the major contributor to variation in serum concentration ratios. Concomitant administration of paracetamol predicted significantly higher morphine metabolic ratios after oral administration of morphine (false discovery rate-corrected P-values<2.1E-12). The regression models explained about 35% of the total variability in the data. CONCLUSION: Genetic variation in the UGT genes together with clinical factors influence morphine metabolic ratios in patients with advanced cancer disease and who are scheduled with oral morphine. This information may be included in future research that develop and test new classification systems for opioid treatment in patients with advanced cancer.

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[718]

TÍTULO / TITLE:  - Overexpression of the secretory small GTPase Rab27B in human breast cancer correlates closely with lymph node metastasis and predicts poor prognosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Transl Med. 2012 Dec 5;10:242. doi: 10.1186/1479-5876-10-242.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1479-5876-10-242

AUTORES / AUTHORS:  - Zhang JX; Huang XX; Cai MB; Tong ZT; Chen JW; Qian D; Liao YJ; Deng HX; Liao DZ; Huang MY; Zeng YX; Xie D; Mai SJ

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, 651# Dongfeng Road East, Guangzhou, 510060, China. xiedan@sysucc.org.cn.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: The secretory small GTPase Rab27b was recently identified as an oncogene in breast cancer (BC) in vivo and in vitro studies. This research  was designed to further explore the clinical and prognostic significance of Rab27B in BC patients. METHODS: The mRNA/protein expression level of Rab27B was examined by performing Real-time PCR, western blot, and immunohistochemistry (IHC) assays in 12 paired BC tissues and matched adjacent noncancerous tissues (NAT). Then we carried out IHC assay in a large cohort of 221 invasive BC tissues, 22 normal breast tissues, 40 fibroadenoma (FA), 30 ductual carcinoma in  situ (DCIS) and 40 metastatic lymph nodes (LNs). The receiver operating characteristic curve method was applied to obtain the optimal cutoff value for high Rab27B expression. Epithelial-mesenchymal transition (EMT) marker expression levels were detected in relation to Rab27B expression. RESULTS: We observed that  the increased expression of Rab27B was dependent upon the magnitude of cancer progression (P < 0.001). The elevated expression of Rab27B was closely correlated with lymph node metastasis, advanced clinical stage, ascending pathology classification, and positive ER status. Furthermore, patients with high expression of Rab27B had inferior survival outcomes. Multivariate Cox regression  analysis proved that Rab27B was a significantly independent risk factor for patients’ survival (P < 0.001). Furthermore, a significant positive relationship  was observed between Rab27B expression and elevated mesenchymal EMT markers. CONCLUSION: Our findings suggest that overexpression of Rab27B in BC coincides with lymph node metastasis and acquisition of a poor prognostic phenotype.

 

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[719]

TÍTULO / TITLE:  - Adenovirus-mediated delivery of interferon-gamma gene inhibits the growth of nasopharyngeal carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Transl Med. 2012 Dec 28;10(1):256.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1479-5876-10-256

AUTORES / AUTHORS:  - Liu RY; Zhu YH; Zhou L; Zhao P; Li HL; Zhu LC; Han HY; Lin HX; Kang L; Wu JX; Huang W

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Interferon-gamma (IFN-gamma) is regarded as a potent antitumor agent, but its clinical application is limited by its short half-life and significant side effects. In this paper, we tried to develop IFN-gamma gene therapy by a replication defective adenovirus encoding the human IFN-gamma (Ad-IFNgamma), and evaluate the antitumoral effects of Ad-IFNgamma on nasopharyngeal carcinoma (NPC) cell lines in vitro and in xenografts model. METHODS: The mRNA levels of human IFN-gamma in Ad-IFNgamma-infected NPC cells were detected by reverse transcription-polymerase chain reaction (RT-PCR), and IFN-gamma protein concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in the culture supernatants of NPC cells and tumor tissues and bloods of nude mice treated with Ad-IFNgamma. The effects of Ad-IFNgamma on NPC cell proliferation was determined using MTT assay, cell cycle distribution was determined by flow cytometry analysis for DNA content, and cells apoptosis were analyzed by Annexin V-FITC/7-AAD binding assay and hoechst 33342/PI double staining. The anti-tumor effects and toxicity of Ad-IFNgamma were evaluated in BALB/c nude mice carrying NPC xenografts. RESULTS: The results demonstrated that  Ad-IFNgamma efficiently expressed human IFN-gamma protein in NPC cell lines in vitro and in vivo. Ad-IFNgamma infection resulted in antiproliferative effects on NPC cells by inducing G1 phase arrest and cell apoptosis. Intratumoral administration of Ad-IFNgamma significantly inhibited the growth of CNE-2 and C666-1 cell xenografts in nude mice, while no significant toxicity was observed.  CONCLUSIONS: These findings indicate IFN-gamma gene therapy mediated by replication defective adenoviral vector is likely a promising approach in the treatment of nasopharyngeal carcinoma.

 

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[720]

TÍTULO / TITLE:  - Gene Expression Signatures That Predict Outcome of Tamoxifen-Treated Estrogen Receptor-Positive, High-Risk, Primary Breast Cancer Patients: A DBCG Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e54078. doi: 10.1371/journal.pone.0054078. Epub 2013 Jan 16.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0054078

AUTORES / AUTHORS:  - Lyng MB; Laenkholm AV; Tan Q; Vach W; Gravgaard KH; Knoop A; Ditzel HJ

INSTITUCIÓN / INSTITUTION:  - Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.

RESUMEN / SUMMARY:  - BACKGROUND: Tamoxifen significantly improves outcome for estrogen receptor-positive (ER+) breast cancer, but the 15-year recurrence rate remains 30%. The aim of this study was to identify gene profiles that accurately predicted the outcome of ER+ breast cancer patients who received adjuvant Tamoxifen mono-therapy. METHODOLOGY/PRINCIPAL FINDINGS: Post-menopausal breast cancer patients diagnosed no later than 2002, being ER+ as defined by >1% IHC staining and having a frozen tumor sample with >50% tumor content were included.  Tumor samples from 108 patients treated with adjuvant Tamoxifen were analyzed for the expression of 59 genes using quantitative-PCR. End-point was clinically verified recurrence to distant organs or ipsilateral breast. Gene profiles were identified using a model building procedure based on conditional logistic regression and leave-one-out cross-validation, followed by a non-parametric bootstrap (1000x re-sampling). The optimal profiles were further examined in 5 previously-reported datasets containing similar patient populations that were either treated with Tamoxifen or left untreated (n = 623). Three gene signatures  were identified, the strongest being a 2-gene combination of BCL2-CDKN1A, exhibiting an accuracy of 75% for prediction of outcome. Independent examination  using 4 previously-reported microarray datasets of Tamoxifen-treated patient samples (n = 503) confirmed the potential of BCL2-CDKN1A. The predictive value was further determined by comparing the ability of the genes to predict recurrence in an additional, previously-published, cohort consisting of Tamoxifen-treated (n = 58, p = 0.015) and untreated patients (n = 62, p = 0.25).  CONCLUSIONS/SIGNIFICANCE: A novel gene expression signature predictive of outcome of Tamoxifen-treated patients was identified. The validation suggests that BCL2-CDKN1A exhibit promising predictive potential.

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[721]

TÍTULO / TITLE:  - Prediction value of XRCC 1 gene polymorphism on the survival of ovarian cancer treated by adjuvant chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian Pac J Cancer Prev. 2012;13(10):5007-10.

AUTORES / AUTHORS:  - Miao J; Zhang X; Tang QL; Wang XY; Kai L

INSTITUCIÓN / INSTITUTION:  - Department of Gynecology and Obstetrics, First Affiliated Hospital of Jinan University, Guangzhou, China.

RESUMEN / SUMMARY:  - OBJECTIVE: We conducted a prospective study to test the association between three amino acid substitution polymorphismic variants of DNA repair genes, XRCC1 (Arg194Trp), XRCC1(Arg280His) and XRCC1 (Arg399Gln), and clinical outcome of ovarian cancer patients undergoing adjuvant chemotherapy. METHODS: 195 patients with primary advanced ovarian cancer and treated by adjuvant chemotherapy were included in our study. All were followed-up from Jan. 2007 to Jan. 2012. Genotyping of XRCC1 polymorphisms was conducted by TaqMan Gene Expression assays. RESULTS: The XRCC1 194 Trp/Trp genotype conferred a significant risk of death from ovarian cancer when compared with Arg/Arg (HR=1.56, 95%CI=1.04-3.15). Similarly, those carrying the XRCC1 399 Gln/Gln genotype had a increased risk of  death as compared to the XRCC1 399Arg/ Arg genotype with an HR (95% CI) of 1.98 (1.09-3.93). CONCLUSION: This study is the first to provide evidence that XRCC1 gene polymorphisms would well be useful as surrogate markers of clinical outcome  in ovarian cancer cases undergoing adjuvant chemotherapy.

 

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[722]

TÍTULO / TITLE:  - Applied research on serum protein fingerprints for prediction of Qi deficiency syndrome and phlegm and blood stasis in patients with non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Tradit Chin Med. 2012 Sep;32(3):350-4.

AUTORES / AUTHORS:  - Liu Z; Yu Z; Ouyang X; Du J; Lan X; Zhao M

INSTITUCIÓN / INSTITUTION:  - Academy of Integrative Medicine of Fujian University ofTCM, Fuzhou, Fujian 350122, China.

RESUMEN / SUMMARY:  - OBJECTIVE: This study screened serum tumor biomarkers by surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) to establish a subset which could be used for the prediction of Qi deficiency syndrome and phlegm and blood stasis in patients with non-small cell lung cancer; and as diagnostic model of Chinese medicine. METHODS: Serum samples from 63 lung  cancer patients with Qi deficiency syndrome and phlegm and blood stasis, and 28 lung cancer patients with non-Qi deficiency syndrome and phlegm and blood stasis  were analyzed using SELDI-TOF-MS with a PBS II-C protein chip reader. Protein profiles were generated using immobilized metal affinity capture (IMAC3) protein  chips. Differentially-expressed proteins were screened. Protein peak clustering and classification analyses were performed using Biomarker Wizard and Biomarker Pattern software packages, respectively. RESULTS: A total of 268 effective protein peaks were detected in the 1,000-10,000 Da molecular range for the 15 serum proteins screened (P<0.05). The decision tree model was M 2284.97, with a sensitivity of 96.2% and a specificity of 66.7%. CONCLUSION: SELDI-TOF-MS techniques, combined with a decision tree model, can help identify serum proteomic biomarkers related to Qi deficiency syndrome and phlegm and blood stasis in lung cancer patients; and the predictive model can be used to discriminate between Chinese medicine diagnostic models of disease.

 

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[723]

TÍTULO / TITLE:  - Gene-guided Gefitinib switch maintenance therapy for patients with advanced EGFR  mutation-positive Non-small cell lung cancer: an economic analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Cancer. 2013 Jan 29;13(1):39.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2407-13-39

AUTORES / AUTHORS:  - Zhu J; Li T; Wang X; Ye M; Cai J; Xu Y; Wu B

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Maintenance therapy with gefitinib notably improves survival in patients with advanced non-small cell lung cancer (NSCLC) and EGFR mutation-positive tumors, but the economic impact of this practice is unclear. METHODS: A decision-analytic model was developed to simulate 21-day patient transitions in a 10-year time horizon. The clinical data were primarily obtained  from the results of a pivotal phase III trial that assessed gefitinib maintenance treatment in patients with advanced NSCLC. The cost data were derived from the perspective of the Chinese health care system. The primary outcome was the incremental cost-effectiveness ratio (ICER) at a willingness-to-pay (WTP) threshold of 3 times the per capita GDP of China. Sensitivity analyses were used  to explore the impact of uncertainty regarding the results. The impact of the gefitinib patient assistance program (GPAP) was evaluated. RESULTS: After EGFR genotyping, gefitinib maintenance treatment for advanced NSCLC with EGFR mutations increased the life expectancy by 0.74 years and 0.46 QALYs compared with routine follow-up at an additional cost of $26,149.90 USD ($7,178.20 with the GPAP). The ICER for gefitinib maintenance was $57,066.40 and $15,664.80 per QALY gained (at a 3% discount rate) without and with the GPAP, respectively. The  utility of progression free survival, the hazard ratio of progression-free survival for gefitinib treatment and the cost of gefitinib per dose were the three factors that had the greatest influence on the results. CONCLUSIONS: These  results indicate that gene-guided maintenance therapy with gefitinib with the GPAP might be a cost-effective treatment option.

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[724]

TÍTULO / TITLE:  - Serum human leukocyte antigen-g and soluble interleukin 2 receptor levels in acute lymphoblastic leukemic pediatric patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian Pac J Cancer Prev. 2012;13(11):5399-403.

AUTORES / AUTHORS:  - Motawi TM; Zakhary NI; Salman TM; Tadros SA

INSTITUCIÓN / INSTITUTION:  - Biochemistry Department, Faculty of Pharmacy, Cairo University, Egypt E-mail : stadros@msa.eun.eg.

RESUMEN / SUMMARY:  - Aims and Background: Human leukocyte antigen-G and interleukin-2 receptor play pivotal roles in the proliferation of lymphocytes, and thus generation of immune  responses. Their overexpression has been evidenced in different malignant hematopoietic diseases. This study aimed to validate serum soluble human leukocyte antigen-G (sHLA-G) and serum soluble interleukin-2 receptor (sIL-2R) as an additional tool for the diagnosis and follow up of acute lymphoblastic leukemia (ALL). Subjects and Methods: Both markers were determined by ELISA in the serum of 33 ALL pediatric patients before treatment and after intensification phase of chemotherapy as well as in the serum of 14 healthy donors that were selected as a control group. Results: ALL patients showed abnormal CBC and high serum lactate dehydrogenase, which were improved after chemotherapy. Also, there  was a non-significant increase in serum sHLA-G in ALL patients compared with the  control group. However, after chemotherapy, sHLA-G was increased significantly compared with before treatment. On the other hand, serum sIL-2R in ALL patients was increased significantly compared with the control group. After chemotherapy,  sIL-2R decreased significantly compared with before treatment. Conclusions: From  these results it could be suggested that measurement of serum sHLA-G might be helpful in diagnosis of ALL, while sIL-2R might be useful in diagnosis and follow-up of ALL in pediatric patients.

 

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[725]

TÍTULO / TITLE:  - Multilocus genotypes of relevance for drug metabolizing enzymes and therapy with  thiopurines in patients with acute lymphoblastic leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Front Genet. 2012;3:309. doi: 10.3389/fgene.2012.00309. Epub 2013 Jan 7.

            ●● Enlace al texto completo (gratuito o de pago) 3389/fgene.2012.00309

AUTORES / AUTHORS:  - Stocco G; Franca R; Verzegnassi F; Londero M; Rabusin M; Decorti G

INSTITUCIÓN / INSTITUTION:  - Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital Memphis, TN, USA ; Department of Life Sciences, University of Trieste Trieste, Italy.

RESUMEN / SUMMARY:  - Multilocus genotypes have been shown to be of relevance for using pharmacogenomic principles to individualize drug therapy. As it relates to thiopurine therapy, genetic polymorphisms of TPMT are strongly associated with the pharmacokinetics and clinical effects of thiopurines (mercaptopurine and azathioprine), influencing their toxicity and efficacy. We have recently demonstrated that TPMT  and ITPA genotypes constitute a multilocus genotype of pharmacogenetic relevance  for children with acute lymphoblastic leukemia (ALL) receiving thiopurine therapy. The use of high-throughput genomic analysis allows identification of additional candidate genetic factors associated with pharmacogenetic phenotypes,  such as TPMT enzymatic activity: PACSIN2 polymorphisms have been identified by a  genome-wide analysis, combining evaluation of polymorphisms and gene expression,  as a significant determinant of TPMT activity in the HapMap CEU cell lines and the effects of PACSIN2 on TPMT activity and mercaptopurine induced adverse effects were confirmed in children with ALL. Combination of genetic factors of relevance for thiopurine metabolizing enzyme activity, based on the growing understanding of their association with drug metabolism and efficacy, is particularly promising for patients with pediatric ALL. The knowledge basis and clinical applications for multilocus genotypes of importance for therapy with mercaptopurine in pediatric ALL is discussed in the present review.

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[726]

TÍTULO / TITLE:  - Feasibility of Azacitidine Added to Standard Chemotherapy in Older Patients with  Acute Myeloid Leukemia - A Randomised SAL Pilot Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e52695. doi: 10.1371/journal.pone.0052695. Epub 2012 Dec 31.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052695

AUTORES / AUTHORS:  - Krug U; Koschmieder A; Schwammbach D; Gerss J; Tidow N; Steffen B; Bug G; Brandts CH; Schaich M; Rollig C; Thiede C; Noppeney R; Stelljes M; Buchner T; Koschmieder S; Duhrsen U; Serve H; Ehninger G; Berdel WE; Muller-Tidow C

INSTITUCIÓN / INSTITUTION:  - Department of Medicine A, University Hospital, Muenster, Germany.

RESUMEN / SUMMARY:  - INTRODUCTION: Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML. TRIAL DESIGN: Prospective, randomised, open, phase II trial with parallel group design  and fixed sample size. PATIENTS AND METHODS: Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of <20,000/microl at the time of study entry and adequate organ function were eligible. Patients were  randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint. RESULTS: Six patients each were  randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75  mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days. CONCLUSIONS: The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this  phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm. TRIAL REGISTRATION: This trial is registered at clinical trials.gov (identifier: NCT00915252).

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[727]

TÍTULO / TITLE:  - Copy number gain of MYCN gene is a recurrent genetic aberration and favorable prognostic factor in Chinese pediatric neuroblastoma patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Diagn Pathol. 2013 Jan 15;8(1):5.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1746-1596-8-5

AUTORES / AUTHORS:  - Wang M; Zhou C; Cai R; Li Y; Gong L

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Amplification of MYCN oncogene is an established marker indicating aggressive tumor progression of neuroblastoma (NBL). But Copy number analyses of MYCN gene in ganglioneuroblastoma (GNBL) and ganglioneuroma(GN) is poorly described in the literature. In the study, we evaluated the copy number aberrations of MYCN gene in clinical samples of NBLs, GNBLs and GNs and analyzed  their association with clinical outcome of the patients. METHODS: In this study,  we analyzed MYCN gene and chromosome 2 aneusomy by using fluorescence in situ hybridization (FISH) method in a total of 220 patients with NBL, GNBL and GN cases. Kaplan-Meier curves were generated by using SPSS 12.0 software. RESULTS: Of 220 patients, 178 (81.0%) were NBLs, 32 (14.5%) were GNBLs and 10 (4.5%) were  GNs. MYCN gain is a recurrent genetic aberration of neuroblastic tumors (71.8%, 158/220), which was found in 129 NBLs (58.6%, 129/220), 25 GNBLs (11.4%, 25/220)  and 4 GN cases (1.8%, 4/220). However, MYCN amplification was only present in 24  NBL tumors (13.5%, 24/178) and 1 GNBL case (3.1%, 1/32). Kaplan-Meier survival analysis indicated that MYCN amplification is significantly correlated with decreased overall survival in NBLs (P=0.017). Furthermore, a better prognosis trend was observed in patients with MYCN gain tumors compared with those with MYCN gene normal copy number tumors and MYCN amplification tumors (P=0.012). CONCLUSIONS: In summary, the frequency of MYCN amplification in NBLs is high and  is rarely observed in GNBLs and GNs, which suggest MYCN plays an important role in neuroblastic tumors differentiation. MYCN gain appeared to define a subgroup of NBLs with much better outcome and classification of MYCN gene copy number alteration as three groups (amplification, gain and normal) can provide a powerful prognostic indicator in NBLs. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6417541528559124.

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[728]

TÍTULO / TITLE:  - Roles of E-cadherin and Cyclooxygenase Enzymes in Predicting Different Survival Patterns of Optimally Cytoreduced Serous Ovarian Cancer Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian Pac J Cancer Prev. 2012;13(11):5715-9.

AUTORES / AUTHORS:  - Taskin S; Dunder I; Erol E; Taskin EA; Kiremitci S; Oztuna D; Sertcelik A

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, Ankara University School of Medicine, Ankara, Turkey E-mail : salihtaskin@yahoo.com.

RESUMEN / SUMMARY:  - The relation between cyclooxygenase enzymes and E-cadherin, along with the roles  of these markers in the prediction of survival in optimally cytoreduced serous ovarian cancer patients was investigated. Individuals who underwent primary staging surgery and achieved optimal cytoreduction (largest residual tumor volume <1 cm) constituted the study population. Specimens of 32 cases were immunohistochemically examined for cyclooxygenase-1, cyclooxygenase-2, and E-cadherin. Two could not be evaluated for E-cadherin and cyclooxygenase-1. Overall, 14/30, 19/30, and 15/32 cases were positive for E-cadherin, cyclooxygenase-1, and cyclooxygenase-2, respectively. The expressions of E-cadherin and cyclooxygenase-2 were inversely correlated (p:0.02). E-cadherin expression was related with favorable survival (p<0.001). The relation between the expression of cyclooxygenase enzymes and poor survival did not reach statistical significance. On multivariate analysis, E-cadherin appeared as an independent prognostic factor for survival. In conclusion, E-cadherin expression  is strongly linked with favorable survival. E-cadherin and cyclooxygenase 2 may interact with each other during the carcinogenesis-invasion process. Further studies clarifying the relation between E-cadherin and cyclooxygenase enzymes may lead to new preventive and therapeutic targets in ovarian cancer.

 

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[729]

TÍTULO / TITLE:  - Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma  (CALGB 500104).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Transl Med. 2012 Dec 10;10(1):246.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1479-5876-10-246

AUTORES / AUTHORS:  - Gajewski TF; Salama AK; Niedzwiecki D; Johnson J; Linette G; Bucher C; Blaskovich MA; Sebti SM; Haluska F

INSTITUCIÓN / INSTITUTION:  - The University of Chicago, Section of Hematology/Oncology, 5841 S, Maryland Ave,, MC2115, Chicago, IL, 60637, USA. tgajewsk@medicine.bsd.uchicago.edu.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Multiple farnesylated proteins are involved in signal transduction in cancer. Farnesyltransferase inhibitors (FTIs) have been developed as a strategy to inhibit the function of these proteins. As FTIs inhibit proliferation of melanoma cell lines, we undertook a study to assess the impact of a FTI in advanced melanoma. As farnesylated proteins are also important for T  cell activation, measurement of effects on T cell function was also pursued. METHODS: A 3-stage trial design was developed with a maximum of 40 patients and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included performance status of 0-1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to biopsy. R115777 was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST. Blood and tumor were analyzed pre-treatment and during  week 7. RESULTS: Fourteen patients were enrolled. Two patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses. All patients analyzed showed potent inhibition of FT activity (85-98%) in tumor tissue; inhibition of phosphorylated  ERK and Akt was also observed. T cells showed evidence of FT inhibition and diminished IFN-gamma production. CONCLUSIONS: Despite potent target inhibition, R115777 showed no evidence of clinical activity in this cohort of melanoma patients. Inhibition of T cell function by FTIs has potential clinical implications.Clinicaltrials.gov number NCT00060125.

 

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[730]

TÍTULO / TITLE:  - The Achievement of a 3-Month Complete Cytogenetic Response to Second-Generation Tyrosine Kinase Inhibitors Predicts Survival in Patients With Chronic Phase Chronic Myeloid Leukemia After Imatinib Failure.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Lymphoma Myeloma Leuk. 2013 Jan 11. pii: S2152-2650(12)00291-1. doi: 10.1016/j.clml.2012.12.005.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clml.2012.12.005

AUTORES / AUTHORS:  - Jabbour E; Kantarjian H; Ghanem H; O’Brien S; Quintas-Cardama A; Garcia-Manero G; Cardenas M; Cortes J

INSTITUCIÓN / INSTITUTION:  - Department of Leukemia, MD Anderson Cancer Center, University of Texas, Houston,  TX. Electronic address: ejabbour@mdanderson.org.

RESUMEN / SUMMARY:  - BACKGROUND: We assessed whether the achievement of a 3-month complete cytogenetic response (CCyR) in 123 patients with chronic myeloid leukemia (CML) in the chronic phase, which was treated with second-generation tyrosine kinase inhibitors (2nd-TKI) after imatinib failure could predict for survival. PATIENTS  AND METHODS: In a multivariate analysis, the lack of a 3-month CCyR to 2nd-TKI therapy was selected as the only independent factor associated with poor event-free survival (hazard ratio [HR] 4.5; P < .001) and overall survival (5.4;  P = .03). RESULTS: The 3-year event-free survival and overall survival rates were 74% and 43%, respectively, for patients with 3-month CCyR, and were 98% and 79%,  respectively, for patients without 3-month CCyR. In a multivariate analysis, high hemoglobin level, previous major cytogenetic response to imatinib therapy, and </=90% Philadelphia-positive metaphases were associated with the achievement of a 3-month CCyR. CONCLUSION: The achievement of a 3-month CCyR is the only predictor of outcome in patients treated with 2nd-TKI therapy after imatinib failure. Patients with <3-month CCyR may not obtain long-term benefit and should be followed-up closely.

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[731]

TÍTULO / TITLE:  - Predictors of patient uptake of colorectal cancer gene environment risk assessment.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Genome Med. 2012 Nov 29;4(11):92.

            ●● Enlace al texto completo (gratuito o de pago) 1186/gm393

AUTORES / AUTHORS:  - Hall MJ; Manne SL; Myers RE; Keenan EM; Balshem AM; Weinberg DS

INSTITUCIÓN / INSTITUTION:  - Cancer Prevention and Control, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19038, USA. michael.hall@fccc.edu.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: In an ongoing clinical trial, the genetic and environmental risk assessment (GERA) blood test offers subjects information about personal colorectal cancer risk through measurement of two novel low-to-moderate risk factors. We sought to examine predictors of uptake of the GERA blood test among participants randomized to the Intervention arm. METHODS: Primary care patients aged 50 to 74 years eligible for colorectal cancer screening are randomized to receive a mailed stool blood test kit to complete at home (Control) or to the control condition plus an in-office blood test called GERA that includes assessment of red blood cell folate and DNA-testing for two MTHFR (methylenetetrahydrofolate reductase) single nucleotide polymorphisms (SNPs) (Intervention). For the present study, baseline survey data are examined in participants randomized to the Intervention. RESULTS: The first 351 intervention  participants (161 African American/190 white) were identified. Overall, 249 (70.9%) completed GERA testing. Predictors of GERA uptake included race (African  American race, odds ratio (OR) 0.51 (0.29 to 0.87)), and being more knowledgeable about GERA and colorectal cancer screening (OR 1.09 (1.01 to 1.18)). Being married (OR 1.81 (1.09 to 3.00)) was also significant in the multivariable model. CONCLUSIONS: Participant uptake of GERA testing was high. GERA uptake varied, however, according to socio-demographic background and knowledge.

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[732]

TÍTULO / TITLE:  - The LCS6 polymorphism in the binding site of let-7 microRNA to the KRAS 3’-untranslated region: its role in the efficacy of anti-EGFR-based therapy in metastatic colorectal cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pharmacogenet Genomics. 2013 Mar;23(3):142-7. doi: 10.1097/FPC.0b013e32835d9b0b.

            ●● Enlace al texto completo (gratuito o de pago) 1097/FPC.0b013e32835d9b0b

AUTORES / AUTHORS:  - Sebio A; Pare L; Paez D; Salazar J; Gonzalez A; Sala N; Del Rio E; Martin-Richard M; Tobena M; Barnadas A; Baiget M

INSTITUCIÓN / INSTITUTION:  - Departments of aMedical Oncology bGenetics cPathology, Hospital of the Holy Cross and Saint Paul, University Autonoma of Barcelona dU-705 CIBERER, Barcelona, España.

RESUMEN / SUMMARY:  - OBJECTIVE: Although KRAS mutation status has been identified as a strong predictor of response to anti-epidermal growth factor receptor (EGFR) therapies,  not all wild-type patients respond. The lethal-7 (let-7) family of microRNAs regulates KRAS activity. A functional polymorphism (rs61764370) has been described in the let-7 complementary site (LCS6). We hypothesized a possible association between this KRAS let-7 LCS6 polymorphism and the response to anti-EGFR treatments in KRAS and BRAF wild-type metastatic colorectal cancer patients (mCRC). MATERIALS AND METHODS: We studied the association of the KRAS let-7 LCS6 polymorphism with the response in 100 refractory mCRC patients treated with anti-EGFR antibodies. To assess the real effect of this polymorphism in relation to the treatment administered, we also studied this association in an independent cohort of patients treated exclusively with chemotherapy. The KRAS let-7 LCS6 polymorphism was genotyped using the BioMark system in blood and tumor DNA samples. The BRAF V600E mutation was analyzed in tumor samples. RESULTS: The  KRAS let-7 LCS6 G-allele showed a statistically significant association with nonresponse to anti-EGFR-based treatment: 31.9% of patients with the T/T genotype presented a complete or a partial response versus no patients with T/G or G/G genotypes (P=0.004). No statistically significant differences were observed in the patients who received chemotherapy only. CONCLUSION: These data support the pharmacogenetic role of the KRAS let-7 LCS6 polymorphism in predicting the efficacy of anti-EGFR-based therapy in mCRC patients with the KRAS and the BRAF wild-type genotype.

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[733]

TÍTULO / TITLE:  - TPEN Induces Apoptosis Independently of Zinc Chelator Activity in a Model of Acute Lymphoblastic Leukemia and Ex Vivo Acute Leukemia Cells through Oxidative Stress and Mitochondria Caspase-3- and AIF-Dependent Pathways.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oxid Med Cell Longev. 2012;2012:313275. doi: 10.1155/2012/313275. Epub 2012 Dec 23.

            ●● Enlace al texto completo (gratuito o de pago) 1155/2012/313275

AUTORES / AUTHORS:  - Mendivil-Perez M; Velez-Pardo C; Jimenez-Del-Rio M

INSTITUCIÓN / INSTITUTION:  - Neuroscience Research Group, Medical Research Institute School of Medicine, University of Antioquia (UdeA), Calle 62 No. 52-59, Building 1, Laboratory 411/412, SIU, Medellin, Colombia.

RESUMEN / SUMMARY:  - Acute lymphoblastic leukemia is still an incurable disease with resistance to therapy developing in the majority of patients. We investigated the effect of TPEN, an intracellular zinc chelator, in Jurkat and in ex vivo acute lymphoblastic leukemia (ALL) cells resistant to chemotherapy. Changes of nuclei morphology, reactive oxygen species generation, presence of hypodiploid cells, phosphatidylserine translocation, mitochondrial membrane depolarization, immunohistochemical identification of cell death signalling molecules, and pharmacological inhibition were assayed to detect the apoptotic cell death pathways. We found that TPEN induces apoptosis in both types of cells by a molecular oxidative stress pathway involving O(2) (*-) > H(2)O(2) >> NF-kappaB (JNK/c-Jun) >p53> loss DeltaPsi(m)> caspase-3, AIF > chromatin condensation/DNA fragmentation. Interestingly, TPEN induced apoptosis independently of glucose; leukemic cells are therefore devoid of survival capacity by metabolic resistance  to treatment. Most importantly, TPEN cytotoxic effect can eventually be regulated by the antioxidant N-acetyl-cysteine and zinc ions. Our data suggest that TPEN can be used as a potential therapeutic prooxidant agent against refractory leukemia. These data contribute to understanding the importance of oxidative stress in the treatment of ALL.

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[734]

TÍTULO / TITLE:  - Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in Philadelphia chromosome positive Malaysian chronic myeloid leukemia patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hematol Rep. 2012 Nov 19;4(4):e23. doi: 10.4081/hr.2012.e23. Epub 2012 Nov 23.

            ●● Enlace al texto completo (gratuito o de pago) 4081/hr.2012.e23

AUTORES / AUTHORS:  - Elias MH; Baba AA; Husin A; Abdullah AD; Hassan R; Sim GA; Wahid SF; Ankathil R

INSTITUCIÓN / INSTITUTION:  - Human Genome Centre;

RESUMEN / SUMMARY:  - Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is mediated by different mechanisms that can be classified as BCR-ABL dependent or BCR-ABL independent pathways. BCR-ABL dependent mechanisms are most frequently associated with point mutations in tyrosine kinase domain (TKD) of BCR-ABL1 and also with BCR-ABL gene amplification. Many different types  and frequencies of mutations have been reported in different studies, probably due to the different composition of study cohorts. Since no reports are available from Malaysia, this study was undertaken to investigate the frequency and pattern of BCR-ABL kinase domain mutations using dHPLC followed by sequencing, and also status of BCR-ABL gene amplification using fluorescence in situ hybridization (FISH) on 40 IM resistant Malaysian CML patients. Mutations were detected in 13 patients (32.5%). Five different types of mutations (T315I, E255K, Y253H, M351T,  V289F) were identified in these patients. In the remaining 27 IM resistant CML patients, we investigated the contribution made by BCR-ABL gene amplification, but none of these patients showed amplification. It is presumed that the mechanisms of resistance in these 27 patients might be due to BCR-ABL independent pathways. Different mutations confer different levels of resistance and, therefore, detection and characterization of TKD mutations is highly important in order to guide therapy in CML patients.

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[735]

TÍTULO / TITLE:  - Tegafur-uracil (UFT) in lower doses is safe for the treatment of colorectal cancer in patients with partial dihydropyrimidine dehydrogenase deficiency: a proof of principle.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ther Adv Med Oncol. 2013 Jan;5(1):93-4. doi: 10.1177/1758834012469430.

            ●● Enlace al texto completo (gratuito o de pago) 1177_1758834012469430 [pii

            ●● Enlace al texto completo (gratuito o de pago) 1177/1758834012469430

AUTORES / AUTHORS:  - Cubero DI; Del Giglio A

INSTITUCIÓN / INSTITUTION:  - Department of Oncology and Haematology, ABC Foundation School of Medicine, Av. Principe de Gales, n.821, anexo 3, Santo Andre/SP, 09060-650, Brazil.

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[736]

TÍTULO / TITLE:  - Emphasizing the role of Wnt5a protein expression to predict favorable outcome after radical prostatectomy in patients with low-grade prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Med. 2012 Aug;1(1):96-104. doi: 10.1002/cam4.5. Epub 2012 Jun 4.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cam4.5

AUTORES / AUTHORS:  - Khaja AS; Egevad L; Helczynski L; Wiklund P; Andersson T; Bjartell A

INSTITUCIÓN / INSTITUTION:  - Division of Urological Cancers, Department of Clinical Sciences, Skane University Hospital, Lund University Malmo, Sweden ; Center for Molecular Pathology, Skane University Hospital, Lund University Malmo, Sweden.

RESUMEN / SUMMARY:  - Wnt5a, a member of non-canonical wingless-related MMTV integration site family is a secreted glycoprotein that plays important roles in development and disease. Recent studies have shown that Wnt5a protein levels are up-regulated in prostate  cancer, but contrasting reports exist on the role of Wnt5a to predict outcome after radical prostatectomy in patients with localized prostate cancer. Our group has recently shown that preserved high protein expression of Wnt5a in prostate cancer is associated with longer relapse-free time after radical prostatectomy. The present tissue microarray study emphasizes the role of Wnt5a protein expression in a different, well-defined, and independent cohort consisting of 312 prostate cancer patients. Kaplan-Meier curves plotted between Wnt5a expression and time to biochemical recurrence revealed that in low-grade prostate cancer, patients with preserved high-Wnt5a protein levels in their tumor cells have a lower risk of recurrence after radical prostatectomy compared to patients with low-Wnt5a protein expression. When Wnt5a protein expression was added to a Cox regression multivariate analysis, both Wnt5a protein expression and surgical margin status independently predict biochemical free survival. Herein we confirm  Wnt5a positivity as a prognostic factor and show that preserved overexpression of Wnt5a protein is associated with increased time to biochemical recurrence in localized low-grade prostate cancer patients after radical prostatectomy. Our results emphasize that Wnt5a can be used as a predictive biomarker, and favoring  the view of Wnt5a as a future therapeutic target in prostate cancer patients with tumor cells displaying low expression of Wnt5a.

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[737]

TÍTULO / TITLE:  - Molecular mechanisms underlying the antitumor activity of 3-aminopropanamide irreversible inhibitors of the epidermal growth factor receptor in non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Neoplasia. 2013 Jan;15(1):61-72.

AUTORES / AUTHORS:  - Galvani E; Giovannetti E; Saccani F; Cavazzoni A; Leon LG; Dekker H; Alfieri R; Carmi C; Mor M; Ardizzoni A; Petronini PG; Peters GJ

INSTITUCIÓN / INSTITUTION:  - Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy ; Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.

RESUMEN / SUMMARY:  - Overcoming the emergence of acquired resistance to clinically approved epidermal  growth factor receptor (EGFR) inhibitors is a major challenge in the treatment of advanced non-small cell lung cancer (NSCLC). The aim of this study was to investigate the effects of a series of novel compounds affecting viability of NSCLC NCI-H1975 cells (carrying the EGFR T790M mutation). The inhibition of the autophosphorylation of EGFR occurred at nanomolar concentrations and both UPR1282 and UPR1268 caused a significant induction of apoptosis. Targeting of EGFR and downstream pathways was confirmed by a peptide substrate array, which highlighted the inhibition of other kinases involved in NSCLC cell aggressive behavior. Accordingly, the drugs inhibited migration (about 30% vs. control), which could be, in part, explained also by the increase of E-cadherin expression. Additionally, we observed a contraction of the volume of H1975 spheroids, associated with the reduction of the cancer stem-like cell hallmark CD133. The activity of UPR1282 was retained in H1975 xenograft models where it determined tumor shrinkage (P < .05) and resulted well tolerated compared to canertinib. Of  note, the kinase activity profile of UPR1282 on xenograft tumor tissues showed overlapping results with respect to the activity in H1975 cells, unraveling the inhibition of kinases involved in pivotal proliferation and invasive signaling pathways. In conclusion, UPR1282 and UPR1268 are effective against various processes involved in malignancy transformation and progression and may be promising compounds for the future treatment of gefitinib-resistant NSCLCs.

 

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[738]

TÍTULO / TITLE:  - Anti-tumor Activity and Apoptosis-regulation Mechanisms of Bufalin in Various Cancers: New Hope for Cancer Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian Pac J Cancer Prev. 2012;13(11):5339-43.

AUTORES / AUTHORS:  - Yin PH; Liu X; Qiu YY; Cai JF; Qin JM; Zhu HR; Li Q

INSTITUCIÓN / INSTITUTION:  - Department of General Surgery and Medical Oncology, Putuo Hospital and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China E-mail : Lzwf@hotmail.com.

RESUMEN / SUMMARY:  - The induction of apoptosis in target cells is a key mechanism for most anti-tumor therapies. Bufalin is a cardiotonic steroid that has the potential to induce differentiation and apoptosis of tumor cells. Research on bufalin has so far mainly involved leukemia, prostate cancer, gastric cancer and liver cancer, and has been confined to in vitro studies. The bufadienolides bufalin and cinobufagin have been shown to induce apoptosis in a wide spectrum of cancer cell. The present article reviews the anticancer effects of bufalin. It induces apoptosis of lung cancer cells via the PI3K/Akt pathway and also suppressed the proliferation of human non-small cell lung cancer A549 cell line in a time and dose dependent manner. Bufalin, bufotalin and gamabufotalin, key bufadienolides,  significantly sensitize human breast cancer cells with differing ER-alpha status  to apoptosis induction by the TNF-related apoptosis-inducing ligand (TRAIL). In addition, bufadienolides induce prostate cancer cell apoptosis more significantly than that in breast epithelial cell lines. Similar effects have been observed with hepatocellular carcinoma (HCC) but the detailed molecular mechanisms of inducing apoptosis in this case are still unclear. Bufalin exerts profound effects on leukemia therapy in vitro. Results of multiple studies indicate that bufalin has marked anti-tumor activities through its ability to induce apoptosis. Large-scale randomized, double-blind, placebo or positive drug parallel controlled studies are now required to confirm the efficacy and apoptosis-inducing potential of bufalin in various cancers in the cliniucal setting.

 

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[739]

TÍTULO / TITLE:  - Phase II trial of sequential subcutaneous interleukin-2 plus interferon alpha followed by sorafenib in renal cell carcinoma (RCC).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Transl Oncol. 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12094-012-0991-z

AUTORES / AUTHORS:  - Maroto JP; Del Muro XG; Mellado B; Perez-Gracia JL; Andres R; Cruz J; Gallardo E; Domenech M; Arranz JA; Meana JA

INSTITUCIÓN / INSTITUTION:  - Hospital de la Santa Creu i Sant Pau, Mas Casanovas 90, 08025, Barcelona, España,  jmaroto@santpau.cat.

RESUMEN / SUMMARY:  - PURPOSE: Immunotherapy (IL-2 and INF-alpha) was the treatment of choice for advanced renal cell carcinoma (RCC) until antiangiogenic therapy with tyrosin kinase inhibitors was developed in the early 2000s. This clinical trial explored  the efficacy and toxicity of sequential treatment of IL-2 plus INF-alpha followed by sorafenib. METHODS: Eligibility criteria included measurable, non-resectable,  histologically confirmed predominantly clear cell RCC, no prior systemic treatment, and ECOG PS 0-2. The treatment regimen was a 6-week cycle of subcutaneous IL-2 at 9 x 10(6) IU on days 1-6 of weeks 1, 2, 4 and 5 plus s.c. INF-alpha at 6 x 10(6) IU on days 1, 3 and 5 of weeks 1-6. Responders received 6  additional weeks of this regimen. All patients received oral sorafenib (400 mg bid) after immunotherapy until disease progression. The primary endpoint was progression-free survival. RESULTS: Forty-one patients were enrolled, median age  57 years. ECOG was 0/1 in 17/20 patients, 35 patients had prior nephrectomy and 18 patients pure clear cell cancer. Median PFS was 7.4 months (95 % CI 6.5-13.1)  and OS was 16.6 months (95 % CI not reached). In 36 patients evaluable for response, ORR was 44.4 % and control rate was 94.4 %. Most adverse events (AEs) were Grade 1 or 2 toxicities (84.7 %). During immunotherapy the most common AEs were pyrexia (82.9 %), asthenia (56.1 %) and anorexia (46.3 %), whereas during sorafenib were diarrhoea (48.8 %) and hand-foot syndrome (46.3 %). CONCLUSIONS: A sequential regimen of IL-2 and INF-alpha followed by sorafenib showed effectiveness and manageable toxicity in patients with advanced RCC.

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[740]

TÍTULO / TITLE:  - Growth advantage of CD34+ cells in trisomy 8 high-risk myelodysplastic syndrome despite enhanced apoptotic signals.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - East Mediterr Health J. 2012 Oct;18(10):1065-71.

AUTORES / AUTHORS:  - Youssef SR; Ismail MM; Abd Al Wahed E; Al Dessoky H

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

RESUMEN / SUMMARY:  - This study examined haematopoietic stem cells of 19 high-risk cases of myelodysplastic syndrome (MDS) for apoptotic and anti-apoptotic signals and cellular proliferation and correlated these with clinical and cytogenetic subtypes, particularly trisomy 8. The aim was to identify cellular and cytogenetic markers of prognostic relevance to survival of high-risk MDS cases. High-risk MDS cases had a significantly higher percentage of apoptotic CD34+ cells and anti-apoptotic survivin+ cells than controls, particularly for trisomy  8 cases. Trisomy 8+ cells showed a significant positive correlation with apoptotic CD34+ cells and capacity for colony formation. The latter was significantly lower in trisomy-8-negative cases than normal controls, while that  oftrisomy 8 cases was comparable to controls. Our results suggest that although trisomy 8 cells are in a pro-apoptotic state, they are checked by the enhanced expression of anti-apoptotic signals which provide them with their proliferative  advantage.

 

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[741]

TÍTULO / TITLE:  - Prognostic value of alpha-fetoprotein and des-gamma-carboxy prothrombin responses in patients with hepatocellular carcinoma treated with transarterial chemoembolization.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Cancer. 2013 Jan 3;13:5. doi: 10.1186/1471-2407-13-5.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2407-13-5

AUTORES / AUTHORS:  - Lee YK; Kim SU; Kim do Y; Ahn SH; Lee KH; Lee do Y; Han KH; Chon CY; Park JY

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Korea. DRPJY@yuhs.ac.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND/AIMS: Alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) have been used as diagnostic tools for hepatocellular carcinoma (HCC). However, prediction of outcome using AFP and DCP has not been elucidated.  We investigated the clinical role of AFP and DCP as predictors of treatment outcome in patients with HCC undergoing trans-arterial chemoembolization (TACE).  METHODS: Between January 2003 and December 2005, we enrolled 115 treatment-naive  patients who received TACE as an initial treatment modality. An AFP or DCP response was defined as a reduction of more than 50% from the baseline level 1 month after TACE. Patients with AFP < 20 ng/mL or DCP < 20 mAU/mL were excluded.  RESULTS: The median age was 59 years and the male gender predominated (n = 81, 70.4%). AFP and DCP response was identified in 91 (79.1%) and 77 (66.9%) patients after TACE. Although progression-free survival (PFS) did not differ according to  AFP response (P = 0.150), AFP responders showed significantly better overall survival (OS) than non-responders (34.9 vs. 13.2 months; P = 0.002). In contrast, DCP response did not influence either PFS or OS (all P > 0.05). Multivariate analyses showed that gamma-glutamyltranspeptidase and baseline AFP were predictors of PFS (all P < 0.05) and that male gender, the presence of liver cirrhosis, baseline DCP, number of measurable tumors and AFP response were independent predictors of OS (all P < 0.05). CONCLUSIONS: AFP response and higher baseline DCP level are significant predictors of OS in treatment-naive patients with HCC receiving TACE who showed pretreatment elevation of both AFP and DCP.

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[742]

TÍTULO / TITLE:  - Tumor Burden is Predictive of Survival in Patients With Non-Small-Cell Lung Cancer and With Activating Epidermal Growth Factor Receptor Mutations Who Receive Gefitinib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Lung Cancer. 2013 Jan 9. pii: S1525-7304(12)00259-8. doi: 10.1016/j.cllc.2012.10.007.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.cllc.2012.10.007

AUTORES / AUTHORS:  - Park JH; Kim TM; Keam B; Jeon YK; Lee SH; Kim DW; Chung DH; Kim YT; Kim YW; Heo DS

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

RESUMEN / SUMMARY:  - BACKGROUND: Although activating epidermal growth factor receptor (EGFR) mutations are excellent predictors of gefitinib outcome in non-small-cell lung cancer (NSCLC), most patients become resistant to gefitinib. Despite our knowledge of the molecular basis of acquired resistance, clinical predictors have not been well elucidated. This study was undertaken to evaluate predictors of clinical outcome in patients with NSCLC and with EGFR mutations treated with gefitinib. PATIENTS AND METHODS: A total of 170 patients with NSCLC and with EGFR mutations  received gefitinib as a first-line (n = 50) and a second-line or more (n = 120) treatment at Seoul National University Hospital. Treatment outcomes were compared between groups based on clinicopathologic factors, such as treatment line, metastatic site, and mutation subtype. RESULTS: Survival outcomes were similar between first-line and second-line or greater gefitinib treatment (overall response rate, 2P = .832; progression-free survival [PFS], 2P = .373; and overall survival [OS], 2P = .290). When the number of metastatic sites was at least 3, significantly reduced survival was observed (median PFS 8.5 vs. 14.0 months, 2P < .001; median OS 21.4 vs. 25.6 months, 2P = .002). In addition, the presence of at least 3 organs with metastases was an independent predictor of PFS (hazard ratio  [HR] 1.97 [95% CI, 1.37-2.85]; 2P < .001) and OS (HR 2.00 [95% CI, 1.18-3.39]; 2P = .010). Patients who failed to respond to gefitinib within 6 months of treatment had more lymph node metastases and more sites of metastasis than those who responded later. CONCLUSIONS: Tumor burden, expressed as the number of metastatic sites, is predictive of inferior survival in patients with NSCLC and with activating EGFR mutations who are treated with gefitinib.

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[743]

TÍTULO / TITLE:  - Apoptosis-associated biomarkers in tuberculosis: promising for diagnosis and prognosis prediction.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Infect Dis. 2013 Jan 28;13(1):45.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2334-13-45

AUTORES / AUTHORS:  - Shu CC; Wu MF; Hsu CL; Huang CT; Wang JY; Hsieh SL; Yu CJ; Lee LN; Yang PC

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Apoptosis-associated biomarkers are rarely studied, especially their role in predicting the development of tuberculosis (TB) from latent TB infection and in prognostication. METHODS: Patients with TB and interferon-gamma release assay (IGRA)-positive and IGRA-negative family contacts  were evaluated to analyze changes in apoptosis-associated serum biomarkers, which included decoy receptor 3 (DcR3), prostaglandin 2 (PGE2), and lipoxin. The prognostic implications of these serum biomarkers were also analyzed. RESULTS: One hundred TB patients and 92 IGRA-negative and 91 IGRA-positive family contacts were recruited. The DcR3 and PGE2 levels decreased from the IGRA-negative group to the IGRA-positive group, and peaked in the TB group. Lipoxin decreased to trough in the TB group. The three apoptosis serum markers and age were independent factors discriminating active TB from latent TB infection. In active  TB, older age, co-morbidity, and higher serum DcR3 and monocyte chemotactic protein (MCP)-1 were independently associated with poorer six-month survival. CONCLUSION: Apoptosis-associated serum biomarkers change along with the status of Mycobacterium tuberculosis infection. In close contacts with positive IGRA, high  DcR3 and PGE2 and low lipoxin may increase the probability of active TB. Older age, co-morbidity, and high DcR3 and MCP-1 levels might be important prognostic factors that warrant further investigation.

 

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[744]

TÍTULO / TITLE:  - Prognostic Impact of [18F]Fluorothymidine and [18F]Fluoro-D-Glucose Baseline Uptakes in Patients with Lung Cancer Treated First-Line with Erlotinib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e53081. doi: 10.1371/journal.pone.0053081. Epub 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0053081

AUTORES / AUTHORS:  - Scheffler M; Zander T; Nogova L; Kobe C; Kahraman D; Dietlein M; Papachristou I; Heukamp L; Buttner R; Boellaard R; Lammertsma AA; Querings S; Stoelben E; Engel-Riedel W; Neumaier B; Wolf J

INSTITUCIÓN / INSTITUTION:  - Department I for Internal Medicine, University Hospital of Cologne, Cologne, Germany ; Center for Integrated Oncology Koln Bonn, Cologne, Germany.

RESUMEN / SUMMARY:  - 3’-deoxy-3’-[(18)F]fluoro-L-thymidine (FLT) and 2’-deoxy-2’-[(18)F]fluoro-D-glucose (FDG) are used to visualize proliferative and metabolic activity of tumors. In this study we aimed at evaluating the prognostic value of FLT and FDG uptake measured by positron emission tomography (PET) in patients with metastatic non-small cell lung cancer (NSCLC) prior to systemic therapy with erlotinib. FLT and FDG maximum standardized uptake (SUVmax) values per patient were analyzed in 40 chemotherapy naive patients with advanced NSCLC (stage IV) before treatment with erlotinib. Prior therapy median SUVmax was 6.6 for FDG and 3.0 for FLT, respectively. In univariate analysis, patients with an FDG SUVmax <6.6 had a significantly better overall survival (16.3 months [95% confidence interval [CI] 7.1-25.4 months]) compared to patients with an FDG SUVmax >/=6.6 (3.1 months [95% CI 0.6-5.5 months]) (p<0.001, log rank). Similarly, low FLT uptake (SUVmax <3.0) was associated with significantly longer  survival (10.3 months (0-23.3 months, 95% CI) compared to high FLT uptake (3.4 months (0-8.1 months, 95% CI) (p = 0.027). The independent prognostic value of baseline FDG uptake was demonstrated in multivariate analysis (p = 0.05, Cox regression). These data suggest that baseline SUVmax values for both FDG and FLT  PET might be further developed as markers for prognostic stratification of patients in advanced NSCLC treated with tyrosine kinase inhibitors (TKI) directed against the epidermal growth factor receptor (EGFR). TRIAL REGISTRATION: Clinicaltrials.gov, Identifier: NCT00568841.

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[745]

TÍTULO / TITLE:  - The Association between Genetic Polymorphism and the Processing Efficiency of miR-149 Affects the Prognosis of Patients with Head and Neck Squamous Cell Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51606. doi: 10.1371/journal.pone.0051606. Epub 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051606

AUTORES / AUTHORS:  - Tu HF; Liu CJ; Chang CL; Wang PW; Kao SY; Yang CC; Yu EH; Lin SC; Chang KW

INSTITUCIÓN / INSTITUTION:  - Department of Dentistry, National Yang-Ming University Hospital, I-Lan, Taiwan ;  Department of Dentistry, National Yang-Ming University, Taipei, Taiwan.

RESUMEN / SUMMARY:  - MicroRNAs (miRNAs) play important roles in modulating the neoplastic process of cancers including head and neck squamous cell carcinoma (HNSCC). A genetic polymorphism (rs2292832, C>T) has been recently identified in the precursor of miR-149; nevertheless its clinicopathological implications remain obscure. In this study, we showed that miR-149 is down-regulated in HNSCC compared to normal  mucosa and this is associated with a poorer patient survival. In addition, HNSCC  patients with the T/T genotype have more advanced tumors and a worse prognosis. Multivariate analysis indicated that patients carried the T/T genotype have a 2.81-fold (95% CI: 1.58-4.97) increased risk of nodal metastasis and 1.66-fold (95% CI: 1.05-2.60) increased risk of mortality compared to other groups. T/T genotype also predicted the worse prognosis of buccal mucosa carcinoma subset of  HNSCC. In vitro analysis indicated that exogenous miR-149 expression reduces the  migration of HNSCC cells. Moreover, HNSCC cell subclones carrying the pri-mir-149 sequence containing the T variant show a low processing efficacy when converting  the pre-mir-149 to mature miR-149. These findings suggest that miR-149 suppresses tumor cell mobility, and that the pre-mir-149 polymorphism may affect the processing of miR-149, resulting in a change in the abundance of the mature form  miRNA, which, in turn, modulates tumor progression and patient survival.

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[746]

TÍTULO / TITLE:  - Panitumumab and irinotecan every 3 weeks is an active and convenient regimen for  second-line treatment of patients with wild-type K-RAS metastatic colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Transl Oncol. 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12094-012-0993-x

AUTORES / AUTHORS:  - Carrato A; Gomez A; Escudero P; Chaves M; Rivera F; Marcuello E; Gonzalez E; Gravalos C; Constenla M; Manzano JL; Losa F; Maurel J; Duenas R; Massuti B; Gallego J; Aparicio J; Anton A; Aranda E

INSTITUCIÓN / INSTITUTION:  - Medical Oncology Department, Ramon y Cajal University Hospital, Ctra. Colmenar Viejo Km. 9,1, 28034, Madrid, España, acarrato@telefonica.net.

RESUMEN / SUMMARY:  - PURPOSE: To evaluate the efficacy and safety profile of the combination of panitumumab and irinotecan every 3 weeks in a phase II trial as second-line treatment in patients with advanced wild-type (WT) K-RAS colorectal cancer (CRC). METHODS: Fifty-three patients received 9 mg/kg of panitumumab followed by 350 mg/m(2) of irinotecan every 21 days until disease progression, unacceptable toxicity or consent withdrawal. RESULTS: Median age of patients included was 67 years. All patients had previously received 5-fluorouracil, 84 % oxaliplatin and  8 % irinotecan as first-line treatment. Patients received a median of five infusions of panitumumab and irinotecan. On an intention-to-treat analysis, 12 patients (23 %) achieved partial responses and 22 patients (41 %) achieved disease stabilization. Median progression-free survival and overall survival were 4.5 and 15.1 months, respectively. The most frequent treatment-related severe toxicities per patient were diarrhoea (35.8 %), followed by skin rash (32.1 %), asthenia (18.9 %) and neutropenia (13.2 %). A significant association between clinical response and incidence and grade of skin toxicity was observed (p = 0.0032). CONCLUSION: This study shows that the administration of panitumumab plus irinotecan every 3 weeks is safe, active and feasible as second-line treatment in patients with advanced WT K-RAS CRC.

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[747]

TÍTULO / TITLE:  - Genome study suggests new treatments for high-risk form of childhood leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - ONS Connect. 2012 Nov;27(11):21.

AUTORES / AUTHORS:  - McBride D

INSTITUCIÓN / INSTITUTION:  - Kaiser Permanente Oakland Medical Center, CA, USA.

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[748]

TÍTULO / TITLE:  - Biological markers and response to neoadjuvant taxane-based chemotherapy in patients with locally advanced breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - ISRN Oncol. 2012;2012:245891. doi: 10.5402/2012/245891. Epub 2012 Dec 17.

            ●● Enlace al texto completo (gratuito o de pago) 5402/2012/245891

AUTORES / AUTHORS:  - El-Sayed MI; Maximous DW; Zakhary MM; Mikhail NN

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt.

RESUMEN / SUMMARY:  - Introduction. Biological markers as Her2/neu, p53, and hormonal receptors (HmRs)  may be reliable parameters for prognostic assessment of patients of locally advanced breast cancer (LABC). This work aims at assessing the potential value of these biological markers for the prediction of disease outcome after neoadjuvant  taxane-based chemotherapy and its implication on the surgical role. Patients and  Methods. From March 2006 to September 2011, 95 patients with LABC were treated by neoadjuvant taxane-based chemotherapy given at intervals of 3 weeks. Expression of Her2/neu and p53 was examined in the initial tissue biopsy by using ELISA technique. Status of HmRs was determined using a commercial enzyme immunoassay. Three weeks after the third cycle, patients underwent surgical resection followed by 3 more cycles of taxane-based chemotherapy and radiotherapy as an adjuvant therapy. Relations of Her2/neu overexpression to p53, HmRs, and conventional prognostic factors were analyzed. Results. Median followup was 61 months. The 5-year DFS and OAS rates were significantly higher in patients with positive HmRs than in those with negative HmRs, patients with Her2- than those with Her2+ breast cancer, and patients with intact p53 breast cancer than those with inactive p53. HER-2 overexpression was statistically significant associated with  loss of HmR positive immunostaining (P < 0.0001), grade III breast cancer (P < 0.0001), advanced nodal status (P = 0.0039), and younger (<50 years) age (P = 0.0108). Conclusion. Her2/neu overexpression was associated with poor DFS and OAS rates, as it was significantly associated with negative HmR and high grade.

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[749]

TÍTULO / TITLE:  - Selected adverse events in cancer patients treated with vascular endothelial growth factor inhibitors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Epidemiol. 2012 Dec 11. pii: S1877-7821(12)00153-1. doi: 10.1016/j.canep.2012.11.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canep.2012.11.001

AUTORES / AUTHORS:  - Dreyfus B; Kawabata H; Gomez A

INSTITUCIÓN / INSTITUTION:  - Department of Epidemiology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: brian.dreyfus@bms.com.

RESUMEN / SUMMARY:  - Introduction: To evaluate the safety profile of new drugs, it is important to quantify the rates of adverse events (AE). There has been little to no research on the safety of vascular endothelial growth factor (VEGF) inhibitors in population-based settings. The purpose of this study was to further the understanding of the incidence of AEs in a population-based representative cancer population receiving VEGF inhibitors where there currently is a deep lack of knowledge. Methods: We conducted a retrospective cohort study using data from an  administrative claims database between January 1, 2004 and December 31, 2010. Patients were included into the study if they had at least two malignant primary  cancer diagnoses codes (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]: 140-209 [not including 196-199.0]) from the same cancer site and a prescription for a VEGF inhibitor. We estimated the incidence rate (IR) and 95% confidence interval (CI) for each adverse event under study. Results: 2326 patients met the inclusion and exclusion criteria. The mean  age for the cohort was 57.3 where 79% of the patients were 50 years of age or older. The most common adverse event was nausea and vomiting (IR=651.7/1000 person-years; 95% CI=589.7-718.4). Other common adverse events were hypertension  (IR=452.9/1000 person-years; 95% CI=394.9-517.1) and hemorrhage (IR=375.2/1000 person-years; 95% CI=332.2-422.3). The least common adverse events were rare dermatologic diseases such as Stevens-Johnson syndrome and toxic epidermal necrolysis where no cases were observed. Conclusions: The rates detailed in this  analysis are helpful in understanding the benefit risk of VEGF inhibitors as they are prescribed in the real world. Although no formal comparisons were conducted,  the VEGF inhibitors evaluated in this study appeared to have overlapping toxicity profiles; however, the manner in which these AEs are listed in the prescribing information was not always consistent.

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[750]

TÍTULO / TITLE:  - Highly Synergistic Effect of Sequential Treatment with Epigenetic and Anticancer  Drugs To Overcome Drug Resistance in Breast Cancer Cells Is Mediated via Activation of p21 Gene Expression Leading to G2/M Cycle Arrest.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Pharm. 2013 Jan 7;10(1):337-52. doi: 10.1021/mp3004622. Epub 2012 Dec 24.

            ●● Enlace al texto completo (gratuito o de pago) 1021/mp3004622

AUTORES / AUTHORS:  - Vijayaraghavalu S; Dermawan JK; Cheriyath V; Labhasetwar V

INSTITUCIÓN / INSTITUTION:  - Department of Biomedical Engineering, Lerner Research Institute, and double daggerTaussig Cancer Institute, Cleveland Clinic , Cleveland, Ohio 44195, United  States.

RESUMEN / SUMMARY:  - Epigenetic alterations such as aberrant DNA methylation and histone modifications contribute substantially to both the cause and maintenance of drug resistance. These epigenetic changes lead to silencing of tumor suppressor genes involved in  key DNA damage-response pathways, making drug-resistant cancer cells nonresponsive to conventional anticancer drug therapies. Our hypothesis is that treating drug-resistant cells with epigenetic drugs could restore the sensitivity to anticancer drugs by reactivating previously silenced genes. To test our hypothesis, we used drug-resistant breast cancer cells (MCF-7/ADR) and two epigenetic drugs that act via different mechanisms-5-aza-2’-deoxycytidine (decitabine, DAC), a demethylating agent, and suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor-in combination with doxorubicin. We show  that the sequential treatment of resistant cells, first with an epigenetic drug (DAC), and then with doxorubicin, induces a highly synergistic effect, thus reducing the IC(50) of doxorubicin by several thousand fold. The sequential treatment caused over 90% resistant cells to undergo G2/M cell cycle arrest, determined to be due to upregulation of p21(WAF1/CIP1) expression, which is responsible for cell-cycle regulation. The induction of p21(WAF1/CIP1) correlated well with the depletion of DNA methyltransferase1 (DNMT1), an enzyme that promotes methylation of DNA, suggesting that the p21(WAF1/CIP1) gene may have been methylated and hence is inactive in MCF-7/ADR cells. Microarray analysis shows expression of several tumor suppressor genes and downregulation of tumor promoter genes, particularly in sequentially treated resistant cells. Sequential  treatment was found to be significantly more effective than simultaneous treatment, and DAC was more effective than SAHA in overcoming doxorubicin resistance. Synergistic effect with sequential treatment was also seen in drug-sensitive breast cancer cells, but the effect was significantly more pronounced in resistant cells. In conclusion, the sequential treatment of an epigenetic drug in combination with doxorubicin induces a highly synergistic effect that overcomes doxorubicin resistance in breast cancer cells.

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[751]

TÍTULO / TITLE:  - Differential outcome of concurrent radiotherapy plus epidermal growth factor receptor inhibitors versus radiotherapy plus cisplatin in patients with human papillomavirus-related head and neck cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Cancer. 2013 Jan 18;13(1):26.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2407-13-26

AUTORES / AUTHORS:  - Pajares B; Trigo JM; Toledo MD; Alvarez M; Gonzalez-Hermoso C; Rueda A; Medina JA; Luque V; Jerez JM; Alba E

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Human papillomavirus (HPV)-related head and neck cancer has been associated with an improved prognosis in patients treated with radiotherapy  (RT) +/- chemotherapy (CT); however, RT combined with epidermal growth factor receptor (EGFR) inhibitors has not been fully studied in this group of patients.  METHODS: Immunohistochemical expression of p16 and PCR of HPV16 DNA were retrospectively analyzed in tumor blocks from 108 stage III/IV head and neck cancer patients treated with RT+CT (56) or RT+EGFR inhibitors (52). Disease-free  survival (DFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. RESULTS: DNA of HPV16 was found in 12 of 108 tumors (11%) and p16 positivity in 18 tumors (17%), with similar rates in both arms of treatment. After a median follow-up time of 35 months (range 6--135), p16-positive patients  treated with RT+EGFR inhibitors showed improved survival compared with those treated with RT+CT (2-year OS 88% vs. 60%, HR 0.18; 95% CI 0.04 to 0.88; p = 0.01; and 2-year DFS 75% vs. 47%, HR 0.17; 95% CI 0.03 to 0.8; p = 0.01). However, no differences were observed in p16-negative patients (2-year OS 56% vs. 53%, HR 0.97; 95% CI 0.55 to 1.7; p = 0.9; and 2-year DFS 43% vs. 45%, HR 0.99; 95% CI 0.57 to 1.7; p = 0.9). CONCLUSIONS: This is the first study to show that p16-positive patients may benefit more from RT+EGFR inhibitors than conventional  RT+CT. These results are hypothesis-generating and should be confirmed in prospective trials.

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[752]

TÍTULO / TITLE:  - Predictive significance of mean apparent diffusion coefficient value for responsiveness of temozolomide-refractory malignant glioma to bevacizumab: preliminary report.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Clin Oncol. 2013 Jan 26.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10147-013-0517-x

AUTORES / AUTHORS:  - Nagane M; Kobayashi K; Tanaka M; Tsuchiya K; Shishido-Hara Y; Shimizu S; Shiokawa Y

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Kyorin University Faculty of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan, mnagane.g@gmail.com.

RESUMEN / SUMMARY:  - BACKGROUND: Recurrent glioblastoma after initial radiotherapy plus concomitant and adjuvant temozolomide is problematic. Here, patients with temozolomide-refractory high-grade gliomas were treated with bevacizumab (BV) and evaluated using apparent diffusion coefficient (ADC) for response. METHODS: Nine  post-temozolomide recurrent or progressive high-grade glioma patients (seven with glioblastoma and two with anaplastic astrocytoma) were treated with BV monotherapy. Average age was 57 years (range, 22-78), median Karnofsky Performance Scale (KPS) was 70 (30-80) and median BV line number was 2 (2-5). Two had additional stereotactic radiotherapy within 6 months prior to BV. Magnetic resonance (MR) imaging after BV therapy was performed within 2 weeks with calculation of mean ADC (mADC) values of enhancing tumor contours. RESULTS: Post-BV treatment MR imaging showed decreased tumor volumes in eight of nine cases (88.9 %). Partial response was obtained in four cases (44.4 %), four cases  had stable disease, and one had progressive disease. Of 15 evaluable enhancing lesions, 11 shrank and four did not. Pretreatment mADC values were above 1100 (10(-6) mm(2)/s) in all responding tumors, while all non-responding lesions scored below 1100 (p = 0.001). mADC decreased after the first BV treatment in all lesions except one. KPS improved in four cases (44.4 %). Median progression-free  survival and overall survival for those having all lesions with high mADC (>1100) were significantly longer than those with a low mADC (<1100) lesion (p = 0.018 and 0.046, respectively). CONCLUSIONS: Bevacizumab monotherapy is effective in patients with temozolomide-refractory recurrent gliomas and tumor mean ADC value  can be a useful marker for prediction of BV response and survival.

 

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[753]

TÍTULO / TITLE:  - Effects of Genetically Engineered Stem Cells Expressing Cytosine Deaminase and Interferon-Beta or Carboxyl Esterase on the Growth of LNCaP Prostate Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2012 Sep 28;13(10):12519-32. doi: 10.3390/ijms131012519.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms131012519

AUTORES / AUTHORS:  - Yi BR; Hwang KA; Kim YB; Kim SU; Choi KC

INSTITUCIÓN / INSTITUTION:  - Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju 361-763, Korea. kchoi@cbu.ac.kr.

RESUMEN / SUMMARY:  - The risk of prostate cancer has been increasing in men by degrees. To develop a new prostate cancer therapy, we used a stem cell-derived gene directed prodrug enzyme system using human neural stem cells (hNSCs) that have a tumor-tropic effect. These hNSCs were transduced with the therapeutic genes for bacterial cytosine deaminase (CD), alone or in combination with the one encoding human interferon-beta (IFN-beta) or rabbit carboxyl esterase (CE) to generate HB1.F3.CD, HB1.F3.CD.IFN-beta, and HB1.F3.CE cells, respectively. CD enzyme can convert the prodrug 5-fluorocytosine (5-FC) into the activated form 5-fluorouracil (5-FU). In addition, CE enzyme can convert the prodrug CPT-11 into a toxic agent, SN-38. In our study, the human stem cells were found to migrate toward LNCaP human prostate cancer cells rather than primary cells. This phenomenon may be due to interactions between chemoattractant ligands and receptors, such as VEGF/VEGFR2 and SCF/c-Kit, expressed as cancer and stem cells, respectively. The HB1.F3.CE, HB.F3.CD, or HB1.F3.CD.IFN-beta cells significantly  reduced the LNCaP cell viability in the presence of the prodrugs 5-FC or CPT-11.  These results indicate that stem cells expressing therapeutic genes can be used to develop a new strategy for selectively treating human prostate cancer.

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[754]

TÍTULO / TITLE:  - Human Leukocyte Antigen Class I Alleles can Predict Response to Pegylated Interferon/Ribavirin Therapy in Chronic Hepatitis C Egyptian Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Arch Iran Med. 2013 Feb;16(2):68-73. doi: 013162/AIM.004.

AUTORES / AUTHORS:  - Farag RE; Arafa MM; El-Etreby S; Saudy NS; Eldeek BS; El-Alfy HA; Goda IF; Ali RM

INSTITUCIÓN / INSTITUTION:  - Tropical Medicine Unit, Mansoura University Hospital, Mansoura Faculty of Medicine, Egypt.raghda.farag@yahoo.com.

RESUMEN / SUMMARY:  - BACKGROUND: Racial differences and broad spectrum response to anti-hepatitis C (anti-HCV) therapy suggest a possible role for host genetic diversity in treatment outcomes. We aim to determine the association and predictive value of certain human leukocyte antigen (HLA) class I alleles with either susceptibility  to viral clearance or persistence following pegylated interferon (Peg-IFN) plus ribavirin therapy in chronic hepatitis C (HCV) genotype 4 patients in Egypt. METHODS: This study included 200 unrelated chronic HCV patients who received Peg-IFN plus ribavirin therapy [112 patients with sustained virological response  (SVR) and 88 non-responders (NR)]. Serological testing of HLA class I antigens (HLA-A and HLA-B alleles) were performed by standard complement-dependent microlymphocytotoxicity assay. RESULTS: The frequency of HLA-A01 was significantly higher in SVR than in NR cases [OR: 0.51; 95% CI: 0.27-0.981; P = 0.042], while the frequency of alleles B38 (P = 0.011), B40 (P < 0.001) and B41 (P < 0.001) was significantly higher in NR cases (OR/95% CI: 7.05/(1.39-18.01), 10.31/3.14-36.1 . On logistic regression analysis, presence of the HLA-A01 allele was associated with SVR (OR: 0.50; 95% CI: 0.28-0.89; P = 0.02) and HLA-B38 can predict non response to therapy (OR: 7.92; 95% CI: 1.67-37.54; P = 0.009) with an overall accuracy of 60%.Severe fibrosis (OR: 3.035; 95% CI: 1.521-6.091; P = 0.002), high viremia (OR: 2.69; 95% CI: 1.11-6.53; P = 0.005) and steatosis (OR:  2.1; 95% CI: 1.002-3.90; P = 0.041) predicted no response with an overall accuracy of 81.8%. CONCLUSION: HLA-A01 and HLA-B38 alleles are associated with and may have a role in the outcome of response to Peg-IFN plus ribavirin therapy  in Egyptian patients diagnosed with chronic HCV infection. The use of immunologic markers to predict the outcome of treatment may help pharmacogenetic personalization of treatment for HCV infection.

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[755]

TÍTULO / TITLE:  - The extended leukocyte differential count using the cytodiff flow cytometric system reveals that higher CD16+ cytotoxic NK+T lymphocyte levels predict superior survival outcomes in patients with metastatic carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cytometry B Clin Cytom. 2012 Dec 26. doi: 10.1002/cyto.b.21063.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cyto.b.21063

AUTORES / AUTHORS:  - Park BG; Park CJ; Yoon CH; Jang S; Chi HS; Ryu MH; Kim SW

INSTITUCIÓN / INSTITUTION:  - Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, South Korea.

RESUMEN / SUMMARY:  - The recently developed Cytodiff flow cytometric system (Beckman Coulter, Miami, FL) enables leukocyte analysis using a single immunophenotyping panel tube composed of six markers and five colors and that can detect 16 leukocyte subpopulations. We performed a preliminary investigation of whether changes in any of 16 leukocyte differentials were associated with survival and treatment outcomes in patients with metastatic carcinoma or not. We measured 16 leukocyte differential counts using the Cytodiff flow cytometric system in peripheral blood samples from 40 patients with metastatic malignancy (27 stomach cancer and 13 lung cancer) before chemotherapy and at 15 day intervals after chemotherapy for 2 months. A higher percentage of CD16+ cytotoxic NK+T lymphocytes was found to be the only significant prognostic factor among by Cox regression analysis and a higher percentage of CD16+ cytotoxic NK+T lymphocytes (>5.0%) showed significantly longer survival outcomes by Kaplan-Meier analysis (P = 0.003). The  Cytodiff system enables 16 leukocyte subpopulations in a one tube assay and also  can operate with only small amounts of sample, although it cannot differentiate NK cells from T lymphocytes. Hence, the monitoring of all leukocyte subpopulations using Cytodiff flow cytometry may be a helpful prognostic tool for patients with metastatic carcinoma. © 2012 International Society for Advancement of Cytometry.

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[756]

TÍTULO / TITLE:  - Overexpression of RNA-binding protein CELF1 prevents apoptosis and destabilizes pro-apoptotic mRNAs in oral cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - RNA Biol. 2013 Jan 16;10(2).

AUTORES / AUTHORS:  - Talwar S; Balasubramanian S; Sundaramurthy S; House R; Wilusz C; Kuppuswamy D; D’Silva N; Gillespie M; Hill E; Palanisamy V

INSTITUCIÓN / INSTITUTION:  - Department of Craniofacial Biology and Center for Oral Health Research; College of Dental Medicine; Medical University of South Carolina; Charleston, SC USA.

RESUMEN / SUMMARY:  - CELF1 RNA-binding protein, otherwise called CUGBP1, associates and coordinates the degradation of GU-rich element (GRE) containing mRNA’s encoding factors important for cell growth, migration and apoptosis. Although many substrates of CELF1 have been identified, the biological significance of CELF1-mediated mRNA decay remains unclear. As the processes modulated by CELF1 are frequently disrupted in cancer, we investigated the expression and role of CELF1 in oral squamous cancer cells (OSCCs). We determined that CELF1 is reproducibly overexpressed in OSCC tissues and cell lines. Moreover, depletion of CELF1 reduced proliferation and increased apoptosis in OSCCs, but had negligible effect in non-transformed cells. We found that CELF1 associates directly with the 3’UTR  of mRNAs encoding the pro-apoptotic factors BAD, BAX and JunD and mediates their  rapid decay. Specifically, 3’UTR fragment analysis of JunD revealed that the GRE  region is critical for binding with CELF1 and expression of JunD in oral cancer cells. In addition, silencing of CELF1 rendered BAD, BAX and JunD mRNAs stable and increased their protein expression in oral cancer cells. Taken together, these results support a critical role for CELF1 in modulating apoptosis and implicate this RNA-binding protein as a cancer marker and potential therapeutic target.

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[757]

TÍTULO / TITLE:  - Oridonin induces apoptosis, inhibits migration and invasion on highly-metastatic  human breast cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Chin Med. 2013;41(1):177-96. doi: 10.1142/S0192415X13500134.

            ●● Enlace al texto completo (gratuito o de pago) 1142/S0192415X13500134

AUTORES / AUTHORS:  - Wang S; Zhong Z; Wan J; Tan W; Wu G; Chen M; Wang Y

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR, 999078, China , Institute of Chinese Medical Sciences, University of Macau, Macau SAR, 999078, China.

RESUMEN / SUMMARY:  - Oridonin, a natural tetracycline diterpenoid isolated from Chinese herb Rabdosia  rubescens, has been reported to be a potent cytotoxic agent against a wide variety of tumors. However, its effect on highly metastatic breast cancer cells has not been addressed. In this study, we investigated the effects of oridonin on growth, migration and invasion of highly-metastatic human breast cancer cells. Our results showed that oridonin induced potent growth inhibition on human breast cancer cells MCF-7 and MDA-MB-231 in a time- and dose-dependent manner. According to the flow cytometric analysis, oridonin suppressed MCF-7 cell growth by cell cycle arrest at the G2/M phase and caused accumulation of MDA-MB-231 cells in the Sub-G1 phase. The induced apoptotic effect of oridonin was further confirmed by a morphologic characteristics assay and TUNEL assay. Oridonin triggered the reduction of Bcl-2/Bax ratio, caspase-8, NF-kappaB (p65), IKKalpha, IKKbeta, phospho-mTOR, and increased expression level of cleaved PARP, Fas and PPARgamma in a time-dependent manner. Immunofluorescent analysis showed that gammaH2AX-containing nuclear foci were significant in oridonin-treated MDA-MB-231 cells. Meanwhile, oridonin significantly suppressed MDA-MB-231 cell migration and invasion, decreased MMP-2/MMP-9 activation and inhibited the expression of Integrin beta1 and FAK. In conclusion, oridonin inhibited the growth and induced  apoptosis in breast cancer cells, which might be related to DNA damage and activation of intrinsic or extrinsic apoptotic pathways. Moreover, oridonin also  inhibited tumor invasion and metastasis in vitro possibly via decreasing the expression of MMPs and regulating the Integrin beta1/FAK pathway in MDA-MB-231 cells.

 

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[758]

TÍTULO / TITLE:  - In vitro increased natural killer cell activity of metastatic melanoma patients with interferon-alpha alone as opposed to its combination with 13-cis retinoic acid is associated with modulation of NKG2D and CD161 activating receptor expression.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J BUON. 2012 Oct-Dec;17(4):761-9.

AUTORES / AUTHORS:  - Konjevic G; Mirjacic-Martinovic K; Vuletic A; Babovic N

INSTITUCIÓN / INSTITUTION:  - Institute of Oncology and Radiology of Serbia, Department of Experimental Oncology, Laboratory for Immunology, Belgrade, Serbia.

RESUMEN / SUMMARY:  - Purpose: Considering tumor-induced suppression of natural killer (NK) cell activity the aim of this study was to investigate the in vitro effect of a standard immunotherapeutic cytokine, interferon (IFN)alpha, and a less investigated agent, 13-cis retinoic acid (RA) on the functional and receptor characteristics of CD16-defined NK cells and their functionally diverse dim and bright subsets in patients with metastatic melanoma (MM). Methods: Peripheral blood lymphocytes (PBL) of patients with clinical stage IV MM were stimulated in  vitro for 18 h in RPMI 1640 culture medium (CM) alone, CM supplemented with IFN-alpha (250 U7sol;ml), RA (10-6M) and their combination. NK cell activity was  determined using standard 4 h radioactive cytotoxicity assay, while the expression of activating (NKG2D, CD1617rpar; and inhibitory (CD158a, CD158b) NK cell receptors on CD3-CD16+ NK cells and their functional bright and dim subsets  were analyzed by flow cytometry. Results: NK cell cytotoxic activity was increased after in vitro treatment with IFN-alpha alone and in combination with RA, while only IFN-alpha induced increase in NKG2D and CD161 activating NK cell receptor expression. Contrary to this, RA treatment increased the expression of inhibitory KIR CD158b. IFN-alpha-obtained increase in CD161 expression was due to its induction on both NK cell subsets, while for NKG2D only on CD16bright subset. Conclusion: The favorable enhancement of NK cell activity of MM patients obtained with IFN-alpha is associated with upregulation of activating NKG2D and CD161 receptors, while the lack of RA-associated upregulation is probably due to the shown increased expression of inhibitory KIR receptor CD158b after in vitro treatment with this agent.

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[759]

TÍTULO / TITLE:  - Polymorphism of TS 3’-UTR predicts survival of Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Transl Oncol. 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12094-012-0979-8

AUTORES / AUTHORS:  - Gao J; He Q; Hua D; Mao Y; Li Y; Shen L

INSTITUCIÓN / INSTITUTION:  - Department of GI Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, No. 52, Fucheng Road, Haidian District, Beijing, 100142, China.

RESUMEN / SUMMARY:  - PURPOSE: Capecitabine-containing chemotherapy was widely used in clinic medication. We investigated the association of the thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and dihydropyrimidine dehydrogenase  (DPD) polymorphisms with the clinical outcome of Chinese advanced gastric cancer  patients receiving first-line capecitabine plus paclitaxel. METHODS: Blood samples were collected prior to treatment from 125 patients with advanced gastric cancer and the TS (two or three repeats of a 28 bp sequence in 5’-untranslated region and 6 bp insertion or deletion in 3’-untranslated region), MTHFR (C677T) and DPD (IVS14+1G > A) polymorphisms were determined using PCR amplification and  Sanger sequencing. RESULTS: The median age of 125 patients was 58 years (range, 23-76) with female 42 and male 83, and the response rate, median progression-free survival and overall survival (OS) were 43.2 %, 5.2 and 11.0 months. The median OS in patients with TS ins6/ins6 genotype (6.8 months) was significantly shorter  than those in patients with ins6/del6 (11.0 months, P = 0.016) and del6/del6 (11.5 months, P = 0.039) genotypes. Cox multivariate analysis also showed that TS ins6/ins6 genotype was the independent poor OS predictor (P = 0.001, HR = 3.182). No significant associations were found between the polymorphisms of TS 5’-UTR/MTHFR and clinical outcome, and no IVS14+1G > A polymorphism of DPD was found in this study. CONCLUSIONS: We first reported that TS 3’-UTR ins6/ins6 genotype could predict the poor survival of advanced gastric cancer patients treated with capecitabine plus paclitaxel, which would be further verified in a large multicenter study.

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[760]

TÍTULO / TITLE:  - Ganglioside-monosialic acid (GM1) prevents oxaliplatin-induced peripheral neurotoxicity in patients with gastrointestinal tumors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Surg Oncol. 2013 Jan 25;11(1):19.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1477-7819-11-19

AUTORES / AUTHORS:  - Zhu Y; Yang J; Jiao S; Ji T

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Oxaliplatin, an effective antineoplastic agent againstgastrointestinal tumors, can cause severe peripheral neurotoxicity, which  seriously limits its clinical application. To date, there are no effective treatments for this complication. Ganglioside-monosialic acid (GM1) has been shown to protect neurons against injuries and degeneration. The aim of this study was to evaluate the effects of GM1 on preventing oxaliplatin-induced neurotoxicity in patients with gastrointestinal tumors. METHODS: In this study, 120 patients with gastrointestinal tumors were enrolled, andthey received the treatment of XELOX (oxaliplatin and capecitabine) and FOLFOX4 (oxaliplatin, leukovolin and 5-fluorouracil). The patients were randomly divided into two groups, the experimental group and control group, with60 patients ineach. On the  day chemotherapy was initiated, the experimental group received GM1 intravenously (100 mg once daily) for 3 days, while no neuroprotective agents were applied in the control group. The incidence rates and classification of neurotoxicity in the two groups were evaluated and the differences between the two groups were examined. Furthermore, whether GM1 affected the therapeutic effects of chemotherapy was also examined. RESULTS: The grade of neurotoxicity in the experimental group was significantly lower than in the control group (P<0.05, Mann—Whitney U test). The probability of occurrence of low-grade neurotoxicity (grade 0 and 1) in the experimental group was higher than that in the control group (logistic ordinal regression); whereas the probability of occurrence of high-grade neurotoxicity (grade 2 and 3) in the experimental group was lower than in the control group (logistic ordinal regression). CONCLUSION: The data suggested that GM1 could reduce the grade of oxaliplatin-induced neurotoxicity and was an effective neuroprotective agent against oxaliplatin-induced high-grade neurotoxicity in patients with gastrointestinal tumors.

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[761]

TÍTULO / TITLE:  - SLC22A1-ABCB1 Haplotype Profiles Predict Imatinib Pharmacokinetics in Asian Patients with Chronic Myeloid Leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51771. doi: 10.1371/journal.pone.0051771. Epub 2012 Dec 18.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051771

AUTORES / AUTHORS:  - Singh O; Chan JY; Lin K; Heng CC; Chowbay B

INSTITUCIÓN / INSTITUTION:  - Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.

RESUMEN / SUMMARY:  - OBJECTIVE: This study aimed to explore the influence of SLC22A1, PXR, ABCG2, ABCB1 and CYP3A5*3 genetic polymorphisms on imatinib mesylate (IM) pharmacokinetics in Asian patients with chronic myeloid leukemia (CML). PATIENTS  AND METHODS: Healthy subjects belonging to three Asian populations (Chinese, Malay, Indian; n = 70 each) and CML patients (n = 38) were enrolled in a prospective pharmacogenetics study. Imatinib trough (C(0h)) and clearance (CL) were determined in the patients at steady state. Haplowalk method was applied to  infer the haplotypes and generalized linear model (GLM) to estimate haplotypic effects on IM pharmacokinetics. Association of haplotype copy numbers with IM pharmacokinetics was defined by Mann-Whitney U test. RESULTS: Global haplotype score statistics revealed a SLC22A1 sub-haplotypic region encompassing three polymorphisms (rs3798168, rs628031 and IVS7+850C>T), to be significantly associated with IM clearance (p = 0.013). Haplotype-specific GLM estimated that the haplotypes AGT and CGC were both associated with 22% decrease in clearance compared to CAC [CL (*10(-2) L/hr/mg): CAC vs AGT: 4.03 vs 3.16, p = 0.017; CAC vs CGC: 4.03 vs 3.15, p = 0.017]. Patients harboring 2 copies of AGT or CGC haplotypes had 33.4% lower clearance and 50% higher C(0h) than patients carrying  0 or 1 copy [CL (*10(-2) L/hr/mg): 2.19 vs 3.29, p = 0.026; C(0h) (*10(-6) 1/ml): 4.76 vs 3.17, p = 0.013, respectively]. Further subgroup analysis revealed SLC22A1 and ABCB1 haplotypic combinations to be significantly associated with clearance and C(0h) (p = 0.002 and 0.009, respectively). CONCLUSION: This exploratory study suggests that SLC22A1-ABCB1 haplotypes may influence IM pharmacokinetics in Asian CML patients.

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[762]

TÍTULO / TITLE:  - The neuropeptide y y(1) receptor: a diagnostic marker? Expression in mcf-7 breast cancer cells is down-regulated by antiestrogens in vitro and in xenografts.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51032. doi: 10.1371/journal.pone.0051032. Epub 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051032

AUTORES / AUTHORS:  - Memminger M; Keller M; Lopuch M; Pop N; Bernhardt G; von Angerer E; Buschauer A

INSTITUCIÓN / INSTITUTION:  - Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany.

RESUMEN / SUMMARY:  - The neuropeptide Y (NPY) Y(1) receptor (Y(1)R) has been suggested as a tumor marker for in vivo imaging and as a therapeutic target. In view of the assumed link between estrogen receptor (ER) and Y(1)R in mammary carcinoma and with respect to the development of new diagnostic tools, we investigated the Y(1)R protein expression in human MCF-7 cell variants differing in ER content and sensitivity against antiestrogens. ER and Y(1)R expression were quantified by radioligand binding using [(3)H]-17beta-estradiol and the Y(1)R selective antagonist [(3)H]-UR-MK114, respectively. The latter was used for cellular binding studies and for autoradiography of MCF-7 xenografts. The fluorescent ligands Cy5-pNPY (universal Y(1)R, Y(2)R and Y(5)R agonist) and UR-MK22 (selective Y(1)R antagonist), as well as the selective antagonists BIBP3226 (Y(1)R), BIIE0246 (Y(2)R) and CGP71683 (Y(5)R) were used to identify the NPY receptor subtype(s) by confocal microscopy. Y(1)R functionality was determined by mobilization of intracellular Ca(2+). Sensitivity of MCF-7 cells against antiestrogen 4-hydroxytamoxifen correlated directly with the ER content. The exclusive expression of Y(1)Rs was confirmed by confocal microscopy. The Y(1)R protein was up-regulated (100%) by 17beta-estradiol (EC(50) 20 pM) and the predominant role of ERalpha was demonstrated by using the ERalpha-selective agonist “propylpyrazole triol”. 17beta-Estradiol-induced over-expression of functional Y(1)R protein was reverted by the antiestrogen fulvestrant (IC(50) 5 nM) in vitro. Furthermore, tamoxifen treatment of nude mice resulted in an almost total loss of Y(1)Rs in MCF-7 xenografts. In conclusion, the value of the Y(1)R as a target for therapy and imaging in breast cancer patients may be compromised  due to Y(1)R down-regulation induced by hormonal (antiestrogen) treatment.

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[763]

TÍTULO / TITLE:  - Pterostilbene induces cell cycle arrest and apoptosis in MOLT4 human leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Folia Histochem Cytobiol. 2012;50(4):574-80. doi: 10.5603/20257.

            ●● Enlace al texto completo (gratuito o de pago) 5603/20257

AUTORES / AUTHORS:  - Siedlecka-Kroplewska K; Jozwik A; Kaszubowska L; Kmiec Z; Boguslawski W

INSTITUCIÓN / INSTITUTION:  - Medical University of Gdansk. ksiedlecka@gumed.edu.pl.

RESUMEN / SUMMARY:  - Pterostilbene, a polyphenolic compound present in grapes and other fruits, has been demonstrated to inhibit growth and induce apoptosis and autophagy in some cancer cell types. We found that pterostilbene at the IC90 concentration of 44 microM inhibited proliferation and induced apoptosis in MOLT4 human leukemia cells. Treatment with pterostilbene resulted in a transient accumulation of cells in the G0/G1-cell cycle phase followed by the S-phase arrest. Pterostilbene-induced apoptotic death of MOLT4 cells was mediated by caspase-3 activation and was accompanied by the disruption of mitochondrial membrane potential, phosphatidylserine externalization and internucleosomal DNA fragmentation. Our results suggest that pterostilbene could serve as a potential  additional chemotherapeutic agent for the treatment of leukemia.

 

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[764]

TÍTULO / TITLE:  - WNT5A-NFAT Signaling Mediates Resistance to Apoptosis in Pancreatic Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Neoplasia. 2013 Jan;15(1):11-22.

AUTORES / AUTHORS:  - Griesmann H; Ripka S; Pralle M; Ellenrieder V; Baumgart S; Buchholz M; Pilarsky C; Aust D; Gress TM; Michl P

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology and Endocrinology, University Hospital, Philipps-University, Marburg, Germany.

RESUMEN / SUMMARY:  - INTRODUCTION: WNT5A belongs to the Wnt family of secreted signaling molecules. Using transcriptional profiling, we previously identified WNT5A as target of the  antiapoptotic transcription factor CUX1 and demonstrated high expression levels in pancreatic cancer. However, the impact of WNT5A on drug resistance and the signaling pathways employed by WNT5A remain to be elucidated. OBJECTIVES: This project aims to decipher the impact of WNT5A on resistance to apoptosis and the signaling pathways employed by WNT5A in pancreatic cancer. METHODS: The impact of WNT5A and its downstream effectors on tumor growth and drug resistance was studied in vitro and in xenograft models in vivo. Tissue microarrays of pancreatic cancer specimens were employed for immunohistochemical studies. RESULTS: Knockdown of WNT5A results in a significant increase in drug-induced apoptosis. In contrast, overexpression of WNT5A or addition of recombinant WNT5A  mediates resistance to apoptosis in vitro. In our attempt to identify downstream  effectors of WNT5A, we identified the transcription factor nuclear factor of activated T cells c2 (NFATc2) as transcriptional target of WNT5A signaling. NFATc2 confers a strong antiapoptotic phenotype mediating at least in part the effects of WNT5A on drug resistance and tumor cell survival. In vivo, WNT5A expression leads to resistance to gemcitabine-induced apoptosis in a xenograft model, which is paralleled by up-regulation of NFATc2. Both WNT5A and NFATc2 proteins are highly expressed in human pancreatic cancer tissues and their expression levels correlated significantly. CONCLUSION: We identified the WNT5A-NFATc2 axis as important mediator of drug resistance in pancreatic cancer.

 

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[765]

TÍTULO / TITLE:  - A REST derived gene signature stratifies glioblastomas into chemotherapy resistant and responsive disease.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Genomics. 2012 Dec 7;13:686. doi: 10.1186/1471-2164-13-686.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2164-13-686

AUTORES / AUTHORS:  - Wagoner MP; Roopra A

INSTITUCIÓN / INSTITUTION:  - Department of Neuroscience, University of Wisconsin at Madison, Madison, USA. asroopra@wisc.edu.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Glioblastomas are the most common central nervous system neoplasia in adults, with 9,000 cases in the US annually. Glioblastoma multiformae, the most aggressive glioma subtype, has an 18% one-year survival rate, and 3% two year survival rate. Recent work has highlighted the role of the  transcription factor RE1 Silencing Transcription Factor, REST in glioblastoma but how REST function correlates with disease outcome has not been described. METHOD: Using a bioinformatic approach and mining of publicly available microarray datasets, we describe an aggressive subtype of gliomas defined by a gene signature derived from REST. Using this REST gene signature we predict that REST  function is enhanced in advanced glioblastoma. We compare disease outcomes between tumors based on REST status and treatment regimen, and describe downstream targets of REST that may contribute to the decreased benefits observed with high dose chemotherapy in REM tumors. RESULTS: We present human data showing that patients with “REST Enhanced Malignancies” (REM) tumors present with a shorter disease free survival compared to non-REM gliomas. Importantly, REM tumors are refractory to multiple rounds of chemotherapy and patients fail to respond to this line of treatment. CONCLUSIONS: This report is the first to describe a REST gene signature that predicts response to multiple rounds of chemotherapy, the mainline therapy for this disease. The REST gene signature may  have important clinical implications for the treatment of glioblastoma.

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[766]

TÍTULO / TITLE:  - BIBR 1532 Increases Arsenic Trioxide-mediated Apoptosis in Acute Promyelocytic Leukemia Cells: Therapeutic Potential for APL.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Anticancer Agents Med Chem. 2012 Dec 24.

AUTORES / AUTHORS:  - Bashash D; Ghaffari SH; Zaker F; Kazerani M; Hezave K; Hassani S; Rostami M; Alimoghaddam K; Ghavamzadeh A

INSTITUCIÓN / INSTITUTION:  - Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran. shghaffari200@yahoo.com.

RESUMEN / SUMMARY:  - The current treatment of acute promyelocytic leukemia with arsenic trioxide (ATO) has increased long-lasting complete remissions; however, a proportion of patients continue to die eventually as a result of disease recurrence. In an effort to enhance the effectiveness of the APL treatment, we designed experiments to evaluate the effects of ATO in combination with the lead compound of non-nucleoside inhibitor of telomerase, BIBR 1532. After combined treatments with BIBR 1532 and ATO, decreased cell viability index with a concomitant increase in  apoptotic cell death was observed in NB4 leukemic cells. Apoptosis induced by the combined treatments was accompanied by elevated Bax/Bcl-2 molecular ratio and enhanced caspase 3 activation. Our study has also demonstrated that the combined  treatment suppressed NB4 cell proliferative capacity and inhibited telomerase activity probably via transcriptional suppression of c-Myc and hTERT. In conclusion, this study may supply insight into the application of this new combination therapy to APL cells intrinsically less sensitive to routine therapies and suggested a novel combination therapy for patients with more aggressive disease; those who may not respond favorably to the arsenic mono-therapy.

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[767]

TÍTULO / TITLE:  - Influence of genetic variants in type I interferon genes on melanoma survival and therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(11):e50692. doi: 10.1371/journal.pone.0050692. Epub 2012 Nov 27.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0050692

AUTORES / AUTHORS:  - Lenci RE; Bevier M; Brandt A; Bermejo JL; Sucker A; Moll I; Planelles D; Requena C; Nagore E; Hemminki K; Schadendorf D; Kumar R

INSTITUCIÓN / INSTITUTION:  - Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.

RESUMEN / SUMMARY:  - Melanoma is an immunogenic tumor; however, the efficacy of immune-therapy shows large inter-individual variation with possible influence of background genetic variation. In this study we report the influence of genetic polymorphisms in the  type I interferon gene cluster on chromosome 9p22 on melanoma survival. We genotyped 625 melanoma patients recruited in an oncology center in Germany for 44 polymorphisms located on chromosome 9p22 that were informative for 299 polymorphisms and spanned 15 type I interferon genes. Our results showed associations between time to metastasis/survival and two linked (r(2) = 0.76) polymorphisms, rs10964859 (C>G) and rs10964862 (C>A). The rs10964859 polymorphism was located at 3’UTR and rs10964862 was 9.40 Kb towards 5’UTR of IFNW1 gene. The  carriers of the variant alleles of the rs10964859 and rs10964862 polymorphisms were associated with a reduced disease-free survival. The validation of data in an independent group of 710 patients from España showed that the direction of the  effect was similar. Stratification based on therapy showed that the adverse effect on metastasis development was statistically significant in the patients from España who did not receive any treatment and were homozygous for variant allele of rs10964862 (HR = 2.52, 95% CI 1.07-5.90; P = 0.03). Patients homozygous for rs10964859 (HR = 2.01, 95% CI 1.17-3.44; P = 0.01) and rs10964862 (HR 1.84, 95%CI 1.03-3.27, P = 0.04) were associated to increased risk of death following metastasis. GTCGACAA haplotype, found in 8.8% of the patients, was associated with an increased risk of death (HR 1.94, 95%CI 1.16-3.26, P = 0.01). In conclusion, our results identified genetic variants in interferon genes that influence melanoma progression and survival with modulation of effect due to treatment status.

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[768]

TÍTULO / TITLE:  - Human Gut Flora-Fermented Nondigestible Fraction from Cooked Bean ( Phaseolus vulgaris L.) Modifies Protein Expression Associated with Apoptosis, Cell Cycle Arrest, and Proliferation in Human Adenocarcinoma Colon Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Agric Food Chem. 2012 Dec 26;60(51):12443-50. doi: 10.1021/jf303940r. Epub 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1021/jf303940r

AUTORES / AUTHORS:  - Campos-Vega R; Garcia-Gasca T; Guevara-Gonzalez R; Ramos-Gomez M; Oomah BD; Loarca-Pina G

INSTITUCIÓN / INSTITUTION:  - Programa de Posgrado en Alimentos del Centro de la Republica (PROPAC), Research and Graduate Studies in Food Science, School of Chemistry, Queretaro State University , Qro 76010 Mexico.

RESUMEN / SUMMARY:  - Metabolism of the nondigested fraction (NDF) from common bean ( Phaseolus vulgaris L.) by the human gut flora (hgf) produces short-chain fatty acids (SCFAs) that may benefit cancer by reducing colorectal tumor risks. This paper reports the effect of fermentation products (FP) by hgf (FP-hgf) from NDF of cooked beans on survival and protein expression associated with apoptosis, cell cycle arrest, and proliferation in human adenocarcinoma colon cancer cells. FP-hgf was the only inoculum eliciting butyrate production after 24 h of NDF fermentation using different bacterial sources. FP-hgf inhibited HT-29 cell growth and modulated protein expression associated with apoptosis, cell cycle arrest, and proliferation, as well as morphological changes linked to apoptosis evaluated by TUNEL and hematoxylin and eosin stains, confirming previous results  on gene expression. The current results suggest that fermentation of NDF from common beans can elicit beneficial chemoprotective effects in colon cancer by modulating protein expression in HT-29 cells.

 

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[769]

TÍTULO / TITLE:  - Expression of glioma-associated oncogene 2 (Gli 2) is correlated with poor prognosis in patients with hepatocellular carcinoma undergoing hepatectomy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Surg Oncol. 2013 Jan 29;11(1):25.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1477-7819-11-25

AUTORES / AUTHORS:  - Zhang D; Cao L; Li Y; Lu H; Yang X; Xue P

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Our previous studies showed that glioma-associated oncogene (Gli)2 plays an important role in the proliferation and apoptosis resistance of hepatocellular carcinoma (HCC) cells. The aim of this study was to explore the clinical significance of Gli2 expression in HCC. METHODS: Expression of Gli2 protein was detected in samples from 68 paired HCC samples, the corresponding paraneoplastic liver tissues, and 20 normal liver tissues using immunohistochemistry. Correlation of the immunohistochemistry results with clinicopathologic parameters, prognosis, and the expression of E-cadherin, N-cadherin, and vimentin were analyzed. RESULTS: Immunohistochemical staining showed high levels of Gli2 protein expression in HCC, compared with paraneoplastic and normal liver tissues (P < 0.05). This high expression level of Gli2 was significantly associated with tumor differentiation, encapsulation, vascular invasion, early recurrence, and intra-hepatic metastasis (P < 0.05). There was a significantly negative correlation between Gli2 and E-cadherin expression (r = -0.302, P < 0.05) and a significantly positive correlation between expression of Gli2 and expression of vimentin (r = -0.468, P < 0.05) and  N-cadherin (r = -0.505, P < 0.05). Kaplan-Meier analysis showed that patients with overexpressed Gli2 had significantly shorter overall survival and disease-free survival times (P < 0.05). Multivariate analysis suggested that the  level of Gli2 expression was an independent prognostic factor for HCC. CONCLUSIONS: Expression of Gli2 is high in HCC tissue, and is associated with poor prognosis in patients with HCC after hepatectomy.

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[770]

TÍTULO / TITLE:  - Evaluation of chemotherapy response with serum squamous cell carcinoma antigen level in cervical cancer patients: a prospective cohort study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e54969. doi: 10.1371/journal.pone.0054969. Epub 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0054969

AUTORES / AUTHORS:  - Yin M; Hou Y; Zhang T; Cui C; Zhou X; Sun F; Li H; Li X; Zheng J; Chen X; Li C; Ning X; Li K; Lou G

INSTITUCIÓN / INSTITUTION:  - Department of Gynecology and Oncology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.

RESUMEN / SUMMARY:  - MRI does not always reflect tumor response after chemotherapy. Therefore, it is necessary to explore additional parameters to more accurately evaluate tumor response for the subsequent clinical determination about radiotherapy or radical  surgery. A training cohort and an external validation cohort were used to examine the predictive performance of SCC-ag to evaluate tumor response from teaching hospital of Harbin Medical University. The study included 397 women with SCC (age: 28-73 years). Patients consecutively enrolled between August 2008 and January 2010 (n = 205) were used as training cohort. Patients consecutively enrolled between February 2010 and May 2011 (n = 192) were used as validation cohort. A multivariate regression analysis of the data from the training cohort indicated that serum SCC-ag level is an independent factor for neo-adjuvant chemotherapy (NACT) response. Analysis of the data from the validation cohort suggested that chemotherapy response could be more accurately predicted by SCC-ag than by magnetic resonance imaging (MRI) (sensitivity (Se): 0.944 vs. 0.794; specificity (Sp): 0.727 vs. 0.636; positive predictive value (PPV): 0.869 vs. 0.806; negative predictive value (NPV): 0.873 vs. 0.618; the area under ROC curve (AUC): 0.898 vs. 0.734). Combining SCC-ag with MRI was more powerful than MRI alone (Se: 0.952 vs. 0.794; Sp: 0.833 vs. 0.636; PPV: 0.916 vs. 0.806; NPV: 0.902 vs. 0.618; AUC: 0.950 vs. 0.734). Our study indicates that serum SCC-ag level is  a sensitive and reliable measure to evaluate cervical cancer response to chemotherapy. Using SCC-ag in combination with MRI findings further improves the  predictive power.

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[771]

TÍTULO / TITLE:  - KLF4 overexpression and apigenin treatment down regulated anti-apoptotic Bcl-2 proteins and matrix metalloproteinases to control growth of human malignant neuroblastoma SK-N-DZ and IMR-32 cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Oncol. 2012 Dec 20. pii: S1574-7891(12)00128-7. doi: 10.1016/j.molonc.2012.12.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.molonc.2012.12.002

AUTORES / AUTHORS:  - Mohan N; Ai W; Chakrabarti M; Banik NL; Ray SK

INSTITUCIÓN / INSTITUTION:  - University of South Carolina School of Medicine, Department of Pathology, Microbiology, and Immunology, Columbia, SC 29209, USA.

RESUMEN / SUMMARY:  - Neuroblastoma is a childhood tumor that arises from immature neuroblasts of the sympathetic nervous system. Krupple-like factor 4 (KLF4) is a transcription factor, the precise function of which in neuroblastoma is unclear. We examined the effects of KLF4 overexpression and apigenin (APG) treatment in human malignant neuroblastoma SK-N-DZ and IMR-32 cell lines. KLF4 overexpression in both SK-N-DZ and IMR-32 cell lines was confirmed by laser scanning immunofluorescent confocal microscopy and Western blotting. We found that 100 nM  KLF4 plasmid and 25 muM APG synergistically inhibited the growth of SK-N-DZ and IMR-32 cells. We also found increase in KLF4 expression in response to treatment  with various concentrations of APG. Combination of KLF4 plasmid and APG treatment significantly increased the amounts of apoptosis in both cell lines when compared with control vector or single treatment. We also noticed that the combination therapy decreased expression of the anti-apoptotic proteins Bcl-2 and Mcl-1, increased expression of the pro-apoptotic proteins Bax, Noxa, and Puma, upregulated p53, and caused activation of caspase-3 for cleavage of the inhibitor of caspase-activated DNase (ICAD) leading to completion of apoptosis machinery. Further, combination of KLF4 overexpression and APG treatment was highly effective in inhibiting migration of both neuroblastoma cell lines and was associated with down regulation of matrix metalloproteinases (MMPs) such as MMP-2 and MMP-9. Collectively, our results from this investigation strongly suggest that KLF4 functions as a tumor suppressor and potentiates the anti-cancer activities of APG in two different human malignant neuroblastoma cell lines.

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[772]

TÍTULO / TITLE:  - (68)Ga-DotaTATE PET-CT followed by Peptide Receptor Radiotherapy in combination with capecitabine in two patients with Merkel Cell Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Clin Exp Med. 2012;5(4):363-6. Epub 2012 Sep 28.

AUTORES / AUTHORS:  - Schmidt MC; Uhrhan K; Markiefka B; Hasselbring L; Schlaak M; Cremer B; Kunze S; Baum RP; Dietlein M

INSTITUCIÓN / INSTITUTION:  - Department of Nuclear Medicine, University Hospital of Cologne Germany.

RESUMEN / SUMMARY:  - Herein, we report about two Caucasian patients with the histopathological diagnosis of Merkel cell carcinoma suffering from extensive lymph node metastases. The extent of the disease was diagnosed by Ga-68-DotaTATE-PET-CT. Both patients had rapid disease progression, one of them despite a three months course of sunitinibe followed by four chemotherapy cycles of cisplatin and etoposide. Both patients were sent for peptide receptor radiotherapy with 90Y-DotaTATE or 177Lu-DotaTATE in combination with capecitabine. Additional external beam radiotherapy of the cervical and inguinal lymph nodes was given to  the patient with progressive disease despite chemotherapy. Temporary partial response in both patients was achieved. Despite extensive therapeutic efforts, fatal outcome could not be prevented 10 and 14 months after first clinical symptoms.

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[773]

TÍTULO / TITLE:  - Joint problems in breast cancer patients receiving adjuvant aromatase inhibitor.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J BUON. 2012 Oct-Dec;17(4):798-9.

AUTORES / AUTHORS:  - Kuria IM; Petekkaya I; Hasanov E; Babacan T; Dizdar O; Altundag K

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Hacettepe University Cancer Institute, Sihhiye, Ankara.

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[774]

TÍTULO / TITLE:  - SOCS1 Mutation Subtypes Predict Divergent Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncotarget. 2012 Dec 9.

AUTORES / AUTHORS:  - Schif B; Lennerz JK; Kohler CW; Bentink S; Kreuz M; Melzner I; Ritz O; Trumper L; Loeffler M; Spang R; Moller P

INSTITUCIÓN / INSTITUTION:  - Institute of Pathology, University of Ulm, Germany.

RESUMEN / SUMMARY:  - Suppressor of cytokine signaling 1 (SOCS1) is frequently mutated in primary mediastinal and diffuse large B-cell lymphomas (DLBCL). Currently, the prognostic relevance of these mutations in DLBCL is unknown. To evaluate the value of the SOCS1 mutation status as a prognostic biomarker in DLBCL patients, we performed full-length SOCS1 sequencing in tumors of 154 comprehensively characterized DLBCL patients. We identified 90 SOCS1 mutations in 16% of lymphomas. With respect to molecular consequences of mutations, we defined two distinct subtypes: those with truncating (major) and those with non-truncating mutations (minor), respectively. The SOCS1 mutated subgroup or the minor/major subtypes cannot be predicted on clinical grounds; however, assignment of four established gene-expression profile-based classifiers revealed significant associations of SOCS1 major cases  with germinal center and specific pathway activation pattern signatures. Above all, SOCS1 major cases have an excellent overall survival, even better than the GCB-like subgroup. SOCS1 minor cases had a dismal survival, even worse than the ABC gene signature group. The SOCS1 mutation subsets retained prognostic significance in uni- and multivariate analyses. Together our data indicate that assessment of the SOCS1 mutation status is a single gene prognostic biomarker in  DLBCL.

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[775]

TÍTULO / TITLE:  - Change in HER2 (ERBB2) gene status after taxane-based chemotherapy for breast cancer: polyploidization can lead to diagnostic pitfalls with potential impact for clinical management.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Genet. 2013 Jan 9. pii: S2210-7762(12)00276-1. doi: 10.1016/j.cancergen.2012.12.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.cancergen.2012.12.001

AUTORES / AUTHORS:  - Valent A; Penault-Llorca F; Cayre A; Kroemer G

INSTITUCIÓN / INSTITUTION:  - Molecular Pathology, Department of Pathology and Medical Biology, and Histocytopathology, Translational Research, Institut Gustave Roussy, Villejuif, France. Electronic address: alexander.valent@igr.fr.

RESUMEN / SUMMARY:  - The status of the HER2 (ERBB2) gene in breast cancer is not static and may change among the primary tumor, lymph node metastases, and distant metastases. This status change can be a consequence of the natural evolution of the tumor or can be induced by therapy. The HER2 gene status is, in the majority of cases, established at the moment of diagnosis. After chemotherapy, monitoring HER2 status can be a challenge because of ploidy changes induced by drugs. The cytogeneticist or the pathologist can face real difficulties in distinguishing between a true HER2 amplification and HER2 copy number increase by polyploidization. We performed a HER2 genetic examination by fluorescence in situ hybridization (FISH) of invasive breast cancers before and after taxane treatment. The majority of patients (91%) were HER2-negative both at diagnosis and after treatment. Thirty of 344 patients (9%) whose tumors were initially HER2-negative were found by FISH to have supernumerary HER2 gene copies (up to 15 copies) after neoadjuvant chemotherapy. This HER2 copy increase could not be attributed to true gene amplifications and instead reflected polyploidization events, which presumably affected all chromosomes. Indeed, when we used other FISH probes, we found other gene copy numbers to parallel those of HER2. We recommend careful checking of invasive breast carcinomas by supplementary FISH probes if the copy number of the HER2 gene is >6. This procedure allows the discrimination of specific HER2 gene amplifications and global increases in ploidy.

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[776]

TÍTULO / TITLE:  - Targeting TORC1/2 enhances sensitivity to EGFR inhibitors in head and neck cancer preclinical models.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Neoplasia. 2012 Nov;14(11):1005-14.

AUTORES / AUTHORS:  - Cassell A; Freilino ML; Lee J; Barr S; Wang L; Panahandeh MC; Thomas SM; Grandis JR

INSTITUCIÓN / INSTITUTION:  - Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.

RESUMEN / SUMMARY:  - Head and neck squamous cell carcinoma (HNSCC) is characterized by overexpression  of the epidermal growth factor receptor (EGFR) where treatments targeting EGFR have met with limited clinical success. Elucidation of the key downstream-pathways that remain activated in the setting of EGFR blockade may reveal new therapeutic targets. The present study was undertaken to test the hypothesis that inhibition of the mammalian target of rapamycin (mTOR) complex would enhance the effects of EGFR blockade in HNSCC preclinical models. Treatment of HNSCC cell lines with the newly developed TORC1/TORC2 inhibitor OSI-027/ASP4876 resulted in dose-dependent inhibition of proliferation with abrogation of phosphorylation of known downstream targets including phospho-AKT (Ser473), phospho-4E-BP1, phospho-p70s6K, and phospho-PRAS40. Furthermore, combined treatment with OSI-027 and erlotinib resulted in enhanced biochemical effects and synergistic growth inhibition in vitro. Treatment of mice bearing HNSCC xenografts with a combination of the Food and Drug Administration (FDA)-approved EGFR inhibitor cetuximab and OSI-027 demonstrated a significant reduction of tumor volumes compared with either treatment alone. These findings suggest that TORC1/TORC2 inhibition in conjunction with EGFR blockade represents  a plausible therapeutic strategy for HNSCC.

 

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[777]

TÍTULO / TITLE:  - Incidence rate of prostate cancer in men treated for erectile dysfunction with phosphodiesterase type 5 inhibitors: retrospective analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian J Androl. 2013 Jan 28. doi: 10.1038/aja.2012.162.

            ●● Enlace al texto completo (gratuito o de pago) 1038/aja.2012.162

AUTORES / AUTHORS:  - Chavez AH; Scott Coffield K; Hasan Rajab M; Jo C

INSTITUCIÓN / INSTITUTION:  - Departments of Urology, Scott & White Healthcare, Temple, Texas 76508, USA.

RESUMEN / SUMMARY:  - The purpose of this study was to determine the incidence rate of prostate cancer  among men with erectile dysfunction (ED) treated with phosphodiesterase type 5 inhibitors (PDE-5i) over a 7-year period vs. men with ED of the same age and with similar risk factors who were not treated with PDE-5i. In a retrospective review  of electronic medical records and billing databases between the years 2000 and 2006, men with ED between the ages of 50 and 69 years and no history of prostate  cancer prior to 2000 were identified. These individuals were divided into two groups: 2362 men who had treatment with PDE-5i, and 2612 men who did not have treatment. Demographic data in each group were compared. During the study period, 97 (4.1%) men with ED treated with PDE-5i were diagnosed with prostate cancer compared with 258 (9.9%) men with ED in the non-treated group (P<00001). A higher percentage of African Americans were treated with PDE-5i vs. those who were not (10.5% vs. 7.1%; P<0.0001). The PDE-5i group had lower documented diagnosis of elevated prostate-specific antigen (10.0% vs. 13.1%; P=0.0008) and higher percentage of benign prostatic hyperplasia (38.4% vs. 35.1%; P=0.0149). Men with  ED treated with PDE-5i tended to have less chance (adjusted odds ratio: 0.4; 95%  confidence intervals: 0.3-0.5; P<0.0001) of having prostate cancer. Our data suggest that men with ED treated with PDE-5i tended to have less of a chance of being diagnosed with prostate cancer. Further research is warranted.Asian Journal of Andrology advance online publication, 28 January 2013; doi:10.1038/aja.2012.162.

 

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[778]

TÍTULO / TITLE:  - Association Between Polymorphisms of XRCC1 Arg399Gln and XPD Lys751Gln Genes and  Prognosis of Colorectal Cancer in a Chinese Population.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian Pac J Cancer Prev. 2012;13(11):5721-4.

AUTORES / AUTHORS:  - Gan Y; Li XR; Chen DJ; Wu JH

INSTITUCIÓN / INSTITUTION:  - Department of General Surgery, 3rd Xiang-Ya Hospital of Central South University, Changsha, China E-mail : wujunhui198005@163.com, wujunhui5678@163.com.

RESUMEN / SUMMARY:  - We conducted this study to detect associations between XRCC1 Arg399Gln and XPD Lys751Gln genotypes and survival of colorectal cancer patients treated with 5-FU/oxalipatin chemotherapy. We included 289 Chinese patients with advanced colorectal cancer, who had received 5-FU/oxalipatin chemotherapy as first-line treatment from January 2005 to January 2007. All patients were followed up till Nov. 2011. Genotyping for XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms was based upon duplex polymerase-chain-reaction with the PCR-RFLP method. In our study, we found the XRCC1 399 Gln/Gln genotype to confer significantly higher rates of response to chemotherapy when compared to the Arg/Arg genotype [OR (95%  CI)= 2.56(1.57-2.55)]. patients with the XPD 751 Gln/Gln genotype had significantly higher rates of response to chemotherapy [OR (95% CI)= 1.54(0.87-2.65)] and those with the XRCC1 399 Gln/Gln genotype had a longer average survival time and significantly lower risk of death than did those with the Arg/Arg genotype [HR (95% CI)= 0.66(0.36- 0.95)]. Similarly, those carrying the XPD 751Gln/Gln genotype had 0.51-fold the risk of death of those with XPD 751Lys/Lys [HR (95% CI)= 0.51(0.33 -0.94)]. In conclusion, it is suggested that the XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms should be routinely assessed  to determine colorectal patients who are more likely to benefit from 5-FU/oxalipatin chemotherapy.

 

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[779]

TÍTULO / TITLE:  - Ketamine used as an acesodyne in human breast cancer therapy causes an undesirable side effect, upregulating anti-apoptosis protein Bcl-2 expression.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Genet Mol Res. 2013 Jan 4;12(AOP).

            ●● Enlace al texto completo (gratuito o de pago) 4238/2013.January.4.7

AUTORES / AUTHORS:  - He H; Chen J; Xie WP; Cao S; Hu HY; Yang LQ; Gong B

INSTITUCIÓN / INSTITUTION:  - Department of Anesthesiology, Shanghai Changning Maternity and Infant Health Hospital, Shanghai, China.

RESUMEN / SUMMARY:  - Ketamine is a dissociative anesthetic agent that has been widely used in surgery  and for relieving pain in chronic cancer patients. We applied ketamine to breast  cancer cell line MDA-MB-231 to detect the effect of treatment and molecular mechanisms involved. We found that ketamine can upregulate the level of anti-apoptosis protein Bcl-2, which promote breast cancer cell invasion and proliferation. Knockdown of Bcl-2 could inhibit the increase of Bcl-2 and reduce  the invasion and proliferation caused by ketamine in human breast cancer cells. Our findings provide new insight into the effects of ketamine in cancer treatment; we suggest that ketamine, which has been widely used in cancer operations and for relieving pain in chronic cancer patients, may be not the best choice because it can worsen the cancer through promotion of anti-apoptosis.

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[780]

TÍTULO / TITLE:  - Predictive markers for the response to 5-fluorouracil therapy in cancer cells: Constant-field gel electrophoresis as a tool for prediction of response to 5-fluorouracil-based chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2013 Jan;5(1):321-327. Epub 2012 Oct 11.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.965

AUTORES / AUTHORS:  - Saleh EM; El-Awady RA; Anis N

INSTITUCIÓN / INSTITUTION:  - Units of Clinical Biochemistry and Molecular Biology and.

RESUMEN / SUMMARY:  - The prediction of response or severe toxicity and therapy individualisation are extremely important in cancer chemotherapy. There are few tools to predict chemoresponse or toxicity in cancer patients. We investigated the correlation between the induction and repair of DNA double-strand breaks (DSBs) using constant-field gel electrophoresis (CFGE) and evaluating cell cycle progression and the sensitivity of four cancer cell lines to 5-fluorouracil (5FU). Using a sulphorhodamine-B assay, colon carcinoma cells (HCT116) were found to be the most sensitive to 5FU, followed by liver carcinoma cells (HepG2) and breast carcinoma  cells (MCF-7). Cervical carcinoma cells (HeLa) were the most resistant. As measured by CFGE, DSB induction, but not residual DSBs, exhibited a significant correlation with the sensitivity of the cell lines to 5FU. Flow cytometric cell cycle analysis revealed that 14% of HCT116 or HepG2 cells and 2% of MCF-7 cells shifted to sub-G1 phase after a 96-h incubation with 5FU. Another 5FU-induced cell cycle change in HCT116, HepG2 and MCF-7 cells was the mild arrest of cells in G1 and/or G2/M phases of the cell cycle. In addition, 5FU treatment resulted in the accumulation of HeLa cells in the S and G2/M phases. Determination of Fas  ligand (Fas-L) and caspase 9 as representative markers for the extrinsic and intrinsic pathways of apoptosis, respectively, revealed that 5FU-induced apoptosis in HCT116 and HepG2 results from the expression of Fas-L (extrinsic pathway). Therefore, the induction of DNA DSBs by 5FU, detected using CFGE, and the induction of apoptosis are candidate predictive markers that may distinguish  cancer cells which are likely to benefit from 5FU treatment and the measurement of DSBs using CFGE may aid the prediction of clinical outcome.

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[781]

TÍTULO / TITLE:  - Endoscopic ultrasound in restaging and predicting pathological response for advanced gastric cancer patients after neoadjuvant chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asia Pac J Clin Oncol. 2012 Dec 21. doi: 10.1111/ajco.12045.

            ●● Enlace al texto completo (gratuito o de pago) 1111/ajco.12045

AUTORES / AUTHORS:  - Guo T; Yao F; Yang AM; Li XY; Zhong DR; Wu DS; Wu X; Lu XH

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

RESUMEN / SUMMARY:  - AIM: To evaluate the role of endoscopic ultrasound (EUS) in restaging and predicting response after neoadjuvant chemotherapy in patients with advanced gastric cancer. METHODS: In all, 48 advanced gastric cancer patients were recruited from June 2007 to December 2010 after providing their written, informed consent. All patients underwent an EUS before and after three cycles of neoadjuvant chemotherapy (FOLFOX 6), and then a radical resection was performed 3-4 weeks after chemotherapy. The results of EUS were compared to the pathological results of the resected specimens. RESULTS: After chemotherapy, the  overall sensitivity of EUS for T classification was 63 percent (T2: 44%, T3: 68%, T4: 90%), and overstaging (31%) was more frequent than understaging (6%). The sensitivity and specificity of EUS for N classification were 56 and 50 percent, respectively (N0: without lymph node metastasis, N1: with lymph node metastasis), with 15 percent overstaged and 32% understaged. EUS revealed that T and/or N downstaging occurred in 46 percent (22/48) of patients after chemotherapy, most of whom had a favorable pathological response to the chemotherapy compared with other patients without T and/or N downstaging. No T or N upstaging was observed after neoadjuvant chemotherapy. CONCLUSIONS: The accuracy of restaging by EUS for T and N classification was not as good as pathological data for locally advanced  gastric cancer patients after neoadjuvant chemotherapy. However, T and/or N downstaging confirmed by EUS correlated well with the degree of pathological response to chemotherapy.

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[782]

TÍTULO / TITLE:  - A phase I pharmacokinetic study of ursolic acid nanoliposomes in healthy volunteers and patients with advanced solid tumors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Nanomedicine. 2013;8:129-36. doi: 10.2147/IJN.S38271. Epub 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 2147/IJN.S38271

AUTORES / AUTHORS:  - Zhu Z; Qian Z; Yan Z; Zhao C; Wang H; Ying G

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute  and Hospital, Tianjin, People’s Republic of China ; Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China.

RESUMEN / SUMMARY:  - BACKGROUND: Ursolic acid is a promising anticancer agent. The current study aims  to evaluate the single- and multiple-dose pharmacokinetics (PK) as well as the safety of ursolic acid nanoliposomes (UANL) in healthy volunteers and in patients with advanced solid tumors. METHODS: Twenty-four healthy volunteers in the single-dose PK study were divided into three different groups, which received 37, 74, and 98 mg/m(2) of UANL. Eight patients in the multiple-dose PK study were administered with 74 mg/m(2) of UANL daily for 14 days. The UA plasma concentrations were determined using ultra-performance liquid chromatograph-tandem mass spectrometry. RESULTS: The plasma concentration profiles of all subjects were characterized by a biexponential decline after infusion. The mean peak plasma concentration (C(max)) increased linearly as a function of the dose (r = 0.999). The mean area under the plasma concentration-time curve (AUC) from 0 to 16 hours also increased proportionally with dose escalation (r = 0.998). However, the clearance was constant over the specific dose interval. In the multiple-dose PK study, the trough and average concentrations remained low. The mean AUC, half-life, C(max), time to C(max), and the volume of distribution on the first day were similar to those on the last day. All subjects tolerated the treatments well. Most UANL-associated adverse events varied from mild to moderate. CONCLUSIONS: UANL exhibits relatively linear PK behavior with dose levels from 37 mg/m(2) to 98 mg/m(2). No drug accumulation  was observed with repeated doses of UANL. The intravenous infusion of UANL was well tolerated by healthy volunteers and patients with advanced tumors.

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[783]

TÍTULO / TITLE:  - Ex vivo evaluation of imatinib mesylate for induction of cell death on canine neoplastic mast cells with mutations in c-Kit exon 11 via apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Vet Res Commun. 2013 Jan 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11259-013-9550-5

AUTORES / AUTHORS:  - Rossi G; Bertani C; Mari S; Marini C; Renzoni G; Ogilvie G; Magi GE

INSTITUCIÓN / INSTITUTION:  - School of Veterinary Medical Science, University of Camerino, Matelica, 62024, Italy.

RESUMEN / SUMMARY:  - Several studies of canine spontaneous mast cell tumours have described mutations  in the c-kit proto-oncogene. These mutations produce a constitutively activated product and have been suggested to play a role in the malignant transformation of mast cells. We hypothesize that the selective tyrosine kinase inhibitor imatinib  mesylate inhibits signal transduction and induces apoptosis when tested in cutaneous canine mast cell tumour samples positive for mutation in c-kit exon 11. Three-dimensional ex vivo cultures of canine grade II mast cell tumour treated with STI-571 at 48, 72, and 96 h and tested for signal transduction and apoptosis using appropriate assays were used. There was a progressive and significant increase in caspase-3 and TUNEL-positive mast cells compared to the untreated cultures. Additionally, a concurrent reduced expression of Ki67 and BCL-2 was observed. Furthermore, the treated cultures showed a marked reduction of Kit expression. Our results demonstrate that STI-571 induces Caspase-dependent apoptosis in a canine neoplastic mast cells possessing mutations in c-kit exon 11.

 

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[784]

TÍTULO / TITLE:  - Impact of serum vascular endothelial growth factor on prognosis in patients with  unresectable hepatocellular carcinoma after transarterial chemoembolization.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Cancer Res. 2012 Mar;24(1):36-43. doi: 10.1007/s11670-012-0036-8.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11670-012-0036-8

AUTORES / AUTHORS:  - Guo JH; Zhu X; Li XT; Yang RJ

INSTITUCIÓN / INSTITUTION:  - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Interventional Therapy, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing 100142, China.

RESUMEN / SUMMARY:  - OBJECTIVE: To investigate the expression level of serum vascular endothelial growth factor (VEGF) in patients with unresectable hepatocellular carcinoma (HCC) and its relationship with the clinicopathological characteristics, and to assess  the impact of serum VEGF as a predictive factor for HCC prognosis during transarterial chemoembolization (TACE) treatments. METHODS: Serum VEGF levels were measured using enzyme-linked immunosorbent assay (ELISA) in 60 random patients who underwent TACE or transarterial infusion (TAI) for unresectable HCC  between May and September 2008 and 12 healthy volunteers were also involved in this study to serve as control. All patients’ clinicopathological features were retrospectively analyzed. Serum VEGF levels were correlated with clinicopathological features of the HCC patients. The patients’ survival rates were analyzed with Kaplan-Meier survival curves and compared by the log-rank test. The prognostic significance of serum VEGF levels and factors related to survival rate were evaluated by univariate and multivariate analysis. RESULTS: The median serum VEGF level in the HCC patients was 285 pg/ml (range 14-1,207 pg/ml), significantly higher than that of healthy controls (P=0.021). The serum VEGF levels were significantly correlated with platelet counts (r=0.396, P=0.002) but not other clinicopathological features. Patients with serum VEGF level >285 pg/ml had worse overall survival compared with those with serum VEGF level <285 pg/ml (P=0.002). By multivariate analysis, the serum VEGF level was a significant prognostic factor. CONCLUSION: High serum VEGF levels may predict poor prognosis  of HCC after TACE. This study highlights the importance of tumor biomarker as a prognostic predictor in TACE therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features.

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[785]

TÍTULO / TITLE:  - Expressions of Thymidylate Synthase,Thymidine Phosphorylase, Class III beta-tubulin, and Excision Repair Cross-complementing Group 1predict Response in  Advanced Gastric Cancer Patients Receiving Capecitabine Plus Paclitaxel or Cisplatin.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Cancer Res. 2011 Dec;23(4):288-94. doi: 10.1007/s11670-011-0288-8.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11670-011-0288-8

AUTORES / AUTHORS:  - Lu M; Gao J; Wang XC; Shen L

INSTITUCIÓN / INSTITUTION:  - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, PekingUniversitySchool of Oncology, BeijingCancerHospital& Institute, Beijing 100142, China.

RESUMEN / SUMMARY:  - OBJECTIVE: Toevaluate the role of class III beta-tubulin (TUBB3), thymidylate synthase (TS), thymidine phosphorylase (TP), and excision repair cross-complementing group 1 (ERCC1) in clinical outcome of advanced gastric cancer patients receiving capecitabine plus paclitaxel or cisplatin. METHODS: The clinical data and tumor specimens from 57 advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel (cohort 1, n=36) and capecitabine plus cisplatin (cohort 2, n=21) were retrospectively collected, and  TUBB3, TS, TP, and ERCC1 expressions were detected by real-time quantitative PCR. The associations between expressions of biomarkers and response or survival were  analyzed statistically. RESULTS: The median age of 57 patients was 57 years (range: 27-75 years) with 38 males and 19 females. Of all patients, the response  rates of patients with high TP, low TP and high TS, low TS expressions were 57.1%, 27.6% (P=0.024), and 55.2%, 28.6% (P=0.042), respectively. Among cohort 1, the response rates and median overall survivals of patients with low and high TUBB3 expressions were 61.1% vs. 33.3% (P=0.095) and 13.8 months vs. 6.6 months (P=0.019), respectively; the response rate (87.5%) of patients with low TUBB3 and high TP expressions was higher than that (14.3%) of patients with high TUBB3 and  low TP expressions (P=0.01). Among cohort 2, the response rates of patients with  low ERCC1 and high ERCC1 expressions were 45.5% and 20.0% respectively (P=0.361). CONCLUSION: TUBB3, TS and TP expressions could predict the response of advanced gastric cancer patients receiving capecitabine-based and paclitaxel-based chemotherapy. These results will be further confirmed in future large samples.

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[786]

TÍTULO / TITLE:  - Germ cell proteins in melanoma: prognosis, diagnosis, treatment, and theories on  expression.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Skin Cancer. 2012;2012:621968. doi: 10.1155/2012/621968. Epub 2012 Nov 12.

            ●● Enlace al texto completo (gratuito o de pago) 1155/2012/621968

AUTORES / AUTHORS:  - Rosa AM; Dabas N; Byrnes DM; Eller MS; Grichnik JM

INSTITUCIÓN / INSTITUTION:  - Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

RESUMEN / SUMMARY:  - Germ cell protein expression in melanoma has been shown to correlate with malignancy, severity of disease and to serve as an immunologic target for therapy. However, very little is known about the role that germ cell proteins play in cancer development. Unique germ cell pathways include those involved in immortalization, genetic evolution, and energy metabolism. There is an ever increasing recognition that within tumors there is a subpopulation of cells with  stem-cell-like characteristics that play a role in driving tumorgenesis. Stem cell and germ cell biology is intertwined. Given the enormous potential and known expression of germ cell proteins in melanoma, it is possible that they represent  a largely untapped resource that may play a fundamental role in tumor development and progression. The purpose of this paper is to provide an update on the current value of germ cell protein expression in melanoma diagnosis, prognosis, and therapy, as well as to review critical germ cell pathways and discuss the potential roles these pathways may play in malignant transformation.

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[787]

TÍTULO / TITLE:  - An update on molecularly targeted therapies in second- and third-line treatment in non-small cell lung cancer: focus on EGFR inhibitors and anti-angiogenic agents.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Transl Oncol. 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12094-012-0964-2

AUTORES / AUTHORS:  - Majem M; Pallares C

INSTITUCIÓN / INSTITUTION:  - Medical Oncology Service, Hospital de la Santa Creu i Sant Pau, c/Sant Antoni Maria Claret 167, 08025, Barcelona, España, mmajem@santpau.cat.

RESUMEN / SUMMARY:  - Docetaxel, pemetrexed and epidermal growth factor receptor tyrosine kinase inhibitors (gefitinib and erlotinib) are recommended second-line therapy for advanced non-small cell lung cancer (NSCLC) patients with disease progression. Although erlotinib is the only recommended third-line therapy, several drugs are  being used in the clinic. Recent studies have focused on combining targeted agents with approved therapies, including broad-spectrum multikinase inhibitors targeting multiple ErbB Family receptors and multitargeted anti-angiogenic agents targeting the vascular endothelial growth factor receptor, platelet-derived growth factor receptor and fibroblast growth factor receptor pathways. Here, we review targeted therapies that are being evaluated in second- and third-line settings in NSCLC, including the ErbB Family Blocker afatinib (BIBW 2992), multityrosine kinase inhibitors (pelitinib [EKB-56]), neratinib [HKI-272], canertinib [CI-1033], lapatinib [GW-572016], dacomitinib [PF-299804]) and multitargeted anti-angiogenic agents (vandetanib [ZD6474], sunitinib [SU11248], sorafenib [BAY43-9006], nintedanib [BIBF1120], axitinib [AG-013736], cediranib [AZD2171], motesanib [AMG 706], linifanib [ABT869] and pazopanib [GW786034]).

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[788]

TÍTULO / TITLE:  - Kaurene diterpene induces apoptosis in U87 human malignant glioblastoma cells by  suppression of anti-apoptotic signals and activation of cysteine proteases.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Braz J Med Biol Res. 2013 Jan 11:1-8.

AUTORES / AUTHORS:  - Lizarte Neto FS; Tirapelli DP; Ambrosio SR; Tirapelli CR; Oliveira FM; Novais PC; Peria FM; Oliveira HF; Carlotti Junior CG; Tirapelli LF

RESUMEN / SUMMARY:  - Gliomas are the most common and malignant primary brain tumors in humans. Studies have shown that classes of kaurene diterpene have anti-tumor activity related to  their ability to induce apoptosis. We investigated the response of the human glioblastoma cell line U87 to treatment with ent-kaur-16-en-19-oic acid (kaurenoic acid, KA). We analyzed cell survival and the induction of apoptosis using flow cytometry and annexin V staining. Additionally, the expression of anti-apoptotic (c-FLIP and miR-21) and apoptotic (Fas, caspase-3 and caspase-8) genes was analyzed by relative quantification (real-time PCR) of mRNA levels in U87 cells that were either untreated or treated with KA (30, 50, or 70 microM) for 24, 48, and 72 h. U87 cells treated with KA demonstrated reduced viability, and an increase in annexin V- and annexin V/PI-positive cells was observed. The percentage of apoptotic cells was 9% for control cells, 26% for cells submitted to 48 h of treatment with 50 microM KA, and 31% for cells submitted to 48 h of treatment with 70 microM KA. Similarly, in U87 cells treated with KA for 48 h, we observed an increase in the expression of apoptotic genes (caspase-8, -3) and a decrease in the expression of anti-apoptotic genes (miR-21 and c-FLIP). KA possesses several interesting properties and induces apoptosis through a unique mechanism. Further experiments will be necessary to determine if KA may be used as a lead compound for the development of new chemotherapeutic drugs for the treatment of primary brain tumors.

 

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[789]

TÍTULO / TITLE:  - Chromatin changes in papillary thyroid carcinomas may predict patient outcome.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Oncol (Dordr). 2012 Dec 5.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s13402-012-0116-2

AUTORES / AUTHORS:  - Ferreira RC; Cunha LL; Matos PS; Adam RL; Soares F; Vassallo J; Ward LS

INSTITUCIÓN / INSTITUTION:  - Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences, University  of Campinas (FCM- Unicamp), Rua Tessalia Vieira de Camargo 126 - Barao Geraldo, 13083-970, Campinas, Sao Paulo, Brazil.

RESUMEN / SUMMARY:  - PURPOSE: New insights in prognostic predictions are urgently needed for papillary thyroid carcinoma (PTC). The present study aimed to investigate whether computerized analysis of chromatin texture allows the identification of PTC patients with a poor prognosis. METHODS: We randomnly selected paraffin-embedded  blocks from surgical specimens of 103 classic cases of PTC. During follow-up, 68  of the patients were classified as free of disease, whereas 35 presented with recurrences. Characteristics of chromatin were obtained from digitized images of  at least 100 randomly selected tumor nuclei per patient. An independent series of 30 goiters was used to validate our observations. RESULTS: Stage, age and distant metastases were found to serve as independent prognostic factors for survival. In addition, multivariate Cox regression confirmed variable cluster prominence as an independent prognostic factor. By comparing malignant and benign nodules, we found that the PTC lesions presented with higher nuclear perimeters, nuclear areas, Minkowski fractal dimensions, optical densities and nuclear longest chords. CONCLUSION: From our results we conclude that, in conjunction with clinical and histopathological data, morphometric data may provide relevant prognostic information in PTC patients.

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[790]

TÍTULO / TITLE:  - Lymphatic biomarkers in primary melanomas as predictors of regional lymph node metastasis and patient outcomes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pigment Cell Melanoma Res. 2013 Jan 8. doi: 10.1111/pcmr.12064.

            ●● Enlace al texto completo (gratuito o de pago) 1111/pcmr.12064

AUTORES / AUTHORS:  - Pasquali S; van der Ploeg AP; Mocellin S; Stretch JR; Thompson JF; Scolyer RA

INSTITUCIÓN / INSTITUTION:  - Melanoma Institute Australia, The University of Sydney, 40 Rocklands Road, Sydney, NSW, 2065, Australia; Department of Oncological & Surgical Sciences, University of Padova, via Giustiniani 2, 35128, Padova, Italy; Melanoma & Sarcoma Unit, Veneto Institute of Oncology, via Gattamelata 64, 35128, Padova, Italy.

RESUMEN / SUMMARY:  - Recently developed lymphatic-specific immunohistochemical markers can now be utilized to assess intra- and/or peritumorallymphatic vessel density (LVD), to detect lymphatic vessel invasion (LVI) by melanoma cells and to identify lymphatic marker expression in melanoma cells themselves. We systematically reviewed the available evidence for the expression of lymphatic markers as predictors of regional node metastasis and survival in melanoma patients. The currently available evidence suggests that LVD (particularly in a peritumoral location) and LVI are predictors of sentinel node metastasis and poorer survival. Nevertheless, adherence to international guidelines inthe conduct and reporting of the studies was generally poor, with wide methodologic variations and heterogeneous findings. Larger, carefully conducted and well-reported studies that confirm these preliminary findings are required before it would be appropriate to recommend the routine application of costly and time-consuming immunohistochemistry for lymphatic markers in the routine clinical assessment of  primary cutaneous melanomas. © 2013 John Wiley & Sons A/S.

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[791]

TÍTULO / TITLE:  - Novel Microemulsion of Tanshinone IIA, Isolated from Salvia miltiorrhiza Bunge, Exerts Anticancer Activity Through Inducing Apoptosis in Hepatoma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Chin Med. 2013;41(1):197-210. doi: 10.1142/S0192415X13500146.

            ●● Enlace al texto completo (gratuito o de pago) 1142/S0192415X13500146

AUTORES / AUTHORS:  - Ma H; Fan Q; Yu J; Xin J; Zhang C

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacy, The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, China.

RESUMEN / SUMMARY:  - Natural product Tanshinone IIA (TanIIA) induces apoptosis and differentiation in  hepatocellular carcinoma (HCC) cells, but its clinical use is limited due to poor water solubility and lack of appropriate formulations for drug delivery. In this  study, we capsulated TanIIA into a microemulsion (ME) that was composed of phospholipid, ethyl oleate, glycerol and pluronic F68. We then determined the anticancer effects and mechanisms of action for TanIIA ME with in vitro and in vivo HCC models. The mRNA and protein levels of apoptosis-related molecules (Bcl-2, Bax and caspase-3) were analyzed in murine hepatoma H22 cells and H22 tumor-bearing mice by flow cytometry, RT-PCR and immunofluorescence staining. Compared with the groups treated with empty ME and drug solution, the mRNA levels of Bax and caspase-3 were up-regulated, and the mRNA and protein levels of Bcl-2  were down-regulated in H22 cells treated with TanIIA ME in a dose-dependent manner. The mRNA and protein levels of Bax and caspase-3 were up-regulated and the Bcl-2 levels were also down-regulated in animals treated with TanIIA ME in a  dose-dependent manner. Our results suggest that as a novel drug delivery system,  microemulsion enhances the antitumor effects of TanIIA.

 

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[792]

TÍTULO / TITLE:  - Individualized Chemotherapy in Advanced NSCLC Patients Based on mRNA Levels of BRCA1 and RRM1.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Cancer Res. 2012 Sep;24(3):226-31. doi: 10.1007/s11670-012-0226-4.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11670-012-0226-4

AUTORES / AUTHORS:  - Ren SX; Li AW; Zhou SW; Zhang L; Wang YS; Li B; Chen XX; Zhang J; Xu JF; Zhou CC

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology.

RESUMEN / SUMMARY:  - OBJECTIVE: Experimental evidence suggests that the overexpression of breast cancer-specific tumor suppressor protein 1 (BRCA1) gene enhances sensitivity to docetaxel and resistance to cisplatin and ribonucleotide reductase M1 (RRM1) gene overexpression enhances resistance to gemcitabine. To further examine the effect  of BRCA1 and RRM1 mRNA levels on outcome in advanced non-small cell lung cancer (NSCLC), we performed this non-randomized phase II clinical trial which tested the hypothesis that customized therapy would confer improved outcome over non-customized therapy. METHODS: RNA was isolated from fresh tumor tissue. Patients received chemotherapy regimen based on their BRCA1 and RRM1 mRNA levels: both low-cisplatin plus gemcitabine (GP); both high-vinorelbine plus cisplatin (NP); BRCA1 low and RRM1 high-cisplatin plus docetaxel (TP); BRCA1 high and RRM1  low-vinorelbine plus gemcitabine (GN). RESULTS: From Dec 2005 to Nov 2008, 94 metastatic and locally advanced NSCLC patients from our institute were enrolled in this study. The median age was 58 years old. Among them, 21 patients received  GP, 30 patients received TP and 43 patients received NP chemotherapy. GP group had a higher response rate, and longer median time to progression (TTP) and median overall survival (OS) time than the other 2 groups. The response rates in  the GP, TP and NP groups were 42.9%, 36.7% and 27.9%, respectively (P=0.568). The median TTP was 5.6, 5.0, 4.8 months (P=0.975), respectively, and the median OS time was 12.5, 11.0, 9.7 months (P=0.808), respectively. CONCLUSION: Chemotherapy customized according to BRCA1 and RRM1 expression levels is associated with higher response rate and longer TTP and OS time in the GP group. This suggests that BRCA1 and RRM1 mRNA levels could be used as biomarkers in individual therapy in NSCLC.

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[793]

TÍTULO / TITLE:  - Cyclin A overexpression is associated with chemosensitivity to paclitaxel-based chemotherapy in patients with esophageal squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2012 Oct;4(4):607-611. Epub 2012 Jul 20.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.814

AUTORES / AUTHORS:  - Huang JX; Shen SL; Lin M; Xiao W; Chen WC; Lin MS; Yu H; Chen P; Qian RY

INSTITUCIÓN / INSTITUTION:  - Departments of Oncology and.

RESUMEN / SUMMARY:  - The aim of this study was to investigate the correlation between cyclin A expression and efficacy of paclitaxel-based chemotherapy in patients with esophageal squamous cell carcinoma (ESCC). The expression of cyclin A was examined in 48 newly diagnosed ESCC patients prior to treatment using the MaxVision immunohistochemistry method. The patients received four cycles of paclitaxel-based chemotherapy, the short-term treatment efficacy was evaluated and a 3-year follow-up was conducted. The response rate was greater in patients with positive cyclin A expression compared with those with negative expression (54.8 vs. 23.5%; chi(2)=4.373; P<0.05). Univariate and multivariate Cox analysis  revealed that clinicopathological stage, degree of differentiation and expression of cyclin A were independent prognosis factors in patients with ESCC following paclitaxel-based chemotherapy. ESCC patients with positive cyclin A expression demonstrated an increased sensitivity to paclitaxel-based chemotherapy, suggesting that cyclin A may be used as a marker to predict the treatment efficacy of paclitaxel in patients with ESCC.

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[794]

TÍTULO / TITLE:  - Beta-asarone induces LoVo colon cancer cell apoptosis by up-regulation of caspases through a mitochondrial pathway in vitro and in vivo.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian Pac J Cancer Prev. 2012;13(10):5291-8.

AUTORES / AUTHORS:  - Zou X; Liu SL; Zhou JY; Wu J; Ling BF; Wang RP

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, The Affiliated Hospital of Nanjing University of Chinese  Medicine, Jiangsu Province, Nanjing, China.

RESUMEN / SUMMARY:  - Beta-asarone is one of the main bioactive constituents in traditional Chinese medicine Acorus calamu. Previous studies have shown that it has antifungal and anthelmintic activities. However, little is known about its anticancer effects. This study aimed to determine inhibitory effects on LoVo colon cancer cell proliferation and to clarify the underlying mechanisms in vitro and in vivo. Dose-response and time-course anti-proliferation effects were examined by MTT assay. Our results demonstrated that LoVo cell viability showed dose- and time-dependence on beta-asarone. We further assessed anti-proliferation effects as beta-asarone-induced apoptosis by annexin V-fluorescein isothiocyanate/propidium iodide assay using a flow cytometer and observed characteristic nuclear fragmentation and chromatin condensation of apoptosis by microscopy. Moreover, we found the apoptosis to be induced through the mitochondrial/caspase pathway by decreasing mitochondrial membrane potential (MMP) and reducing the Bcl-2-to-Bax ratio, in addition to activating the caspase-9 and caspase-3 cascades. Additionally, the apoptosis could be inhibited  by a pan-caspase inhibitor, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK). When nude mice bearing LoVo tumor xenografts were treated with beta-asarone, tumor volumes were reduced and terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assays of excised tissue also demonstrated apoptotic changes. Taken together, these findings for the first time provide evidence that  beta-asarone can suppress the growth of colon cancer and the induced apoptosis is possibly mediated through mitochondria/caspase pathways.

 

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[795]

TÍTULO / TITLE:  - M-3M3FBS-Induced Ca(2) (+) Movement and Apoptosis in HA59T Human Hepatoma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Physiol. 2013 Feb 28;56(1):xxx. doi: 10.4077/CJP.2013.BAA091.

            ●● Enlace al texto completo (gratuito o de pago) 4077/CJP.2013.BAA091

AUTORES / AUTHORS:  - Liu SI; Lin KL; Lu T; Lu YC; Hsu SS; Tsai JY; Liao WC; Huang FD; Chi CC; Liang WZ; Tseng LL; Chiang AJ; Jan CR

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, Republic of China.

RESUMEN / SUMMARY:  - The effect of 2,4,6-trimethyl-N-(meta-3-trifluoromethyl-phenyl)-benzenesulfonamide (m-3M3FBS),  a presumed phospholipase C activator, on cytosolic free Ca(2) (+) concentrations  ([Ca(2) (+) ]i ) in HA59T human hepatoma cells is unclear. This study explored whether m-3M3FBS elevated basal [Ca(2) (+) ]i levels in suspended cells by using  fura-2 as a Ca(2) (+) -sensitive fluorescent dye. M-3M3FBS at concentrations of 10- 50 muM increased [Ca(2) (+) ]i in a concentration-dependent fashion. The Ca(2) (+) signal was reduced partly by removing extracellular Ca(2) (+) . M-3M3FBS-induced Ca(2) (+) influx was inhibited by nifedipine, econazole, SK&F96365, aristolochic acid, and GF109203X. In Ca(2) (+) -free medium, 50 muM m-3M3FBS pretreatment inhibited the [Ca(2) (+) ]i rise induced by the endoplasmic reticulum Ca(2) (+) pump inhibitor thapsigargin. Conversely, pretreatment with thapsigargin partly reduced m-3M3FBS-induced [Ca(2) (+) ]i rise. Inhibition of inositol 1,4,5-trisphosphate formation with U73122 did not alter m-3M3FBS-induced [Ca(2) (+) ]i rise. At concentrations between 10 and 40 muM m-3M3FBS killed cells in a concentration-dependent manner. The cytotoxic effect of m-3M3FBS was not reversed by prechelating cytosolic Ca(2) (+) with 1,2-bis(2- aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid (BAPTA). Annexin V/propidium iodide staining data suggest that m-3M3FBS induced apoptosis in a concentration-dependent manner. M-3M3FBS also increased levels of reactive oxygen species. Together, in human hepatoma cells, m-3M3FBS induced a [Ca(2) (+) ]i rise by inducing phospholipase C-independent Ca(2) (+) release from the endoplasmic reticulum and Ca(2) (+) entry via protein kinase C-sensitive store-operated Ca(2) (+) channels. M-3M3FBS induced cell death that might involve apoptosis via mitochondrial pathways.

 

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[796]

TÍTULO / TITLE:  - Effectiveness and response predictive factors of erlotinib in a non-small cell lung cancer unselected European population previously treated: A retrospective, observational, multicentric study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Oncol Pharm Pract. 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 1177/1078155212465994

AUTORES / AUTHORS:  - Cioffi P; Marotta V; Fanizza C; Giglioni A; Natoli C; Petrelli F; Grappasonni I

INSTITUCIÓN / INSTITUTION:  - Hospital Pharmacy, SS Annunziata Hospital, Chieti, Italy.

RESUMEN / SUMMARY:  - Aims and background:Erlotinib approval was supported by the positive results of a large multicentric phase III trial (BR.21 study) that included 10% Asiatic patients and the remaining were North-American Caucasian. It is well-known that the efficacy of tyrosine kinase inhibitors is strongly influenced by ethnicity and other genetic factors. It is, therefore, relevant to establish whether the same profile of efficacy is seen in an unselected population and whether the results of BR.21 can be generalized to other patient populations, such as that described here. METHODS: In this retrospective, observational, multicentric study, we assessed effectiveness and potentially response predictive factors in 222 unselected Italian patients, with stage IIIB/IV non-small-cell lung cancer, with performance status from 0 to 3, who had received at least one line of chemotherapy, treated with the standard dose of erlotinib (150 mg once daily) until disease progression or unacceptable toxicity. RESULTS: The disease control  rate was 60.9% (135 patients). Median progression-free survival and overall survival times were 3.1 months and 7.97 months, respectively. The characteristics of non-smoker, female gender, performance status 0 or 1 were associated with a significantly better prognosis in terms of disease control rate and were also predictive of longer overall survival and progression-free survival. The 1-year survival rate was 38.79%. Even though Italian patients baseline characteristics were strongly different to those reported in pivotal BR.21 trial in terms of age, performance status, line treatment and ethnic group, our study confirms the favorable effectiveness profile in real clinical practice of erlotinib according  to results from the pivotal study BR.21. CONCLUSIONS: Today, we know that epidermal growth factor receptor (EGFR) status assessment is mandatory before starting first-line therapy and that the presence of only certain clinical characteristics initially associated with sensitivity to EGFR-tyrosine kinase inhibitors, as reported in this study, is not sufficient in selecting patients candidates to such treatments.

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[797]

TÍTULO / TITLE:  - EZH2 Promotes Malignant Behaviors via Cell Cycle Dysregulation and Its mRNA Level Associates with Prognosis of Patient with Non-Small Cell Lung Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e52984. doi: 10.1371/journal.pone.0052984. Epub 2012 Dec 31.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052984

AUTORES / AUTHORS:  - Cao W; Ribeiro Rde O; Liu D; Saintigny P; Xia R; Xue Y; Lin R; Mao L; Ren H

INSTITUCIÓN / INSTITUTION:  - Shanghai Key Laboratory of Stomatology, Department of Oral Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ; Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America.

RESUMEN / SUMMARY:  - BACKGROUND: Epigenetic silencing is a common mechanism to inactivate tumor suppressor genes during carcinogenesis. Enhancer of Zeste 2 (EZH2) is the histone methyltransferase subunit in polycomb repressive complex 2 which mediates transcriptional repression through histone methylation. EZH2 overexpression has been linked to aggressive phenotypes of certain cancers. However, the mechanism that EZH2 played in promoting malignancy in non-small cell lung cancer (NSCLC) remains unclear. In addition, the correlation of EZH2 overexpression and the prognosis of NSCLC patients in non-Asian cohort need to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Up-regulation of EZH2 was found in NSCLC cells compared with normal human bronchial epithelial cells by western blot assay. Upon EZH2 knockdown using small interfering RNA (siRNA), the proliferation, anchorage-independent growth and invasion of NSCLC cells were remarkably suppressed with profound induction of G1 arrest. Furthermore, the expression of cyclin D1 was notably reduced whereas p15(INK4B), p21(Waf1/Cip1) and p27(Kip1) were increased in NSCLC cells after EZH2-siRNA delivery. To determine whether EZH2 expression contributes to disease progression in patients with NSCLC, Taqman quantitative real-time RT-PCR was used to measure the expression of EZH2 in paired tumor and normal samples. Univariate analysis revealed that patients with  NSCLC whose tumors had a higher EZH2 expression had significantly inferior overall, disease-specific, and disease-free survivals compared to those whose tumors expressed lower EZH2 (P = 0.005, P = 0.001 and P = 0.003, respectively). In multivariate analysis, EZH2 expression was an independent predictor of disease-free survival (hazard ratio = 0.450, 95% CI: 0.270 to 0.750, P = 0.002).  CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that EZH2 overexpression is critical for NSCLC progression. EZH2 mRNA levels may serve as a prognostic predictor for patients with NSCLC.

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[798]

TÍTULO / TITLE:  - Effect of Bufalin on Cellular Proliferation and Apoptosis in Human Esophageal Squamous Carcinoma EC9706 Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2012 Dec 20;34(6):556-62. doi: 10.3881/j.issn.1000-503X.2012.06.004.

            ●● Enlace al texto completo (gratuito o de pago) 3881/j.issn.1000-503X.2012.06.004

AUTORES / AUTHORS:  - Xin T; Ying L; Yong-Bo Y; Cheng-Guang S; Fan-Dong M; Yun-Peng L

INSTITUCIÓN / INSTITUTION:  - Molecular Oncology Laboratory of Cancer Research Institute,the First Affiliated Hospital, China Medical University,Shenyang 110001,China.

RESUMEN / SUMMARY:  - Objective To investigate the effect of bufalin on nucleus-mitochondria localization of human telomerase reverse transcriptase(hTERT) by exploring its effect on proliferation and apoptosis in human esophageal squamous carcinoma EC9706 cells. Methods EC9706 cells were treated with bufalin at various concentrations, and then the cell growth inhibition of EC9706 cells was examined  by CCK-8 assay and the 50% inhibitory concentration (IC(50)) was calculated.Cell  cycle analysis was performed by flow cytometry with PI staining, and nucleus morphology of apoptosis were observed by fluorescence microscopy with Hoechst 33342 staining. The apoptotic index was measured by flow cytometry with Annexin V-FITC/PI double staining. hTERT subcellular localization and protein expression  were determined by Western blotting and multiple immunofluorescence labling combined with laser confocal scanning microscopy. Results The proliferation of EC 9706 cells was significantly inhibited by bufalin along with the increase of processing time and concentrations (p<0.01). After the EC9706 cells were exposed  to 100 nmol/L bufalin,the number of cells gradually decreased in G(1) phase and increased in S and G(2)/M phases(p<0.05). The typical nucleus morphological changes of apoptosis were observed and the apoptotic index was increased(p<0.01). The expression of hTERT decreased in nucleus but increased in mitochondria(p<0.05). Conclusions Bufalin can inhibit the proliferation of human  esophageal squamous carcinoma EC9706 cells in a time- and dose-dependent manner.  It can arrest cell cycle in S and G(2)/M phases and induce the apoptosis of EC 9706 cells. hTERT is localized in both nucleus and mitochondria,and can be partially translocated from nucleus to mitochondria during the bufalin-induced apoptosis.

 

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[799]

TÍTULO / TITLE:  - Prediction of breast cancer metastasis by gene expression profiles: a comparison  of metagenes and single genes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Inform. 2012;11:193-217. doi: 10.4137/CIN.S10375. Epub 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 4137/CIN.S10375

AUTORES / AUTHORS:  - Burton M; Thomassen M; Tan Q; Kruse TA

INSTITUCIÓN / INSTITUTION:  - Institute of Clinical Research, Research Unit of Human Genetics, University of Southern Denmark, Odense, Denmark ; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.

RESUMEN / SUMMARY:  - BACKGROUND: The popularity of a large number of microarray applications has in cancer research led to the development of predictive or prognostic gene expression profiles. However, the diversity of microarray platforms has made the  full validation of such profiles and their related gene lists across studies difficult and, at the level of classification accuracies, rarely validated in multiple independent datasets. Frequently, while the individual genes between such lists may not match, genes with same function are included across such gene  lists. Development of such lists does not take into account the fact that genes can be grouped together as metagenes (MGs) based on common characteristics such as pathways, regulation, or genomic location. Such MGs might be used as features  in building a predictive model applicable for classifying independent data. It is, therefore, demanding to systematically compare independent validation of gene lists or classifiers based on metagene or individual gene (SG) features. METHODS: In this study we compared the performance of either metagene-or single gene-based feature sets and classifiers using random forest and two support vector machines  for classifier building. The performance within the same dataset, feature set validation performance, and validation performance of entire classifiers in strictly independent datasets were assessed by 10 times repeated 10-fold cross validation, leave-one-out cross validation, and one-fold validation, respectively. To test the significance of the performance difference between MG-  and SG-features/classifiers, we used a repeated down-sampled binomial test approach. RESULTS: MG- and SG-feature sets are transferable and perform well for  training and testing prediction of metastasis outcome in strictly independent data sets, both between different and within similar microarray platforms, while  classifiers had a poorer performance when validated in strictly independent datasets. The study showed that MG- and SG-feature sets perform equally well in classifying independent data. Furthermore, SG-classifiers significantly outperformed MG-classifier when validation is conducted between datasets using similar platforms, while no significant performance difference was found when validation was performed between different platforms. CONCLUSION: Prediction of metastasis outcome in lymph node-negative patients by MG- and SG-classifiers showed that SG-classifiers performed significantly better than MG-classifiers when validated in independent data based on the same microarray platform as used  for developing the classifier. However, the MG- and SG-classifiers had similar performance when conducting classifier validation in independent data based on a  different microarray platform. The latter was also true when only validating sets of MG- and SG-features in independent datasets, both between and within similar and different platforms.

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[800]

TÍTULO / TITLE:  - Effect of trichostatin A and paclitaxel on the proliferation and apoptosis of lung adenocarcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin Med J (Engl). 2013 Jan;126(1):129-34.

AUTORES / AUTHORS:  - Zhang S; Zhang QC; Jiang SJ

INSTITUCIÓN / INSTITUTION:  - Department of Respiratory Diseases, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.

RESUMEN / SUMMARY:  - BACKGROUND: Histone deacetylase inhibitors can regulate gene expression through modulation of the degree of acetylation of histone and non-histone, thus affecting cell proliferation, survival and chemosensitivity. Histone deacetylase  inhibitors combined with paclitaxel may enhance the inhibitory effect of drugs on lung cancer cells. This study aimed to observe the effect of trichostatin A (TSA)/paclitaxel on the proliferation and apoptosis in human A549 lung adenocarcinoma cells, and to investigate its mechanism. METHODS: A549 cells were  cultured in Dulbecco modified Eagle’s medium (DMEM) in the presence of paclitaxel and the histone deacetylase inhibitor TSA, and the growth curve was obtained by trypan-blue exclusion assay and cell count. Apoptosis was assessed using Hoechst  33258 staining and flow cytometry analysis, and cell cycle was detected by flow cytometry analysis. The proteins poly ADP-ribose polymerase (PARP), caspase-3, survivin, and tubulin acetylation were detected by Western blotting. RESULTS: A significant reduction of proliferation was observed in A549 lung adenocarcinoma cells treated by paclitaxel or TSA. Combined treatment with TSA/paclitaxel caused the greatest inhibition of cell proliferation. The combined treatment with TSA and paclitaxel induced more severe apoptosis, and significantly more cells were arrested in G2/M phase (P < 0.05) then with a single drug. Using Western blotting, we demonstrated that treatment with TSA/paclitaxel led to synergistic increase in acetylated tubulin, PARP, caspase-3, and reduced the expression of survivin. CONCLUSION: TSA and paclitaxel have a synergistic activity that can inhibit cell growth and induce apoptosis.

 

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[801]

TÍTULO / TITLE:  - Apoptotic susceptibility to DNA damage of pluripotent stem cells facilitates pharmacologic purging of teratoma risk.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Stem Cells. Acceso gratuito al texto completo.

            ●● Enlace a la Editora de la Revista http://stemcells.alphamedpress.org/ 

            ●● Cita: Stem Cells: <> Transl Med. 2012 Oct;1(10):709-18. doi: 10.5966/sctm.2012-0066. Epub 2012 Sep 27.

            ●● Enlace al texto completo (gratuito o de pago) 5966/sctm.2012-0066

AUTORES / AUTHORS:  - Smith AJ; Nelson NG; Oommen S; Hartjes KA; Folmes CD; Terzic A; Nelson TJ

INSTITUCIÓN / INSTITUTION:  - Department of Medicine and Transplant Center, Mayo Clinic, Rochester, MN 55905, USA.

RESUMEN / SUMMARY:  - Pluripotent stem cells have been the focus of bioengineering efforts designed to  generate regenerative products, yet harnessing therapeutic capacity while minimizing risk of dysregulated growth remains a challenge. The risk of residual  undifferentiated stem cells within a differentiated progenitor population requires a targeted approach to eliminate contaminating cells prior to delivery.  In this study we aimed to validate a toxicity strategy that could selectively purge pluripotent stem cells in response to DNA damage and avoid risk of uncontrolled cell growth upon transplantation. Compared with somatic cell types,  embryonic stem cells and induced pluripotent stem cells displayed hypersensitivity to apoptotic induction by genotoxic agents. Notably, hypersensitivity in pluripotent stem cells was stage-specific and consistently lost upon in vitro differentiation, with the mean half-maximal inhibitory concentration increasing nearly 2 orders of magnitude with tissue specification.  Quantitative polymerase chain reaction and Western blotting demonstrated that the innate response was mediated through upregulation of the BH3-only protein Puma in both natural and induced pluripotent stem cells. Pretreatment with genotoxic etoposide purged hypersensitive pluripotent stem cells to yield a progenitor population refractory to teratoma formation upon transplantation. Collectively, this study exploits a hypersensitive apoptotic response to DNA damage within pluripotent stem cells to decrease risk of dysregulated growth and augment the safety profile of transplant-ready, bioengineered progenitor cells.

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[802]

TÍTULO / TITLE:  - A nomogram based on age, prostate-specific antigen level, prostate volume and digital rectal examination for predicting risk of prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian J Androl. 2013 Jan;15(1):129-33. doi: 10.1038/aja.2012.111. Epub 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 1038/aja.2012.111

AUTORES / AUTHORS:  - Tang P; Chen H; Uhlman M; Lin YR; Deng XR; Wang B; Yang WJ; Xie KJ

INSTITUCIÓN / INSTITUTION:  - 1] Postgraduate Institute, Southern Medical University, Guangzhou 510515, China [2] Department of Urology, Guangzhou First Municipal People’s Hospital, Guangzhou Medical College, Guangzhou 510180, China.

RESUMEN / SUMMARY:  - Nomograms for predicting the risk of prostate cancer developed using other populations may introduce sizable bias when applied to a Chinese cohort. In the present study, we sought to develop a nomogram for predicting the probability of  a positive initial prostate biopsy in a Chinese population. A total of 535 Chinese men who underwent a prostatic biopsy for the detection of prostate cancer in the past decade with complete biopsy data were included. Stepwise logistic regression was used to determine the independent predictors of a positive initial biopsy. Age, prostate-specific antigen (PSA), prostate volume (PV), digital rectal examination (DRE) status, % free PSA and transrectal ultrasound (TRUS) findings were included in the analysis. A nomogram model was developed that was based on these independent predictors to calculate the probability of a positive  initial prostate biopsy. A receiver-operating characteristic curve was used to assess the accuracy of using the nomogram and PSA levels alone for predicting positive prostate biopsy. The rate for positive initial prostate biopsy was 41.7% (223/535). The independent variables used to predict a positive initial prostate  biopsy were age, PSA, PV and DRE status. The areas under the receiver-operating characteristic curve for a positive initial prostate biopsy for PSA alone and the nomogram were 79.7% and 84.8%, respectively. Our results indicate that the risk of a positive initial prostate biopsy can be predicted to a satisfactory level in a Chinese population using our nomogram. The nomogram can be used to identify and counsel patients who should consider a prostate biopsy, ultimately enhancing accuracy in diagnosing prostate cancer.

 

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[803]

TÍTULO / TITLE:  - Luteolin Induced-growth Inhibition and Apoptosis of Human Esophageal Squamous Carcinoma Cell Line Eca109 Cells in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian Pac J Cancer Prev. 2012;13(11):5455-61.

AUTORES / AUTHORS:  - Wang TT; Wang SK; Huang GL; Sun GJ

INSTITUCIÓN / INSTITUTION:  - Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China E-mail : guiju.sun@gmail.com.

RESUMEN / SUMMARY:  - Luteolin is a plant flavonoid which exhibits anti-oxidative, anti-inflammatory and anti-tumor effects. However, the antiproliferative potential of luteolin is not fully understood. In this study, we investigated the effect of luteolin on cell cycling and apoptosis in human esophageal squamous carcinoma cell line Eca109 cells. MTT assays showed that luteolin had obvious cytotoxicity on Eca109  with an IC50 of 70.7+/-1.72muM at 24h. Luteolin arrested cell cycle progression in the G0/G1 phase and prevented entry into S phase in a dose- and time-dependent manner. as assessed by FCM. Luteolin induced apoptosis of Eca109 cells was demonstrated by AO/EB staining assay and annexin V-FITC/PI staining. Moreover, luteolin downregulated the expression of cyclin D1, survivin and c-myc, and it also upregulated the expression of p53, in line with the fact that luteolin was able to inhibit Eca109 cell proliferation.

 

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[804]

TÍTULO / TITLE:  - Involvement of heat shock protein 27 in the susceptibility of KT human breast cancer cells to UVC and interferon lethality.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Exp Ther Med. 2012 Nov;4(5):913-917. Epub 2012 Sep 4.

            ●● Enlace al texto completo (gratuito o de pago) 3892/etm.2012.696

AUTORES / AUTHORS:  - Tong XB; Kita K; Chen SP; Jiang X; Sugaya S; Jing WL; Zhang SF; Suzuki N

INSTITUCIÓN / INSTITUTION:  - Department of Physiology, Chengde Medical University, Chengde 067000, P.R. China  ; ; Department of Environmental Biochemistry, Graduate School of Medicine, Chiba  University, Chiba 260-8670, Japan.

RESUMEN / SUMMARY:  - Revealing the key molecules regulating the stress-response pathways in human cells is an intriguing problem. Chaperones, such as glucose-regulated protein 78  (GRP78) and heat shock protein 27 (HSP27), are important molecules for protecting the viability of human cells; however, it remains to be further clarified whether the molecules differentially modulate cellular responses to various types of stressors, such as DNA-damaging ultraviolet ray C (principally 254-nm wavelength, UVC) and cytocidal cytokine interferons. In the present study, the human breast cancer cell lines KT and MCF-7 were examined for GRP78 and HSP27 expression following exposure to UVC and human interferon-beta (HuIFN-beta). The KT cells demonstrated a higher sensitivity to both UVC and HuIFN-beta lethality than MCF-7 cells. The cellular expression levels of GRP78 in KT cells, assessed by western blot analysis, were approximately 2-fold higher than that in MCF-7 cells, while the expression of HSP27 in the KT cells was 20% of the expression in the MCF-7 cells. Decreased resistance to UVC lethality was observed in GRP78 siRNA-transfected KT cells. In addition, HSP27 cDNA transfection of KT cells resulted in an increased resistance to UVC lethality. The cDNA-transfected KT cells showed an increased viability against HuIFN-beta, compared with that of empty vector-transfected cells. By contrast, KT cells pretreated with HuIFN-beta  and irradiated with UVC demonstrated an increased resistance to UVC lethality, in association with increased levels of HSP27 expression. Thus, HSP27 may control the survival response pathways to both UVC and HuIFN-beta in the human cells examined.

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[805]

TÍTULO / TITLE:  - Potentiation of in vitro and in vivo antitumor efficacy of doxorubicin by cyclin-dependent kinase inhibitor P276-00 in human non-small cell lung cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Cancer. 2013 Jan 23;13(1):29.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2407-13-29

AUTORES / AUTHORS:  - Rathos MJ; Khanwalkar H; Joshi K; Manohar SM; Joshi KS

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: In the present study, we show that the combination of doxorubicin with the cyclin-dependent kinase inhibitor P276-00 was synergistic at suboptimal doses in the non-small cell lung carcinoma (NSCLC) cell lines and induces extensive apoptosis than either drug alone in H-460 human NSCLC cells. METHODS: Synergistic effects of P276-00 and doxorubicin on growth inhibition was  studied using the Propidium Iodide (PI) assay. The doses showing the best synergistic effect was determined and these doses were used for further mechanistic studies such as western blotting, cell cycle analysis and RT-PCR. The in vivo efficacy of the combination was evaluated using the H-460 xenograft model. RESULTS: The combination of 100 nM doxorubicin followed by 1200 nM P276-00 showed synergistic effect in the p53-positive and p53-mutated cell lines H-460 and H23 respectively as compared to the p53-null cell line H1299. Abrogation of doxorubicin-induced G2/M arrest and induction of apoptosis was observed in the combination treatment. This was associated with induction of tumor suppressor protein p53 and reduction of anti-apoptotic protein Bcl-2. Furthermore, doxorubicin alone greatly induced COX-2, a NF-kappaB target and Cdk-1, a target of P276-00, which was downregulated by P276-00 in the combination. Doxorubicin when combined with P276-00 in a sequence-specific manner significantly inhibited  tumor growth, compared with either doxorubicin or P276-00 alone in H-460 xenograft model. CONCLUSION: These findings suggest that this combination may increase the therapeutic index over doxorubicin alone and reduce systemic toxicity of doxorubicin most likely via an inhibition of doxorubicin-induced chemoresistance involving NF-kappaB signaling and inhibition of Cdk-1 which is involved in cell cycle progression.

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[806]

TÍTULO / TITLE:  - Fucoxanthin Enhances Cisplatin-Induced Cytotoxicity via NF&#954;B-Mediated Pathway and Downregulates DNA Repair Gene Expression in Human Hepatoma HepG2 Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mar Drugs. 2013 Jan 8;11(1):50-66. doi: 10.3390/md11010050.

            ●● Enlace al texto completo (gratuito o de pago) 3390/md11010050

AUTORES / AUTHORS:  - Liu CL; Lim YP; Hu ML

INSTITUCIÓN / INSTITUTION:  - Department of Food Science and Biotechnology, National Chung Hsing University, Taichung 402, Taiwan. mlhuhu@nchu.edu.tw.

RESUMEN / SUMMARY:  - Cisplain, a platinum-containing anticancer drug, has been shown to enhance DNA repair and to inhibit cell apoptosis, leading to drug resistance. Thus, the combination of anticancer drugs with nutritional factors is a potential strategy  for improving the efficacy of cisplatin chemotherapy. In this study, we investigated the anti-proliferative effects of a combination of fucoxanthin, the  major non-provitamin A carotenoid found in Undaria Pinnatifida, and cisplatin in  human hepatoma HepG2 cells. We found that fucoxanthin (1-10 muMu) pretreatment for 24 h followed by cisplatin (10 muMu) for 24 h significantly decreased cell proliferation, as compared with cisplatin treatment alone. Mechanistically, we showed that fucoxanthin attenuated cisplatin-induced NFkappaB expression and enhanced the NFkappaB-regulated Bax/Bcl-2 mRNA ratio. Cisplatin alone induced mRNA expression of excision repair cross complementation 1 (ERCC1) and thymidine  phosphorylase (TP) through phosphorylation of ERK, p38 and PI3K/AKT pathways. However, fucoxanthin pretreatment significantly attenuated cisplatin-induced ERCC1 and TP mRNA expression, leading to improvement of chemotherapeutic efficacy of cisplatin. The results suggest that a combined treatment with fucoxanthin and  cisplatin could lead to a potentially important new therapeutic strategy against  human hepatoma cells.

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[807]

TÍTULO / TITLE:  - A Clinicopathological Study of Resected Small-Sized Squamous Cell Carcinomas of the Peripheral Lung: Prognostic Significance of Serum Carcinoembryonic Antigen Levels.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Thorac Cardiovasc Surg. 2012 Dec 13.

AUTORES / AUTHORS:  - Nagashima T; Sakao Y; Mun M; Ishikawa Y; Nakagawa K; Masuda M; Okumura S

INSTITUCIÓN / INSTITUTION:  - Department of Thoracic Surgical Oncology, Japanese Foun dation for Cancer Research, Cancer Institute Hospital, Tokyo, Japan.

RESUMEN / SUMMARY:  - Purpose: The purpose of this retrospective study was to evaluate common clinicopathological factors and clarify the prognostic factors of small-sized peripheral-lung squamous cell carcinomas.Methods: We retrospectively reviewed 71  patients with peripheral squamous cell carcinoma </=3 cm in diameter, who were surgically treated between January 1989 and December 2010. Patients undergoing partial lung resection without lymph node dissection were excluded. The median follow-up for living patients was 63 months.Results: The overall 3- and 5-year survival rates were 83.9% and 74.7%, respectively.Although the ROC curve of serum carcinoembryonic antigen (CEA) levels showed marginally significance (P = 0.050), multivariate analyses revealed that age (P = 0.043), lymph node metastasis (P = 0.004), and preoperative serum carcinoembryonic antigen (CEA) level (P = 0.037) were independent prognostic factors. For pathologic N0 patients, there was a significant difference for recurrence-free survival based on CEA levels: patients with normal CEA levels (n = 40), 5-year-recurrence-free rate = 93.5%;elevated CEA (n = 14), 5-year-recurrence-free rate = 72.7% (P = 0.0160). The distribution of tumor cells immunoreactive for CEA was significantly associated with serum CEA levels (P = 0.033).Conclusion: Age, lymph node metastasis, and serum CEA level are independent prognostic factors for small-sized peripheral-lung squamous cell  carcinoma.

 

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[808]

TÍTULO / TITLE:  - Salinomycin inhibits proliferation and induces apoptosis of human hepatocellular  carcinoma cells in vitro and in vivo.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e50638. doi: 10.1371/journal.pone.0050638. Epub 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0050638

AUTORES / AUTHORS:  - Wang F; He L; Dai WQ; Xu YP; Wu D; Lin CL; Wu SM; Cheng P; Zhang Y; Shen M; Wang CF; Lu J; Zhou YQ; Xu XF; Xu L; Guo CY

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology, Shanghai tenth People’s Hospital, Tongji University of Medicine, Shanghai, People’s Republic of China.

RESUMEN / SUMMARY:  - The anti-tumor antibiotic salinomycin (Sal) was recently identified as a selective inhibitor of breast cancer stem cells; however, the effect of Sal on hepatocellular carcinoma (HCC) is not clear. This study aimed to determine the anti-tumor efficacy and mechanism of Sal on HCC. HCC cell lines (HepG2, SMMC-7721, and BEL-7402) were treated with Sal. Cell doubling time was determinated by drawing growth curve, cell viability was evaluated using the Cell Counting Kit 8. The fraction of CD133(+) cell subpopulations was assessed by flow cytometry. We found that Sal inhibits proliferation and decreases PCNA levels as  well as the proportion of HCC CD133(+)cell subpopulations in HCC cells. Cell cycle was analyzed using flow cytometry and showed that Sal caused cell cycle arrest of the various HCC cell lines in different phases. Cell apoptosis was evaluated using flow cytometry and Hoechst 33342 staining. Sal induced apoptosis  as characterized by an increase in the Bax/Bcl-2 ratio. Several signaling pathways were selected for further mechanistic analyses using real time-PCR and Western blot assays. Compared to control, beta-catenin expression is significantly down-regulated upon Sal addition. The Ca(2+) concentration in HCC cells was examined by flow cytometry and higher Ca(2+) concentrations were observed in Sal treatment groups. The anti-tumor effect of Sal was further verified in vivo using the hepatoma orthotopic tumor model and the data obtained  showed that the size of liver tumors in Sal-treated groups decreased compared to  controls. Immunohistochemistry and TUNEL staining also demonstrated that Sal inhibits proliferation and induces apoptosis in vivo. Finally, the role of Sal on in vivo Wnt/beta-catenin signaling was evaluated by Western blot and immunohistochemistry. This study demonstrates Sal inhibits proliferation and induces apoptosis of HCC cells in vitro and in vivo and one potential mechanism is inhibition of Wnt/beta-catenin signaling via increased intracellular Ca(2+) levels.

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[809]

TÍTULO / TITLE:  - Safety and efficacy of cabazitaxel in the docetaxel-treated patients with hormone-refractory prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Med Insights Oncol. 2013;7:1-12. doi: 10.4137/CMO.S7256. Epub 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 4137/CMO.S7256

AUTORES / AUTHORS:  - Calcagno F; Nguyen T; Dobi E; Villanueva C; Curtit E; Kim S; Montcuquet P; Kleinclauss F; Pivot X; Thiery-Vuillemin A

INSTITUCIÓN / INSTITUTION:  - Centre Hospitalier Universitaire Besancon, Oncology, Besancon, France.

RESUMEN / SUMMARY:  - Prostate cancer (PC) is one of the most common cancers and is a leading cause of  death. Its initial growth is dependent on androgens; most patients show an initial response to hormonal therapy but will experience disease progression when PC becomes resistant to castration. In 2004, two key randomized controlled trials demonstrated a benefit for docetaxel-based regimens in the treatment of men with  castration-resistant prostate cancer (CRPC). Cabazitaxel (XRP6258, TXD258, and RPR116258A), a tubulin-binding taxane drug as potent as docetaxel in cell lines,  was the first treatment able to prolong survival for metastatic CRPC in the post-docetaxel setting. This review describes pharmacologic parameters of this agent followed by a review of clinical trials involving cabazitaxel. Other available treatments and the place of cabazitaxel in metastatic CRPC setting are  discussed.

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[810]

TÍTULO / TITLE:  - Interferon-alpha in chronic myeloid leukemia revisited: A long-term retrospective study in Central and Northern Moravia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012 Nov 27. doi: 10.5507/bp.2012.068.

            ●● Enlace al texto completo (gratuito o de pago) 5507/bp.2012.068

AUTORES / AUTHORS:  - Faber E; Kuba A; Zapletalova J; Divoka M; Rohon P; Holzerova M; Jarosova M; Indrak K

INSTITUCIÓN / INSTITUTION:  - Department of Hemato-Oncology, University Hospital Olomouc, Czech Republic.

RESUMEN / SUMMARY:  - AIMS: We assessed the long-term outcome of consecutive patients in the chronic phase of chronic myeloid leukemia (CML) treated with interferon-alpha (INF-alpha) in Central and Northern Moravia between 1989 and 2006. METHODS: A retrospective study focused on the response, prognostic factors and side-effects of INF-alpha.  RESULTS: 118 patients (67 males and 51 females, median age 50 years; range 18-71) were analyzed. The median follow-up was 82.6 months (12.4-212.6). Thirty-six patients (30.5%) achieved major cytogenetic response (CyR) in median of 18.3 months (3.7-47.3) and maintained it for a median of 64.0 months (7.0-176.0). Sixty-one patients treated with INF-alpha for more than 12 months had an overall  survival (OS) of 137.0 months (95% CI 117.6-156.4). Eighteen (29.5%) achieved complete CyR (CCyR). 109 patients discontinued the treatment with INF-alpha because of hematologic or cytogenetic resistance in 53 (48.7%), progression of CML in 31 (28.4%) and intolerance to INF-alpha in 17 (15.6%) patients. The percentage of peripheral blasts, leukocyte count (>50x10(9)/L), splenomegaly, anemia (Hgb</=110 g/L) and Sokal score had statistical impact on the OS in univariate assessment but only the Sokal score remained significant in multivariate analysis. Additional cytogenetic abnormalities at diagnosis were associated with poor prognosis. CONCLUSIONS: In most patients, treatment with INF-alpha had to be stopped because of a failure to induce response, progression  of CML or side-effects but nearly one third of patients treated at least for one  year had a long-term benefit from INF-alpha. The best prognosis was associated with achievement of CCyR and negativity of BCR-ABL in nested RT-PCR.

 

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[811]

TÍTULO / TITLE:  - Expression of p53 and p21(WAF-1), apoptosis, and proliferation of smooth muscle cells in normal myometrium during the menstrual cycle: implication of DNA damage  and repair for leiomyoma development.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Mol Morphol. 2012 Dec;45(4):214-21. doi: 10.1007/s00795-011-0562-3. Epub 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00795-011-0562-3

AUTORES / AUTHORS:  - Suzuki A; Kariya M; Matsumura N; Baba T; Yagi H; Mandai M; Konishi I; Fujii S

INSTITUCIÓN / INSTITUTION:  - Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto 606-8507, Japan. flapper@kuhp.kyoto-u.ac.jp

RESUMEN / SUMMARY:  - Uterine leiomyoma is the most common tumor in the female genital tract, although  its pathogenesis remains unclear. Molecular analyses have demonstrated that each  leiomyoma nodule is monoclonal and harbors various DNA abnormalities, suggesting  that DNA damage in normal smooth muscle cells plays an important role in the pathogenesis of leiomyoma. The aim of this study is to evaluate precisely when and where DNA damage occurs in the myometrium. The localization of damaged, apoptotic, and proliferating cells was evaluated by immunohistochemical staining  of p53, p21(WAF-1), TUNEL, and the cell proliferation marker, Ki-67, in normal myometrium during the menstrual cycle. p53-positive cells and p21(WAF-1)-positive cells were observed during the follicular phase, mostly in the submucosal layer of the myometrium. TUNEL-positive cells were sporadically identified in this layer during either the menstrual or follicular phase. In contrast, the number of Ki-67-positive cells was higher in the luteal phase. These results suggest that DNA damage, repair, and apoptosis occur cyclically in normal myometrium during the follicular phase. In addition, smooth muscle cells proliferate in the luteal  phase, which may be a vulnerable period for DNA damage. Thus, these cyclic events during the menstrual cycle may contribute to a high incidence of leiomyoma development.

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[812]

TÍTULO / TITLE:  - Simultaneous Inactivation of the p16, p15 and p14 Genes Encoding Cyclin-Dependent Kinase Inhibitors in Canine T-Lymphoid Tumor Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Vet Med Sci. 2013 Jan 24.

AUTORES / AUTHORS:  - Fujiwara-Igarashi A; Goto-Koshino Y; Mochizuki H; Maeda S; Fujino Y; Ohno K; Tsujimoto H

INSTITUCIÓN / INSTITUTION:  - Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo.

RESUMEN / SUMMARY:  - The p16, p15 and p14 genes are widely known as tumor suppressor genes in human medicine. Although a large number of genetic and epigenetic aberrations in these  genes have been reported in human malignancies, canine malignancies have not been well analyzed on the aberrations of these genes. In this study, the full-length complementary DNA (cDNA) of the canine p16 gene was cloned using the 5’ and 3’ rapid amplification of cDNA ends methods. Based on the sequence data, primers specific for p16, p15 and p14 were designed. Using these primers, the expression  of p16, p15 and p14 mRNAs could be individually evaluated by reverse transcriptase polymerase chain reaction. Genomic aberrations were also examined using genomic polymerase chain reaction. Two of the six canine lymphoid tumor cell lines did not express detectable levels of p16, p15 and p14 mRNAs, and wide-ranging deletions in the p15-p14-p16 genomic locus were suspected. Wide-ranging deletions were also speculated in 2 of 14 dogs with T-cell lymphoid  tumors. On the other hand, similar failure of amplification suggesting wide-ranging deletions were not observed in any of the 14 dogs with B-cell lymphoma. Deletion of the p15-p14-p16 genomic locus could be one of the molecular aberrations in canine lymphoid tumor cells.

 

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[813]

TÍTULO / TITLE:  - Wild-Type KRAS and BRAF Could Predict Response to Cetuximab in Chinese Colorectal Cancer Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Cancer Res. 2011 Dec;23(4):271-5. doi: 10.1007/s11670-011-0271-4.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11670-011-0271-4

AUTORES / AUTHORS:  - Gao J; Wang TT; Yu JW; Li YY; Shen L

INSTITUCIÓN / INSTITUTION:  - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University School of  Oncology, Beijing Cancer Hospital & Institute, Beijing 100142, China.

RESUMEN / SUMMARY:  - OBJECTIVE: To analyze the relationship between KRAS, BRAF mutations and the response toCetuximab in Chinese colorectal cancer patients. METHODS: A total of273 Chinese colorectal cancer patients were evaluated for KRAS and BRAF mutations by Sanger sequencing. Among them, 59 patients with metastatic colorectal cancer (mCRC) were treated with Cetuximab in combination with chemotherapy from August 2005 to July 2009. Statistical analysis was conducted to assess the relationship between KRAS, BRAF mutations and the response or survival of 59 mCRC patients. RESULTS: KRAS and BRAF mutation rates were 38.5% (105/273) and 5.1% (14/273), respectively, and KRAS/BRAF mutations were mutually exclusive. Among 59 patients treated with Cetuximab plus chemotherapy, KRAS and BRAF mutations were identified in 11and 5 patients, respectively. The response rates and median progression-free survivals (PFS) in KRAS wild-type and mutant patients were 35.4% (17/48) vs. 9.1% (1/11) (P=0.054) and 153 days vs. 99 days (P=0.01), respectively.Also, the response rates and median PFS in BRAF wild-type and mutant patients were 37.2% (16/43) vs. 20% (1/5) (P=0.016) and 138 days vs. 90 days (P=0.036), respectively. CONCLUSION: Besides KRAS, assessing BRAF mutation should also be required to select patients eligible for Cetuximab. Further prospective evaluation in large samples should be performed to confirm these preliminary findings.

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[814]

TÍTULO / TITLE:  - Glutathione S-transferase P1 and DNA Polymorphisms Influence Response to Chemotherapy and Prognosis of Bone Tumors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian Pac J Cancer Prev. 2012;13(11):5925-8.

AUTORES / AUTHORS:  - Yang LM; Li XH; Bao CF

INSTITUCIÓN / INSTITUTION:  - Department of Orthopaedics, The First Affiliated Hospital of Liaoning Medical College, Jinzhou, China E-mail : qiangwangw_2001@163.com.

RESUMEN / SUMMARY:  - Osteosarcoma is the most common primary bone malignancy in children and adolescents, and its clinical outcome is poor. We evaluated the influence of GSTP1, ERCC1 and ERCC2 polymorphisms on response to chemotherapy among osteosarcoma patients, and the significnace of these genes for prognosis. A total of 187 patients with osteosarcoma were administered methotrexate, cisplatin/adriamycin, actinomycin D, cyclophosphamide, or vincristine. GSTP1, ERCC1 and ERCC2 polymorphisms were genotyped by PCR-RFLP assay. The results showed the average survival time of 187 patients were 38.4 months. Some 97 patients showed response to neoadjuvant chemotherapy. The GSTP1 Val and ERCC2 A/A genotypes had significantly higher rates of response to chemotherapy, with adjusted OR (95% CI) of 2.19 (1.15-6.21) and 2.88 (1.14-13.3). Individuals with the ERCC2 A/A genotype were likely to have a lower risk of death from oseosarcoma, and the adjusted HR was 0.32 (0.13-0.95). Our study indicated that GSTP1 and ERCC2 Lys751Gln polymorphisms might be candidate pharmacogenomic factors to be explored in the future to identify osteosarcoma patients who might  benefit from chemotherapy.

 

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[815]

TÍTULO / TITLE:  - Tanshinone IIA inhibits the growth of pancreatic cancer BxPC3 cells by decreasing protein expression of TCTP, MCL1 and BclxL.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Med Report. 2013 Jan 25. doi: 10.3892/mmr.2013.1290.

            ●● Enlace al texto completo (gratuito o de pago) 3892/mmr.2013.1290

AUTORES / AUTHORS:  - Huang CY; Chiu TL; Kuo SJ; Chien SY; Chen DR; Su CC

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Changhua Christian Hospital, Changhua 50006, Taiwan, R.O.C.

RESUMEN / SUMMARY:  - Pancreatic cancer remains a challenging disease worldwide. Tanshinone IIA (TanIIA) is one of the active constituents of Danshen (Radix Salviae miltiorrhizae). TanIIA has been hypothesized to inhibit numerous human cancer cells by various molecular mechanisms. However, the efficacy and molecular mechanism of TanIIA action in pancreatic cancer has not been well studied. In the present study, the cytotoxicity of TanIIA in human pancreatic cancer BxPC3 cells  was evaluated by MTT assay. Cell cycle analysis of BxPC3 cells treated with TanIIA was performed by flow cytometry (FACS). Protein expression levels of TCTP, Mcl1, BclxL, Bax and Caspase3 in BxPC3 cells were measured by western blot analysis. The results revealed that TanIIA inhibited BxPC3 cells in a time and dosedependent manner. FACS analysis demonstrated that TanIIA increases the rate of subG1 phase. BxPC3 cells treated with TanIIA were identified to upregulate protein expression of Bax and Caspase3 and downregulate expression of TCTP, Mcl1  and BclxL. These results indicate that TanIIA may inhibit BxPC3 human pancreatic  cancer cells through the induction of apoptosis by decreasing protein expression  of TCTP, Mcl1 and BclxL and increasing Bax expression in vitro. The chemotherapeutic potential of TanIIA for human pancreatic cancer warrants further study.

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[816]

TÍTULO / TITLE:  - A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Cancer. 2013 Jan 15;13(1):20.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2407-13-20

AUTORES / AUTHORS:  - Connor JP; Cristea MC; Lewis NL; Lewis LD; Komarnitsky PB; Mattiacci MR; Felder M; Stewart S; Harter J; Henslee-Downey J; Kramer D; Neugebauer R; Stupp R

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Humanized KS-interleukin-2 (huKS-IL2), an immunocytokine with specificity for epithelial cell adhesion molecule (EpCAM), has demonstrated  favorable tolerability and immunologic activity as a single agent. METHODS: Phase 1b study in patients with EpCAM-positive advanced solid tumors to determine the maximum tolerated dose (MTD) and safety profile of huKS-IL2 in combination with low-dose cyclophosphamide. Treatment consisted of cyclophosphamide (300 mg/m2 on  day 1), and escalating doses of huKS-IL2 (0.5--4.0 mg/m2 IV continuous infusion over 4 hours) on days 2, 3, and 4 of each 21-day cycle. Safety, pharmacokinetic profile, immunogenicity, anti-tumor and biologic activity were evaluated. RESULTS: Twenty-seven patients were treated for up to 6 cycles; 26 were evaluable for response. The MTD of huKS-IL2 in combination with 300 mg/m2 cyclophosphamide  was 3.0 mg/m2. At higher doses, myelosuppression was dose-limiting. Transient lymphopenia was the most common grade ¾ adverse event (AE). Other significant AEs included hypotension, hypophosphatemia, and increase in serum creatinine. All patients recovered from these AEs. The huKS-IL2 exposure was dose-dependent, but  not dose-proportional, accumulation was negligible, and elimination half-life and systemic clearance were independent of dose and time. Most patients had a transient immune response to huKS-IL2. Immunologic activity was observed at all doses. Ten patients (38%) had stable disease as best response, lasting for >= 4 cycles in 3 patients. CONCLUSION: The combination of huKS-IL2 with low-dose cyclophosphamide was well tolerated. Although no objective responses were observed, the combination showed evidence of immunologic activity and 3 patients  showed stable disease for >= 4 cycles.Trial registration: NCT00132522.

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[817]

TÍTULO / TITLE:  - Efficacy of taxotere, thalidomide, and prednisolone in patients with hormone-resistant metastatic prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Urol J. 2012 Fall;9(4):673-7.

AUTORES / AUTHORS:  - Rezvani H; Haghighi S; Ghadyani M; Attarian H

INSTITUCIÓN / INSTITUTION:  - Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

RESUMEN / SUMMARY:  - PURPOSE: To evaluate the efficacy and safety of combination treatment with thalidomide and taxotere in patients with hormone-resistant prostate cancer. MATERIALS AND METHODS: This clinical trial was performed on 16 patients with hormone-resistant prostate cancer. RESULTS: Mean age of the participants was 72.7 +/- 5.39 years (range, 65 to 85 years). In 94% of patients who received the drug  combination, prostate-specific antigen level decreased more than 50%. The mean time to progression was 15 months and mean survival time was 23 months. This combination therapy had some adverse events. CONCLUSION: Addition of anti-angiogenic agents, such as thalidomide, can improve therapeutic outcome in this group of patients.

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[818]

TÍTULO / TITLE:  - BRCA1 mRNA Expression as a Predictive and Prognostic Marker in Advanced Esophageal Squamous Cell Carcinoma Treated with Cisplatin- or Docetaxel-Based Chemotherapy/Chemoradiotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e52589. doi: 10.1371/journal.pone.0052589. Epub 2013 Jan 9.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052589

AUTORES / AUTHORS:  - Gao Y; Zhu J; Zhang X; Wu Q; Jiang S; Liu Y; Hu Z; Liu B; Chen X

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Huai’an First People’s Hospital, Nanjing Medical  University, Huai’an, China.

RESUMEN / SUMMARY:  - BACKGROUND: The molecular backgrounds that determine therapeutic effectiveness in esophageal cancer remain largely unknown. Breast cancer susceptibility gene 1 (BRCA1) expression has been found to switch the response to cisplatin- or paclitaxel-based chemotherapy. It remains unclear how variations in BRCA1 expression influence clinical outcomes in esophageal cancer. PATIENTS AND METHODS: Quantitative real-time polymerase chain reaction (qPCR) was performed to examine BRCA1 mRNA expressions in paraffin-embedded specimens from 144 patients with advanced or metastatic esophageal squamous cell carcinoma who received cisplatin- or docetaxel-based first-line treatments. RESULTS: Low BRCA1 mRNA expression correlated with increased response rate (RR; P = 0.025 and 0.017, respectively) and median overall survival (mOS; P = 0.002 and P<0.001, respectively) in cisplatin-based chemotherapy or chemoradiotherapy group and also correlated with decreased RR (P = 0.017 and 0.024, respectively) and mOS (both P<0.001) in docetaxel-based chemotherapy or chemoradiotherapy group. Multivariate analysis revealed that low BRCA1 expression was an independent prognostic factor  in cisplatin-based chemotherapy (HR 0.29; 95%CI 0.12-0.71; P = 0.007) or chemoradiotherapy (HR 0.12; 95%CI 0.04-0.37; P<0.001) group and higher risk for mortality in docetaxel-based chemotherapy (HR 5.02; 95%CI 2.05-12.28; P<0.001) or chemoradiotherapy (HR 7.02; 95%CI 2.37-27.77; P<0.001) group. CONCLUSIONS: BRCA1  mRNA expression could be used as a predictive and prognostic marker in esophageal cancer who underwent first-line cisplatin- or docetaxel-based treatments.

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[819]

TÍTULO / TITLE:  - Inhibitor of apoptosis protein-like protein-2 as a novel serological biomarker for breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2012 Dec 7;13(12):16737-50. doi: 10.3390/ijms131216737.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms131216737

AUTORES / AUTHORS:  - Xiang M; Zhou W; Gao D; Fang X; Liu Q

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry & Molecular Biology, College of Medical Science, Jishou University, Jishou 416000, China. xmj688@163.com.

RESUMEN / SUMMARY:  - Inhibitor of apoptosis protein-like protein-2 (ILP-2) has only been detected in the testis and in lymphoblastoid cells. Although previous studies have not reported the presence of ILP-2 in breast cancer tissues, this study indicates the presence of ILP-2 in breast cancer serum samples. To validate whether ILP-2 is a  novel serological biomarker for breast cancer, we conducted two-dimensional gel electrophoresis (2DE) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry analysis on 400 breast cancer serum samples and 40 non-cancer serum samples (i.e., healthy controls). We then performed a Western blot analysis of 10 breast cancer serum samples and 10 non-cancer serum samples.  Finally, we analyzed 35 serum samples from healthy controls or subjects with breast cancer, other types of cancer, galactophore hyperplasia or breast cancer post-surgery by using 2DE and enzyme-linked immunosorbent assay. Our results indicate that ILP-2 is a novel breast cancer biomarker in the peripheral blood.

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[820]

TÍTULO / TITLE:  - The role of serum testosterone to prostate-specific antigen ratio as a predictor  of prostate cancer risk.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Kaohsiung J Med Sci. 2012 Dec;28(12):649-53. doi: 10.1016/j.kjms.2012.01.003. Epub 2012 Mar 31.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.kjms.2012.01.003

AUTORES / AUTHORS:  - Gurbuz C; Canat L; Atis G; Guner B; Caskurlu T

INSTITUCIÓN / INSTITUTION:  - Department of 2nd Urology, Istanbul Goztepe Training and Research Hospital, Istanbul, Turkey. gurbuzcenk@yahoo.com

RESUMEN / SUMMARY:  - We analyzed the ratio of serum total testosterone (sTT) to prostate-specific antigen (PSA) as a predictor of prostate cancer risk. One-hundred-four consecutive men with a normal digital rectal examination and a serum PSA level of 2.5-10 ng/ml underwent transrectal ultrasonography-guided biopsy using a 10-core  scheme. The sTT level was determined before the procedure using a chemiluminescent assay, and the ratio of sTT to PSA (sTT/PSA) was calculated after transforming sTT measurements from ng/dL to ng/mL. The overall cancer detection rate was 17.3%. The median sTT level was 332 ng/dl in men with cancer and 413 ng/dL in those without (p = 0.032). The median sTT/PSA ratio in these groups was 0.55 and 0.74, respectively (p = 0.035). The receiver operator characteristic (ROC) method was used to evaluate the properties of the sTT/PSA ratio, with testosterone and PSA as predictors of prostate cancer risk. The accuracy of the sTT/PSA ratio in prostate cancer diagnosis, represented by the area under the curve (AUC), was 0.739 (95% CI 0.640-0.823, p < 0.05). Optimizing  the sensitivity and specificity of the sTT/PSA ratio using the ROC provided a cutoff point of 0.60, which corresponded to 82% sensitivity and 62% specificity.  When the patients were divided into normal- and low-sTT level groups according to testosterone value (300 ng/dl), the probability of detecting prostate cancer was  3.3-fold higher in hypogonadal men as compared with eugonadal men. These results  support the use of the sTT-to-PSA ratio for predicting the risk of prostate cancer and increasing the specificity of PSA measurement.

 

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[821]

TÍTULO / TITLE:  - FLT3 Mutations in Early T-Cell Precursor ALL Characterize a Stem Cell Like Leukemia and Imply the Clinical Use of Tyrosine Kinase Inhibitors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e53190. doi: 10.1371/journal.pone.0053190. Epub 2013 Jan 24.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0053190

AUTORES / AUTHORS:  - Neumann M; Coskun E; Fransecky L; Mochmann LH; Bartram I; Farhadi Sartangi N; Heesch S; Gokbuget N; Schwartz S; Brandts C; Schlee C; Haas R; Duhrsen U; Griesshammer M; Dohner H; Ehninger G; Burmeister T; Blau O; Thiel E; Hoelzer D; Hofmann WK; Baldus CD

INSTITUCIÓN / INSTITUTION:  - Charite, University Hospital Berlin, Campus Benjamin Franklin, Department of Hematology and Oncology, Berlin, Germany.

RESUMEN / SUMMARY:  - Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has been identified as high-risk subgroup of acute T-lymphoblastic leukemia (T-ALL) with a high rate  of FLT3-mutations in adults. To unravel the underlying pathomechanisms and the clinical course we assessed molecular alterations and clinical characteristics in a large cohort of ETP-ALL (n = 68) in comparison to non-ETP T-ALL adult patients. Interestingly, we found a high rate of FLT3-mutations in ETP-ALL samples (n = 24, 35%). Furthermore, FLT3 mutated ETP-ALL was characterized by a specific immunophenotype (CD2+/CD5-/CD13+/CD33-), a distinct gene expression pattern (aberrant expression of IGFBP7, WT1, GATA3) and mutational status (absence of NOTCH1 mutations and a low frequency, 21%, of clonal TCR rearrangements). The observed low GATA3 expression and high WT1 expression in combination with lack of NOTCH1 mutations and a low rate of TCR rearrangements point to a leukemic transformation at the pluripotent prothymocyte stage in FLT3 mutated ETP-ALL. The clinical outcome in ETP-ALL patients was poor, but encouraging in those patients  with allogeneic stem cell transplantation (3-year OS: 74%). To further explore the efficacy of targeted therapies, we demonstrate that T-ALL cell lines transfected with FLT3 expression constructs were particularly sensitive to tyrosine kinase inhibitors. In conclusion, FLT3 mutated ETP-ALL defines a molecular distinct stem cell like leukemic subtype. These data warrant clinical studies with the implementation of FLT3 inhibitors in addition to early allogeneic stem cell transplantation for this high risk subgroup.

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[822]

TÍTULO / TITLE:  - Treatment of Breast and Lung Cancer Cells with a N-7 Benzyl Guanosine Monophosphate Tryptamine Phosphoramidate Pronucleotide (4Ei-1) Results in Chemosensitization to Gemcitabine and Induced eIF4E Proteasomal Degradation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Pharm. 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1021/mp300699d

AUTORES / AUTHORS:  - Li S; Jia Y; Jacobson BA; McCauley J; Kratzke R; Bitterman PB; Wagner CR

RESUMEN / SUMMARY:  - The development of cancer and fibrotic diseases has been shown to be highly dependent on disregulation of cap-dependent translation. Binding protein eIF4E to N7-methylated guanosine capped mRNA has been found to be the rate-limiting step governing translation initiation; and therefore represents an attractive target for drug discovery. Our group has found that 7-benzyl guanosine monophosphate (7Bn-GMP) is a potent antagonist of eIF4E cap binding (Kd = 0.8 uM). Recent X-ray crystallographic studies have revealed that the cap-dependent pocket undergoes a  unique structural change in order to accommodate the benzyl group. Unfortunately, 7Bn-GMP is not cell permeable. Recently, we have prepared a tryptamine phosphoramidate prodrug of 7Bn-GMP, 4ei1, and shown that it is a substrate for human histidine triad nucleotide binding protein (hHINT1) and is inhibit eIF4E initiated epithelial-mesenchymal transition (EMT) by Zebra fish embryo cells. To  assess the intracellular uptake of 4ei1 and conversion to 7Bn-GMP by cancer cells, we developed a sensitive assay using LC-ESI-MS/MS for the intracellular quantitation of 4ei1 and 7Bn-GMP. When incubated with the breast cancer cell line MDA-231; or lung cancer cell lines H460, H383 and H2009, 4ei1 was found to be rapidly internalized and converted to 7Bn-GMP. Since oncogenic mRNAs are predicted to have the highest eIF4E requirement for translation, we carried out chemosensitization studies with 4ei1. The prodrug was found to chemosensitize both breast and lung cancer cells to non-toxic levels of gemcitabine. Further mechanistic studies revealed that the expressed levels of eIF4E were substantially reduced in cells treated with 4ei1 in a dose dependent manner. The  levels of eI4E could be restored by treatment with the proteasome inhibitor MG-132. Taken together, our results demonstrate that 4ei1 is likely to inhibit translation initiation by eIF4E cap binding by both antagonizing eIF4E cap binding and initiating eIF4E proteasomal degradation.

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[823]

TÍTULO / TITLE:  - A Pan-BCL2 Inhibitor Renders Bone-Marrow-Resident Human Leukemia Stem Cells Sensitive to Tyrosine Kinase Inhibition.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Stem Cell. 2013 Jan 15. pii: S1934-5909(12)00716-3. doi: 10.1016/j.stem.2012.12.011.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.stem.2012.12.011

AUTORES / AUTHORS:  - Goff DJ; Recart AC; Sadarangani A; Chun HJ; Barrett CL; Krajewska M; Leu H; Low-Marchelli J; Ma W; Shih AY; Wei J; Zhai D; Geron I; Pu M; Bao L; Chuang R; Balaian L; Gotlib J; Minden M; Martinelli G; Rusert J; Dao KH; Shazand K; Wentworth P; Smith KM; Jamieson CA; Morris SR; Messer K; Goldstein LS; Hudson TJ; Marra M; Frazer KA; Pellecchia M; Reed JC; Jamieson CH

INSTITUCIÓN / INSTITUTION:  - Stem Cell Program, Department of Medicine, Moores Cancer Center, University of California San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.

RESUMEN / SUMMARY:  - Leukemia stem cells (LSCs) play a pivotal role in the resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors (TKIs) and its progression to blast crisis (BC), in part, through the alternative splicing of self-renewal and survival genes. To elucidate splice-isoform regulators of human BC LSC maintenance, we performed whole-transcriptome RNA sequencing, splice-isoform-specific quantitative RT-PCR (qRT-PCR), nanoproteomics, stromal coculture, and BC LSC xenotransplantation analyses. Cumulatively, these studies show that the alternative splicing of multiple prosurvival BCL2 family genes promotes malignant transformation of myeloid progenitors into BC LSCS that are quiescent in the marrow niche and that contribute to therapeutic resistance. Notably, sabutoclax, a pan-BCL2 inhibitor, renders marrow-niche-resident BC LSCs  sensitive to TKIs at doses that spare normal progenitors. These findings underscore the importance of alternative BCL2 family splice-isoform expression in BC LSC maintenance and suggest that the combinatorial inhibition of prosurvival BCL2 family proteins and BCR-ABL may eliminate dormant LSCs and obviate resistance.

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[824]

TÍTULO / TITLE:  - Elevated expression of the serine-arginine protein kinase 1 gene in ovarian cancer and its role in Cisplatin cytotoxicity in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51030. doi: 10.1371/journal.pone.0051030. Epub 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051030

AUTORES / AUTHORS:  - Odunsi K; Mhawech-Fauceglia P; Andrews C; Beck A; Amuwo O; Lele S; Black JD; Huang RY

INSTITUCIÓN / INSTITUTION:  - Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.

RESUMEN / SUMMARY:  - Alternatively spliced variants of several oncogenes and tumor suppressors have been shown to be important for their tumorigenicity. In the present study we have tested whether serine-arginine protein kinase 1 (SRPK1), a major regulator of splicing factors, is involved in ovarian cancer progression and plays a role in chemo-sensitivity. By Western blot analyses, SRPK1 protein was found to be overexpressed in 4 out of 6 ovarian cancer cell lines as compared with an immortalized ovarian surface epithelial cell line; and in 55% of ovarian tumor samples as compared with non-neoplastic ovarian tissue samples. Reduction of SRPK1 expression using small interfering RNA (siRNA) encoding small hairpin RNA in ovarian cancer cells led to (i) reduced cell proliferation rate, slower cell cycle progression and compromised anchorage-independent growth and migration ability in vitro, (ii) decreased level of phosphorylation of multiple serine-arginine proteins, and P44/42MAPK and AKT proteins, and (iii) enhanced sensitivity to cisplatin. Together, these results suggest that elevated SRPK1 expression may play a role in ovarian tumorigenesis and SRPK1 may be a potential  target for ovarian cancer therapy.

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[825]

TÍTULO / TITLE:  - Sulforaphane induces cell cycle arrest and apoptosis in acute lymphoblastic leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51251. doi: 10.1371/journal.pone.0051251. Epub 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051251

AUTORES / AUTHORS:  - Suppipat K; Park CS; Shen Y; Zhu X; Lacorazza HD

INSTITUCIÓN / INSTITUTION:  - Texas Children’s Cancer and Hematology Centers, Texas Children’s Hospital, Houston, Texas, United States of America.

RESUMEN / SUMMARY:  - Acute lymphoblastic leukemia (ALL) is the most common hematological cancer in children. Although risk-adaptive therapy, CNS-directed chemotherapy, and supportive care have improved the survival of ALL patients, disease relapse is still the leading cause of cancer-related death in children. Therefore, new drugs are needed as frontline treatments in high-risk disease and as salvage agents in  relapsed ALL. In this study, we report that purified sulforaphane, a natural isothiocyanate found in cruciferous vegetables, has anti-leukemic properties in a broad range of ALL cell lines and primary lymphoblasts from pediatric T-ALL and pre-B ALL patients. The treatment of ALL leukemic cells with sulforaphane resulted in dose-dependent apoptosis and G2/M cell cycle arrest, which was associated with the activation of caspases (3, 8, and 9), inactivation of PARP, p53-independent upregulation of p21(CIP1/WAF1), and inhibition of the Cdc2/Cyclin B1 complex. Interestingly, sulforaphane also inhibited the AKT and mTOR survival  pathways in most of the tested cell lines by lowering the levels of both total and phosphorylated proteins. Finally, the administration of sulforaphane to the ALL xenograft models resulted in a reduction of tumor burden, particularly following oral administration, suggesting a potential role as an adjunctive agent to improve the therapeutic response in high-risk ALL patients with activated AKT  signaling.

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[826]

TÍTULO / TITLE:  - Induction of Apoptosis by Costunolide in Bladder Cancer Cells is Mediated through ROS Generation and Mitochondrial Dysfunction.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Molecules. 2013 Jan 24;18(2):1418-33. doi: 10.3390/molecules18021418.

            ●● Enlace al texto completo (gratuito o de pago) 3390/molecules18021418

AUTORES / AUTHORS:  - Rasul A; Bao R; Malhi M; Zhao B; Tsuji I; Li J; Li X

INSTITUCIÓN / INSTITUTION:  - Dental Hospital, Jilin University, Changchun 130041, China. lijiang69@yahoo.com.cn.

RESUMEN / SUMMARY:  - Despite the availability of several therapeutic options, a safer and more effective modality is urgently needed for treatment of bladder cancer. Costunolide, a member of sesquiterpene lactone family, possesses potent anticancer properties. In this study, for the first time we investigated the effects of costunolide on the cell viability and apoptosis in human bladder cancer T24 cells. Treatment of T24 cells with costunolide resulted in a dose-dependent inhibition of cell viability and induction of apoptosis which was  associated with the generation of ROS and disruption of mitochondrial membrane potential (Deltapsim). These effects were significantly blocked when the cells were pretreated with N-acetyl- cysteine (NAC), a specific ROS inhibitor. Exposure of T24 cells to costunolide was also associated with increased expression of Bax, down-regulation of Bcl-2, survivin and significant activation of caspase-3, and its downstream target PARP. These findings provide the rationale for further in vivo and clinical investigation of costunolide against human bladder cancer.

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[827]

TÍTULO / TITLE:  - Integrated analysis of gene expression profiles associated with response of platinum/paclitaxel-based treatment in epithelial ovarian cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e52745. doi: 10.1371/journal.pone.0052745. Epub 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052745

AUTORES / AUTHORS:  - Han Y; Huang H; Xiao Z; Zhang W; Cao Y; Qu L; Shou C

INSTITUCIÓN / INSTITUTION:  - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, China.

RESUMEN / SUMMARY:  - PURPOSE: This study aims to explore gene expression signatures and serum biomarkers to predict intrinsic chemoresistance in epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Gene expression profiling data of 322 high-grade EOC cases between 2009 and 2010 in The Cancer Genome Atlas project (TCGA) were used to develop and validate gene expression signatures that could discriminate different responses to first-line platinum/paclitaxel-based treatments. A gene regulation network was then built to further identify hub genes responsible for differential gene expression between the complete response (CR) group and the progressive disease (PD) group. Further, to find more robust serum biomarkers for clinical application, we integrated our gene signatures and gene signatures reported previously to identify secretory protein-encoding genes by searching the DAVID database. In the end, gene-drug interaction network was constructed by searching Comparative Toxicogenomics Database (CTD) and literature. RESULTS: A 349-gene predictive model and an 18-gene model independent of key clinical features with high accuracy were developed for prediction of chemoresistance in EOC. Among them, ten important hub genes and six critical signaling pathways were identified to have important implications in chemotherapeutic response. Further,  ten potential serum biomarkers were identified for predicting chemoresistance in  EOC. Finally, we suggested some drugs for individualized treatment. CONCLUSION: We have developed the predictive models and serum biomarkers for platinum/paclitaxel response and established the new approach to discover potential serum biomarkers from gene expression profiles. The potential drugs that target hub genes are also suggested.

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[828]

TÍTULO / TITLE:  - Direct regulation of caspase3 by the transcription factor AP2alpha is involved in aspirininduced apoptosis in MDAMB453 breast cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Med Report. 2013 Jan 2. doi: 10.3892/mmr.2013.1257.

            ●● Enlace al texto completo (gratuito o de pago) 3892/mmr.2013.1257

AUTORES / AUTHORS:  - Yan F; He Q; Hu X; Li W; Wei K; Li L; Zhong Y; Ding X; Xiang S; Zhang J

INSTITUCIÓN / INSTITUTION:  - Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China,College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China.

RESUMEN / SUMMARY:  - Aspirin has been reported to trigger apoptosis in various cancer cell lines. However, the detailed mechanisms involved remain elusive. The present study aimed to investigate whether aspirin plays a role in apoptosis of MDA-MB-453 cells. The effect of aspirin on the proliferation of human MDA-MB-453 cells breast cancer cells was evaluated using MTT assay, flow cytometry and western blotting. The present study reports that aspirin induces the apoptosis of MDAMB453 breast cancer cells which was attributed to the increased expression and activation of caspase3. Moreover, AP2alpha, a transcription factor highly expressed in MDAMB453 cells, was identified as a negative regulator of caspase3 transcription and AP2alpha was attenuated following aspirin treatment. Therefore, aspirin may increase the expression of caspase3 by inducing the degradation of AP2alpha, which increases activated caspase3 expression, thereby triggering apoptosis in MDAMB453 cells. Thus, aspirin may be used in breast cancer therapy.

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[829]

TÍTULO / TITLE:  - Disrupting BCR-ABL in Combination with Secondary Leukemia-Specific Pathways in CML Cells Leads to Enhanced Apoptosis and Decreased Proliferation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Pharm. 2013 Jan 7;10(1):270-7. doi: 10.1021/mp300405n. Epub 2012 Dec 18.

            ●● Enlace al texto completo (gratuito o de pago) 1021/mp300405n

AUTORES / AUTHORS:  - Woessner DW; Lim CS

INSTITUCIÓN / INSTITUTION:  - Departments of daggerPharmacology and Toxicology, and double daggerPharmaceutics  and Pharmaceutical Chemistry, University of Utah College of Pharmacy , Salt Lake  City, Utah, United States.

RESUMEN / SUMMARY:  - Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by expression of the fusion gene BCR-ABL following a chromosomal translocation in the hematopoietic stem cell. Therapeutic management of CML uses tyrosine kinase inhibitors (TKIs), which block ABL-signaling and effectively kill peripheral cells with BCR-ABL. However, TKIs are not curative, and chronic use is required in order to treat CML. The primary failure for TKIs is through the development of a resistant population due to mutations in the TKI binding regions. This led us to develop the mutant coiled-coil, CC(mut2), an alternative method for BCR-ABL signaling inhibition by targeting the N-terminal oligomerization domain of BCR, necessary for ABL activation. In this article, we explore additional pathways that are important for leukemic stem cell survival in K562 cells. Using a candidate-based approach, we test the combination of CC(mut2) and inhibitors of unique secondary pathways in leukemic cells. Transformative potential was reduced following silencing of the leukemic stem cell factor Alox5 by RNA interference. Furthermore, blockade of the oncogenic protein MUC-1 by the novel peptide GO-201  yielded reductions in proliferation and increased cell death. Finally, we found that inhibiting macroautophagy using chloroquine in addition to blocking BCR-ABL  signaling with the CC(mut2) was most effective in limiting cell survival and proliferation. This study has elucidated possible combination therapies for CML using novel blockade of BCR-ABL and secondary leukemia-specific pathways.

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[830]

TÍTULO / TITLE:  - Role of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of esophageal carcinoma and the suggested mechanisms of action.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2013 Jan;5(1):19-24. Epub 2012 Oct 24.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.994

AUTORES / AUTHORS:  - Xu Y; Sheng L; Mao W

INSTITUCIÓN / INSTITUTION:  - Departments of Radiation Oncology and.

RESUMEN / SUMMARY:  - Cumulative evidence indicates that epidermal growth factor receptor (EGFR) is one of the most commonly altered genes in human cancer, via overexpression, amplification and mutation. Targeted inhibition of EGFR activity suppresses signal transduction pathways which control tumor cell growth, proliferation and resistance to apoptosis. Small molecule tyrosine kinase inhibitors (TKIs) are among the most common EGFR-targeting agents and have been used clinically to treat various malignancies. This review discusses the mechanism of action and clinical data that are relevant to the use of EGFR-TKIs in the treatment of esophageal carcinoma. The clinical and basic scientific experience of these agents thus far have implications for the future of therapeutic targeting of EGFR.

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[831]

TÍTULO / TITLE:  - A long-term survival case of liver epithelioid hemangioendothelioma with multiple lung metastases that regressed by long-term administration of interleukin-2.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Nihon Shokakibyo Gakkai Zasshi. 2012;109(12):2097-102.

AUTORES / AUTHORS:  - Otani K; Ishikawa T; Aizawa Y; Fujise K; Koyama T; Ohkusa T; Tajiri H

INSTITUCIÓN / INSTITUTION:  - Department of Emergency Medicine, Kashiwa Hospital, The Jikei University School of Medicine.

RESUMEN / SUMMARY:  - A patient was a 46-year-old man. Multiple lung tumors had been pointed out on a medical examination at age 24. He came to our hospital for further examination. Multiple liver and lung tumors were found out, and epithelioid hemangioendothelioma (EHE) derived from the liver was diagnosed by biopsy. At first we gave recombinant interleukin-2 (rIL-2) by intra-arterial and local injection and then continued it by intramuscular injection for 22 years as maintenance therapy. The tumors have regressed, with partial necrosis. EHE is a rare tumor, but we do not have a standard antitumor therapy except surgical resection. This case suggests that rIL-2 may become a new therapy for EHE. We think that the report of the long-term survival of a case of EHE in which rIL-2 treatment was effective is extremely valuable.

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[832]

TÍTULO / TITLE:  - Down-regulation of cellular FLICE-inhibitory protein (Long Form) contributes to apoptosis induced by Hsp90 inhibition in human lung cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Cell Int. 2012 Dec 21;12(1):54. doi: 10.1186/1475-2867-12-54.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1475-2867-12-54

AUTORES / AUTHORS:  - Wang Q; Sun W; Hao X; Li T; Su L; Liu X

INSTITUCIÓN / INSTITUTION:  - Key Laboratory for Experimental Teratology of the Ministry of Education and School of Life Sciences, Shandong University, Jinan, China. suling@sdu.edu.cn.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Cellular FLICE-Inhibitory Protein (long form, c-FLIPL) is a critical negative regulator of death receptor-mediated apoptosis. Overexpression  of c-FLIPL has been reported in many cancer cell lines and is associated with chemoresistance. In contrast, down-regulation of c-FLIP may drive cancer cells into cellular apoptosis. This study aims to demonstrate that inhibition of the heat shock protein 90 (Hsp90) either by inhibitors geldanamycin/17-N-Allylamino-17-demethoxygeldanamycin (GA/17-AAG) or siRNA technique in human lung cancer cells induces c-FLIPL degradation and cellular apoptosis through C-terminus of Hsp70-interacting protein (CHIP)-mediated mechanisms. METHODS: Calu-1 and H157 cell lines (including H157-c-FLIPL overexpressing c-FLIPL and control cell H157-lacZ) were treated with 17-AAG and the cell lysates were prepared to detect the given proteins by Western Blot and the cell survival was assayed by SRB assay. CHIP and Hsp90 alpha/beta proteins were knocked down by siRNA technique. CHIP and c-FLIPL plasmids were transfected  into cells and immunoprecipitation experiments were performed to testify the interactions between c-FLIPL, CHIP and Hsp90. RESULTS: c-FLIPL down-regulation induced by 17-AAG can be reversed with the proteasome inhibitor MG132, which suggested that c-FLIPL degradation is mediated by a ubiquitin-proteasome system.  Inhibition of Hsp90alpha/beta reduced c-FLIPL level, whereas knocking down CHIP expression with siRNA technique inhibited c-FLIPL degradation. Furthermore, c-FLIPL and CHIP were co-precipitated in the IP complexes. In addition, overexpression of c-FLIPL can rescue cancer cells from apoptosis. When 17-AAG was combined with an anti-cancer agent celecoxib(CCB), c-FLIPL level declined further and there was a higher degree of caspase activation. CONCLUSION: We have elucidated c-FLIPL degradation contributes to apoptosis induced by Hsp90 inhibition, suggesting c-FLIP and Hsp90 may be the promising combined targets in  human lung cancer treatment.

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[833]

TÍTULO / TITLE:  - MART-10, a New Generation of Vitamin D Analog, Is More Potent than 1alpha,25-Dihydroxyvitamin D(3) in Inhibiting Cell Proliferation and Inducing Apoptosis in ER+ MCF-7 Breast Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Evid Based Complement Alternat Med. 2012;2012:310872. doi: 10.1155/2012/310872. Epub 2012 Dec 11.

            ●● Enlace al texto completo (gratuito o de pago) 1155/2012/310872

AUTORES / AUTHORS:  - Chiang KC; Yeh CN; Chen SC; Shen SC; Hsu JT; Yeh TS; Pang JH; Su LJ; Takano M; Kittaka A; Juang HH; Chen TC

INSTITUCIÓN / INSTITUTION:  - General Surgery Department, Chang Gung Memorial Hospital, 222 Mai-Chin Road, Keelung 204, Taiwan ; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan.

RESUMEN / SUMMARY:  - Hormone antagonist therapy for estrogen receptor positive (ER+) breast cancer patients post radical surgery and radiation therapy has a poor prognosis and also causes bone loss. 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] is a potent antitumor agent in pre-clinical studies, but caused hypercalcemia when its effective antitumor doses were used. Therefore, we investigated the effects of a  less-calcemic 1alpha,25(OH)(2)D(3) analog, 19-nor-2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxyvitamin D(3 )(MART-10), on ER+MCF-7 cells. We demonstrate that MART-10 is 500- to 1000-fold more potent than 1alpha,25(OH)(2)D(3) in inhibiting cell growth in a dose- and time-dependent manner. MART-10 is also much more potent in arresting MCF-7cell cycle progression at G(0)/G(1) phase as compared to 1alpha,25(OH)(2)D(3), possibly mediated by a greater induction of p21 and p27 expression. Moreover, MART-10 is more active than 1alpha,25(OH)(2)D(3) in causing cell apoptosis, likely through a higher BAX/Bcl expression ratio and the subsequent cytochrome C release from mitochondria to cytosol. Based on our in vitro findings, MART-10 could be a promising vitamin D analog for the potential treatment of breast cancer, for example, ER+ patients, to decrease the tumor relapse rate and the side effect on  bone caused by antihormone regimens. Thus, further in vivo animal study is warranted.

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[834]

TÍTULO / TITLE:  - Deltonin induces apoptosis in MDAMB231 human breast cancer cells via reactive oxygen speciesmediated mitochondrial dysfunction and ERK/AKT signaling pathways.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Med Report. 2013 Jan 11. doi: 10.3892/mmr.2013.1273.

            ●● Enlace al texto completo (gratuito o de pago) 3892/mmr.2013.1273

AUTORES / AUTHORS:  - Zhang S; He Y; Tong Q; Chen Q; Wu X; Huang W

INSTITUCIÓN / INSTITUTION:  - Laboratory of Ethnopharmacology, Regenerative Medicine Research Center, Institute for Nanobiomedical Technology and Membrane Biology, West China Hospital/Medical School, Sichuan University, Sichuan 610041, P.R. China.

RESUMEN / SUMMARY:  - Deltonin, a steroidal saponin isolated from Dioscorea zingiberensis Wright, exhibits high cytotoxic activity in cancer cells. In the present study, the effects of deltonin on cell proliferation and apoptosis were evaluated in the MDAMB231 human breast carcinoma cell line. Following treatment with deltonin, the viability of MDAMB231 cells was analyzed using MTT assay and apoptosis, mitochondrial membrane potential (Psim) alternation and intracellular reactive oxygen species (ROS) generation was determined by flow cytometry. In addition, western blot analysis was performed to examine the expression of apoptosisassociated proteins. The results demonstrated that deltonin induced apoptosis in MDAMB231 cells in a time and concentrationdependent manner. Apoptosis was associated with depolarization of Psim and timedependent ROS generation. Deltonin treatment also resulted in Bax upregulation, Bcl-2 downregulation, activation of caspase3 and 8 and poly (ADP ribose) polymerase cleavage. Decreased levels of phosphorylated extracellular signalregulated kinase (ERK) and phosphorylated AKT were also observed. Results indicate that the proliferation inhibitory effect of deltonin is associated with its apoptosisinducing effect, which may correlate with ROSmediated mitochondrial dysfunction as well as activation of the ERK/AKT signaling pathways. Therefore, deltonin may be a potential chemotherapeutic agent for the treatment of breast cancer.

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[835]

TÍTULO / TITLE:  - Molecular markers in sex hormone pathway genes associated with the efficacy of androgen-deprivation therapy for prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e54627. doi: 10.1371/journal.pone.0054627. Epub 2013 Jan 24.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0054627

AUTORES / AUTHORS:  - Yu CC; Huang SP; Lee YC; Huang CY; Liu CC; Hour TC; Huang CN; You BJ; Chang TY; Huang CH; Bao BY

INSTITUCIÓN / INSTITUTION:  - Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital,  Kaohsiung, Taiwan ; Department of Pharmacy, Tajen University, Pingtung, Taiwan ;  School of Medicine, National Yang-Ming University, Taipei, Taiwan.

RESUMEN / SUMMARY:  - Although most advanced prostate cancer patients respond to androgen-deprivation therapy (ADT), the efficacy is widely variable. We investigated whether the host  genetic variations in sex hormone pathway genes are associated with the efficacy  of ADT. A cohort of 645 patients with advanced prostate cancer treated with ADT was genotyped for 18 polymorphisms across 12 key genes involved in androgen and estrogen metabolism. We found that after adjusting for known risk factors in multivariate Cox regression models, AKR1C3 rs12529 and AR-CAG repeat length remained significantly associated with prostate cancer-specific mortality (PCSM)  after ADT (P</=0.041). Furthermore, individuals carrying two unfavorable genotypes at these loci presented a 13.7-fold increased risk of PCSM compared with individuals carrying zero (P<0.001). Our results identify two candidate molecular markers in key genes of androgen and estrogen pathways associated with  PCSM after ADT, establishing the role of pharmacogenomics in this therapy.

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[836]

TÍTULO / TITLE:  - Salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis through DR5 and survivin-dependent mechanisms.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Death Dis. 2013 Jan 24;4:e471. doi: 10.1038/cddis.2012.200.

            ●● Enlace al texto completo (gratuito o de pago) 1038/cddis.2012.200

AUTORES / AUTHORS:  - Charette N; De Saeger C; Horsmans Y; Leclercq I; Starkel P

INSTITUCIÓN / INSTITUTION:  - Laboratory of Gastroenterology, Institut de Recherche Experimentale et Clinique,  Universite Catholique de Louvain, Brussels, Belgium.

RESUMEN / SUMMARY:  - Ras activation is a frequent event in human hepatocarcinoma that may contribute to resistance towards apoptosis. Salirasib is a ras and mTOR inhibitor that induces a pro-apoptotic phenotype in human hepatocarcinoma cell lines. In this work, we evaluate whether salirasib sensitizes those cells to TRAIL-induced apoptosis. Cell viability, cell death and apoptosis were evaluated in vitro in HepG2, Hep3B and Huh7 cells treated with DMSO, salirasib and YM155 (a survivin inhibitor), alone or in combination with recombinant TRAIL. Our results show that pretreatment with salirasib sensitized human hepatocarcinoma cell lines, but not  normal human hepatocytes, to TRAIL-induced apoptosis. Indeed, FACS analysis showed that 25 (Huh7) to 50 (HepG2 and Hep3B) percent of the cells treated with both drugs were apoptotic. This occurred through activation of the extrinsic and  the intrinsic pathways, as evidenced by a marked increase in caspase 3/7 (five to ninefold), caspase 8 (four to sevenfold) and caspase 9 (eight to 12-fold) activities in cells treated with salirasib and TRAIL compared with control. Survivin inhibition had an important role in this process and was sufficient to sensitize hepatocarcinoma cells to apoptosis. Furthermore, TRAIL-induced apoptosis in HCC cells pretreated with salirasib was dependent on activation of death receptor (DR) 5. In conclusion, salirasib sensitizes hepatocarcinoma cells  to TRAIL-induced apoptosis by a mechanism involving the DR5 receptor and survivin inhibition. These results in human hepatocarcinoma cell lines and primary hepatocytes provide a rationale for testing the combination of salirasib and TRAIL agonists in human hepatocarcinoma.

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[837]

TÍTULO / TITLE:  - Induction of apoptosis, G(0)/G(1) phase arrest and microtubule disassembly in K562 leukemia cells by Mere15, a novel polypeptide from Meretrix meretrix Linnaeus.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mar Drugs. 2012 Nov 21;10(11):2596-607. doi: 10.3390/md10112596.

            ●● Enlace al texto completo (gratuito o de pago) 3390/md10112596

AUTORES / AUTHORS:  - Liu M; Zhao X; Zhao J; Xiao L; Liu H; Wang C; Cheng L; Wu N; Lin X

INSTITUCIÓN / INSTITUTION:  - Institute of Oceanology, Chinese Academy of Science, 7 Nanhai Rd, Qingdao 266071, China.

RESUMEN / SUMMARY:  - Mere15 is a novel polypeptide from Meretrix meretrix Linnaeus with cytotoxicity in solid cancer cells. In this study, we investigated its activity on human K562  chronic myelogenous leukemia cells. Mere15 inhibited the growth of K562 cells with IC(5)(0) values of 38.2 mug/mL. Mere15 also caused concentration dependent induction of apoptosis, with overproduction of reactive oxygen species and loss of mitochondrial membrane potential. Moreover, Mere15 arrested cell cycle progression at G(0)/G(1) phase of K562 cells in a concentration dependent manner. In addition, Mere15 caused the disassembly of the microtubule cytoskeleton in K562 cells and inhibited the polymerization of tubulin in a cell free system via  interaction with tubulin. We concluded that Mere15 was cytotoxic to K562 leukemia cells and the cytotoxicity was related to the apoptosis induction, cell cycle arrest and microtubule disassembly. These results implied that Merer15 was a broad spectrum anticancer polypeptide, not only cytotoxic to various solid cancer cells but also to the chronic myelogenous leukemia cells. Mere15 may have therapeutic potential for the treatment of leukemia.

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[838]

TÍTULO / TITLE:  - Cytotoxicity, Antiproliferative Effects, and Apoptosis Induction of Methanolic Extract of Cynometra cauliflora Linn. Whole Fruit on Human Promyelocytic Leukemia HL-60 Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Evid Based Complement Alternat Med. 2012;2012:127373. doi: 10.1155/2012/127373. Epub 2012 Nov 4.

            ●● Enlace al texto completo (gratuito o de pago) 1155/2012/127373

AUTORES / AUTHORS:  - Tajudin TJ; Mat N; Siti-Aishah AB; Yusran AA; Alwi A; Ali AM

INSTITUCIÓN / INSTITUTION:  - Department of Biotechnology, Faculty of Agriculture and Biotechnology, Universiti Sultan Zainal Abidin, Gang Badak Campus, 21300 Kuala Terengganu, Terengganu, Malaysia.

RESUMEN / SUMMARY:  - Methanolic extract of Cynometra cauliflora whole fruit was assayed for cytotoxicity against the human promyelocytic leukemia HL-60 and the normal mouse  fibroblast NIH/3T3 cell lines by using the MTT assay. The CD(50) of the extract for 72 hours was 0.9 mug/mL whereas the value for the cytotoxic drug vincristine  was 0.2 mug/mL. The viability of the NIH/3T3 cells was at 80.0% when treated at 15.0 mug/mL. The extract inhibited HL-60 cell proliferation with dose dependence. AO/PI staining of HL-60 cells treated with the extract revealed that majority of  cells were in the apoptotic cell death mode. Flow cytometry analysis of HL-60 cells treated at CD(50) of the extract showed that the early apoptotic cells were 31.0, 26.3 and 19.9% at 24, 48, and 72 hours treatment, respectively. The percentage of late apoptotic cells was increased from 62.0 at 24 hours to 64.1 and 70.2 at 48 and 72 hours, respectively. Meanwhile, percent of necrotic cells were 4.9, 6.6, and 8.5 at 24, 48, and 72 hours, respectively. This study has shown that the methanolic extract of C. cauliflora whole fruit was cytotoxic towards HL-60 cells and induced the cells into apoptotic cell death mode, but less cytotoxic towards NIH/3T3 cells.

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[839]

TÍTULO / TITLE:  - Suppression of STAT5A and STAT5B chronic myeloid leukemia cells via siRNA and antisense-oligonucleotide applications with the induction of apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Blood Res. 2013;3(1):58-70. Epub 2013 Jan 17.

AUTORES / AUTHORS:  - Kaymaz BT; Selvi N; Gokbulut AA; Aktan C; Gunduz C; Saydam G; Sahin F; Cetintas VB; Baran Y; Kosova B

INSTITUCIÓN / INSTITUTION:  - Ege University, Faculty of Medicine, Department of Medical Biology Bornova, Izmir, Turkey.

RESUMEN / SUMMARY:  - Signal transducers and activators of transcription (STAT) proteins function in the JAK/STAT signaling pathway and are activated by phosphorylation. As a result  of this signaling event, they affect many cellular processes including cell growth, proliferation, differentiation, and survival. Increases in the expressions of STAT5A and STAT5B play a remarkable role in the development of leukemia in which leukemic cells gain uncontrolled proliferation and angiogenesis ability. At the same time, these cells acquire ability to escape from apoptosis and host immune system. In this study, we aimed to suppress STAT-5A and -5B genes in K562 CML cells by siRNA transfection and antisense oligonucleotides (ODN) targeting and then to evaluate apoptosis rate. Finally, we compared the transfection efficiencies of these approaches. Quantitative RT-PCR and Western blot results indicated that STAT expressions were downregulated at both mRNA and  protein levels following siRNA transfection. However, electroporation mediated ODN transfection could only provide limited suppression rates at mRNA and protein levels. Moreover, it was displayed that apoptosis were significantly induced in siRNA treated leukemic cells as compared to ODN treated cells. As a conclusion, siRNA applications were found to be more effective in terms of gene silencing when compared to ODN treatment based on the higher apoptosis and mRNA suppression rates. siRNA application could be a new and alternative curative method as a supporting therapy in CML patients.

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[840]

TÍTULO / TITLE:  - Mycophenolic Acid overcomes imatinib and nilotinib resistance of chronic myeloid  leukemia cells by apoptosis or a senescent-like cell cycle arrest.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Res Treatment. 2012;2012:861301. doi: 10.1155/2012/861301. Epub 2012 Feb 23.

            ●● Enlace al texto completo (gratuito o de pago) 1155/2012/861301

AUTORES / AUTHORS:  - Drullion C; Lagarde V; Gioia R; Legembre P; Priault M; Cardinaud B; Lippert E; Mahon FX; Pasquet JM

INSTITUCIÓN / INSTITUTION:  - Laboratoire Hematopoiese Leucemique et Cibles Therapeutiques, INSERM U1035, Universite Bordeaux Segalen, 146 Rue Leo Saignat Bat TP 4e etage, 33076 Bordeaux, France.

RESUMEN / SUMMARY:  - We used K562 cells sensitive or generated resistant to imatinib or nilotinib to investigate their response to mycophenolic acid (MPA). MPA induced DNA damage leading to cell death with a minor contribution of apoptosis, as revealed by annexin V labeling (up to 25%). In contrast, cell cycle arrest and positive staining for senescence-associated beta-galactosidase activity were detected for  a large cell population (80%). MPA-induced cell death was potentialized by the inhibition of autophagy and this is associated to the upregulation of apoptosis.  In contrast, senescence was neither decreased nor abrogated in autophagy deficient K562 cells. Primary CD34 cells from CML patients sensitive or resistant to imatinib or nilotinib respond to MPA although apoptosis is mainly detected. These results show that MPA is an interesting tool to overcome resistance in vitro and in vivo mainly in the evolved phase of the disease.

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[841]

TÍTULO / TITLE:  - Long CAG Repeat Sequence and Protein Expression of Androgen Receptor Considered as Prognostic Indicators in Male Breast Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e52271. doi: 10.1371/journal.pone.0052271. Epub 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052271

AUTORES / AUTHORS:  - Song YN; Geng JS; Liu T; Zhong ZB; Liu Y; Xia BS; Ji HF; Li XM; Zhang GQ; Ren YL; Li ZG; Pang D

INSTITUCIÓN / INSTITUTION:  - Department of Breast Surgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, China.

RESUMEN / SUMMARY:  - BACKGROUND: The androgen receptor (AR) expression and the CAG repeat length within the AR gene appear to be involved in the carcinogenesis of male breast carcinoma (MBC). Although phenotypic differences have been observed between MBC and normal control group in AR gene, there is lack of correlation analysis between AR expression and CAG repeat length in MBC. The purpose of the study was  to investigate the prognostic value of CAG repeat lengths and AR protein expression. METHODS: 81 tumor tissues were used for immunostaining for AR expression and CAG repeat length determination and 80 normal controls were analyzed with CAG repeat length in AR gene. The CAG repeat length and AR expression were analyzed in relation to clinicopathological factors and prognostic indicators. RESULTS: AR gene in many MBCs has long CAG repeat sequence compared with that in control group (P = 0.001) and controls are more likely to exhibit short CAG repeat sequence than MBCs. There was statistically significant  difference in long CAG repeat sequence between AR status for MBC patients (P = 0.004). The presence of long CAG repeat sequence and AR-positive expression were  associated with shorter survival of MBC patients (CAG repeat: P = 0.050 for 5y-OS; P = 0.035 for 5y-DFS AR status: P = 0.048 for 5y-OS; P = 0.029 for 5y-DFS, respectively). CONCLUSION: The CAG repeat length within the AR gene might be one  useful molecular biomarker to identify males at increased risk of breast cancer development. The presence of long CAG repeat sequence and AR protein expression were in relation to survival of MBC patients. The CAG repeat length and AR expression were two independent prognostic indicators in MBC patients.

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[842]

TÍTULO / TITLE:  - Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Zhejiang Univ Sci B. 2013 Jan;14(1):8-24. doi: 10.1631/jzus.B1200189.

            ●● Enlace al texto completo (gratuito o de pago) 1631/jzus.B1200189

AUTORES / AUTHORS:  - Fu Q; He C; Mao ZR

INSTITUCIÓN / INSTITUTION:  - Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou 310058, China.

RESUMEN / SUMMARY:  - Epstein-Barr virus (EBV), a human gammaherpesvirus carried by more than 90% of the world’s population, is associated with malignant tumors such as Burkitt’s lymphoma (BL), Hodgkin lymphoma, post-transplant lymphoma, extra-nodal natural killer/T cell lymphoma, and nasopharyngeal and gastric carcinomas in immune-compromised patients. In the process of infection, EBV faces challenges: the host cell environment is harsh, and the survival and apoptosis of host cells  are precisely regulated. Only when host cells receive sufficient survival signals may they immortalize. To establish efficiently a lytic or long-term latent infection, EBV must escape the host cell immunologic mechanism and resist host cell apoptosis by interfering with multiple signaling pathways. This review details the apoptotic pathway disrupted by EBV in EBV-infected cells and describes the interactions of EBV gene products with host cellular factors as well as the function of these factors, which decide the fate of the host cell. The relationships between other EBV-encoded genes and proteins of the B-cell leukemia/lymphoma (Bcl) family are unknown. Still, EBV seems to contribute to establishing its own latency and the formation of tumors by modifying events that impact cell survival and proliferation as well as the immune response of the infected host. We discuss potential therapeutic drugs to provide a foundation for further studies of tumor pathogenesis aimed at exploiting novel therapeutic strategies for EBV-associated diseases.

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[843]

TÍTULO / TITLE:  - Effect of TSLC1 gene on growth and apoptosis in human esophageal carcinoma Eca109 cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Arch Med Sci. 2012 Dec 20;8(6):987-92. doi: 10.5114/aoms.2012.31251. Epub 2012 Oct 16.

            ●● Enlace al texto completo (gratuito o de pago) 5114/aoms.2012.31251

AUTORES / AUTHORS:  - Liang QL; Wang BR; Li ZY; Chen GQ; Zhou Y

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Affiliated Hospital, Guangdong Medical College, Zhanjiang, China.

RESUMEN / SUMMARY:  - INTRODUCTION: To explore the effect of tumor suppressor in lung cancer 1 (TSLC1)  on proliferation and apoptosis in esophageal cancer Eca109 cells. MATERIAL AND METHODS: Eca109 cells were divided into three groups: TSLC1 transfected group (TTG), mock group (MG) and untransfected group (UTG). The TTG and MG were transfected transiently with the pIRES2-EGFP-TSLC1 eukaryotic expression vector and pIRES2-EGFP vector respectively. The UTG was a blank control. The TSLC1 expression in TTG was analyzed with the fluorogram and RT-PCR method. Cell proliferation was measured with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT) assay. Cell cycle  was measured by flow cytometry (FCM). Cell apoptosis was detected by Annexin-V/PI double staining FCM. RESULTS: Green color was found in TTG and MG. The band of TSLC1 mRNA of TTG was located at about 1400 bp by RT-PCR and agarose gel electrophoresis assay. The TSLC1 inhibited cell proliferation significantly in MTT assay, and the cell proliferation was slower in TTG than MG and UTG. After TSLC1 transfection, cell numbers increased in G0/G1 phase and decreased in S phase. Forty-eight hours after transfection, the apoptosis rate and death rate of TTG were higher than MG and UTG. Thus TSLC1 induced Eca109 cells to apoptosis. CONCLUSIONS: The TSLC1 gene had a potent effect on cell proliferation inhibition, G1/S cell cycle arrest and induction of cell apoptosis in Eca109 cells.

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[844]

TÍTULO / TITLE:  - Functional polymorphisms in xenobiotic metabolizing enzymes and their impact on the therapy of breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Front Genet. 2012;3:329. doi: 10.3389/fgene.2012.00329. Epub 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 3389/fgene.2012.00329

AUTORES / AUTHORS:  - Vianna-Jorge R; Festa-Vasconcellos JS; Goulart-Citrangulo SM; Leite MS

INSTITUCIÓN / INSTITUTION:  - Programa de Farmacologia, Coordenacao de Pesquisa, Instituto Nacional do Cancer Rio de Janeiro, Brazil ; Instituto de Ciencias Biomedicas, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil.

RESUMEN / SUMMARY:  - Breast cancer is the top cancer among women, and its incidence is increasing worldwide. Although the mortality tends to decrease due to early detection and treatment, there is great variability in the rates of clinical response and survival, which makes breast cancer one of the most appealing targets for pharmacogenomic studies. The recognition that functional CYP2D6 polymorphisms affect tamoxifen pharmacokinetics has motivated the attempts of using CYP2D6 genotyping for predicting breast cancer outcomes. In addition to tamoxifen, the chemotherapy of breast cancer includes combinations of cytotoxic drugs, which are substrates for various xenobiotic metabolizing enzymes. Because of these drugs’ narrow therapeutic window, it has been postulated that impaired biotransformation could lead to increased toxicity. In the present review, we performed a systematic search of all published data exploring associations between polymorphisms in xenobiotic metabolizing enzymes and clinical outcomes of breast  cancer. We retrieved 43 original articles involving either tamoxifen or other chemotherapeutic protocols, and compiled all information regarding response or toxicity. The data indicate that, although CYP2D6 polymorphisms can indeed modify tamoxifen pharmacokinetics, CYP2D6 genotyping alone is not enough for predicting  breast cancer outcomes. The studies involving other chemotherapeutic protocols explored a great diversity of pharmacogenetic targets, but the number of studies  for each functional polymorphism is still very limited, with usually no confirmation of positive associations. In conclusion, the application of pharmacogenetics to predict breast cancer outcomes and to select one individual’s chemotherapeutic protocol is still far from clinical routine. Although some very  interesting results have been produced, no clear practical recommendations are recognized yet.

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[845]

TÍTULO / TITLE:  - Use of a urine anastrozole assay to determine treatment discontinuation among women with hormone-sensitive breast cancer: a pilot study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Oncol Pract. 2012 Sep;8(5):e100-4. doi: 10.1200/JOP.2011.000487. Epub 2012 Jun  26.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JOP.2011.000487

AUTORES / AUTHORS:  - Clarke Hillyer G; Neugut AI; Crew KD; Kalinsky K; Maurer MA; Rotsides DZ; Danaceau J; Hershman DL

INSTITUCIÓN / INSTITUTION:  - Columbia University, New York, NY; and Sports Medicine Research and Testing Laboratory, Salt Lake City, UT.

RESUMEN / SUMMARY:  - PURPOSE: Multiple studies have shown that adherence to adjuvant hormonal therapy  in women with breast cancer is suboptimal. Measurements of compliance with self-report, pill counts, and/or pharmacy records are susceptible to bias. We assessed the feasibility of using a urine anastrozole assay as an objective biomarker of nonadherence to anastrozole treatment. PATIENTS AND METHODS: We recruited consecutive postmenopausal women, age >/= 18 years, with hormone-sensitive nonmetastatic breast cancer who were prescribed anastrozole at  least 3 months before enrollment. Each completed a short survey to gather information on demographics, anastrozole compliance history, and self-reported medication history, tumor characteristics, and treatment received. A single, random 15-mL urine sample was collected and tested for the presence of anastrozole using a previously validated assay. Patients were told they were part of a study to determine if anastrozole could be detected in the urine. RESULTS: Among 96 participants, mean age was 63.7 years (range, 51 to 70 years). The population was diverse, with 56.5% white, 57.6% US born, 59.8% unemployed, and 56.6% college educated. Prior treatment included chemotherapy (50%) and/or radiotherapy (58.7%). Mean duration of anastrozole treatment was 2.2 years (standard deviation, 1.6). Four participants reported nonadherence and declined to submit urine samples, and two had no detectable level of anastrozole (six of 96; 6.3%). Detectable levels among adherent women ranged from 49.3 to 632.8 ng/mL. CONCLUSION: We demonstrated that collection of urine to measure anastrozole levels is feasible and reliable. Identifying biomarkers to measure adherence is critical for studies investigating interventions to improve hormonal therapy compliance.

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[846]

TÍTULO / TITLE:  - The mTORC1 Inhibitor Everolimus Prevents and Treats Emu-Myc Lymphoma by Restoring Oncogene-Induced Senescence.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Discov. 2013 Jan;3(1):82-95. Epub 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 1158/2159-8290.CD-12-0404

AUTORES / AUTHORS:  - Wall M; Poortinga G; Stanley KL; Lindemann RK; Bots M; Chan CJ; Bywater MJ; Kinross KM; Astle MV; Waldeck K; Hannan KM; Shortt J; Smyth MJ; Lowe SW; Hannan RD; Pearson RB; Johnstone RW; McArthur GA

INSTITUCIÓN / INSTITUTION:  - 1Divisions of Research and 2Cancer Medicine, Peter MacCallum Cancer Centre, East  Melbourne, Victoria; 3Department of Medicine and 4Victorian Cancer Cytogenetics Service, St. Vincent’s Hospital, University of Melbourne, Fitzroy, Victoria; 5Departments of Biochemistry and Molecular Biology and 6Pathology and 7Sir Peter  MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria; 8Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, and 9Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Prahran, Victoria; and 10School of Biomedical Sciences, The University of Queensland, Queensland, Australia; 11Cold Spring Harbor Laboratory, Cold Spring Harbor; 12Howard Hughes Medical Institute, Cold Spring Harbor, New York; and 13Merck Serono TA Oncology, Merck KGaA, Darmstadt, Germany.

RESUMEN / SUMMARY:  - MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in Emu-Myc mice occur in almost all cases of Burkitt lymphoma as well as  in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of Emu-Myc lymphoma. Everolimus selectively cleared premalignant  B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established Emu-Myc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes.

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[847]

TÍTULO / TITLE:  - Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Med. 2012 Dec 11;10:161. doi: 10.1186/1741-7015-10-161.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1741-7015-10-161

AUTORES / AUTHORS:  - Brana I; Siu LL

INSTITUCIÓN / INSTITUTION:  - Drug Development Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada. Lillian.Siu@uhn.ca.

RESUMEN / SUMMARY:  - ABSTRACT: The phosphatidylinositol 3-kinase (PI3K) pathway is commonly deregulated in cancer. In recent years, the results of the first phase I clinical trials with PI3K inhibitors have become available. In comparison to other targeted agents such v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors in melanoma or crizotinib in anaplastic lymphoma receptor tyrosine kinase (ALK) translocated tumors, the number of objective responses to PI3K inhibitors is less dramatic. In this review we propose possible strategies to optimize the clinical development of PI3K inhibitors: by exploring the potential  role of PI3K isoform-specific inhibitors in improving the therapeutic index, molecular characterization as a basis for patient selection, and the relevance of performing serial tumor biopsies to understand the associated mechanisms of drug  resistance. The main focus of this review will be on PI3K isoform-specific inhibitors by describing the functions of different PI3K isoforms, the preclinical activity of selective PI3K isoform-specific inhibitors and the early  clinical data of these compounds.

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[848]

TÍTULO / TITLE:  - Sphingosine 1-phosphate receptors and sphingosine kinase 1: novel biomarkers for  clinical prognosis in breast, prostate, and hematological cancers.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Front Oncol. 2012;2:168. doi: 10.3389/fonc.2012.00168. Epub 2012 Dec 3.

            ●● Enlace al texto completo (gratuito o de pago) 3389/fonc.2012.00168

AUTORES / AUTHORS:  - Pyne S; Edwards J; Ohotski J; Pyne NJ

INSTITUCIÓN / INSTITUTION:  - Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde Glasgow, UK.

RESUMEN / SUMMARY:  - There is substantial evidence for a role in cancer of the bioactive lipid sphingosine 1-phosphate (S1P), the enzyme sphingosine kinase 1 (that catalyses S1P formation) and S1P-specific G protein-coupled receptors. This perspective highlights recent findings demonstrating that sphingosine kinase 1 and S1P receptors are new important biomarkers for detection of early cancer and progression to aggressive cancer. The impact of the sub-cellular distribution of  S1P metabolizing enzymes and S1P receptors and their spatial functional interaction with oncogenes is considered with respect to prognostic outcome. These findings suggest that S1P, in addition to being a biomarker of clinical prognosis, might also be a new therapeutic target for intervention in cancer.

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[849]

TÍTULO / TITLE:  - Her-2/neu expression is a negative prognosticator in ovarian cancer cases that do not express the follicle stimulating hormone receptor (FSHR).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Ovarian Res. 2013 Jan 22;6(1):6. doi: 10.1186/1757-2215-6-6.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1757-2215-6-6

AUTORES / AUTHORS:  - Heublein S; Vrekoussis T; Mayr D; Friese K; Lenhard M; Jeschke U; Dian D

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynaecology - Campus Innenstadt, Ludwig-Maximilians-University of Munich, Maistrasse 11, 80337, Munich, Germany. udo.jeschke@med.uni-muenchen.de.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Anti-Her-2 treatment is successfully administered to Her-2  overexpressing breast cancer patients and significantly implicates upon their survival. Building on these promising results, anti-Her-2 treatment protocols were tested as an option for epithelial ovarian cancer (EOC) as well. However Her-2 signalling is known to be modulated by G-protein coupled receptors (GPCR).  Since a common GPCR in ovarian cancer is the FSH receptor (FSHR), we investigated the prognostic significance of Her-2 in patients that had been stratified according to their FSHR status. FINDINGS: A total number of 153 EOC patients were included in this study. Her-2 positivity was assessed using a standard protocol.  Intriguingly Her-2 turned out to be an independent prognostic marker for poor overall survival only in those patients that did not express FSHR. This did neither apply for the whole panel nor in case of FSHR co-expression. CONCLUSIONS: We thus conclude that Her-2 can be a negative prognosticator only in FSHR negative EOC cases. Hence by stratifying EOC patients according to their FSHR expression status, we introduce a diagnostic protocol to effectively select EOC patients that would most probably respond to anti-Her-2 treatment. This observation could be of clinical importance in terms of selecting the patient that would most likely benefit from anti-Her-2 treatment.

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[850]

TÍTULO / TITLE:  - Cell survival and apoptosis signaling as therapeutic target for cancer: marine bioactive compounds.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2013 Jan 24;14(2):2334-54. doi: 10.3390/ijms14022334.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms14022334

AUTORES / AUTHORS:  - Kalimuthu S; Se-Kwon K

INSTITUCIÓN / INSTITUTION:  - Marine Bioprocess Research Center, Department of Chemistry, Pukyong National University, Busan 608-737, Korea. sknkim@pknu.ac.kr.

RESUMEN / SUMMARY:  - Inhibition of apoptosis leads to activation of cell survival factors (e.g., AKT)  causes continuous cell proliferation in cancer. Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. A number of discoveries have clarified the molecular mechanism of apoptosis, thus clarifying the link between apoptosis and cell survival factors, which has a therapeutic outcome. Induction of apoptosis and inhibition of cell survival by anticancer agents has been shown to correlate with tumor response. Cellular damage induces growth arrest and tumor suppression by inducing apoptosis, necrosis and senescence; the  mechanism of cell death depends on the magnitude of DNA damage following exposure to various anticancer agents. Apoptosis is mainly regulated by cell survival and  proliferating signaling molecules. As a new therapeutic strategy, alternative types of cell death might be exploited to control and eradicate cancer cells. This review discusses the signaling of apoptosis and cell survival, as well as the potential contribution of marine bioactive compounds, suggesting that new therapeutic strategies might follow.

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[851]

TÍTULO / TITLE:  - Overexpression of SERBP1 (Plasminogen activator inhibitor 1 RNA binding protein)  in human breast cancer is correlated with favourable prognosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Cancer. 2012 Dec 13;12:597. doi: 10.1186/1471-2407-12-597.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2407-12-597

AUTORES / AUTHORS:  - Serce NB; Boesl A; Klaman I; von Serenyi S; Noetzel E; Press MF; Dimmler A; Hartmann A; Sehouli J; Knuechel R; Beckmann MW; Fasching PA; Dahl E

INSTITUCIÓN / INSTITUTION:  - Molecular Oncology Group, Institute of Pathology, University Hospital of the RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. edahl@ukaachen.de.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Plasminogen activator inhibitor 1 (PAI-1) overexpression is an important prognostic and predictive biomarker in human breast cancer. SERBP1,  a protein that is supposed to regulate the stability of PAI-1 mRNA, may play a role in gynaecological cancers as well, since upregulation of SERBP1 was described in ovarian cancer recently. This is the first study to present a systematic characterisation of SERBP1 expression in human breast cancer and normal breast tissue at both the mRNA and the protein level. METHODS: Using semiquantitative realtime PCR we analysed SERBP1 expression in different normal human tissues (n = 25), and in matched pairs of normal (n = 7) and cancerous breast tissues (n = 7). SERBP1 protein expression was analysed in two independent cohorts on tissue microarrays (TMAs), an initial evaluation set, consisting of 193 breast carcinomas and 48 normal breast tissues, and a second large validation set, consisting of 605 breast carcinomas. In addition, a collection of benign (n  = 2) and malignant (n = 6) mammary cell lines as well as breast carcinoma lysates (n = 16) were investigated for SERBP1 expression by Western blot analysis. Furthermore, applying non-radioisotopic in situ hybridisation a subset of normal  (n = 10) and cancerous (n = 10) breast tissue specimens from the initial TMA were analysed for SERBP1 mRNA expression. RESULTS: SERBP1 is not differentially expressed in breast carcinoma compared to normal breast tissue, both at the RNA and protein level. However, recurrence-free survival analysis showed a significant correlation (P = 0.008) between abundant SERBP1 expression in breast  carcinoma and favourable prognosis. Interestingly, overall survival analysis also displayed a tendency (P = 0.09) towards favourable prognosis when SERBP1 was overexpressed in breast cancer. CONCLUSIONS: The RNA-binding protein SERBP1 is abundantly expressed in human breast cancer and may represent a novel breast tumour marker with prognostic significance. Its potential involvement in the plasminogen activator protease cascade warrants further investigation.

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[852]

TÍTULO / TITLE:  - Anacardic acid (6-pentadecylsalicylic acid) induces apoptosis of prostate cancer  cells through inhibition of androgen receptor and activation of p53 signaling.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Cancer Res. 2012 Dec;24(4):275-83. doi: 10.3978/j.issn.1000-9604.2012.10.07.

            ●● Enlace al texto completo (gratuito o de pago) 3978/j.issn.1000-9604.2012.10.07

AUTORES / AUTHORS:  - Tan J; Chen B; He L; Tang Y; Jiang Z; Yin G; Wang J; Jiang X

INSTITUCIÓN / INSTITUTION:  - Department of Urology, the third Xiangya Hospital of Xiangya Medical College, Central South University, Changsha 410013, China.

RESUMEN / SUMMARY:  - Anacardic acid (AA) is a mixture of 2-hydroxy-6-alkylbenzoic acid homologs. It is widely regarded as a non-specific histone acetyltransferase inhibitor of p300. The effects and the mechanisms of AA in LNCaP cells (prostate cancer cells) remain unknown. To investigate the effect of AA on LNCaP cells, we had carried out several experiments and found that AA inhibits LNCaP cell proliferation, induces G1/S cell cycle arrest and apoptosis of LNCaP cell. The mechanisms via which AA acts on LNCaP cells may be due to the following aspects. First, AA can regulate p300 transcription and protein level except for its mechanisms regulating function of p300 through post-translational modification in LNCaP cells. Second, AA can activate p53 through increasing the phosphorylation of p53  on Ser15 in LNCaP cells. AA can selectively activate p21 (target genes of p53). Third, AA can down-regulates androgen receptor (AR) through supressing p300. Our  study suggests that AA has multiple anti-tumor activities in LNCaP cells and warrants further investigation.

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[853]

TÍTULO / TITLE:  - Apoptosis of breast cancer cells induced by hypocrellin B under light-emitting diode irradiation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Photodiagnosis Photodyn Ther. 2012 Dec;9(4):337-43. doi: 10.1016/j.pdpdt.2012.03.009. Epub 2012 May 29.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.pdpdt.2012.03.009

AUTORES / AUTHORS:  - Jiang Y; Xia X; Leung AW; Xiang J; Xu C

INSTITUCIÓN / INSTITUTION:  - Department of Photodynamic and Sonodynamic Therapy, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.

RESUMEN / SUMMARY:  - OBJECTIVES: Breast cancer is a common disease which threatens the life of women.  To explore an alternative modality for combating breast cancer, a light-emitting  diode (LED) that activates hypocrellin B was used in the present study to investigate apoptosis induction in breast cancer MDA-MB-231 cells. MATERIALS AND  METHODS: Photocytotoxicity was investigated 24h after photodynamic treatment of hypocrellin B using MTT reduction assay and light microscopy. Apoptosis was observed 6h after photodynamic treatment using flow cytometry with Annexin V/PI staining as well as fluorescent microscopy with Hoechst33258 staining. The ultrastructure of the treated cells was observed using transmission electron microscopy (TEM). RESULTS: Hypocrellin B-induced photocytotoxicity in MDA-MB-231  cells exhibited a dose-dependent manner. The amount of MDA-MB-231 cells attached  to the bottom of well decreased significantly after photodynamic treatment of hypocrellin B. Flow cytometry showed that the early and late apoptotic rate of MDA-MB-231 cells increased remarkably up to 17.46% and 32.80%, respectively, after treatment of LED-activated hypocrellin B. In addition, nuclear condensation, fragmentation and chromatin margination, and topical apoptotic body in the treated cells were observed by nuclear staining and TEM. CONCLUSION: Photodynamic action of hypocrellin B irradiated by light-emitting diodes could significantly kill breast cancer cells and induce apoptotic cell death, which suggests LED-activated hypocrellin B is a promising strategy for combating breast cancer.

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[854]

TÍTULO / TITLE:  - Survivin selective inhibitor YM155 induce apoptosis in SK-NEP-1 Wilms tumor cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Cancer. 2012 Dec 26;12:619. doi: 10.1186/1471-2407-12-619.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2407-12-619

AUTORES / AUTHORS:  - Tao YF; Lu J; Du XJ; Sun LC; Zhao X; Peng L; Cao L; Xiao PF; Pang L; Wu D; Wang N; Feng X; Li YH; Ni J; Wang J; Pan J

INSTITUCIÓN / INSTITUTION:  - Department of Hematology and Oncology, Children’s Hospital of Soochow University, Suzhou, China. wj196312@vip.163.com.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Survivin, a member of the family of inhibitor of apoptosis  proteins, functions as a key regulator of mitosis and programmed cell death. YM155, a novel molecular targeted agent, suppresses survivin, which is overexpressed in many tumor types. The aim of this study was to determine the antitumor activity of YM155 in SK-NEP-1 cells. METHODS: SK-NEP-1 cell growth in vitro and in vivo was assessed by MTT and nude mice experiments. Annexin V/propidium iodide staining followed by flow cytometric analysis was used to detect apoptosis in cell culture. Then gene expression profile of tumor cells treated with YM155 was analyzed with real-time PCR arrays. We then analyzed the expression data with MEV (Multi Experiment View) cluster software. Datasets representing genes with altered expression profile derived from cluster analyses  were imported into the Ingenuity Pathway Analysis tool. RESULTS: YM155 treatment  resulted in inhibition of cell proliferation of SK-NEP-1cells in a dose-dependent manner. Annexin V assay, cell cycle, and activation of caspase-3 demonstrates that YM155 induced apoptosis in SK-NEP-1 cells. YM155 significantly inhibited growth of SK-NEP-1 xenografts (YM155 5 mg/kg: 1.45 +/- 0.77 cm3; YM155 10 mg/kg:  0.95 +/- 0.55 cm3) compared to DMSO group (DMSO: 3.70 +/- 2.4 cm3) or PBS group cells (PBS: 3.78 +/- 2.20 cm3, ANOVA P < 0.01). YM155 treatment decreased weight  of tumors (YM155 5 mg/kg: 1.05 +/- 0.24 g; YM155 10 mg/kg: 0.72 +/- 0.17 g) compared to DMSO group (DMSO: 2.06 +/- 0.38 g) or PBS group cells (PBS: 2.36 +/-  0.43 g, ANOVA P < 0.01). Real-time PCR array analysis showed between Test group and control group there are 32 genes significantly up-regulated and 54 genes were significantly down-regulated after YM155 treatment. Ingenuity pathway analysis (IPA) showed cell death was the highest rated network with 65 focus molecules and the significance score of 44. The IPA analysis also groups the differentially expressed genes into biological mechanisms that are related to cell death, cellular function maintenance, cell morphology, carbohydrate metabolism and cellular growth and proliferation. Death receptor signaling (3.87E-19), TNFR1 signaling, induction of apoptosis by HIV1, apoptosis signaling and molecular mechanisms of cancer came out to be the top four most significant pathways. IPA analysis also showed top molecules up-regulated were BBC3, BIRC3, BIRC8, BNIP1, CASP7, CASP9, CD5, CDKN1A, CEBPG and COL4A3, top molecules down-regulated were ZNF443, UTP11L, TP73, TNFSF10, TNFRSF1B, TNFRSF25, TIAF1, STK17A, SST and SPP1, upstream regulator were NR3C1, TP53, dexamethasone , TNF and Akt. CONCLUSIONS: The present study demonstrates that YM155 treatment resulted in apoptosis and inhibition of cell proliferation of SK-NEP-1cells. YM155 had significant role and little side effect in the treatment of SK-NEP-1 xenograft tumors. Real-time PCR array analysis firstly showed expression profile of genes dyes-regulated after YM155 treatment. IPA analysis also represents new molecule mechanism of YM155 treatment, such as NR3C1 and dexamethasone may be new target of YM155. And our results may provide new clues of molecular mechanism of apoptosis induced by YM155.

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[855]

TÍTULO / TITLE:  - 5-Geranyloxy-7-Methoxycoumarin Inhibits Colon Cancer (SW480) Cells Growth by Inducing Apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Planta Med. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1055/s-0032-1328130

AUTORES / AUTHORS:  - Patil JR; Jayaprakasha GK; Kim J; Murthy KN; Chetti MB; Nam SY; Patil BS

INSTITUCIÓN / INSTITUTION:  - Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University, College Station, Texas, USA.

RESUMEN / SUMMARY:  - For the first time, three coumarins were isolated from the hexane extract of limes (Citrus aurantifolia) and purified by flash chromatography. The structures  were identified by NMR (1D, 2D) and mass spectral analyses as 5-geranyloxy-7-methoxycoumarin, limettin, and isopimpinellin. These compounds inhibited human colon cancer (SW-480) cell proliferation, with 5-geranyloxy-7-methoxycoumarin showing the highest inhibition activity (67 %) at  25 microM. Suppression of SW480 cell proliferation by 5-geranyloxy-7-methoxycoumarin was associated with induction of apoptosis, as evidenced by annexin V staining and DNA fragmentation. In addition, 5-geranyloxy-7-methoxycoumarin arrested cells at the G0/G1 phase, and induction of apoptosis was demonstrated through the activation of tumour suppressor gene p53, caspase8/3, regulation of Bcl2, and inhibition of p38 MAPK phosphorylation.  These findings suggest that 5-geranyloxy-7-methoxycoumarin has potential as a cancer preventive agent.

 

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[856]

TÍTULO / TITLE:  - Group VIB Phospholipase A(2) promotes proliferation of INS-1 insulinoma cells and attenuates lipid peroxidation and apoptosis induced by inflammatory cytokines and oxidant agents.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oxid Med Cell Longev. 2012;2012:989372. doi: 10.1155/2012/989372. Epub 2012 Nov 11.

            ●● Enlace al texto completo (gratuito o de pago) 1155/2012/989372

AUTORES / AUTHORS:  - Bao S; Song H; Tan M; Wohltmann M; Ladenson JH; Turk J

INSTITUCIÓN / INSTITUTION:  - Mass Spectrometry Resource, Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.

RESUMEN / SUMMARY:  - Group VIB Phospholipase A(2) (iPLA(2)gamma) is distributed in membranous organelles in which beta-oxidation occurs, that is, mitochondria and peroxisomes, and is expressed by insulin-secreting pancreatic islet beta-cells and INS-1 insulinoma cells, which can be injured by inflammatory cytokines, for example, IL-1beta and IFN-gamma, and by oxidants, for example, streptozotocin (STZ) or t-butyl-hydroperoxide (TBHP), via processes pertinent to mechanisms of beta-cell  loss in types 1 and 2 diabetes mellitus. We find that incubating INS-1 cells with IL-1beta and IFN-gamma, with STZ, or with TBHP causes increased expression of iPLA(2)gamma mRNA and protein. We prepared INS-1 knockdown (KD) cell lines with reduced iPLA(2)gamma expression, and they proliferate more slowly than control INS-1 cells and undergo increased membrane peroxidation in response to cytokines  or oxidants. Accumulation of oxidized phospholipid molecular species in STZ-treated INS-1 cells was demonstrated by LC/MS/MS scanning, and the levels in  iPLA(2)gamma-KD cells exceeded those in control cells. iPLA(2)gamma-KD INS-1 cells also exhibited higher levels of apoptosis than control cells when incubated with STZ or with IL-1beta and IFN-gamma. These findings suggest that iPLA(2)gamma promotes beta-cell proliferation and that its expression is increased during inflammation or oxidative stress as a mechanism to mitigate membrane injury that  may enhance beta-cell survival.

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[857]

TÍTULO / TITLE:  - Usefulness of carcinoembryonic antigen for monitoring tumor progression during palliative chemotherapy in metastatic colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Yonsei Med J. 2013 Jan 1;54(1):116-22. doi: 10.3349/ymj.2013.54.1.116.

            ●● Enlace al texto completo (gratuito o de pago) 3349/ymj.2013.54.1.116

AUTORES / AUTHORS:  - Kim G; Jung EJ; Ryu CG; Hwang DY

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Konkuk University Medical Center, Gwangjin-gu, Seoul, Korea.

RESUMEN / SUMMARY:  - PURPOSE: To evaluate the efficacy of carcinoembryonic antigen (CEA) measurement for monitoring tumor progression during palliative chemotherapy in metastatic colorectal cancer. MATERIALS AND METHODS: Forty-eight patients with initially unresectable metastatic colorectal cancer (n=26, 54.2%) or recurrent unresectable metastatic colorectal cancer (n=22, 45.8%) received FOLFOX-4 chemotherapy for palliation. Serum CEA levels and carbohydrate antigen 19-9 levels were measured and computed tomography (CT) studies were performed prior to chemotherapy and after 3 cycles of chemotherapy. From the CT images, tumor responses were evaluated according to the Response Evaluation Criteria in Solid Tumors criteria  and categorized as complete response, partial response, stable disease, and progressive disease. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of tumor marker assessments for determining tumor response were calculated. RESULTS: The sensitivity, specificity and diagnostic accuracy of CEA assessment for prediction of disease progression were 50%, 77% and 69%, respectively. When the patients were dichotomized according to baseline CEA level, the initially elevated CEA group showed higher sensitivity and higher diagnostic accuracy compared to the initially normal CEA group (sensitivity=67% vs. 20%; diagnostic accuracy=71% vs.  62%). CONCLUSION: CEA assessment could be useful for monitoring tumor progression during palliative chemotherapy in only patients with initially elevated CEA level.

 

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[858]

TÍTULO / TITLE:  - Inhibition of p85, the non-catalytic subunit of phosphatidylinositol 3-kinase, exerts potent antitumor activity in human breast cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Death Dis. 2012 Dec 6;3:e440. doi: 10.1038/cddis.2012.179.

            ●● Enlace al texto completo (gratuito o de pago) 1038/cddis.2012.179

AUTORES / AUTHORS:  - Folgiero V; Di Carlo SE; Bon G; Spugnini EP; Di Benedetto A; Germoni S; Pia Gentileschi M; Accardo A; Milella M; Morelli G; Bossi G; Mottolese M; Falcioni R

INSTITUCIÓN / INSTITUTION:  - Department of Experimental Oncology, Regina National Elena Cancer Institute, Via  delle Messi d’Oro 156, Rome, Italy. folgiero@ifo.it

RESUMEN / SUMMARY:  - The phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of the catalytic subunit p110 and the regulatory subunit p85. The PI3K/Akt pathway is strongly deregulated in breast cancer (BC) representing one of the mechanisms of  resistance to therapies. Therefore, the identification of inhibitors of PI3K components represents one of the main goals to produce therapeutic agents. Here,  we evaluated the efficacy of a phosphopeptide 1257 (P-1257) that targeting p85 strongly inhibits PI3K activity. We tested the effects of P-1257 administration in vitro and in vivo using BC cells expressing different levels of ErbB-2 and resistant or responsive to Trastuzumab. We demonstrated that inhibition of p85 activity by P-1257 induces cell death and sensitizes JIMT-1 and KPL-4 ErbB-2-overexpressing BC cells to Trastuzumab treatment. It is noteworthy that P-1257 delivery in vivo by electroporation or liposomes significantly inhibits the proliferation of tumor cells engrafted at subcutaneous and visceral sites. Overall, our data indicate that the p85 subunit is a valid target for therapeutic approaches and suggest that the structure of the peptide used in our study could  be utilized for the development of novel drugs to apply in combination with therapies that fail to cure BCs with high PI3K activity.

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[859]

TÍTULO / TITLE:  - Epidermal growth factor receptor (EGFR) mutation and personalized therapy in advanced nonsmall cell lung cancer (NSCLC).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Target Oncol. 2013 Jan 30.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11523-013-0258-9

AUTORES / AUTHORS:  - Kobayashi K; Hagiwara K

INSTITUCIÓN / INSTITUTION:  - Saitama Medical University, Moroyama, Japan, kobakuni@saitama-med.ac.jp.

RESUMEN / SUMMARY:  - Before 2009, nonsmall cell lung cancer (NSCLC) was one disease entity treated by  cytotoxic chemotherapy that provided a response rate of 20-35 % and a median survival time (MST) of 10-12 months. In 2004, it was found that activated mutations of the epidermal growth factor receptor (EGFR) gene were present in a subset of NSCLC and that tumors with EGFR mutations were highly sensitive to EGFR tyrosine kinase inhibitors (TKI). Four phase III studies (North East Japan (NEJ)  002, West Japan Thoracic Oncology Group (WJTOG) 3405, OPTIMAL, and EUROTAC) prospectively compared TKI (gefitinib or erlotinib) with cytotoxic chemotherapy as first-line therapy in EGFR-mutated NSCLC. These studies confirmed that progression-free survival (PFS) with TKIs (as the primary endpoint) was significantly longer than that with standard chemotherapy (hazard ratio [HR] = 0.16-0.49) from 2009 to 2011. Although the NEJ 002 study showed identical overall survival (OS) between the arms (HR = 0.89), quality of life (QoL) was maintained  much longer in patients treated with gefitinib. In conclusion, TKI should be considered as the standard first-line therapy in advanced EGFR-mutated NSCLC. Since 2009, a new step has been introduced in the treatment algorithm for advanced NSCLC.

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[860]

TÍTULO / TITLE:  - Effects of curcumin on global gene expression profiles in the highly invasive human breast carcinoma cell line MDA-MB 231: A gene network-based microarray analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Exp Ther Med. 2013 Jan;5(1):23-27. Epub 2012 Oct 19.

            ●● Enlace al texto completo (gratuito o de pago) 3892/etm.2012.754

AUTORES / AUTHORS:  - Cine N; Limtrakul P; Sunnetci D; Nagy B; Savli H

INSTITUCIÓN / INSTITUTION:  - Department of Medical Genetics and Clinical Research Unit, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey ;

RESUMEN / SUMMARY:  - Curcumin, or diferuloylmethane, is a major chemical component of turmeric (Curcuma longa Linn.) that has been consumed as a dietary spice through the ages. This yellow-colored polyphenol has a notably wide range of beneficial properties, including anti-inflammatory, antioxidant, antitumoral, anti-invasive and anti-metastatic activity. In the present study, microarray gene expression analysis was applied to identify the curcumin-regulated genes in a highly invasive human breast carcinoma cell line (MDA-MB 231). Cells were cultured with  curcumin (20 muM) for 24 h; total RNA was isolated and hybridized to Whole Human  Genome Microarray slides. Gene set enrichment analyses on our whole genome expression data revealed downregulation of the EGF pathway elements following curcumin treatment. Furthermore, gene network analysis identified a significantly relevant network among the differentially expressed genes, centered on the EGR1 and FOS genes. The members of these pathways and networks play an essential role  in the regulation of cancer cell growth and development; the majority exhibited decreased expression levels following treatment with curcumin. These observations suggest that curcumin is an excellent candidate for the prevention and treatment  of breast cancer.

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[861]

TÍTULO / TITLE:  - Targeting Death Receptor TRAIL-R2 by Chalcones for TRAIL-Induced Apoptosis in Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2012 Nov 20;13(11):15343-59. doi: 10.3390/ijms131115343.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms131115343

AUTORES / AUTHORS:  - Szliszka E; Jaworska D; Ksek M; Czuba ZP; Krol W

INSTITUCIÓN / INSTITUTION:  - Chair and Department of Microbiology and Immunology, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland. wkrol@sum.edu.pl.

RESUMEN / SUMMARY:  - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells without toxicity to normal cells. TRAIL binds to death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) expressed on cancer cell surface and activates  apoptotic pathways. Endogenous TRAIL plays an important role in immune surveillance and defense against cancer cells. However, as more tumor cells are reported to be resistant to TRAIL mediated death, it is important to search for and develop new strategies to overcome this resistance. Chalcones can sensitize cancer cells to TRAIL-induced apoptosis. We examined the cytotoxic and apoptotic  effects of TRAIL in combination with four chalcones: chalcone, isobavachalcone, licochalcone A and xanthohumol on HeLa cancer cells. The cytotoxicity was measured by MTT and LDH assays. The apoptosis was detected using annexin V-FITC staining by flow cytometry and fluorescence microscopy. Death receptor expression was analyzed using flow cytometry. The decreased expression of death receptors in cancer cells may be the cause of TRAIL-resistance. Chalcones enhance TRAIL-induced apoptosis in HeLa cells through increased expression of TRAIL-R2. Our study has indicated that chalcones augment the antitumor activity of TRAIL and confirm their cancer chemopreventive properties.

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[862]

TÍTULO / TITLE:  - Pomolic acid induces apoptosis in SK-OV-3 human ovarian adenocarcinoma cells through the mitochondrial-mediated intrinsic and death receptor-induced extrinsic pathways.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2013 Jan;5(1):386-390. Epub 2012 Oct 22.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.985

AUTORES / AUTHORS:  - Yoo KH; Park JH; Lee DK; Fu YY; Baek NI; Chung IS

INSTITUCIÓN / INSTITUTION:  - Department of Genetic Engineering and ; Graduate School of Biotechnology, Kyung Hee University, Yongin 446-701, Republic of Korea.

RESUMEN / SUMMARY:  - The cytotoxic effect of pomolic acid (PA), a pentacyclic triterpene isolated from flowers of Osmanthus fragrans var. aurantiacus Makino, was investigated in SK-OV-3 human ovarian adenocarcinoma cells. PA dose-dependently inhibited the viability of SK-OV-3 cells. PA-induced apoptosis was further characterized by detection of cell surface annexin V and sub-G1 apoptotic cell populations. The number of cells immunostained with annexin V-fluorescein isothiocyanate (FITC) increased following treatment with PA. The sub-G1 cell populations also increased in PA-treated SK-OV-3 cells. PA induced the activation of caspase-8, -9 and -3, critical mediators of apoptosis signaling. PA decreased the mitochondrial transmembrane potential (DeltaPsi(m)), resulting in the activation of caspase-9.  In addition, PA increased the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis signaling-related death receptor 5 (DR5), mediating caspase-8-involved extrinsic pathway. Taken together, our results indicate that PA induces apoptosis in SK-OV-3 cells, which is mediated by the mitochondrial-mediated intrinsic and death receptor-induced extrinsic pathways.

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[863]

TÍTULO / TITLE:  - Molecular Mechanisms of Cardiotoxicity Induced by ErbB Receptor Inhibitor Cancer  Therapeutics.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2012 Sep 26;13(10):12268-86. doi: 10.3390/ijms131012268.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms131012268

AUTORES / AUTHORS:  - Hervent AS; De Keulenaer GW

INSTITUCIÓN / INSTITUTION:  - Laboratory of Physiopharmacology (Building T2), University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. gilles.dekeulenaer@ua.ac.be.

RESUMEN / SUMMARY:  - The introduction of the so-called “targeted therapies”, particularly those drugs  that inhibit the activity of tyrosine kinases, has represented a remarkable progress in the treatment of cancer. Although these drugs improve survival rates  in cancer, significant cardiotoxicity, manifesting as left vertricular dysfunction and/or heart failure, has emerged. The ErbB receptor tyrosine kinases are being pursued as therapeutic targets because of their important roles in normal physiology and in cancer. Besides the fact that the ErbB receptors are indispensable during development and in normal adult physiology, epidermal growth factor (EGFR) and ErbB2 in particular have been implicated in the development of  many human cancers. This review focuses on the rationale for targeting members of ErbB receptor family and numerous agents that are in use for inhibiting the pathway. We summarize the current knowledge on the physiological role of ErbB signaling in the ventricle and on structural aspects of ErbB receptor activation  in cancer and cardiac cells. We examine the underlying mechanisms that result in  on-target or off-target cardiotoxicities of ErbB inhibitors, which can influence  the design of future anticancer therapies.

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[864]

TÍTULO / TITLE:  - Restoration of klotho expression induces apoptosis and autophagy in hepatocellular carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Oncol (Dordr). 2012 Dec 18.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s13402-012-0118-0

AUTORES / AUTHORS:  - Shu G; Xie B; Ren F; Liu DC; Zhou J; Li Q; Chen J; Yuan L; Zhou J

INSTITUCIÓN / INSTITUTION:  - Departemt of Geriatric Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.

RESUMEN / SUMMARY:  - PURPOSE: Klotho has been identified as a tumor suppressor in several human malignancies including hepatocellular carcinoma (HCC). However, the signaling pathways involved in the tumor suppressive role of klotho in HCC have not been reported. Here, we investigated the role of klotho in HCC cell proliferation, apoptosis, autophagy, and invasion, as well as its associated signal transduction pathways. METHODS: Restoration of klotho gene expression was established by delivering a klotho gene expression vector into the human HCC cell lines HepG2 and MHCC-97-H. Cell viability was measured using a cell counting (CCK-8) assay and apoptosis was analyzed through flow cytometry. Autophagy was measured via LC3-I and LC3-II protein expression levels and tumor cell invasion was assessed using a Matrigel invasion chamber assay. Expression and phosphorylation of several apoptosis and survival related proteins were assessed using Western blot  assays. RESULTS: Exogenous klotho gene expression significantly inhibited HCC cell proliferation, induced HCC cell apoptosis, increased LC3-I and LC3-II protein expression in HCC cells, and decreased migration of HCC cells in a Matrigel invasion chamber assay. Exogenous klotho gene expression also down-regulated the phosphorylation levels of the IGF-1 receptor, and the downstream Akt, ERK, and p70S6K proteins. Both apoptosis and autophagy inhibitors decreased klotho-induced apoptosis and autophagy. CONCLUSION: Klotho is a tumor suppressor that, through the regulation of IGF-1R phosphorylation and subsequent  activation of downstream Akt-p70S6K and ERK signaling, regulates HCC tumor cell proliferation, apoptosis, autophagy and invasion.

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[865]

TÍTULO / TITLE:  - Adenovirus-mediated combined anti-angiogenic and pro-apoptotic gene therapy enhances antitumor efficacy in hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2013 Jan;5(1):348-354. Epub 2012 Oct 23.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.987

AUTORES / AUTHORS:  - Yan F; Zheng Y; Huang L

INSTITUCIÓN / INSTITUTION:  - The Shenzhen Key Lab of Gene and Antibody Therapy, Center for Biotech and Bio-Medicine and Division of Life Sciences, Graduate School at Shenzhen, Tsinghua University; ; Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, P.R. China.

RESUMEN / SUMMARY:  - A previous study reported that combinatorial human endostatin and soluble tumor necrosis factor (TNF)-related apoptosis-inducing ligand (sTRAIL) gene transfer suppresses human hepatocellular carcinoma (HCC) growth and angiogenesis using the pVAX1 plasmid vector. The current study investigated the antitumor efficacy in HCC through adenovirus-mediated combination gene therapy. Human endostatin and sTRAIL (114 to 281 AA) genes were amplified and cloned into the Adeno-X expression vector. The recombinant adenoviruses (Ad-E and Ad-T) were packaged, amplified in the HEK 293 cells and used to infect human umbilical vein endothelial cells (HUVECs) and HepG2 cells, respectively. The results revealed that a significant cell growth inhibition was observed in the two types of cells  using a cell viability assay. Intratumoral administration with Ad-E and Ad-T revealed a significant enhanced regression of the tumors compared with treatment  with either recombinant adenovirus alone. Histology and immunohistochemistry examination further indicated that the inhibition of tumor growth appeared to result from increased apoptosis and reduced angiogenesis in tumor xenografts. In  conclusion, these data further confirm the enhancement of antitumor efficacy through combined endostatin and TRAIL gene therapy and provide a promising application prospect by virtue of adenovirus-mediated anti-angiogenic and pro-apoptotic cancer gene therapy.

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[866]

TÍTULO / TITLE:  - Antiproliferative effect of gold(I) compound auranofin through inhibition of STAT3 and telomerase activity in MDA-MB 231 human breast cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMB Rep. 2013 Jan;46(1):59-64.

AUTORES / AUTHORS:  - Kim NH; Park HJ; Oh MK; Kim IS

INSTITUCIÓN / INSTITUTION:  - Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul 137-710, Korea ikim@catholic.ac.kr.

RESUMEN / SUMMARY:  - Signal transducer and activator of transcription 3 (STAT3) and telomerase are considered attractive targets for anticancer therapy. The in vitro anticancer activity of the gold(I) compound auranofin was investigated using MDA-MB 231 human breast cancer cells, in which STAT3 is constitutively active. In cell culture, auranofin inhibited growth in a dose-dependent manner, and N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS), markedly blocked the effect of auranofin. Incorporation of 5-bromo-2’-deoxyuridine into DNA and anchorage-independent cell growth on soft agar were decreased by auranofin treatment. STAT3 phosphorylation and telomerase activity were also attenuated in cells exposed to auranofin, but NAC pretreatment restored STAT3 phosphorylation and telomerase activity in these cells. These findings indicate that auranofin exerts in vitro antitumor effects in MDA-MB 231 cells and its activity involves inhibition of STAT3 and telomerase. Thus, auranofin shows potential as a novel anticancer drug that targets STAT3 and telomerase. [BMB Reports 2013; 46(1): 059-064].

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[867]

TÍTULO / TITLE:  - MicroRNAs miR-146-5p and let-7f as prognostic tools for aggressive papillary thyroid carcinoma: a case report.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Arq Bras Endocrinol Metabol. 2012 Nov;56(8):552-7.

AUTORES / AUTHORS:  - Geraldo MV; Fuziwara CS; Friguglieti CU; Costa RB; Kulcsar MA; Yamashita AS; Kimura ET

INSTITUCIÓN / INSTITUTION:  - Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.

RESUMEN / SUMMARY:  - Papillary thyroid cancer (PTC) is the most incident histotype of thyroid cancer.  A certain fraction of PTC cases (5%) are irresponsive to conventional treatment,  and refractory to radioiodine therapy. The current prognostic factors for aggressiveness are mainly based on tumor size, the presence of lymph node metastasis, extrathyroidal invasion and, more recently, the presence of the BRAFT1799A mutation. MicroRNAs (miRNAs) have been described as promising molecular markers for cancer as their deregulation is observed in a wide range of tumors. Recent studies indicate that the over-expression of miR-146b-5p is associated with aggressiveness and BRAFT1799A mutation. Furthermore, down-regulation of let-7f is observed in several types of tumors, including PTC.  In this study, we evaluated the miR146b-5p and let-7f status in a young male patient with aggressive, BRAFT1799A-positive papillary thyroid carcinoma, with extensive lymph node metastases and short-time recurrence. The analysis of miR-146b-5p and let-7f expression revealed a distinct pattern from a cohort of PTC patients, suggesting caution in evaluating miRNA expression data as molecular markers of PTC diagnosis and prognosis. Arq Bras Endocrinol Metab. 2012;56(8):552-7.

 

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[868]

TÍTULO / TITLE:  - IFNB1/interferon-beta-induced autophagy in MCF-7 breast cancer cells counteracts  its proapoptotic function.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Autophagy. 2012 Dec 7;9(3).

AUTORES / AUTHORS:  - Ambjorn M; Ejlerskov P; Liu Y; Lees M; Jaattela M; Issazadeh-Navikas S

INSTITUCIÓN / INSTITUTION:  - Biotech Research and Innovation Centre (BRIC); University of Copenhagen; Copenhagen, Denmark.

RESUMEN / SUMMARY:  - IFNB1/interferon (IFN)-beta belongs to the type I IFNs and exerts potent antiproliferative, proapoptotic, antiangiogenic and immunemodulatory functions. Despite the beneficial effects of IFNB1 in experimental breast cancers, clinical  translation has been disappointing, possibly due to induction of survival pathways leading to treatment resistance. Defects in autophagy, a conserved cellular degradation pathway, are implicated in numerous cancer diseases. Autophagy is induced in response to cancer therapies and can contribute to treatment resistance. While the type II IFN, IFNG, which in many aspects differs  significantly from type I IFNs, can induce autophagy, no such function for any type I IFN has been reported. We show here that IFNB1 induces autophagy in MCF-7, MDAMB231 and SKBR3 breast cancer cells by measuring the turnover of two autophagic markers, MAP1LC3B/LC3 and SQSTM1/p62. The induction of autophagy in MCF-7 cells occurred upstream of the negative regulator of autophagy MTORC1, and  autophagosome formation was dependent on the known core autophagy molecule ATG7 and the IFNB1 signaling molecule STAT1. Using siRNA-mediated silencing of several core autophagy molecules and STAT1, we provide evidence that IFNB1 mediates its antiproliferative effects independent of autophagy, while the proapoptotic function of IFNB1 was strongly enhanced in the absence of autophagy. This suggests that autophagy induced by IFNB1 promoted survival, which might contribute to tumor resistance against IFNB1 treatment. It may therefore be clinically relevant to reconcile a role for IFNB1 in the treatment of breast cancer with concomitant inhibition of autophagy.

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[869]

TÍTULO / TITLE:  - Gene expression profiles for predicting metastasis in breast cancer: a cross-study comparison of classification methods.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - ScientificWorldJournal. 2012;2012:380495. doi: 10.1100/2012/380495. Epub 2012 Nov 28.

            ●● Enlace al texto completo (gratuito o de pago) 1100/2012/380495

AUTORES / AUTHORS:  - Burton M; Thomassen M; Tan Q; Kruse TA

INSTITUCIÓN / INSTITUTION:  - Research Unit of Human Genetics, Institute of Clinical Research, University of Southern Denmark, Sdr. Boulevard 29, 5000 Odense C, Denmark ; Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C,  Denmark.

RESUMEN / SUMMARY:  - Machine learning has increasingly been used with microarray gene expression data  and for the development of classifiers using a variety of methods. However, method comparisons in cross-study datasets are very scarce. This study compares the performance of seven classification methods and the effect of voting for predicting metastasis outcome in breast cancer patients, in three situations: within the same dataset or across datasets on similar or dissimilar microarray platforms. Combining classification results from seven classifiers into one voting decision performed significantly better during internal validation as well as external validation in similar microarray platforms than the underlying classification methods. When validating between different microarray platforms, random forest, another voting-based method, proved to be the best performing method. We conclude that voting based classifiers provided an advantage with respect to classifying metastasis outcome in breast cancer patients.

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[870]

TÍTULO / TITLE:  - Analysis of complete response by MRI following neoadjuvant chemotherapy predicts  pathological tumor responses differently for molecular subtypes of breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2013 Jan;5(1):83-89. Epub 2012 Oct 30.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.1004

AUTORES / AUTHORS:  - Hayashi Y; Takei H; Nozu S; Tochigi Y; Ichikawa A; Kobayashi N; Kurosumi M; Inoue K; Yoshida T; Nagai SE; Oba H; Tabei T; Horiguchi J; Takeyoshi I

INSTITUCIÓN / INSTITUTION:  - Division of Breast Surgery, Saitama Cancer Center, Saitama 362-0806; ; Department of Thoracic and Visceral Organ Surgery, Graduate School of Medicine, Gunma University, Gunma 371-8511;

RESUMEN / SUMMARY:  - In the present study, clinical tumor response following neoadjuvant chemotherapy  (NAC) was diagnosed by magnetic resonance imaging (MRI) and clinicopathological factors, including molecular subtypes at baseline, were analyzed for correlations with pathological tumor responses. In addition, clinicopathological factors were  analyzed for a correlation with the MRI capacity to predict pathological complete response (pCR). Clinical tumor response evaluated by MRI following NAC was determined as a clinical CR (cCR) or a residual tumor. cCR was confirmed if no gadolinium enhancement or an enhancement equal to or less than that of glandular  tissue was observed in any phase of the MRI. Pathological tumor responses following NAC were classified into grades 0 (no change) to 3 (no residual invasive cancer) according to criteria of the Japanese Breast Cancer Society. pCR was defined as grade 3 in the present study. Of 264 cases of invasive breast cancer in 260 patients (4 synchronous bilateral breast cancer cases), 59 (22%) were diagnosed by MRI following NAC as cCR and 98 (37%) were pathologically diagnosed as pCR. In terms of predicting pCR by MRI, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were 44, 90, 73, 73 and 73%, respectively. Tumor size, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, molecular subtype and histological type were significantly correlated with pathological tumor responses. pCR rates increased in the following order: luminal/HER2-negative (14%), luminal/HER2-positive (32%), triple-negative (46%) and non-luminal/HER2-positive (73%) tumors. Sensitivity and specificity were the  highest (60 and 100%, respectively) in triple-negative tumors. PPV decreased in the following order: triple-negative (100%), non-luminal/HER2-positive (92%), luminal/HER2-positive (46%) and luminal/HER2-negative (33%) tumors. In conclusion, MRI evaluation is useful for predicting pCR following NAC, particularly for triple-negative tumors.

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[871]

TÍTULO / TITLE:  - Glycogen Synthase Kinase 3beta Inhibitor (2’Z,3’E)-6-Bromo-indirubin- 3’-Oxime Enhances Drug Resistance to 5-Fluorouracil Chemotherapy in Colon Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Cancer Res. 2012 Jun;24(2):116-23. doi: 10.1007/s11670-012-0116-9.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11670-012-0116-9

AUTORES / AUTHORS:  - Liu KP; Luo F; Xie SM; Tang LJ; Chen MX; Wu XF; Zhong XY; Zhao T

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China ; Department of Pathology, Qingyuan Hospital, Medical College, Jinan University, Qingyuan 511518, China.

RESUMEN / SUMMARY:  - OBJECTIVE: To explore the effects and mechanism of glycogen synthase kinase 3beta (GSK-3beta) inhibitor (2’Z,3’E)-6-bromo-indirubin-3’-oxime (BIO) on drug resistance in colon cancer cells. METHODS: The colon cancer SW480 and SW620 cells were treated with BIO, 5-fluorouracil (5-FU) and BIO/5-FU, separately. Cell cycle distribution, apoptosis level and efflux ability of rhodamine 123 (Rh123) were detected by flow cytometry. The protein expressions of P-glycoprotein (P-gp), multidrug resistance protein 2 (MRP2), thymidylate synthase (TS), beta-catenin, E2F-1 and Bcl-2 were detected by Western blot. beta-catenin and P-gp were stained with double immunofluorescence and observed under a confocal microscope. RESULTS: BIO up-regulated beta-catenin, P-gp, MRP2 and TS, enhanced the efflux ability of  Rh123, decreased Bcl-2 protein and gave the opposite effect to E2F-1 protein in SW480 and SW620 cells. Furthermore, BIO significantly inhibited cell apoptosis, increased S and G(2)/M phase cells, and reduced the cell apoptosis induced by 5-FU in SW480 cells, whereas the effects were slight or not obvious in SW620 cells. CONCLUSION: GSK-3beta was involved in drug resistance regulation, and activation of beta-catenin and inhibition of E2F-1 may be the most responsible for the enhancement of 5-FU chemotherapy resistance induced by GSK-3beta inhibitor BIO in colon cancer.

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[872]

TÍTULO / TITLE:  - Effects of resveratrol on vascular endothelial growth factor expression in osteosarcoma cells and cell proliferation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2012 Oct;4(4):837-839. Epub 2012 Jul 25.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.824

AUTORES / AUTHORS:  - Liu Z; Li Y; Yang R

INSTITUCIÓN / INSTITUTION:  - Department of Orthopedics, First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100;

RESUMEN / SUMMARY:  - The aim of the current study was to investigate the effects of resveratrol (Res)  on vascular endothelial growth factor (VEGF) expression and cell proliferation in the human osteosarcoma cell line U20S. U20S cells were treated with Res at various concentrations (0, 10, 20 and 40 mumol/l) for various times (24, 48 and 72 h). The inhibitory effect of Res on U20S proliferation was observed using methyl thiazolyl tetrazolium (MTT) colorimetry. VEGF expression was determined using real-time polymerase chain reaction (RT-PCR) and western blot analysis. The inhibitory effect of Res on U20S proliferation increased as the concentration of  Res increased. The inhibitory effect also increased with time. Res had an inhibitory effect on VEGF expression and significantly inhibited U20S cell proliferation. Res may exert an anti-osteosarcoma effect by inhibiting VEGF expression in tumor cells.

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[873]

TÍTULO / TITLE:  - Maternal serum tumour necrosis factor receptor 1 (TNF-R1) at 30-33 weeks in the prediction of preeclampsia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Matern Fetal Neonatal Med. 2012 Dec 3.

            ●● Enlace al texto completo (gratuito o de pago) 3109/14767058.2012.755168

AUTORES / AUTHORS:  - Mosimann B; Wagner M; Birdir C; Poon LC; Nicolaides KH

INSTITUCIÓN / INSTITUTION:  - Harris Birthright Research Centre of Fetal Medicine, King’s College Hospital, London, UK.

RESUMEN / SUMMARY:  - Abstract Objective: To investigate the potential value of maternal serum concentration of tumour necrosis factor receptor 1 (TNF-R1) at 30-33 weeks’ gestation in the prediction of preeclampsia (PE) developing at or after 34 weeks. Methods: Serum TNF-R1 was measured at 11-13 and at 30-33 weeks’ gestation in a case-control study of 50 cases that developed PE at or after 34 weeks and 250 unaffected controls. The measured values of TNF-R1 were converted into multiples  of the unaffected median (MoM) and the MoM values in the PE and control groups were compared. Results: The median MoM TNF-R1 was significantly increased at both 11-13 weeks (1.094 MoM vs. 1.003 MoM) and at 30-33 weeks (1.101 MoM vs. 1.006 MoM). In screening for PE by a combination of maternal characteristics and serum  TNF-R1 at 30-33 weeks the estimated detection rates of PE, at false positive rates of 5% and 10%, were 32.0% and 40.0%, respectively. Conclusion: Screening by maternal characteristics and serum TNF-R1 at 30-33 weeks could be effective in identifying some of the cases that will subsequently develop PE.

 

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[874]

TÍTULO / TITLE:  - Resveratrol induces apoptosis of pancreatic cancers cells by inhibiting miR-21 regulation of BCL-2 expression.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Transl Oncol. 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12094-012-0999-4

AUTORES / AUTHORS:  - Liu P; Liang H; Xia Q; Li P; Kong H; Lei P; Wang S; Tu Z

INSTITUCIÓN / INSTITUTION:  - Department of Medical Laboratory, Chongqing University of Medical Science, Chongqing, China.

RESUMEN / SUMMARY:  - OBJECTIVE: Resveratrol is an edible polyphenolic phytoalexin present in different plant species and plays important role in inhibiting proliferation and inducing apoptosis of pancreatic cancer cells. In this paper, the mechanism of resveratrol on PANC-1, CFPAC-1 and MIA Paca-2 cells apoptosis was examined. METHODS: We first evaluated the effect of resveratrol on viability of PANC-1, CFPAC-1 and MIA Paca-2 cells using MTT assay. Next, we performed real-time PCR to assess the effect of resveratrol on miR-21 expression. We also used Western blot to measure  BCL-2 protein levels after down-regulation of miR-21 expression. Finally, we evaluated the effect of miR-21 on resveratrol-induced anti-tumor activity using miR-21 mimic. RESULTS: Resveratrol induced a significant inhibition of PANC-1, CFPAC-1 and MIA Paca-2 cells viability in a dose-dependent manner. Resveratrol also decreased the expression of miR-21. Besides, down-regulation of miR-21 expression can inhibit BCL-2 expression in PANC-1, CFPAC-1 and MIA Paca-2 cells.  Over-expression of miR-21 expression can reverse down-regulation of BCL-2 expression and apoptosis induced by resveratrol. CONCLUSIONS: In this study, we demonstrated that the effect of resveratrol on apoptosis is due to inhibiting miR-21 regulation of BCL-2 expression.

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[875]

TÍTULO / TITLE:  - Nuclear Expression of beta-Catenin Promotes RB Stability and Resistance to TNF-Induced Apoptosis in Colon Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Cancer Res. 2013 Jan 21.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1541-7786.MCR-12-0670

AUTORES / AUTHORS:  - Han J; Soletti RC; Sadarangani A; Sridevi P; Ramirez M; Eckmann L; Borges HL; Wang JY

INSTITUCIÓN / INSTITUTION:  - University of California San Diego.

RESUMEN / SUMMARY:  - Tumor necrosis factor-alpha (TNF) promotes tumor development under chronic inflammation. Because TNF also activates caspase-8, selective inhibition of TNF-induced extrinsic apoptosis would be required for inflammation-associated tumor growth. In a mouse model of inflammation-associated colon carcinogenesis, we found nuclear expression of beta-catenin in tumors of wild type but not mutant mice that were made resistant to TNF-induced apoptosis by a germline mutation blocking caspase cleavage of the retinoblastoma protein (RB), despite similar frequencies of beta-catenin exon-3 mutations in these two genetic backgrounds. TNF-induced apoptosis was also attenuated in human colon cancer cell lines with genetically activated beta-catenin. However, we found that HCT116 cells, which contain an activated allele of beta-catenin but do not express nuclear beta-catenin, were sensitive to TNF-induced apoptosis. In HCT116 cells, TNF stimulated efficient RB cleavage that preceded chromatin condensation. By contrast, TNF did not induce RB cleavage in colon cancer cells expressing nuclear beta-catenin and these cells could be sensitized to basal and/or TNF-induced apoptosis by the knockdown of beta-catenin or RB. In the apoptosis-resistant colon cancer cells, knockdown of beta-catenin led to a reduction in the RB protein without affecting RB mRNA. Furthermore, ectopic expression of the caspase-resistant, but not the wild type RB, re-established resistance to TNF-induced caspase activation in colon cancer cells with beta-catenin knockdown. Together, these results suggest that nuclear beta-catenin dependent RB stabilization suppresses TNF-induced apoptosis in caspase-8-positive colon cancer cells.

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[876]

TÍTULO / TITLE:  - Chemoimmunotherapy for advanced gastrointestinal carcinomas: A successful combination of gene therapy and cyclophosphamide.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncoimmunology. 2012 Dec 1;1(9):1626-1628.

            ●● Enlace al texto completo (gratuito o de pago) 4161/onci.21651

AUTORES / AUTHORS:  - Malvicini M; Piccioni F; Bayo J; Fiore E; Atorrasagasti C; Alaniz L; Garcia M; Aquino JB; Gidekel M; Matar P; Mazzolini G

INSTITUCIÓN / INSTITUTION:  - Gene Therapy Laboratory; Liver Unit; School of Medicine; Austral University; Buenos Aires, Argentina.

RESUMEN / SUMMARY:  - The combination of a single low dose of cyclophosphamide (Cy) with the adenovirus-mediated gene transfer of interleukin-12 (AdIL-12) might represent a successful therapy for experimental gastrointestinal tumors. This approach has been proven to revert immunosuppressive mechanisms elicited by cancer cells and to synergistically promote antitumor immunity. In addition, this therapeutic regimen has been shown to be more efficient in achieving complete tumor regressions in mice than the application of a metronomic schedule of Cy plus AdIL-12.

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[877]

TÍTULO / TITLE:  - Dual inhibition of Janus and Src family kinases by novel indirubin derivative blocks constitutively-activated Stat3 signaling associated with apoptosis of human pancreatic cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Oncol. 2012 Nov 16. pii: S1574-7891(12)00122-6. doi: 10.1016/j.molonc.2012.10.013.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.molonc.2012.10.013

AUTORES / AUTHORS:  - Nam S; Wen W; Schroeder A; Herrmann A; Yu H; Cheng X; Merz KH; Eisenbrand G; Li H; Yuan YC; Jove R

INSTITUCIÓN / INSTITUTION:  - Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA. Electronic address: snam@coh.org.

RESUMEN / SUMMARY:  - Constitutively-activated JAK/Stat3 or Src/Stat3 signaling plays a crucial role in tumor cell survival, proliferation, angiogenesis and immune suppression. Activated JAK/Stat3 or Src/Stat3 has been validated as a promising molecular target for cancer therapy. However, prolonged inhibition of Src family kinases (SFKs) leads to reactivation of signal transducer and activator of transcript 3 (Stat3) and tumor cell survival through altered JAK/Stat3 interaction. This compensatory feedback suggests that dual inhibition of Janus kinases (JAKs) and SFKs might be a promising strategy for targeting downstream Stat3 signaling in the clinic. In this study, we identify that the natural product derivative E738 is a novel dual inhibitor of JAKs and SFKs. The IC(50) values of E738 against recombinant JAKs and SFKs in vitro are in the ranges of 0.7-74.1 nM and 10.7-263.9 nM, respectively. We observed that phosphorylation of both Jak2 and Src was substantially inhibited in the submicromolar range by E738 in cultured human pancreatic tumor cells, followed by blockade of downstream Stat3 activation. E738 down-regulated expression of the Stat3 target proteins Mcl-1 and survivin, associated with induction of apoptosis. Computational models and molecular dynamics simulations of E738/Tyk2 or E738/Src in silico suggest that E738 inhibits both tyrosine kinase 2 (Tyk2) and Src as an ATP-competitive ligand. Moreover, the planar E738 molecule demonstrates a strong binding affinity in the  compact ATP-binding site of Tyk2. In sum, E738 is the first dual inhibitor of JAKs and SFKs, followed by inhibition of Stat3 signaling. Thus, according to in vitro experiments, E738 is a promising new therapeutic agent for human pancreatic cancer treatment by blocking both oncogenic pathways simultaneously.

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[878]

TÍTULO / TITLE:  - Preclinical Rationale for PI3K/Akt/mTOR Pathway Inhibitors as Therapy for Epidermal Growth Factor Receptor Inhibitor-Resistant Non-Small-Cell Lung Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Lung Cancer. 2013 Jan 15. pii: S1525-7304(12)00266-5. doi: 10.1016/j.cllc.2012.12.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.cllc.2012.12.001

AUTORES / AUTHORS:  - Gadgeel SM; Wozniak A

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, MI; Department of Oncology, Karmanos Cancer Institute, Wayne  State University, Detroit, MI. Electronic address: gadgeels@karmanos.org.

RESUMEN / SUMMARY:  - Mutations in the epidermal growth factor receptor gene (EGFR) are frequently observed in non-small-cell lung cancer (NSCLC), occurring in about 40% to 60% of  never-smokers and in about 17% of patients with adenocarcinomas. EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have transformed therapy for patients with EGFR-mutant NSCLC and have proved superior to chemotherapy as first-line treatment for this patient group. Despite these benefits, there are currently 2 key challenges associated with EGFR inhibitor therapy for patients with NSCLC. First, only 85% to 90% of patients with the EGFR mutation derive clinical benefit from EGFR TKIs, with the remainder demonstrating innate resistance to therapy. Second, acquired resistance to EGFR TKIs inevitably occurs in patients who initially respond to therapy, with a median duration of response of about 10 months. Mutant EGFR activates various subcellular signaling  cascades, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which demonstrates maintained activity in a variety  of TKI-resistant cancers. Given the fundamental role of the PI3K/Akt/mTOR pathway in tumor oncogenesis, proliferation, and survival, PI3K pathway inhibitors have emerged as a possible solution to the problem of EGFR TKI resistance. However resistance to EGFR TKIs is associated with considerable heterogeneity and complexity. Preclinical experiments investigating these phenomena suggest that in some patients, PI3K inhibitors will have to be paired with other targeted agents  if they are to be effective. This review discusses the preclinical data supporting PI3K/Akt/mTOR pathway inhibitor combinations in EGFR TKI-resistant NSCLC from the perspective of the various agents currently being investigated in  clinical trials.

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[879]

TÍTULO / TITLE:  - Genetic variations in the transforming growth factor Beta pathway as predictors of bladder cancer risk.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51758. doi: 10.1371/journal.pone.0051758. Epub 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051758

AUTORES / AUTHORS:  - Wei H; Kamat AM; Aldousari S; Ye Y; Huang M; Dinney CP; Wu X

INSTITUCIÓN / INSTITUTION:  - Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

RESUMEN / SUMMARY:  - Bladder cancer is the fifth most common cancer in the United States, and identifying genetic markers that may predict susceptibility in high-risk population is always needed. The purpose of our study is to determine whether genetic variations in the transforming growth factor-beta (TGF-beta) pathway are  associated with bladder cancer risk. We identified 356 single-nucleotide polymorphisms (SNPs) in 37 key genes from this pathway and evaluated their association with cancer risk in 801 cases and 801 controls. Forty-one SNPs were significantly associated with cancer risk, and after adjusting for multiple comparisons, 9 remained significant (Q-value </=0.1). Haplotype analysis further  revealed three haplotypes within VEGFC and two haplotypes in EGFR were significantly associated with increased bladder cancer risk compared to the most  common haplotype. Classification and regression tree analysis further revealed potential high-order gene-gene interactions, with VEGFC: rs3775194 being the initial split, which suggests that this variant is responsible for the most variation in risk. Individuals carrying the common genotype for VEGFC: rs3775194  and EGFR: rs7799627 and the variant genotype for VEGFR: rs4557213 had a 4.22-fold increase in risk, a much larger effect magnitude than that conferred by common genotype for VEGFR: rs4557213. Our study provides the first epidemiological evidence supporting a connection between TGF-beta pathway variants and bladder cancer risk.

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[880]

TÍTULO / TITLE:  - Bak is a key molecule in apoptosis induced by methanol extracts of Codonopsis lanceolata and Tricholoma matsutake in HSC-2 human oral cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2012 Dec;4(6):1379-1383. Epub 2012 Sep 6.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.898

AUTORES / AUTHORS:  - Shin JA; Kim JS; Hong IS; Cho SD

INSTITUCIÓN / INSTITUTION:  - Department of Oral Pathology, School of Dentistry, Institute of Oral Bioscience,  Chonbuk National University, Jeonju;

RESUMEN / SUMMARY:  - Since the 5-year survival rate of oral cancer remains low, more effective and non-toxic therapeutic and preventive strategies are required. Certain natural products possess anti-cancer properties. The present study investigated the effects of the methanol extracts of Codonopsis lanceolata (MECI) and Tricholoma matsutake (METM) and identified the molecular target in HSC-2 human oral cancer cells. The results revealed that MECI and METM inhibited growth and induced apoptosis, as demonstrated by poly (ADP-ribose) polymerase (PARP) cleavage and nuclear condensation and fragmentation. The compounds also increased Bak protein  expression, while Bax, Bcl-XL and Mcl-1 were not affected. The results of the present study show that MECI and METM induce apoptosis to inhibit tumor growth of HSC-2 cells by modulating the Bak protein and suggest that Codonopsis lanceolata  and Tricholoma matsutake are potential anticancer drug candidates for oral cancer.

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[881]

TÍTULO / TITLE:  - Recurrent prognostic factors and expression of GLUT-1, PI3K and p-Akt in adenoid  cystic carcinomas of the head and neck: Clinicopathological features and biomarkers of adenoid cystic carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2012 Dec;4(6):1234-1240. Epub 2012 Sep 5.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.895

AUTORES / AUTHORS:  - Fang J; Bao YY; Zhou SH; Luo XM; Yao HT; He JF; Wang QY

INSTITUCIÓN / INSTITUTION:  - Department of Otolaryngology, The Second Hospital of Jiaxing City, Jiaxing 314000; ; Departments of Otolaryngology.

RESUMEN / SUMMARY:  - The purpose of this study was to explore the factors associated with the recurrence of adenoid cystic carcinomas (ACCs). We examined the recurrence values of clinicopathological variables and GLUT-1, p-Akt and PI3K expression in 42 patients with ACC. Of the 42 patients, 17 developed recurrence following initial  surgery. The positive rates of GLUT-1, PI3K and p-Akt protein expression in ACC were 38.1, 38.1 and 50.0%, respectively. The expression of GLUT-1, p-Akt or PI3K  protein in ACC was higher than that in inflammatory lesions or benign tumors. Our study demonstrated that T stage, a positive resection margin, perineural invasion, surgery without postoperative radiotherapy and the expression of GLUT-1, PI3K and p-Akt were factors predictive of recurrence by univariate analyses. In multivariate analyses, perineural invasion, a positive resection margin and p-Akt were significant predictors of recurrence. Initial surgery is very significant in the recurrence of ACC. Overexpression of GLUT-1, PI3K and p-Akt may also play a role in its development and recurrence.

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[882]

TÍTULO / TITLE:  - Rituximab for managing acquired hemophilia A in a case of chronic neutrophilic leukemia with the JAK2 kinase V617F mutation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Blood Med. 2012;3:157-61. doi: 10.2147/JBM.S37631. Epub 2012 Dec 5.

            ●● Enlace al texto completo (gratuito o de pago) 2147/JBM.S37631

AUTORES / AUTHORS:  - Imashuku S; Kudo N; Kubo K; Saigo K; Okuno N; Tohyama K

INSTITUCIÓN / INSTITUTION:  - Division of Hematology, Takasagoseibu Hospital, Takasago, Japan.

RESUMEN / SUMMARY:  - BACKGROUND: Acquired hemophilia A is rarely found in association with myeloproliferative neoplasms, such as the JAK2 kinase V617F mutation-positive chronic neutrophilic leukemia (CNL). CASE REPORT: An 80-year-old Japanese male was diagnosed with acquired hemophilia A. He had compartment-like symptoms due to soft tissue hemorrhage in his left forearm and right lower extremity. A blood examination showed neutrophilia with a white blood cell count of 31,900/muL (91.9% neutrophils), an activated partial thromboplastin time of 69.0 seconds, coagulation factor VIII (FVIII) < 1.0%, and anti-FVIII inhibitor, 190 BU/mL. The  bleeding episodes were controlled with intravenous activated prothrombin complex  concentrate (FEIBA(®)) followed by recombinant factor VIIa (NovoSeven(®)). In addition, oral prednisolone (maximum dose, 30 mg/day) plus four doses of rituximab effectively suppressed anti-FVIII inhibitor levels while simultaneously reducing the neutrophil count. CNL with the JAK2 kinase V617F mutation was identified as the underlying disease. CONCLUSION: This report describes the effectiveness of a combination of prednisolone and rituximab in managing acquired hemophilia A in an elderly man with a rare case of JAK2 kinase V617F mutation-positive CNL.

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[883]

TÍTULO / TITLE:  - Prognostic significance of the expression of GFRalpha1, GFRalpha3 and Syndecan-3, proteins binding ARTEMIN, in mammary carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Cancer. 2013 Jan 26;13(1):34.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2407-13-34

AUTORES / AUTHORS:  - Wu ZS; Pandey V; Wu WY; Ye S; Zhu T; Lobie PE

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Artemin (ARTN) has been implicated in promoting oncogenicity, tumor growth and invasiveness in diverse human malignancies. However, the clinical and prognostic significance of upstream ligand binding components, potentially mediating ARTN oncogenicity, largely remain to be determined in mammary carcinoma. METHODS: We determined the mRNA and protein expression of three proteins demonstrated to bind ARTN, namely GFRalpha1, GFRalpha3 and Syndecan-3 (SDC3), in benign breast disease and mammary carcinoma by in situ hybridization and immunohistochemistry, respectively. Their prognostic significance combined with ARTN expression was also investigated in mammary carcinoma. RESULTS: The expression of GFRalpha1 and GFRalpha3, but not SDC3, was  significantly increased in mammary carcinoma and positively associated with tumor lymph node metastases, higher clinical stage and HER-2 positivity. Moreover, both GFRalpha1 and GFRalpha3 expression were significantly associated with survival outcome of patients with mammary carcinoma by univariate and multivariate analyses, whereas expression of SDC3 was not. Interestingly, co-expression of ARTN with either GFRalpha1 or GFRalpha3, but not SDC3, produced synergistic increases in the odds ratio for both relapse-free and overall survival in patients with mammary carcinoma. Furthermore, significant association of GFRalpha1 and GFRalpha3 expression with survival outcome observed herein were restricted to ER negative or HER-2 negative mammary carcinoma. CONCLUSIONS: The expression of GFRalpha1 and/or GFRalpha3, especially when combined with ARTN expression, may be useful predictors of disease progression and outcome in specific subtypes of mammary carcinoma.

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[884]

TÍTULO / TITLE:  - The green algae Ulva fasciata Delile extract induces apoptotic cell death in human colon cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - In Vitro Cell Dev Biol Anim. 2013 Jan;49(1):74-81. doi: 10.1007/s11626-012-9547-3. Epub 2013 Jan 9.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11626-012-9547-3

AUTORES / AUTHORS:  - Ryu MJ; Kim AD; Kang KA; Chung HS; Kim HS; Suh IS; Chang WY; Hyun JW

INSTITUCIÓN / INSTITUTION:  - Food and Nutrition, Duksung Women’s University, Seoul, 132-714, Republic of Korea.

RESUMEN / SUMMARY:  - This study investigated the mechanisms underlying the cytotoxicity of the green algae Ulva fasciata Delile. U. fasciata extract (UFE) inhibited the growth of HCT 116 human colon cancer cells by 50% at a concentration of 200 mug/ml. In addition, UFE stimulated the production of intracellular reactive oxygen species, an effect that was abolished by pretreatment with N-acetyl cysteine, which also inhibited the cytotoxic effects of UFE. UFE also induced morphological changes indicative of apoptosis, such as the formation of apoptotic bodies, DNA fragmentation, an increase in the population of apoptotic sub-G(1) phase cells, and mitochondrial membrane depolarization. Concomitant activation of the mitochondria-dependent apoptotic pathway occurred via modulation of Bax and Bcl-2 expression, resulting in disruption of the mitochondrial membrane potential and activation of caspase-9 and caspase-3. This is the first report to demonstrate the cytotoxic effect of U. fasciata on human colon cancer cells and to provide a  possible mechanism for this activity.

 

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[885]

TÍTULO / TITLE:  - DNA methyltransferase inhibitor zebularine inhibits human hepatic carcinoma cells proliferation and induces apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e54036. doi: 10.1371/journal.pone.0054036. Epub 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0054036

AUTORES / AUTHORS:  - Nakamura K; Aizawa K; Nakabayashi K; Kato N; Yamauchi J; Hata K; Tanoue A

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.

RESUMEN / SUMMARY:  - Hepatocellular carcinoma is one of the most common cancers worldwide. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine (1-(beta-(D)-ribofuranosyl)-1,2-dihydropyrimidin-2-one) acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in  vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on hepatocellular carcinoma cell line HepG2. We demonstrate  that zebularine exhibits antitumor activity on HepG2 cells by inhibiting cell proliferation and inducing apoptosis, however, it has little effect on DNA methylation in HepG2 cells. On the other hand, zebularine treatment downregulated CDK2 and the phosphorylation of retinoblastoma protein (Rb), and upregulated p21(WAF/CIP1) and p53. We also found that zebularine treatment upregulated the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK). These results  suggest that the p44/42 MAPK pathway plays a role in zebularine-induced cell-cycle arrest by regulating the activity of p21(WAF/CIP1) and Rb. Furthermore, although the proapoptotic protein Bax levels were not affected, the  antiapoptotic protein Bcl-2 level was downregulated with zebularine treatment. In addition, the data in the present study indicate that inhibition of the double-stranded RNA-dependent protein kinase (PKR) is involved in inducing apoptosis with zebularine. These results suggest a novel mechanism of zebularine-induced cell growth arrest and apoptosis via a DNA methylation-independent pathway in hepatocellular carcinoma.

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[886]

TÍTULO / TITLE:  - Molecular cytogenetics as a clinical test for prognostic and predictive biomarkers in newly diagnosed ovarian cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Ovarian Res. 2013 Jan 4;6(1):2.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1757-2215-6-2

AUTORES / AUTHORS:  - Gunn S; Reveles X; Weldon K; Barrera A; Ishaque M; Taylor D; McCaskill C; Kim J; Shah R; Mohammed M; Barry T; Kaiser B; Patnaik A; Tolcher A

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: There is a clinical need for routinely available genomic biomarker testing in newly diagnosed ovarian cancer. In the current study we performed molecular cytogenetics using a validated array based comparative genomic hybridization (array CGH) assay to screen for the presence of predictive  and prognostic biomarkers in archival diagnostic tissue from ovarian cancer patients. We hypothesized that biomarkers of high-risk disease would be detectable in tumor samples from patients with treatment refractory, advanced disease, and would be detected less frequently in tumor samples from patients with more favorable outcomes. In addition, we predicted that the use of a genome-wide copy number analysis (CNA) testing platform would enable us to identify novel potentially targetable chromosomal alterations of therapeutic significance in a percentage of cases. METHODS: Formalin-fixed paraffin-embedded  tissue (FFPE) tumor bank specimens were retrieved from the initial surgical resection for 18 ovarian cancer patients. Molecular cytogenetics was performed by array CGH for the detection of somatic chromosomal alterations associated with high-risk disease including amplifications of the CCNE1 and HER2 genes. Genomic risk stratification results were correlated with available clinical data. CGH data from each patient’s tumor genome was also surveyed for the presence of potentially targetable aberrations. Relevant therapeutic agents and open studies  for investigational drugs were reported for each patient. RESULTS: High-risk genomic alterations were identified in 12/18 (67%) of cases and all patients with high-risk markers had advanced, treatment refractory disease. Three tumors with minimal genomic changes had no high-risk markers and were from patients with Stage I/II disease that had been completely resected and under surveillance for recurrence. Eleven patients (61%) had at least one potentially targetable genomic alteration including CCNE1, HER2, KRAS gene amplifications, and somatic BRCA1 and/or BRCA2 gene deletions. Bi-allelic PTEN gene deletion was detected in one patient’s tumor. CONCLUSIONS: Clinical genomic profiling of ovarian tumors by array CGH augments pathologic grade and stage to help stratify newly diagnosed ovarian cancer into high and low-risk disease. This personalized genomic information can also help guide treatment planning and disease monitoring by identifying novel potentially targetable genomic alterations that can be used by  clinicians to choose rational directed therapies for patients with chemo-resistant disease.

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[887]

TÍTULO / TITLE:  - Modulation of miR122 expression affects the interferon response in human hepatoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Med Report. 2013 Feb;7(2):585-90. doi: 10.3892/mmr.2012.1233. Epub 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 3892/mmr.2012.1233

AUTORES / AUTHORS:  - Li A; Qian J; He J; Zhang Q; Zhai A; Song W; Li Y; Ling H; Zhong Z; Zhang F

INSTITUCIÓN / INSTITUTION:  - Department of Microbiology, Harbin Medical University, Ministry of Education of China, Harbin 150081, P.R. China.

RESUMEN / SUMMARY:  - Type I interferon (IFN) is believed to play significant roles in limiting tumor growth. It has been revealed that the induction of endogenous IFN expression is one of the key mechanisms for successful IFN therapy. However, recent studies have shown that the efficacy of type I IFN therapy has limitations in the clinical treatment of certain tumors, including hepatocellular carcinoma (HCC). It has been revealed that the expression of miR122 is significantly decreased in  HCC and that restoration of miR122 expression may improve the prognosis of this condition. Previous studies also showed that patients with low miR122 levels in the liver responded poorly to the IFN therapy. We previously identified that the  IFN expression was reduced when miR122 was suppressed in human oligodendrocytes.  Based on these studies, it was hypothesized that the expression of miR122 may modulate the endogenous IFN expression and subsequently affect the treatment outcome of IFN therapy for HCC. The results of the present study showed that miR122abundant Huh7 cells responded more significantly than miR122deficient HepG2 cells when treated with exogenous IFN. Upregulation of miR122 significantly increased the ability of exogenous IFNinduced IFN expression, while downregulation of miR122 decreased this ability. These data indicate that a high  level of miR122 expression may promote the expression of type I IFN induced by exogenous IFNs and further contribute to IFN therapy for HCC.

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[888]

TÍTULO / TITLE:  - Successful autologous stem cell collection with filgrastim and plerixafor after long-term lenalidomide therapy for multiple myeloma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hematol Rep. 2012 Nov 19;4(4):e26. doi: 10.4081/hr.2012.e26. Epub 2012 Dec 6.

            ●● Enlace al texto completo (gratuito o de pago) 4081/hr.2012.e26

AUTORES / AUTHORS:  - Agarwal R; Abidi MH

INSTITUCIÓN / INSTITUTION:  - UT Houston MD Anderson Cancer Center, Houston, TX;

RESUMEN / SUMMARY:  - Novel agents such as lenalidomide have demonstrated responses similar to high-dose melphalan and autologous stem cell transplant in multiple myeloma. For  patients who are started on lenalidomide, it is advisable to collect stem cells early if future transplant is contemplated. We are reporting a patient who underwent successful stem cell mobilization after 68 cycles of lenalidomide. A 60-year old male presented with back pain. He was diagnosed with stage IIA, IgA multiple myeloma. He was enrolled in a clinical trial and was randomized to receive lenalidomide plus dexamethasone. He received a total of 68 cycles of lenalidomide before progressing. He underwent mobilization of stem cells using filgrastim and plerixafor. He underwent successful stem cell transplant. Longer duration of lenalidomide adversely effects stem cell mobilization. To the best of our knowledge, there has been no other case reported in which stem cell mobilization was feasible after such a long (68 months) duration of uninterrupted lenalidomide therapy.

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[889]

TÍTULO / TITLE:  - Mutant N-Ras protects colorectal cancer cells from stress-induced apoptosis and contributes to cancer development and progression.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Discov. 2012 Dec 28.

            ●● Enlace al texto completo (gratuito o de pago) 1158/2159-8290.CD-12-0198

AUTORES / AUTHORS:  - Wang Y; Velho S; Vakiani E; Peng S; Bass AJ; Chu GC; Gierut J; Bugni JM; Der CJ; Philips M; Solit DB; Haigis KM

INSTITUCIÓN / INSTITUTION:  - 1Molecular Pathology Unit, Massachusetts General Hospital.

RESUMEN / SUMMARY:  - N-Ras is one member of a family of oncoproteins that are commonly mutated in cancer. Activating mutations in N-Ras occur in a subset of colorectal cancers, but little in known about how the mutant protein contributes to onset and progression of the disease. Using genetically engineered mice, we find that mutant N-Ras strongly promotes tumorigenesis in the context of inflammation. The  pro-tumorigenic nature of mutant N-Ras is related to its anti-apoptotic function, which is mediated by activation of a non-canonical MAPK pathway that signals through Stat3. As a result, inhibition of MEK selectively induces apoptosis in autochthonous colonic tumors expressing mutant N-Ras. The translational significance of this finding is highlighted by our observation that NRAS mutation correlates with a less favorable clinical outcome for colorectal cancer patients. These data demonstrate for the first time the important role that N-Ras plays in  colorectal cancer.

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[890]

TÍTULO / TITLE:  - Expression of insulin-like growth factor II mRNA-binding protein 3 predicts early recurrence and poor prognosis in intrahepatic cholangiocarcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Surg. 2013;11(1):85-91. doi: 10.1016/j.ijsu.2012.11.021. Epub 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ijsu.2012.11.021

AUTORES / AUTHORS:  - Chen YL; Jeng YM; Hsu HC; Lai HS; Lee PH; Lai PL; Yuan RH

INSTITUCIÓN / INSTITUTION:  - Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.

RESUMEN / SUMMARY:  - INTRODUCTION: Insulin-like growth factor-II mRNA-binding protein 3 (IMP3), a newly identified oncofetal RNA-binding protein, plays a pivotal role in the regulation of cell growth and migration during early stages of embryogenesis, and is found to be expressed in various human cancers. In this study, we elucidated the clinicopathological significance of IMP3 expression in intrahepatic cholangiocarcinoma (ICC). METHODS: From March 1995 to December 2003, 61 surgically resected, unifocal primary ICCs were studied. IMP3 protein expression  was detected by immunohistochemical staining. RESULTS: IMP3 protein was expressed in 25 of 61 ICCs (41.0%). In addition to correlating with tumor grade (p = 0.0276), tumor stage (p = 0.0059), lymphovascular invasion (p = 0.0198), serum carbohydrate antigen 19-9 level (p = 0.0146), IMP3 expression predicted early tumor recurrence (ETR) (p = 0.0059) and was a strong indicator of worse disease-free survival (p = 0.0001) and overall survival (p = 0.0007). Even though we did not find that IMP3 expression exerted prognostic impact independent of tumor stage, multivariate analysis confirmed that IMP3 expression was an independent risk factor of high-stage tumor and ETR (p = 0.0170, and p = 0.0052,  respectively), and thus it contributed to poor prognosis in ICC patients. CONCLUSIONS: IMP3 expression can serve as a novel maker for ETR and prognostic prediction, and may be a target for adjuvant therapy of patients with ICC after tumor resection.

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[891]

TÍTULO / TITLE:  - Mitochondrial telomerase protects cancer cells from nuclear DNA damage and apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e52989. doi: 10.1371/journal.pone.0052989. Epub 2013 Jan 9.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052989

AUTORES / AUTHORS:  - Singhapol C; Pal D; Czapiewski R; Porika M; Nelson G; Saretzki GC

INSTITUCIÓN / INSTITUTION:  - Institute for Ageing and Health, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, United Kingdom.

RESUMEN / SUMMARY:  - Most cancer cells express high levels of telomerase and proliferate indefinitely. In addition to its telomere maintenance function, telomerase also has a pro-survival function resulting in an increased resistance against DNA damage and decreased apoptosis induction. However, the molecular mechanisms for this protective function remain elusive and it is unclear whether it is connected to telomere maintenance or is rather a non-telomeric function of the telomerase protein, TERT. It was shown recently that the protein subunit of telomerase can shuttle from the nucleus to the mitochondria upon oxidative stress where it protects mitochondrial function and decreases intracellular oxidative stress. Here we show that endogenous telomerase (TERT protein) shuttles from the nucleus  into mitochondria upon oxidative stress in cancer cells and analyzed the nuclear  exclusion patterns of endogenous telomerase after treatment with hydrogen peroxide in different cell lines. Cell populations excluded TERT from the nucleus upon oxidative stress in a heterogeneous fashion. We found a significant correlation between nuclear localization of telomerase and high DNA damage, while cells which excluded telomerase from the nucleus displayed no or very low DNA damage. We modeled nuclear and mitochondrial telomerase using organelle specific  localization vectors and confirmed that mitochondrial localization of telomerase  protects the nucleus from inflicted DNA damage and apoptosis while, in contrast,  nuclear localization of telomerase correlated with higher amounts of DNA damage and apoptosis. It is known that nuclear DNA damage can be caused by mitochondrially generated reactive oxygen species (ROS). We demonstrate here that mitochondrial localization of telomerase specifically prevents nuclear DNA damage by decreasing levels of mitochondrial ROS. We suggest that this decrease of oxidative stress might be a possible cause for high stress resistance of cancer cells and could be especially important for cancer stem cells.

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[892]

TÍTULO / TITLE:  - 8-Chloroadenosine 3’,5’-monophosphate induces cell cycle arrest and apoptosis in  multiple myeloma cells through multiple mechanisms.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2012 Dec;4(6):1384-1388. Epub 2012 Sep 11.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.905

AUTORES / AUTHORS:  - Cheng YM; Zhu Q; Yao YY; Tang Y; Wang MM; Zou LF

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China.

RESUMEN / SUMMARY:  - The aim of this study was to investigate the molecular mechanism of 8-chloroadenosine 3’,5’-monophosphate (8-Cl-cAMP) in the inhibition of the growth and induction of apoptosis of multiple myeloma (MM) cells. Two MM-derived cell lines, RPMI-8226 and U266, were used. Cell viability, apoptosis induction and mitochondrial transmembrane potential were determined and the expression levels of cell cycle regulatory proteins (Cdk2, cyclin E, p27 and c-myc) and p38 mitogen-activated protein kinase (MAPK) protein were detected. Following treatment with 8-Cl-cAMP, the percentage of apoptotic cells increased in a concentration- and time-dependent manner and the mitochondrial transmembrane potential collapsed to reveal typical apoptotic features. Our data further demonstrated that 8-Cl-cAMP induced progressive phosphorylation of p38 MAPK and that the expression levels of p27 proteins in the MM cells were increased whereas those of c-myc were significantly decreased. Notably, the proapoptotic effect of  8-Cl-cAMP was largely prevented by a p38 MAPK inhibitor. Furthermore, knockdown of p27 was able to decrease the 8-Cl-cAMP-induced apoptosis in the MM cells. These results indicate that 8-Cl-cAMP induced p27-dependent cell cycle arrest and apoptosis in the MM cells, which demonstrates the potential of cAMP-modulating agents for use in the treatment of MM.

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[893]

TÍTULO / TITLE:  - Chemosensitization role of endocrine hormones in cancer chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin Med J (Engl). 2013 Jan;126(1):175-80.

AUTORES / AUTHORS:  - Huang JB; Ji GY; Xing L; Wang ZW; Li HY; Ren GS; Wu KN; Kong LQ

INSTITUCIÓN / INSTITUTION:  - Department of Endocrine and Breast Surgery, First Affiliated Hospital, Chongqing  Medical University, Chongqing 400016, China.

 

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[894]

TÍTULO / TITLE:  - Neohesperidin induces cellular apoptosis in human breast adenocarcinoma MDA-MB-231 cells via activating the Bcl-2/Bax-mediated signaling pathway.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Nat Prod Commun. 2012 Nov;7(11):1475-8.

AUTORES / AUTHORS:  - Xu F; Zang J; Chen D; Zhang T; Zhan H; Lu M; Zhuge H

INSTITUCIÓN / INSTITUTION:  - Department of Laboratory Medicine, Wuxi Municipal Women and Children Health Hospital, Wuxi 214002, Jiangsu Province, China.

RESUMEN / SUMMARY:  - Neohesperidin, a flavonoid compound found in high amounts in Poncirus trifoliata, has free radical scavenging activity. For the first time, our study indicated that neohesperidin also induces cell apoptosis in human breast adenocarcinoma MDA-MB-231 cells, which was possibly mediated by regulating the P53/Bcl-2/Bax pathway. MDA-MB-231 cells were subjected to treatment with neohesperidin. MTT and Trypan blue exclusion assays were applied to assess the cell viability. The morphological changes of cells were observed using an inverted microscope, and cell apoptosis was detected by flow cytometric analysis. Immunoblot analysis was  conducted to evaluate the protein expressions of apoptosis-related genes, including P53, Bcl-2 and Bax. Our results indicated that the proliferation of MDA-MB-231 cells was inhibited by the treatment with neohesperidin in a time- and dose-dependent manner. The IC50 values of neohesperidin at 24 and 48 h were 47.4  +/- 2.6 microM and 32.5 +/- 1.8 microM, respectively. The expressions of P53 and  Bax in the neohesperidin-treated cells were significantly up-regulated, while that of Bcl-2 was down-regulated. Our study suggested that neohesperidin could induce apoptosis of MDA-MB-231 cells, a process which was associated with the activation of the Bcl-2/Bax-mediated signaling pathway.

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[895]

TÍTULO / TITLE:  - Ratio of involved/uninvolved immunoglobulin quantification by Hevylite assay: clinical and prognostic impact in multiple myeloma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Exp Hematol. Acceso gratuito al texto completo.

            ●● Enlace a la Editora de la Revista http://www.medicinedirect.com/journal 

            ●● Cita: Experimental Hematology: <> Oncol. 2012 Apr 23;1(1):9. doi: 10.1186/2162-3619-1-9.

            ●● Enlace al texto completo (gratuito o de pago) 1186/2162-3619-1-9

AUTORES / AUTHORS:  - Koulieris E; Panayiotidis P; Harding SJ; Kafasi N; Maltezas D; Bartzis V; Tzenou T; Dimou M; Georgiou G; Mirbahai L; Bradwell AR; Kyrtsonis MC

INSTITUCIÓN / INSTITUTION:  - Haematology Section of 1st Department of Propedeutic Internal Medicine, Athens Medical School, Athens, Greece. A.R.Bradwell@bham.ac.uk.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: HevyLite is a new, recently developed method that facilitates separate quantification of the kappa- and lambda-bounded amounts of a given immunoglobulin (Ig). Using this method, we measured intact immunoglobulin (heavy/light chain; HLC) IgG-kappa, IgG-lambda, IgA-kappa, IgA-lambda individually, as well as their deriving ratios (HLCR) in a series of IgG or IgA multiple myeloma (MM) patients, to investigate and assess the contribution of these tests to disease evaluation. PATIENTS AND METHODS: HevyLite assays were used in sera from 130 healthy individuals (HI) and 103 MM patients, at time of diagnosis. In patients, the level of paraprotein was IgG in 78 (52 IgG-kappa, 26  IgG-lambda) and IgAlpha in 25 (13 IgAlpha-kappa, 12 IgAlpha-lambda). Durie-Salmon and International Staging System stages were evenly distributed. Symptomatic patients (n = 77) received treatment while asymptomatic ones (n = 26) were followed. Patients’ median follow-up was at 32.6 months. HLCR was calculated with the involved Ig (either G or A) as numerator. RESULTS: In HI, median IgG-kappa was 6.85, IgG-lambda 3.81, IgA-kappa 1.19 and IgA-lambda 0.98 g/L. The corresponding median involving HLC values in MM patients were 25.8, 23.45, 28.9 and 36.4 g/L. HLC-IgG related to anemia, high serum free light chain ratio and extensive bone marrow infiltration, while high HLCR correlated with the same plus increased beta2-microglobulin. In addition, increased HLCR and the presence of immunoparesis correlated with time to treatment. Patients with high HLCR had a significantly shorter survival (p = 0.022); HLCR retained its prognostic value in multivariate analysis. CONCLUSIONS: HLC and HLCR quantify the precise amount of the involved immunoglobulin more accurately than other methods; moreover, they carry prognostic information regarding survival in MM patients.

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[896]

TÍTULO / TITLE:  - A case of successful treatment of granulocyte colony-stimulating factor producing hepatocellular carcinoma accompanying type B hepatitis with tegafur-uracil.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Nihon Shokakibyo Gakkai Zasshi. 2012;109(12):2088-96.

AUTORES / AUTHORS:  - Ito T; Okubo K; Shiomi M; Narita M; Morita K; Takeuchi A; Kanazawa H; Shimizu J; Takeyama T; Hashizume K; Shibahara H; Nishimura D; Katada N; Katano Y; Goto H

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Toyota Kosei Hospital.

RESUMEN / SUMMARY:  - A 37-year-old man underwent lobectomy of the right liver for granulocyte colony-stimulating factor (G-CSF) producing hepatocellular carcinoma accompanying type B hepatitis. Within two months after the surgery, lung metastases were revealed and administration of sorafenib was begun, however, the lung metastases  continued to enlarge. Changing the patient’s medication to tegafur-uracil provided remarkable reduction of the lung metastases. The patient is alive two years after diagnosis and receives outpatient chemotherapy. We concluded that this case is valuable with regard to the extreme rarity of G-CSF producing hepatocellular carcinoma and its successful treatment in this case.

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[897]

TÍTULO / TITLE:  - Hsp90 inhibitors are efficacious against Kaposi Sarcoma by enhancing the degradation of the essential viral gene LANA, of the viral co-receptor EphA2 as well as other client proteins.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS Pathog. 2012 Nov;8(11):e1003048. doi: 10.1371/journal.ppat.1003048. Epub 2012 Nov 29.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.ppat.1003048

AUTORES / AUTHORS:  - Chen W; Sin SH; Wen KW; Damania B; Dittmer DP

INSTITUCIÓN / INSTITUTION:  - Department of Microbiology and Immunology, Program in Global Oncology, Lineberger Comprehensive Cancer Center, Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

RESUMEN / SUMMARY:  - Heat-shock protein 90 (Hsp90) inhibitors exhibit activity against human cancers.  We evaluated a series of new, oral bioavailable, chemically diverse Hsp90 inhibitors (PU-H71, AUY922, BIIB021, NVP-BEP800) against Kaposi sarcoma (KS). All Hsp90 inhibitors exhibited nanomolar EC(50) in culture and AUY922 reduced tumor burden in a xenograft model of KS. KS is associated with KS-associated herpesvirus (KSHV). We identified the viral latency associated nuclear antigen (LANA) as a novel client protein of Hsp90 and demonstrate that the Hsp90 inhibitors diminish the level of LANA through proteasomal degradation. These Hsp90 inhibitors also downregulated EphA2 and ephrin-B2 protein levels. LANA is essential for viral maintenance and EphA2 has recently been shown to facilitate KSHV infection; which in turn feeds latent persistence. Further, both molecules are required for KS tumor formation and both were downregulated in response to Hsp90 inhibitors. This provides a rationale for clinical testing of Hsp90 inhibitors in KSHV-associated cancers and in the eradication of latent KSHV reservoirs.

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[898]

TÍTULO / TITLE:  - Prognostic significance of AKT/mTOR signaling in advanced neuroendocrine tumors treated with somatostatin analogs.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Onco Targets Ther. 2012;5:409-16. doi: 10.2147/OTT.S36330. Epub 2012 Nov 28.

            ●● Enlace al texto completo (gratuito o de pago) 2147/OTT.S36330

AUTORES / AUTHORS:  - Fernandes I; Pacheco TR; Costa A; Santos AC; Fernandes AR; Santos M; Oliveira AG; Casimiro S; Quintela A; Fernandes A; Ramos M; Costa L

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Hospital Santa Maria, CHLN, Lisboa, Portugal; ; Clinical and Translational Oncology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal;

RESUMEN / SUMMARY:  - INTRODUCTION: Somatostatin analogs (SSAs) are used as part of standard treatment  for advanced neuroendocrine tumors (NETs). The mechanisms behind the antiproliferative action of SSAs remain largely unknown, but a connection with the mammalian target of rapamycin (mTOR) signaling pathway has been suggested. Our purpose was to evaluate the activation status of the AKT/mTOR pathway in advanced metastatic NETs and identify biomarkers of response to SSA therapy. PATIENTS AND METHODS: Expression of phosphatase and tensin homolog (PTEN), phosphorylated (p)-AKT(Ser473), and p-S6(Ser240/244) was evaluated using immunohistochemistry in archival paraffin samples from 23 patients. Expression levels were correlated with clinicopathological parameters and progression-free survival under treatment with SSAs. RESULTS: A positive association between p-AKT and p-S6 expression was identified (P = 0.01) and higher expression of both markers was observed in pancreatic NETs. AKT/mTOR activation was observed without the loss of PTEN expression. Tumors showing AKT/mTOR signaling activation progressed faster when treated with SSAs: higher expression of p-AKT or p-S6 predicted a median progression-free survival of 1 month vs 26.5 months for lower  expression (P = 0.02). CONCLUSION: Constitutive activation of the AKT/mTOR pathway was associated with shorter time-to-progression in patients undergoing treatment with SSAs. Larger case series are needed to validate whether p-AKT(Ser473) and p-S6(Ser240/244) can be used as prognostic markers of response  to therapy with SSAs.

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[899]

TÍTULO / TITLE:  - Protection of Neuroblastoma Neuro2A Cells from Hypoxia-Induced Apoptosis by Cyclic Phosphatidic Acid (cPA).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51093. doi: 10.1371/journal.pone.0051093. Epub 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051093

AUTORES / AUTHORS:  - Gotoh M; Sano-Maeda K; Murofushi H; Murakami-Murofushi K

INSTITUCIÓN / INSTITUTION:  - The Division of Life Sciences, Ochanomizu University, Tokyo, Japan.

RESUMEN / SUMMARY:  - Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator with a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. We have previously shown that cPA significantly suppresses ischemia-induced delayed neuronal death and the accumulation of glial fibrillary  acidic protein in the CA1 region of the rat hippocampus. These results indicated  that the systemic administration of cPA can protect hippocampal neurons against ischemia-induced delayed neuronal cell death. In the current study, we investigated the effects of cPA on neuronal cell death caused by hypoxia in vitro and the molecular mechanisms underlying these effects. We used cobalt chloride (CoCl(2)) to expose cells to hypoxic conditions in vitro. Treating mouse neuroblastoma (Neuro2A) cells with CoCl(2) induced nuclear DNA condensation and phosphatidylserine exposure. However, adding cPA led to the suppression of CoCl(2)-induced apoptosis in a cPA dose-dependent manner and attenuated the increase in the Bax/Bcl-2 ratio caused by CoCl(2). Quantitative PCR analysis showed that Neuro2A cells strongly express the LPA(1), LPA(2), and LPA(6), which  are G-protein coupled receptors that can be activated by cPA. To date, LPA(1) and LPA(2) have been reported to exhibit antiapoptotic activity. Therefore, to assess the roles of LPA(1) and LPA(2) on cPA-induced neuroprotective functions, Ki16425, a selective LPA(1) and LPA(3) antagonist, was adopted to know the LPA(1) function and siRNA was used to knockdown the expression of LPA(2). On the basis of our results, we propose that cPA-induced protection of Neuro2A cells from CoCl(2)-induced hypoxia damage is mediated via LPA(2).

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[900]

TÍTULO / TITLE:  - High DNA Methyltransferase DNMT3B Levels: A Poor Prognostic Marker in Acute Myeloid Leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51527. doi: 10.1371/journal.pone.0051527. Epub 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051527

AUTORES / AUTHORS:  - Hayette S; Thomas X; Jallades L; Chabane K; Charlot C; Tigaud I; Gazzo S; Morisset S; Cornillet-Lefebvre P; Plesa A; Huet S; Renneville A; Salles G; Nicolini FE; Magaud JP; Michallet M

INSTITUCIÓN / INSTITUTION:  - Service d’Hematologie Biologique, Centre Hospitalier Lyon-Sud, Pierre-Benite France, Hospices Civils de Lyon, Lyon, France ; UMR5239 Pathologies des cellules  lymphoides, Universite Claude Bernard, Lyon, France.

RESUMEN / SUMMARY:  - It has been recently shown that DNA methyl transferase overexpression is correlated with unfavourable prognosis in human malignancies while methylation deregulation remains a hallmark that defines acute myeloid leukemia (AML). The oncogenic transcription factor EVI1 is involved in methylation deregulation and its overexpression plays a major role for predicting an adverse outcome. Moreover, the identification of DNMT3A mutations in AML patients has recently been described as a poor prognostic indicator. In order to clarify relationship between these key actors in methylation mechanisms and their potential impact on  patient outcomes, we analysed 195 de novo AML patients for the expression of DNMT3A, 3B (and its non-catalytic variant 3B(NC)) and their correlations with the outcome and the expression of other common prognostic genetic biomarkers (EVI1, NPM1, FLT3ITD/TKD and MLL) in adult AML. The overexpression of DNMT3B/3B(NC) is (i) significantly correlated with a shorter overall survival, and (ii) inversely  significantly correlated with event-free survival and DNMT3A expression level. Moreover, multivariate analysis showed that a high expression level of DNMT3B/3B(NC) is statistically a significant independent poor prognostic indicator. This study represents the first report showing that the overexpression of DNMT3B/3B(NC) is an independent predictor of poor survival in AML. Its quantification should be implemented to the genetic profile used to stratify patients for therapeutical strategies and should be useful to identify patients who may benefit from therapy based on demethylating agents.

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[901]

TÍTULO / TITLE:  - Apoptotic and Immune Restoration Effects of Ganoderic Acids Define a New Prospective for Complementary Treatment of Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Cell Immunol. 2011 Dec 11;S3:4.

            ●● Enlace al texto completo (gratuito o de pago) 4172/2155-9899.S3-004

AUTORES / AUTHORS:  - Radwan FF; Perez JM; Haque A

INSTITUCIÓN / INSTITUTION:  - Department of Microbiology and Immunology, Hollings Cancer Center, and Children’s Research Institute, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425.

RESUMEN / SUMMARY:  - Considering the fact that a key factor in tumor development is the evasion of immune detection, the search for natural products, which have reduced toxicity towards normal tissues as well as immunostimulatory capabilities has received growing interest. One attractive source of antitumor products is the Ganoderma lucidum mushroom, which has been used for centuries as an herbal medicine for the prevention and treatment of a variety of diseases, including cancer, and has been shown to improve immune function. Interestingly, its methanol soluble triterpenoid extracts, namely Ganoderic Acids (GAs), have been the subject of several recent investigations on their chemotherapeutic effects. While current research has revealed GAs’ role in inducing apoptosis of cancer cells with a much lower toxicity to healthy cells, little information is available on their in vitro and/or in vivo immune activities. In this review, we aim to discuss the current knowledge on GAs, and their potential as apoptosis inducing as well as immune activating molecules that could be a potential alternative approach for designing novel chemoimmunotherapeutics against malignant diseases. We also discuss other new approaches for exploiting the advantages of using a nanoparticle polymer-GA conjugate as a tool for a sustained and targeted delivery of drug in vivo.

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[902]

TÍTULO / TITLE:  - Reduction of Raf Kinase Inhibitor Protein Expression is Associated with Lymph Node Metastasis in Resectable Non-small Cell Lung Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Open Respir Med J. 2012;6:135-8. doi: 10.2174/1874306401206010135. Epub 2012 Nov  30.

            ●● Enlace al texto completo (gratuito o de pago) 2174/1874306401206010135

AUTORES / AUTHORS:  - Yan H; Guoqiang L; Shengxi C; Zhenghao D; Lingjin H

INSTITUCIÓN / INSTITUTION:  - Department of Infectious Disease, Xiangya Hospital, Central South University, Xiangya Road, Changsha, China.

RESUMEN / SUMMARY:  - INTRODUCTION: Raf kinase inhibitor protein (RKIP) had been identified as one of prognostic indictor in various malignant diseases. Association of RKIP expression and the clinical-pathological features were not investigated in patients with resectable non-small cell lung cancer (NSCLC). MATERIALS AND METHODOLOGY: 159 sectioned samples from surgical NSCLC patients were investigated by immunohistochemistry in order to reveal the associations between RKIP expression  and clinical-pathologic features. RESULTS: Statistically, Lower RKIP expression level was found in the group with higher N stage (P<0.01) and higher TNM stage (P<0.05). No significant correlation was observed between RKIP expressions and histologic type (P>0.05) and tumor size (P>0.05). CONCLUSIONS: Down expression level of RKIP was found relating to lymph node metastasis in resectable NSCLC patients in this study.

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[903]

TÍTULO / TITLE:  - Synergetic downregulation of 67 kDa laminin receptor by the green tea (Camellia sinensis) secondary plant compound epigallocatechin gallate: a new gateway in metastasis prevention?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Complement Altern Med. 2012 Dec 18;12:258. doi: 10.1186/1472-6882-12-258.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1472-6882-12-258

AUTORES / AUTHORS:  - Muller J; Pfaffl MW

INSTITUCIÓN / INSTITUTION:  - Physiology Weihenstephan, Technische Universitat Munchen, Research Center for Nutrition and Food Science, Weihenstephaner Berg 3, 85350 Freising, Germany. jakob.mueller@wzw.tum.de.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: In traditional Chinese medicine, green tea is considered to have a life-prolonging effect, possibly as a result of its rich content of antioxidant tea polyphenols, and hence has the potential to prevent cancer. This  study investigated the role of the major tea secondary plant compound epigallocatechin gallate (EGCG) for its inhibitory effects on the metastasis-associated 67 kDa laminin receptor (67LR). METHODS: To clarify the impact of EGCG on siRNA-silenced expression of 67LR, we applied an adenoviral-based intestinal in vitro knockdown model, porcine IPEC-J2 cells. Quantitative real-time polymerase chain reaction was performed to analyze 67LR gene expression following treatment with physiological and pharmacological concentrations of EGCG (1.0 g/l, 0.1 g/l, 0.02 g/l and 0.002 g/l). RESULTS: We report co-regulation of EGCG and 67LR, which is known to be an EGCG receptor. siRNA selectively and highly significantly suppressed expression of 67LR under the impact of EGCG in a synergetic manner. CONCLUSIONS: Our findings suggest that 67LR expression is regulated by EGCG via a negative feedback loop. The explicit occurrence of this effect in synergy with a small RNA pathway and a plant-derived drug reveals a new mode of action. Our findings may help to provide insights into the many unsolved health-promoting activities of other natural pharmaceuticals.

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[904]

TÍTULO / TITLE:  - Suppression of AKT Anti-Apoptotic Signaling by a Novel Drug Candidate Results in  Growth Arrest and Apoptosis of Hepatocellular Carcinoma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e54595. doi: 10.1371/journal.pone.0054595. Epub 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0054595

AUTORES / AUTHORS:  - Cuconati A; Mills C; Goddard C; Zhang X; Yu W; Guo H; Xu X; Block TM

INSTITUCIÓN / INSTITUTION:  - Institute for Hepatitis and Virus Research, Hepatitis B Foundation, Doylestown, Pennsylvania, United States of America.

RESUMEN / SUMMARY:  - Hepatocellular carcinoma (HCC) is the third most common cause of cancer fatalities worldwide, with limited treatment options and five year survival rates of between <5 and 15%. To address this medical need, we conducted a screen of a drug-like small molecule library for HCC-selective cytotoxins. We report here the identification of a disubstituted aminothiazole termed HBF-0079, with remarkable  selective toxicity for HCC-derived cell lines versus non-HCC liver lines and most other cancer lines. HBF-0079 caused irreversible growth arrest and apoptosis of the HCC lines Huh7, Hep3B, HepaRG as well as the hepatoblastoma line HepG2, with  CC(50) values from approximately 0.7-7.7 microM, while more than 45 microM was needed to achieve CC(50) values for the immortalized normal hepatocyte lines THLE-2 and PH5CH. Of the sixty cancer lines from the National Cancer Institute panel, only five exhibited >50% growth inhibition by HBF-0079. In Huh7 cells, HBF-0079 induced cell cycle arrest in G1 and concomitant apoptosis, and its effects were irreversible after removal of the compound. These observations corroborate a loss of AKT phosphorylation at the mTORC2-targeted residue S473, with concurrent loss of phosphorylation of the mTORC1 targets SK6 and 4EBP1 in Huh7 but not PH5CH cells. Finally, growth of Hep3B-derived tumors in a murine xenograft model was significantly repressed by the compound through either systemic or intratumoral administration of formulated HBF-0079. The potential for development of this drug candidate is discussed.

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[905]

TÍTULO / TITLE:  - Tautomycetin Induces Apoptosis by Inactivating Akt Through a PP1-Independent Signaling Pathway in Human Breast Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Pharmacol Sci. 2013 Jan 19;121(1):17-24. Epub 2012 Dec 26.

AUTORES / AUTHORS:  - Niu M; Sun Y; Liu X; Tang L; Qiu R

INSTITUCIÓN / INSTITUTION:  - Research Center for Molecular Medicine, School of Life Science and Biotechnology, Dalian University of Technology, China.

RESUMEN / SUMMARY:  - Tautomycetin (TMC), originally isolated from Streptomyces griseochromogenes, has  been suggested as a potential drug retaining specificity toward colorectal cancer. However, we found that TMC exhibited inhibitory effects on cell proliferation of many cancer cell lines including adriamycin-resistant human breast adenocarcinoma. We investigated its anti-tumor activity and mechanisms in  human breast cancer cells for the first time. In this study, we showed that TMC effectively inhibited breast cancer cell proliferation, migration, and invasion.  TMC also induced apoptosis in MCF-7 cells. This apoptotic response was in part mediated by Bcl-2 cleavage, leading to the release of cytochrome c, which facilitates binding of Apaf-1 to caspase-9 in its presence and subsequent activation of caspase-7 in apoptosis induction signaling pathways. Furthermore, we identified that TMC induced apoptosis by suppressing Akt signaling pathway activation, which is independent of protein phosphatase PP1 inhibition. The levels of downstream targets of Akt, including phospho-forkhead transcription factor and Bad, were also reduced after TMC treatment. Overall, our results indicate that TMC could be used as a potential drug candidate for breast cancer therapy. More importantly, our study provides new mechanisms for the anticancer effects of TMC.

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[906]

TÍTULO / TITLE:  - Apoptosis Induction of Human Prostate Carcinoma DU145 Cells by Diallyl Disulfide  via Modulation of JNK and PI3K/AKT Signaling Pathways.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2012 Nov 2;13(11):14158-71. doi: 10.3390/ijms131114158.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms131114158

AUTORES / AUTHORS:  - Shin DY; Kim GY; Lee JH; Choi BT; Yoo YH; Choi YH

INSTITUCIÓN / INSTITUTION:  - Dongnam Institute of Radiological &amp; Medicine Sciences, Busan 619-953, Korea.  yhyoo@dau.ac.kr.

RESUMEN / SUMMARY:  - Diallyl disulfide (DADS), a sulfur compound derived from garlic, has various biological properties, such as anticancer, antiangiogenic and anti-inflammatory effects. However, the mechanisms of action underlying the compound’s anticancer activity have not been fully elucidated. In this study, the apoptotic effects of  DADS were investigated in DU145 human prostate carcinoma cells. Our results showed that DADS markedly inhibited the growth of the DU145 cells by induction of apoptosis. Apoptosis was accompanied by modulation of Bcl-2 and inhibitor of apoptosis protein (IAP) family proteins, depolarization of the mitochondrial membrane potential (MMP, &#916;&#936;m) and proteolytic activation of caspases. We also found that the expression of death-receptor 4 (DR4) and Fas ligand (FasL) proteins was increased and that the level of intact Bid proteins was down-regulated by DADS. Moreover, treatment with DADS induced phosphorylation of  mitogen-activated protein kinases (MAPKs), including extracellular-signal regulating kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK). A specific JNK inhibitor, SP600125, significantly blocked DADS-induced-apoptosis, whereas inhibitors of the ERK (PD98059) and p38 MAPK (SB203580) had no effect. The induction of apoptosis was also accompanied by inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt and the PI3K inhibitor LY29004 significantly increased DADS-induced cell death. These findings provide evidence  demonstrating that the proapoptotic effect of DADS is mediated through the activation of JNK and the inhibition of the PI3K/Akt signaling pathway in DU145 cells.

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[907]

TÍTULO / TITLE:  - Green Tea Polyphenols Induce p53-Dependent and p53-Independent Apoptosis in Prostate Cancer Cells through Two Distinct Mechanisms.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e52572. doi: 10.1371/journal.pone.0052572. Epub 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052572

AUTORES / AUTHORS:  - Gupta K; Thakur VS; Bhaskaran N; Nawab A; Babcook MA; Jackson MW; Gupta S

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Case Western Reserve University, Cleveland, Ohio, United States of America.

RESUMEN / SUMMARY:  - Inactivation of the tumor suppressor gene p53 is commonly observed in human prostate cancer and is associated with therapeutic resistance. We have previously demonstrated that green tea polyphenols (GTP) induce apoptosis in prostate cancer cells irrespective of p53 status. However, the molecular mechanisms underlying these observations remain elusive. Here we investigated the mechanisms of GTP-induced apoptosis in human prostate cancer LNCaP cells stably-transfected with short hairpin-RNA against p53 (LNCaPshp53) and control vector (LNCaPshV). GTP treatment induced p53 stabilization and activation of downstream targets p21/waf1 and Bax in a dose-dependent manner specifically in LNCaPshV cells. However, GTP-induced FAS upregulation through activation of c-jun-N-terminal kinase resulted in FADD phosphorylation, caspase-8 activation and truncation of BID, leading to apoptosis in both LNCaPshV and LNCaPshp53 cells. In parallel, treatment of cells with GTP resulted in inhibition of survival pathway, mediated  by Akt deactivation and loss of BAD phosphorylation more prominently in LNCaPshp53 cells. These distinct routes of cell death converged to a common pathway, leading to loss of mitochondrial transmembrane potential, cytochrome c release and activation of terminal caspases, resulting in PARP-cleavage. GTP-induced apoptosis was attenuated with JNK inhibitor, SP600125 in both cell lines; whereas PI3K-Akt inhibitor, LY294002 resulted in increased cell death prominently in LNCaPshp53 cells, establishing the role of two distinct pathways of GTP-mediated apoptosis. Furthermore, GTP exposure resulted in inhibition of class I HDAC protein, accumulation of acetylated histone-H3 in total cellular chromatin, resulting in increased accessibility of transcription factors to bind  with the promoter sequences of p21/waf1 and Bax, regardless of the p53 status of  cells, consistent with effects elicited by an HDAC inhibitor, trichostatin A. These results demonstrate that GTP induces prostate cancer cell death by two distinct mechanisms regardless of p53 status, thus identifying specific well-defined molecular mechanisms that may be targeted by chemopreventive and/or  therapeutic strategies.

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[908]

TÍTULO / TITLE:  - Isoliquiritigenin inhibits proliferation and induces apoptosis of U87 human glioma cells in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Med Report. 2013 Feb;7(2):531-6. doi: 10.3892/mmr.2012.1218. Epub 2012 Dec 3.

            ●● Enlace al texto completo (gratuito o de pago) 3892/mmr.2012.1218

AUTORES / AUTHORS:  - Zhou GS; Song LJ; Yang B

INSTITUCIÓN / INSTITUTION:  - Neurosurgery Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.

RESUMEN / SUMMARY:  - Isoliquiritigenin (ISL), a member of the flavonoids, has been demonstrated to possess antitumor activity in various cancer cell lines in vitro and in vivo. In  this study, we investigated the antitumor effects of ISL on U87 glioma cells in vitro. As determined by MTT assay, ISL inhibited the proliferation of U87 cells in a time-dependent and dose-dependent manner. The results of fluorescence-activated cell sorting (FACS) analysis suggested that ISL induced the apoptosis of the U87 cells and blocked cell cycle progression at the S and G2/M phases. Moreover, it was identified that ISL induced the apoptosis of the U87 cells in a caspase-dependent manner. Although treatment with the pan-caspase  inhibitor Z-VAD-FMK efficiently blocked the ISL-induced caspase activation, it did not eliminate the ISL-induced cell death. Further examination using western blot analysis revealed that ISL upregulated p21/WAF1 and p27. These results indicate that cell cycle arrest and the caspase-mediated apoptosis pathway may participate in the antiproliferative activity of ISL in U87 cells by regulating the expression of specific molecules.

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[909]

TÍTULO / TITLE:  - E series prostaglandins alter the proliferative, apoptotic and migratory properties of T98G human glioma cells in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Lipids Health Dis. 2012 Dec 11;11:171. doi: 10.1186/1476-511X-11-171.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1476-511X-11-171

AUTORES / AUTHORS:  - Gomes RN; Colquhoun A

INSTITUCIÓN / INSTITUTION:  - Department of Cell and Developmental Biology, University of Sao Paulo, Sao Paulo, CEP 05508-900, SP, Brazil. alison@usp.br.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: In many types of cancer, prostaglandin E2 (PGE2) is associated with tumour related processes including proliferation, migration, angiogenesis and apoptosis. However in gliomas the role of this prostanoid is poorly understood. Here, we report on the proliferative, migratory, and apoptotic effects of PGE1, PGE2 and Ibuprofen (IBP) observed in the T98G human glioma cell  line in vitro. METHODS: T98G human glioma cells were treated with IBP, PGE1 or PGE2 at varying concentrations for 24-72 hours. Cell proliferation, mitotic index and apoptotic index were determined for each treatment. Caspase-9 and caspase-3 activity was measured using fluorescent probes in live cells (FITC-LEHD-FMK and FITC-DEVD-FMK respectively). The migratory capacity of the cells was quantified using a scratch migration assay and a transwell migration assay. RESULTS: A significant decrease was seen in cell number (54%) in the presence of 50 muM IBP. Mitotic index and bromodeoxyuridine (BrdU) incorporation were also decreased 57%  and 65%, respectively, by IBP. The apoptotic index was increased (167%) and the in situ activity of caspase-9 and caspase-3 was evident in IBP treated cells. The inhibition of COX activity by IBP also caused a significant inhibition of cell migration in the monolayer scratch assay (74%) and the transwell migration assay  (36%).In contrast, the presence of exogenous PGE1 or PGE2 caused significant increases in cell number (37% PGE1 and 45% PGE2). When mitotic index was measured no change was found for either PG treatment. However, the BrdU incorporation rate was significantly increased by PGE1 (62%) and to a greater extent by PGE2 (100%). The apoptotic index was unchanged by exogenous PGs. The addition of exogenous PGs caused an increase in cell migration in the monolayer scratch assay (43% PGE1 and 44% PGE2) and the transwell migration assay (28% PGE1 and 68% PGE2). CONCLUSIONS: The present study demonstrated that treatments which alter PGE1 and PGE2 metabolism influence the proliferative and apoptotic indices of T98G glioma cells. The migratory capacity of the cells was also significantly affected by the change in prostaglandin metabolism. Modifying PG metabolism remains an interesting target for future studies in gliomas.

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[910]

TÍTULO / TITLE:  - PIK3CA Genotype and a PIK3CA Mutation-Related Gene Signature and Response to Everolimus and Letrozole in Estrogen Receptor Positive Breast Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e53292. doi: 10.1371/journal.pone.0053292. Epub 2013 Jan 2.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0053292

AUTORES / AUTHORS:  - Loi S; Michiels S; Baselga J; Bartlett JM; Singhal SK; Sabine VS; Sims AH; Sahmoud T; Dixon JM; Piccart MJ; Sotiriou C

INSTITUCIÓN / INSTITUTION:  - Breast Cancer Translational Research Laboratory (BCTL), Jules Bordet Institute, Brussels, Belgium.

RESUMEN / SUMMARY:  - The phosphatidylinositol 3’ kinase (PI3K) pathway is commonly activated in breast cancer and aberrations such as PI3K mutations are common. Recent exciting clinical trial results in advanced estrogen receptor-positive (ER) breast cancer  support mTOR activation is a major means of estrogen-independent tumor growth. Hence the means to identify a responsive breast cancer population that would most benefit from these compounds in the adjuvant or earlier stage setting is of high  interest. Here we study PIK3CA genotype as well as a previously reported PI3K/mTOR-pathway gene signature (PIK3CA-GS) and their ability to estimate the level of PI3K pathway activation in two clinical trials of newly diagnosed ER-positive breast cancer patients- a total of 81 patients- one of which was randomized between letrozole and placebo vs letrozole and everolimus. The main objectives were to correlate the baseline PIK3CA genotype and GS with the relative change from baseline to day 15 in Ki67 (which has been shown to be prognostic in breast cancer) and phosphorylated S6 (S240) immunohistochemistry (a substrate of mTOR). In the randomized dataset, the PIK3CA-GS could identify those patients with the largest relative decreases in Ki67 to letrozole/everolimus (R = -0.43, p = 0.008) compared with letrozole/placebo (R = 0.07, p = 0.58; interaction test p = 0.02). In a second dataset of pre-surgical everolimus alone, the PIK3CA-GS was not significantly correlated with relative change in Ki67 (R =  -0.11, p = 0.37) but with relative change in phosphorlyated S6 (S240) (R = -0.46, p = 0.028). PIK3CA genotype was not significantly associated with any endpoint in either datasets. Our results suggest that the PIK3CA-GS has potential to identify those ER-positive BCs who may benefit from the addition of everolimus to letrozole. Further evaluation of the PIK3CA-GS as a predictive biomarker is warranted as it may facilitate better selection of responsive patient populations for mTOR inhibition in combination with letrozole.

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[911]

TÍTULO / TITLE:  - Clinical and Prognostic Association of Transcription Factor SOX4 in Gastric Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e52804. doi: 10.1371/journal.pone.0052804. Epub 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052804

AUTORES / AUTHORS:  - Fang CL; Hseu YC; Lin YF; Hung ST; Tai C; Uen YH; Lin KY

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, School of Medicine, College of Medicine, Taipei Medical  University, Taipei, Taiwan ; Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.

RESUMEN / SUMMARY:  - Gastric cancer (GC) is one of the most common malignant cancers worldwide. However, little is known about the molecular process by which this disease develops and progresses. This study investigated correlations between the expression of nuclear transcription factor SOX4 and various clinicopathologic parameters as well as patients’ survival. Expression levels of nuclear SOX4 were  analyzed by immunohistochemistry; the data comprised gastric tissues from 168 patients with GC. Paired t tests were used to analyze the differences in nuclear  SOX4 expression between tumor and non-tumor tissues from each patient. Two-tailed Chi(2) tests were performed to determine whether the differences in nuclear SOX4  expression and clinicopathologic parameters were significant. Time-to-event endpoints for clinicopathologic parameters were plotted using the Kaplan-Meier method, and statistical significance was determined using univariate log-rank tests. Cox proportional hazard model was used for multivariate analysis to determine the independence of prognostic effects of nuclear SOX4 expression. Overexpression of nuclear SOX4 was significantly correlated with depth of invasion (P<0.0001), nodal status (P = 0.0055), distant metastasis (P = 0.0195),  stage (P = 0.0003), and vascular invasion (P = 0.0383). Patients who displayed high expression levels of nuclear SOX4 achieved a significantly poorer disease-free survival rate, compared with patients with low SOX4 expression levels (P = 0.003). Univariate Cox regression analysis showed that overexpression of nuclear SOX4 was a clear prognostic marker for GC (P = 0.004). Overexpression  of nuclear SOX4 can be used as a marker to predict the outcome of patients with GC.

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[912]

TÍTULO / TITLE:  - CUG-binding protein 1 (CUGBP1) expression and prognosis of non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Transl Oncol. 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12094-013-1005-5

AUTORES / AUTHORS:  - Jiao W; Zhao J; Wang M; Wang Y; Luo Y; Zhao Y; Tang D; Shen Y

INSTITUCIÓN / INSTITUTION:  - Department of Thoracic Surgery, The Affiliated Hospital of Medical College, Qingdao University, 16 Jiangsu Road, Qingdao, 266003, People’s Republic of China.

RESUMEN / SUMMARY:  - BACKGROUND AND AIMS: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. As CUGBP1 may also play a great role in tumor genesis and deterioration, the purpose of this study was to detect the expression of CUGBP1 mRNA and CUGBP1 and assess the prognostic significance of CUGBP1 in NSCLC. METHODS: Expression of CUGBP1 mRNA and CUGBP was detected by Semi-quantitative PCR and Immunohistochemistry, respectively, from 57 NSCLC patients. The percentage of CUGBP1 mRNA and CUGBP1 expression was correlated with clinical characteristics using chi (2) test. The prognostic significance was assessed by univariate and multivariate analyses in the Cox hazard model. RESULTS: The expression of CUGBP1 mRNA and CUGBP1 was over-expressed in cancer group and was correlated with TNM stage and Differentiation. By both univariate and multivariate survival analyses, CUGBP1 expression (P = 0.0074, HR = 3.701, 95 % CI 1.420-9.648), TNM-stage (HR = 4.043, 95 % CI 2.098-7.794) and age (HR = 3.207, 95 % CI 1.544-6.664) were noted to be independent indicators of a shorter postsurgical survival. CONCLUSIONS: The expression of CUGBP1 independently predicted a shorter postsurgical survival in NSCLC.

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[913]

TÍTULO / TITLE:  - Sensitization of melanoma cells for TRAIL-induced apoptosis by BMS-345541 correlates with altered phosphorylation and activation of Bax.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Death Dis. 2013 Jan 24;4:e477. doi: 10.1038/cddis.2012.198.

            ●● Enlace al texto completo (gratuito o de pago) 1038/cddis.2012.198

AUTORES / AUTHORS:  - Berger A; Quast SA; Plotz M; Kammermeier A; Eberle J

INSTITUCIÓN / INSTITUTION:  - Department of Dermatology and Allergy, Skin Cancer Center, University Medical Center Charite, Berlin, Germany.

RESUMEN / SUMMARY:  - Resistance to TRAIL (TNF-related apoptosis-inducing ligand)- induced apoptosis limits its therapeutic use. Different strategies of TRAIL sensitization and a dependency on Bax have been reported, but common principles of TRAIL resistance and the way of Bax activation remained poorly understood. Applying a melanoma model of TRAIL-sensitive and -resistant cell lines, efficient sensitization for TRAIL-induced apoptosis is demonstrated by the kinase inhibitor BMS-345541 (N-(1,8-dimethylimidazo(1,2-a)quinoxalin-4-yl)-1,2-ethanediamine hydrochloride),  which targets IkappaB (inhibitor of kappaB proteins) kinase beta (IKKbeta). This  effect was completely abrogated by Bax knockout as well as by Bcl-2 overexpression, in accordance with a Bax dependency. Early loss of the mitochondrial membrane potential, release of cytochrome c and Smac (second mitochondria-derived activator of caspases) clearly indicated the activation of mitochondrial apoptosis pathways. Of note, BMS-345541 alone resulted in an early  Bax activation, seen by conformational changes and by Bax translocation. The synergistic effects can be explained by Bid activation through TRAIL, which inhibits Bcl-2, and the activation of Bax through BMS-345541. The critical roles  of XIAP (X-chromosome-linked inhibitor of apoptosis protein), Smac and Bid were clearly proven by overexpression and siRNA knockdown, respectively. The way of Bax activation by BMS-345541 was unraveled by establishing new assays for Bax activation. These showed reduction of the inactivating Bax phosphorylation at serine-184, while the activating Bax phosphorylation at threonine-167 was enhanced. Thus, modulation of Bax phosphorylation appeared as tightly related to  TRAIL sensitivity/resistance in melanoma cells, and therapeutic strategies may be considered.

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[914]

TÍTULO / TITLE:  - Silencing of mutant p53 by siRNA induces cell cycle arrest and apoptosis in human bladder cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Surg Oncol. 2013 Jan 28;11(1):22.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1477-7819-11-22

AUTORES / AUTHORS:  - Zhu HB; Yang K; Xie YQ; Lin YW; Mao QQ; Xie LP

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: p53 is the most frequently mutated tumor-suppressor gene in human cancers. It has been reported that mutations in p53 result not only in the  loss of its ability as a tumor suppressor, but also in the gain of novel cancer-related functions that contribute to oncogenesis. The present study evaluated the potential of silencing of mutant p53 by small interfering RNA in the treatment of bladder cancer cells in vitro. METHODS: We used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess cell viability and flow cytometry to detect cell cycle alterations and apoptosis. The related molecular mechanisms were assessed by western blotting. We also used the MTT assay and flow cytometry to investigate if silencing of mutant  p53 by knockdown with small interfering (si)RNA would change the sensitivity to cisplatin treatment. RESULTS: Using 5637 and T24 human bladder cancer cell lines  characterized by mutations in p53, we found that silencing of the mutant p53 by RNA interference induced evident inhibition of cell proliferation and viability,  which was related to the induction of G2 phase cell cycle arrest and apoptosis. Moreover, our study also showed that the p53-targeting siRNA cooperated with cisplatin in the inhibition of bladder cancer cells. CONCLUSIONS: These findings  suggest that RNA interference targeting mutant p53 may be a promising therapeutic strategy for the treatment of bladder cancer.

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[915]

TÍTULO / TITLE:  - In vitro effects of thermoablation on apoptosis of giant cell tumor of bone: a preliminary report.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Med Assoc Thai. 2012 Sep;95 Suppl 9:S138-45.

AUTORES / AUTHORS:  - Phimolsarnti R; Charoenlap C; Ariyaboonsiri B; Wongkajornsilpa A; Waikakul S

INSTITUCIÓN / INSTITUTION:  - Department of Orthopaedic Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.

RESUMEN / SUMMARY:  - BACKGROUND: Giant cell tumor of bone is a common benign aggressive bone tumor. Recurrent rate in the patients who have the tumor with soft tissue invasion is rather high. Use of strong chemicals such as phenol and liquid nitrogen to lessen the recurrent rate might not be used in this lesion. OBJECTIVE: The experiment was carried out to discover apoptotic effects of thermoablation on giant cell tumor of bone to find out a possibility to use thermoablation in the clinic in the patients with extensive lesion. MATERIAL AND METHOD: Tumor cell suspension was prepared from 4 patients who had definite diagnosis of giant cell tumor of bone. The tumor cells were subjected to thermoablation at 45, 47 and 50 degrees C for 10 to 30 minutes before were cultured at 37 degrees C for another 3 days. Osteoblasts and chondrocytes from the last 3 patients were collected,prepared and underwent thermoablation in the same fashion. Apoptosis of tumor cells, chondrocytes and osteoblasts were carried out by the use of flow cytometry. RESULTS: Thermoablation at 47 degrees C for 30 minutes resulted in < 50% chondrocyte and osteoblast apoptosis and 70-90% tumor cells apoptosis of ¾ patients. Thermoablation at 47 and 50 degrees C for 20 to 30 minutes has more negative effect on giant cell tumor of bone than chondrocytes and osteoblasts. CONCLUSION: Thermoablation might be a useful tool for local tumor control in the  clinic.

 

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[916]

TÍTULO / TITLE:  - Apoptosis induction, cell cycle arrest and in vitro anticancer activity of gonothalamin in a cancer cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian Pac J Cancer Prev. 2012;13(10):5131-6.

AUTORES / AUTHORS:  - Alabsi AM; Ali R; Ali AM; Al-Dubai SA; Harun H; Abu Kasim NH; Alsalahi A

INSTITUCIÓN / INSTITUTION:  - Department of Biotechnology, Universiti Sultan Zainal Abidin (UniSZA), Kuala Terengganu, Malaysia. aied_absi@yahoo.com

RESUMEN / SUMMARY:  - Cancer is one of the major health problems worldwide and its current treatments have a number of undesired adverse side effects. Natural compounds may reduce these. Currently, a few plant products are being used to treat cancer. In this study, goniothalamin, a natural occurring styryl-lactone extracted from Goniothalamus macrophyllus, was investigated for cytotoxic properties against cervical cancer (HeLa), breast carcinoma (MCF-7) and colon cancer (HT29) cells as well as normal mouse fibroblast (3T3) using MTT assay. Fluorescence microscopy showed that GTN is able to induce apoptosis in HeLa cells in a time dependent manner. Flow cytometry further revealed HeLa cells treated with GTN to be arrested in the S phase. Phosphatidyl serine properties present during apoptosis  enable early detection of the apoptosis in the cells. Using annexin V/PI double staining it could be shown that GTN induces early apoptosis on HeLa cells after 24, 48 and 72 h. It could be concluded that goniothalamin showing a promising cytotoxicity effect against several cancer cell lines including cervical cancer cells (HeLa) with apoptosis as the mode of cell death induced on HeLa cells by Goniothalamin was.

 

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[917]

TÍTULO / TITLE:  - PRIMA-1 increases cisplatin sensitivity in chemoresistant ovarian cancer cells with p53 mutation: a requirement for Akt down-regulation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Ovarian Res. 2013 Jan 26;6(1):7.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1757-2215-6-7

AUTORES / AUTHORS:  - Kobayashi N; Abedini M; Sakuragi N; Tsang BK

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Since ovarian cancer is associated with high frequency of p53 mutation, the availability of p53 reactivation and induction of massive apoptosis (PRIMA-1) offers a possible new therapeutic strategy for overcoming this devastating disease. Although Akt activation is believed to be a determinant in chemoresistance in ovarian cancer, whether Akt plays a role in regulating the  effectiveness of PRIMA-1 in sensitizing chemoresistant ovarian cancer cells with  p53 mutation to cisplatin (CDDP), remains to be determined. METHODS: In the present studies, we examined the influence of Akt down-regulation following dominant-negative (DN-Akt) expression on the ability of PRIMA-1 (0--10 muM) to facilitate CDDP (0--10 muM)-induced apoptosis in p53-mutated chemoresistant ovarian cancer cells (A2780cp). RESULTS: Apoptosis rate was significantly higher  at the combined treatment of low PRIMA-1 concentrations (0.156 - 0.938 muM) plus  CDDP (10 muM) in the DN-Akt groups than control (p<0.001). Apoptosis in cells treated with PRIMA-1 (0.156 muM) and CDDP treatment (10 muM) was significantly suppressed by p53-siRNA. PRIMA-1 increased phospho-p53 (Ser15) content in Akt down-regulated cells treated with CDDP. CONCLUSIONS: These results demonstrate that PRIMA-1 can sensitize chemoresistant ovarian cancer cells with p53 mutation  to CDDP when Akt is down-regulated, and the action of PRIMA-1 is associated with  p53 activation. Our findings raise the possibility that PRIMA-1 may be useful candidate for adjuvant therapy with CDDP in chemoresistant ovarian cancer with p53 mutation when Akt is down-regulated.

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[918]

TÍTULO / TITLE:  - Docosahexaenoic acid (DHA) induces apoptosis in human hepatocellular carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Clin Exp Pathol. 2013;6(2):281-9. Epub 2013 Jan 15.

AUTORES / AUTHORS:  - Sun SN; Jia WD; Chen H; Ma JL; Ge YS; Yu JH; Li JS

INSTITUCIÓN / INSTITUTION:  - Department of General Surgery, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Hospital Affiliated with Anhui Medical University No. 17 Lujiang Road, Hefei 230001, Anhui Province, China.

RESUMEN / SUMMARY:  - The docosahexaenoic (DHA), a omega-3 fatty acid, could play a beneficial inhibition of the incidence and progress of a series of human diseases including  cancer. It has been report that DHA is involved in cell apoptosis. Recent studies show that the signal transduction pathway links with bcl-2, bax, caspase-3 and MMP-9 molecules. Therefore, we tested the relationship between DHA and cell apoptosis in human hepatocellular carcinoma cells (Bel-7402 cells). We show here  that DHA induces Bel-7402 cells apoptosis after pre-treating cells with DHA. DHA  down-regulates the protein expression of Bcl-2 and Bim mRNA level, and up-regulates caspase-3 activity and Bax expression level. We also found that DHA  inhibits Bel-7402 cells migration. Basic on our studies, DHA may play a role in tumor invasion and survival.

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[919]

TÍTULO / TITLE:  - Depletion of Bmi-1 enhances 5-fluorouracil-induced apoptosis and autophagy in hepatocellular carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2012 Oct;4(4):723-726. Epub 2012 Jul 16.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.805

AUTORES / AUTHORS:  - Wu J; Hu D; Zhang R

INSTITUCIÓN / INSTITUTION:  - Department of Medical Immunology, School of Medicine, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China.

RESUMEN / SUMMARY:  - 5-fluorouracil (5-FU) is one of the standard chemoradiotherapy regimens for hepatocellular carcinoma (HCC) treatment. B-cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1) has been demonstrated to regulate proliferation. Additionally, Bmi-1 overexpression has been identified in HCC cell lines and correlates with the advanced invasive stage of tumor progression and poor prognosis. In this study, we examined the effects of 5-FU treatment on cell growth in HCC cells with or without Bmi-1 depletion. The IC(50) values of 5-FU were significantly decreased to a greater extent in cells with Bmi-1 knockdown. Depletion of Bmi-1 increased sensitivity of the cells to 5-FU and increased apoptosis. Knockdown of endogenous Bmi-1 led to a substantial reduction in the levels of phospho-AKT and Bcl-2 with a concomitant increase in the levels of Bax. Additionally, 5-FU induced the conversion/turnover of microtubule-associated protein 1 light chain 3 (LC3). Knockdown of endogenous Bmi-1 led to an increase in the levels of Beclin-1 and the accumulation of LC3-II. Together, these findings reveal that Bmi-1 depletion enhanced the chemosensitivity of HCC cells by inducing apoptosis and autophagy, which is associated with the PI3K/AKT and Bcl-2/Beclin-1 pathways.

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[920]

TÍTULO / TITLE:  - Polymorphisms in the methotrexate transport pathway: a new tool for MTX plasma level prediction in pediatric acute lymphoblastic leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pharmacogenet Genomics. 2013 Feb;23(2):53-61.

            ●● Enlace al texto completo (gratuito o de pago) 1097/FPC.0b013e32835c3b24

AUTORES / AUTHORS:  - Lopez-Lopez E; Ballesteros J; Pinan MA; Sanchez de Toledo J; Garcia de Andoin N; Garcia-Miguel P; Navajas A; Garcia-Orad A

INSTITUCIÓN / INSTITUTION:  - aDepartment of Genetics, Physical Anthropology and Animal Physiology, Faculty of  Medicine and Dentistry bDepartment of Neurosciences, University of the Basque Country (UPV/EHU), Leioa cService of Hematology and Hemotherapy, University Hospital Cruces, Bilbao dService of Pediatric Oncology and Hematology, University Hospital Vall d’ Hebron, VHIR, Barcelona eUnit of Pediatric Oncohematology, University Hospital Donostia, San Sebastian fService of Pediatric Oncohematology, University Hospital La Paz, Madrid gUnit of Pediatric Hematology/Oncology, University Hospital Cruces, Bilbao, España.

RESUMEN / SUMMARY:  - OBJECTIVES: Methotrexate (MTX) is an important component of therapy for pediatric acute lymphoblastic leukemia (ALL). Treatment with MTX often causes toxicity, which can necessitate dose reduction or treatment cessation. Interindividual differences in adverse reactions can be due to different factors, including polymorphisms in key genes. Recently, we confirmed the association between SLCO1B1 rs11045879 polymorphism and toxicity previously proposed by Trevino and colleagues. As SLCO1B1 is a transporter involved in MTX elimination, other polymorphisms in genes from this pathway could also have a role in MTX toxicity.  The aim of the present study was to analyze in depth the role of polymorphisms in the genes of the MTX transport pathway as putative toxicity predictors in pediatric ALL. METHODS: We analyzed 384 single nucleotide polymorphisms in 12 transporter genes (SLCO1B1, SLCO1B3, SLCO1A2, ABCB1, ABCG2, ABCC1, ABCC2, ABCC3,  ABCC4, SLC19A1, SLC22A6 and SLC22A8) and their correlation with different toxicity parameters in 151 pediatric ALL patients treated using the LAL/SHOP protocol. RESULTS: A significant association with MTX plasma levels was found for 21 polymorphisms from seven genes and 15 haplotypes. After correction, rs9516519  in ABCC4, rs3740065 in ABCC2, and haplotype GCGGG in ABCC2 remained significantly associated. CONCLUSION: Our results suggest that polymorphisms in ABCC4 and ABCC2 could be novel markers for MTX toxicity in pediatric ALL.

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[921]

TÍTULO / TITLE:  - KRAS mutation is a predictor of oxaliplatin sensitivity in colon cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(11):e50701. doi: 10.1371/journal.pone.0050701. Epub 2012 Nov 28.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0050701

AUTORES / AUTHORS:  - Lin YL; Liau JY; Yu SC; Ou DL; Lin LI; Tseng LH; Chang YL; Yeh KH; Cheng AL

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

RESUMEN / SUMMARY:  - Molecular biomarkers to determine the effectiveness of targeted therapies in cancer treatment have been widely adopted in colorectal cancer (CRC), but those to predict chemotherapy sensitivity remain poorly defined. We tested our hypothesis that KRAS mutation may be a predictor of oxaliplatin sensitivity in CRC. KRAS was knocked-down in KRAS-mutant CRC cells (DLD-1(G13D) and SW480(G12V)) by small interfering RNAs (siRNA) and overexpressed in KRAS-wild-type CRC cells (COLO320DM) by KRAS-mutant vectors to generate paired CRC cells. These paired CRC cells were tested by oxaliplatin, irinotecan and 5FU to determine the change in drug sensitivity by MTT assay and flow cytometry. Reasons for sensitivity alteration were further determined by western blot and real-time quantitative reverse transcriptase polymerase chain reaction (qRT -PCR). In KRAS-wild-type CRC cells (COLO320DM), KRAS overexpression by mutant vectors caused excision repair cross-complementation group 1 (ERCC1) downregulation in protein and mRNA levels,  and enhanced oxaliplatin sensitivity. In contrast, in KRAS-mutant CRC cells (DLD-1(G13D) and SW480(G12V)), KRAS knocked-down by KRAS-siRNA led to ERCC1 upregulation and increased oxaliplatin resistance. The sensitivity of irinotecan  and 5FU had not changed in the paired CRC cells. To validate ERCC1 as a predictor of sensitivity for oxaliplatin, ERCC1 was knocked-down by siRNA in KRAS-wild-type CRC cells, which restored oxaliplatin sensitivity. In contrast, ERCC1 was overexpressed by ERCC1-expressing vectors in KRAS-mutant CRC cells, and caused oxaliplatin resistance. Overall, our findings suggest that KRAS mutation is a predictor of oxaliplatin sensitivity in colon cancer cells by the mechanism of ERCC1 downregulation.

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[922]

TÍTULO / TITLE:  - Investigating the antiproliferative activity of high affinity DNA aptamer on cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e50964. doi: 10.1371/journal.pone.0050964. Epub 2013 Jan 16.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0050964

AUTORES / AUTHORS:  - Kaur H; Li JJ; Bay BH; Yung LY

INSTITUCIÓN / INSTITUTION:  - Department of Chemical and Biomolecular Engineering, Faculty of Engineering, National University of Singapore, Singapore, Singapore.

RESUMEN / SUMMARY:  - Vascular endothelial growth factor (VEGF) is an angiogenic mitogen involved in promoting tumor angiogenesis inside the body. VEGF is a key protein required for  progression of tumor from benign to malignant phenotype. In this study, we investigated the binding affinity of a previously selected 26-mer DNA aptamer sequence (SL(2)-B) against heparin binding domain (HBD) of VEGF(165) protein. The SL(2)-B was first chemically modified by introduction of phosphorothioate linkages (PS-linkages). Subsequently, surface plasmon resonance (SPR) spectroscopy and circular dichroism (CD) were used to determine the binding affinity, specificity and to deduce the conformation of PS-modified SL(2)-B sequence. Finally, antiproliferative activity of the modified SL(2)-B sequence on Hep G2 cancer cells was investigated. Our results demonstrate a marked enhancement in the biostability of the SL(2)-B sequence after PS modification. The modified SL(2)-B sequence also exhibits enhanced antiproliferative activity against Hep G2 cancer cells in hypoxia conditions. In addition, modified SL(2)-B  sequence inhibits the expression of Jagged-1 protein, which is one of the ligands to VEGF linked delta/jagged-notch signaling pathway.

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[923]

TÍTULO / TITLE:  - Oxidative stress contributes to cobalt oxide nanoparticles-induced cytotoxicity and DNA damage in human hepatocarcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Nanomedicine. 2013;8:17-23. doi: 10.2147/IJN.S37924. Epub 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 2147/IJN.S37924

AUTORES / AUTHORS:  - Alarifi S; Ali D; Y AO; Ahamed M; Siddiqui MA; Al-Khedhairy AA

INSTITUCIÓN / INSTITUTION:  - Cell and Molecular Laboratory, Department of Zoology, Faculty of Science, King Saud University, Riyadh, Saudi Arabia.

RESUMEN / SUMMARY:  - BACKGROUND: Cobalt oxide nanoparticles (Co(3)O(4)NPs) are increasingly recognized for their utility in biological applications, magnetic resonance imaging, and drug delivery. However, little is known about the toxicity of Co(3)O(4)NPs in human cells. METHODS: We investigated the possible mechanisms of genotoxicity induced by Co(3)O(4)NPs in human hepatocarcinoma (HepG2) cells. Cell viability, reactive oxygen species (ROS), glutathione, thiobarbituric acid reactive substance, apoptosis, and DNA damage were assessed in HepG2 cells after Co(3)O(4)NPs and Co(2+) exposure. RESULTS: Co(3)O(4)NPs elicited a significant (P < 0.01) reduction in glutathione with a concomitant increase in lipid hydroperoxide, ROS generation, superoxide dismutase, and catalase activity after  24- and 48-hour exposure. Co(3)O(4)NPs had a mild cytotoxic effect in HepG2 cells; however, it induced ROS and oxidative stress, leading to DNA damage, a probable mechanism of genotoxicity. The comet assay showed a statistically significant (P < 0.01) dose- and time-related increase in DNA damage for Co(3)O(4)NPs, whereas Co(2+) induced less change than Co(3)O(4)NPs but significantly more than control. CONCLUSION: Our results demonstrated that Co(3)O(4)NPs induced cytotoxicity and genotoxicity in HepG2 cells through ROS and oxidative stress.

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[924]

TÍTULO / TITLE:  - Interferon-gamma-induced activation of Signal Transducer and Activator of Transcription 1 (STAT1) up-regulates the tumor suppressing microRNA-29 family in  melanoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Commun Signal. 2012 Dec 17;10(1):41. doi: 10.1186/1478-811X-10-41.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1478-811X-10-41

AUTORES / AUTHORS:  - Schmitt MJ; Philippidou D; Reinsbach SE; Margue C; Wienecke-Baldacchino A; Nashan D; Behrmann I; Kreis S

INSTITUCIÓN / INSTITUTION:  - Signal Transduction Laboratory, University of Luxembourg, 162A Avenue de la Faiencerie, Luxembourg, L-1511, Luxembourg. Stephanie.Kreis@uni.lu.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: The type-II-cytokine IFN-gamma is a pivotal player in innate immune responses but also assumes functions in controlling tumor cell growth by orchestrating cellular responses against neoplastic cells. The role of  IFN-gamma in melanoma is not fully understood: it is a well-known growth inhibitor of melanoma cells in vitro. On the other hand, IFN-gamma may also facilitate melanoma progression. While interferon-regulated genes encoding proteins have been intensively studied since decades, the contribution of miRNAs  to effects mediated by interferons is an emerging area of research.We recently described a distinct and dynamic regulation of a whole panel of microRNAs (miRNAs) after IFN-gamma-stimulation. The aim of this study was to analyze the transcriptional regulation of miR-29 family members in detail, identify potential interesting target genes and thus further elucidate a potential signaling pathway IFN-gamma --> Jak--> P-STAT1 --> miR-29 --> miR-29 target genes and its implication for melanoma growth. RESULTS: Here we show that IFN-gamma induces STAT1-dependently a profound up-regulation of the miR-29 primary cluster pri-29a~b-1 in melanoma cell lines. Furthermore, expression levels of pri-29a~b-1 and mature miR-29a and miR-29b were elevated while the pri-29b-2~c cluster was almost undetectable. We observed an inverse correlation between miR-29a/b expression and the proliferation rate of various melanoma cell lines. This finding could be corroborated in cells transfected with either miR-29 mimics or inhibitors. The IFN-gamma-induced G1-arrest of melanoma cells involves down-regulation of CDK6, which we proved to be a direct target of miR-29 in these cells. Compared to nevi and normal skin, and metastatic melanoma samples, miR-29a and miR-29b levels were found strikingly elevated in certain patient samples derived from primary melanoma. CONCLUSIONS: Our findings reveal that the miR-29a/b1 cluster is to be included in the group of IFN- and STAT-regulated genes. The up-regulated miR-29 family members may act as effectors of cytokine signalling in melanoma and other cancer cells as well as in the immune system.

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[925]

TÍTULO / TITLE:  - Alpinetin promotes Bax translocation, induces apoptosis through the mitochondrial pathway and arrests human gastric cancer cells at the G2/M phase.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Med Report. 2012 Dec 18. doi: 10.3892/mmr.2012.1243.

            ●● Enlace al texto completo (gratuito o de pago) 3892/mmr.2012.1243

AUTORES / AUTHORS:  - Wang Z; Lu W; Li Y; Tang B

INSTITUCIÓN / INSTITUTION:  - Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, P.R. China.

RESUMEN / SUMMARY:  - Alpinetin is a natural flavonoid widely distributed in Zingiberaceae. Previous studies have demonstrated that alpinetin markedly inhibits tumour growth. However, the molecular mechanisms underlying the antitumour effects of alpinetin  are unclear. Bcl2associated X protein (Bax) translocation is known to activate the mitochondrialdependent endogenous apoptosis pathway. The aim of the current study was to investigate the roles of Bax and the mitochondrial pathway during alpinetininduced gastric cancer cell apoptosis and the effects of alpinetin on the cell cycle. Human gastric cancer cells were treated with various doses of alpinetin and an MTT assay was performed to measure cell viability, flow cytometry to measure the apoptotic rate, changes in the cell cycle and mitochondrial membrane potential and western blot analysis to detect the expression levels of relevant proteins. Results demonstrate that alpinetin induces apoptosis in human gastric cancer cells in a dose and timedependent manner. During the early stages of apoptosis, alpinetin may alter mitochondrial membrane potential leading to release of cytochrome c from mitochondria, activation of caspase family members and ultimately apoptosis of human gastric cancer cells. Results of the present study indicate that alpinetininduced human gastric cancer cell apoptosis is associated with the mitochondrial pathway.

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[926]

TÍTULO / TITLE:  - SLUG is activated by nuclear factor kappa B and confers human alveolar epithelial A549 cells resistance to tumor necrosis factor-alpha-induced apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Surg Oncol. 2013 Jan 22;11(1):12.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1477-7819-11-12

AUTORES / AUTHORS:  - Wang Y; Yue B; Yu X; Wang Z; Wang M

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: The role of tumor necrosis factor alpha (TNF-alpha) in cancer is complex with both apoptotic and anti-apoptotic roles proposed. However  the mechanism is not clear. In the study, we designed to investigate the effect of TNF-alpha on the activation and expression of nuclear factor kappa B (NF-kappaB)/p65/SLUG/PUMA/Bcl-2 levels in human lung cancer A549 cell line, and in conditions of TNF-alpha-induced apoptosis. METHODS: We have engineered three A549 cell lines that were transiently transfected with PUMA siRNA, SLUG siRNA and Bcl-2 siRNA, respectively. We have measured the in vitro effects of siRNA on apoptosis, and sensitivity to 20 ng/ml of TNF-alpha treatment for 24--48 h. RESULTS: We found the NF-kappaB activity and PUMA mRNA/protein was significantly  increased after treatment of TNF-alpha for 24 h in untreated A549 cells, and led  to a significant increase in TNF-alpha-induced apoptosis, no significant increase of SLUG and Bcl-2 level was shown. However, after treatment of TNF-alpha for 48 h in untreated A549 cells, SLUG and Bcl-2 level was significant increased, and PUMA level was significant decreased, and TNF-alpha-induced apoptosis was significantly decreased compared to the apoptosis level after treatment of TNF-alpha for 24 h. Inhibition of the NF-kappaB activity could effectively decrease the PUMA level and increase the SLUG and Bcl-2 level. PUMA silencing by  siRNA led to a significant decrease in TNF-alpha-induced apoptosis after treatment of TNF-alpha for 24 h. Bcl-2 and SLUG silencing by siRNA led to a significant increase in TNF-alpha-induced apoptosis for 48 h. Furthermore, SLUG silencing increased PUMA level and decreased Bcl-2 level. CONCLUSIONS: The findings suggested that TNF-alpha treatment promoted apoptosis via the NF-kappaB-dependent PUMA pathway. The anti-apoptotic role of TNF-alpha was via NF-kappaB-dependent SLUG and Bcl-2 pathway at a later time.

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[927]

TÍTULO / TITLE:  - Membrane microdomain-associated uroplakin IIIa contributes to Src-dependent mechanisms of anti-apoptotic proliferation in human bladder carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biol Open. 2012 Oct 15;1(10):1024-34. doi: 10.1242/bio.20121115. Epub 2012 Aug 17.

            ●● Enlace al texto completo (gratuito o de pago) 1242/bio.20121115

AUTORES / AUTHORS:  - Kihira S; Yoshida J; Kawada Y; Hitomi Y; Asada T; Hisatomi R; Ohta A; Iwasaki T; Mahbub Hasan AK; Fukami Y; Sato K

INSTITUCIÓN / INSTITUTION:  - Division of Biotechnology, The Graduate School of Engineering, Kyoto Sangyo University , Kyoto 603-8555 , Japan.

RESUMEN / SUMMARY:  - Our previous study demonstrated that tyrosine phosphorylation of p145(met)/beta-subunit of hepatocyte growth factor receptor by epidermal growth factor receptor and Src contributes to the anti-apoptotic growth of human bladder carcinoma cell 5637 under serum-starved conditions. Here, we show that some other cell lines of human bladder carcinoma, but not other types of human cancer cells, also exhibit Src-dependent, anti-apoptotic proliferation under serum-starved conditions, and that low-density, detergent-insoluble membrane microdomains (MD)  serve as a structural platform for signaling events involving p145(met), EGFR, and Src. As an MD-associated molecule that may contribute to bladder carcinoma-specific cellular function, we identified uroplakin IIIa (UPIIIa), an urothelium-specific protein. Results obtained so far revealed: 1) UPIIIa undergoes partial proteolysis in serum-starved cells; 2) a specific antibody to the extracellular domain of UPIIIa inhibits the proteolysis of UPIIIa and the activation of Src, and promotes apoptosis in serum-starved cells; and 3) knockdown of UPIIIa by short interfering RNA also promotes apoptosis in serum-starved cells. GM6001, a potent inhibitor of matrix metalloproteinase (MMP), inhibits the proteolysis of UPIIIa and promotes apoptosis in serum-starved cells. Furthermore, serum starvation promotes expression and secretion of the heparin-binding EGF-like growth factor in a manner that depends on the functions  of MMP, Src, and UPIIIa. These results highlight a hitherto unknown signaling network involving a subset of MD-associated molecules in the anti-apoptotic mechanisms of human bladder carcinoma cells.

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[928]

TÍTULO / TITLE:  - Azacitidine in Fludarabine-Refractory Chronic Lymphocytic Leukemia: A Phase II Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Lymphoma Myeloma Leuk. 2012 Dec 19. pii: S2152-2650(12)00254-6. doi: 10.1016/j.clml.2012.11.009.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clml.2012.11.009

AUTORES / AUTHORS:  - Malik A; Shoukier M; Garcia-Manero G; Wierda W; Cortes J; Bickel S; Keating MJ; Estrov Z

INSTITUCIÓN / INSTITUTION:  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.

RESUMEN / SUMMARY:  - BACKGROUND: Treatment of fludarabine-refractory disease in patients with chronic  lymphocytic leukemia (CLL) remains a challenge. Because a recent genome-wide methylation analysis of CLL cells suggested that demethylation therapy might be beneficial in CLL, we conducted a phase II trial with the hypomethylating agent azacitidine in patients with recurrent fludarabine-refractory CLL. PATIENTS AND METHODS: Nine patients with recurrent fludarabine-refractory Rai stage IV CLL (median age, 74 years; range, 49-81 years) were enrolled. Azacitidine (75 mg/m(2)) was administered by subcutaneous injection daily for 7 consecutive days  every 3 to 8 weeks, and the data were analyzed at a median follow-up of 9 months  (range 3-47 months). RESULTS: The trial was prematurely discontinued because of lack of response and slow accrual. The number of cycles administered ranged from  1 to 6. Three patients received 1 cycle, 3 patients received 2 cycles, and the remaining 3 patients received 4, 5, or 6 cycles. Side effects included grade 2 or 3 infectious episodes (resulting from immunosuppression and drug-induced neutropenia), diarrhea, rash, vomiting, anemia, and thrombocytopenia. One patient experienced reduction of hepatosplenomegaly and a substantial increase in platelet count after 4 cycles of therapy. However this response did not qualify as a partial response according to the National Cancer Institute International Workshop on CLL (NCI-IWCLL) criteria. At a median follow-up of 9 months after the start of azacitidine treatment, 3 patients (33%) who went on to receive other treatments were alive. CONCLUSIONS: Although no partial or complete responses occurred in these heavily pretreated patients, the encouraging response in 1 of these patients may warrant further studies to investigate the effects of azacitidine in CLL.

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[929]

TÍTULO / TITLE:  - Proteomic approach toward personalized sarcoma treatment: Lessons from prognostic biomarker discovery in gastrointestinal stromal tumor.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Proteomics Clin Appl. 2013 Jan;7(1-2):70-8. doi: 10.1002/prca.201200085.

            ●● Enlace al texto completo (gratuito o de pago) 1002/prca.201200085

AUTORES / AUTHORS:  - Kondo T; Suehara Y; Kikuta K; Kubota D; Tajima T; Mukaihara K; Ichikawa H; Kawai A

INSTITUCIÓN / INSTITUTION:  - Division of Pharmacoproteomics, National Cancer Center Research Institute, Tokyo, Japan.

RESUMEN / SUMMARY:  - Sarcomas range from curable tumors to those causing death via metastasis and recurrence. Thus, there is an urgent need for biomarker identification in order to assess the degree of malignancy, predict prognosis, and evaluate possible therapies. Various proteomic approaches and different clinical materials have been used to this end, and candidate biomarkers have been reported for the different types of sarcomas. However, the sample size used in these biomarker studies was generally insufficient, and thus far, no biomarker has been proved useful in clinics. Given that sarcomas are rare, biomarker validation in this setting is more challenging than in other malignancies. In gastrointestinal stromal tumor, adjuvant therapy has proven to be effective. However, only 40% patients experience metastasis after curative surgery alone, and the rest of the  patients may not need adjuvant therapy. Using a proteomic approach, we identified pfetin (potassium channel tetramerization domain containing 12, KCTD 12) as a novel prognostic biomarker for sarcoma, and immunohistochemically confirmed its clinical usefulness by a multiinstitutional validation study. Here, we describe our experience and discuss the critical points in the discovery of this biomarker.

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[930]

TÍTULO / TITLE:  - Apoptosis in cancer—an update.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Asian Pac J Cancer Prev. 2012;13(10):4873-8.

AUTORES / AUTHORS:  - Sankari SL; Masthan KM; Babu NA; Bhattacharjee T; Elumalai M

INSTITUCIÓN / INSTITUTION:  - Department of Oral Pathology and Microbiology, Sree Balaji Dental College and Hospital, Bharath University, Chennai, India.

RESUMEN / SUMMARY:  - Apoptosis is programmed cell death which is essential for development and survival of living organisms. It is a sequentially regulated suicidal programme where cells activate certain enzymes which dissolute their own nuclear component  and various protein component of nucleus and cytoplasm. Disturbance of this regulatory pathway may lead to various diseases like autoimmune diseases, neurodegenerative diseases and cancers. The potential mechanisms of apoptosis and its role in cancer are discussed. The ability of apoptosis to modulate the life or death of a cell is also recognized for its immense therapeutic potential. Understanding the mechanisms from this review will give us better insight to the  pathogenesis of various diseases including cancer and will open new horizons to therapeutic approaches.

 

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[931]

TÍTULO / TITLE:  - Ent-11alpha-Hydroxy-15-oxo-kaur-16-en-19-oic-acid Inhibits Growth of Human Lung Cancer A549 Cells by Arresting Cell Cycle and Triggering Apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Cancer Res. 2012 Jun;24(2):109-15. doi: 10.1007/s11670-012-0109-8.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11670-012-0109-8

AUTORES / AUTHORS:  - Li L; Chen GG; Lu YN; Liu Y; Wu KF; Gong XL; Gou ZP; Li MY; Liang NC

INSTITUCIÓN / INSTITUTION:  - Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical College, Zhanjiang 524023, China.

RESUMEN / SUMMARY:  - OBJECTIVE: To examine the apoptotic effect of ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F), a compound isolated from  Pteris semipinnata L (PsL), in human lung cancer A549 cells. METHODS: A549 cells  were treated with 5F (0-80 mug/ml) for different time periods. Cytotoxicity was examined using a MTT method. Cell cycle was examined using propidium iodide staining. Apoptosis was examined using Hoechst 33258 staining, enzyme-linked immunosorbent assay (ELISA) and caspase-3 activity analysis. Expression of representative apoptosis-related proteins was evaluated by Western blot analysis. Reactive oxygen species (ROS) level was measured using standard protocols. Potential interaction of 5F with cisplatin was also examined. RESULTS: 5F inhibited the proliferation of A549 cells in a concentration- and time-dependent  manner. 5F increased the accumulation of cells in sub-G1 phase and arrested the cells in the G2 phase. Exposure to 5F induced morphological changes and DNA fragmentation that are characteristic of apoptosis. The expression of p21 was increased. 5F exposure also increased Bax expression, release of cytochrome c and apoptosis inducing factor (AIF), and activation of caspase-3. 5F significantly sensitized the cells to cisplatin toxicity. Interestingly, treatment with 5F did  not increase ROS, but reduced ROS production induced by cisplatin. CONCLUSION: 5F could inhibit the proliferation of A549 cells by arresting the cells in G2 phase  and by inducing mitochondrial-mediated apoptosis.

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[932]

TÍTULO / TITLE:  - Anticancer Effects of Bufalin on Human Hepatocellular Carcinoma HepG2 Cells: Roles of Apoptosis and Autophagy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2013 Jan 11;14(1):1370-82. doi: 10.3390/ijms14011370.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms14011370

AUTORES / AUTHORS:  - Miao Q; Bi LL; Li X; Miao S; Zhang J; Zhang S; Yang Q; Xie YH; Zhang J; Wang SW

INSTITUCIÓN / INSTITUTION:  - Institute of Materia Medica, Fourth Military Medical University, Xi’an 710032, China. zhangjian197011@gmail.com.

RESUMEN / SUMMARY:  - The traditional Chinese medicine bufalin, extracted from toad’s skin, has been demonstrated to exert anticancer activities in various kinds of human cancers. The mechanisms of action lie in its capacity to induce apoptosis, or termed type  I programmed cell death (PCD). However, type II PCD, or autophagy, participates in cancer proliferation, progression, and relapse, as well. Recent studies on autophagy seem to be controversial because of the dual roles of autophagy in cancer survival and death. In good agreement with previous studies, we found that 100 nM bufalin induced extensive HepG2 cell apoptosis. However, we also noticed bufalin triggered autophagy and enhanced Beclin-1 expression, LC3-I to LC3-II conversion, as well as decreased p62 expression and mTOR signaling activation in  HepG2 cells. Blockage of autophagy by selective inhibitor 3-MA decreased apoptotic ratio in bufalin-treated HepG2 cells, suggesting a proapoptotic role of bufalin-induced autophagy. Furthermore, we investigated the underlying mechanisms of bufalin-induced autophagy. Bufalin treatment dose-dependently promoted AMPK phosphorylation while AMPK inhibition by compound C significantly attenuated bufalin-induced autophagy. Taken together, we report for the first time that bufalin induces HepG2 cells PCD, especially for autophagy, and the mechanism of action is, at least in part, AMPK-mTOR dependent.

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[933]

TÍTULO / TITLE:  - Antitumor effects of rapamycin in pancreatic cancer cells by inducing apoptosis and autophagy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2012 Dec 21;14(1):273-85. doi: 10.3390/ijms14010273.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms14010273

AUTORES / AUTHORS:  - Dai ZJ; Gao J; Ma XB; Kang HF; Wang BF; Lu WF; Lin S; Wang XJ; Wu WY

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, the Second Affiliated Hospital, Medical School of Xi’an Jiaotong University, Xi’an 710004, China. dzj0911@126.com.

RESUMEN / SUMMARY:  - Rapamycin (Rapa), an inhibitor of mammalian target of Rapamycin (mTOR), is an immunosuppressive agent that has anti-proliferative effects on some tumors. This  study aims to investigate the effects of Rapa suppressing proliferation of pancreatic carcinoma PC-2 cells in vitro and its molecular mechanism involved in  antitumor activities. MTT assays showed that the inhibition of proliferation of PC-2 cells in vitro was in a time- and dose-dependent manner. By using transmission electron microscopy, apoptosis bodies and formation of abundant autophagic vacuoles were observed in PC-2 cells after Rapa treatment. Flow cytometry assays also showed Rapa had a positive effect on apoptosis. MDC staining showed that the fluorescent density was higher and the number of MDC-labeled particles in PC-2 cells was greater in the Rapa treatment group than  in the control group. RT-PCR revealed that the expression levels of p53, Bax and  Beclin 1 were up-regulated in a dose-dependent manner, indicating that Beclin 1 was involved in Rapa induced autophagy and Rapa induced apoptosis as well as p53  up-regulation in PC-2 cells. The results demonstrated that Rapa could effectively inhibit proliferation and induce apoptosis and autophagy in PC-2 cells.

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[934]

TÍTULO / TITLE:  - Active Targeting to Osteosarcoma Cells and Apoptotic Cell Death Induction by the  Novel Lectin Eucheuma serra Agglutinin Isolated from a Marine Red Alga.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Drug Deliv. 2012;2012:842785. doi: 10.1155/2012/842785. Epub 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1155/2012/842785

AUTORES / AUTHORS:  - Hayashi K; Walde P; Miyazaki T; Sakayama K; Nakamura A; Kameda K; Masuda S; Umakoshi H; Kato K

INSTITUCIÓN / INSTITUTION:  - Division of Chemical Engineering, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama-cho, Toyonaka 560-8531, Osaka, Japan.

RESUMEN / SUMMARY:  - Previously, we demonstrated that the novel lectin Eucheuma serra agglutinin from  a marine red alga (ESA) induces apoptotic cell death in carcinoma. We now find that ESA induces apoptosis also in the case of sarcoma cells. First, propidium iodide assays with OST cells and LM8 cells showed a decrease in cell viability after addition of ESA. With 50 mug/ml ESA, the viabilities after 24 hours decreased to 54.7 +/- 11.4% in the case of OST cells and to 41.7 +/- 12.3% for LM8 cells. Second, using fluorescently labeled ESA and flow cytometric and fluorescence microscopic measurements, it could be shown that ESA does not bind to cells that were treated with glycosidases, indicating importance of the carbohydrate chains on the surface of the cells for efficient ESA-cell interactions. Third, Span 80 vesicles with surface-bound ESA as active targeting  ligand were shown to display sarcoma cell binding activity, leading to apoptosis  and complete OST cell death after 48 hours at 2 mug/ml ESA. The findings indicate that Span 80 vesicles with surface-bound ESA are a potentially useful drug delivery system not only for the treatment of carcinoma but also for the treatment of osteosarcoma.

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[935]

TÍTULO / TITLE:  - Silica Nanoparticles Sensitize Human Multiple Myeloma Cells to Snake (Walterinnesia aegyptia) Venom-Induced Apoptosis and Growth Arrest.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oxid Med Cell Longev. 2012;2012:386286. doi: 10.1155/2012/386286. Epub 2012 Dec 9.

            ●● Enlace al texto completo (gratuito o de pago) 1155/2012/386286

AUTORES / AUTHORS:  - Sayed D; Al-Sadoon MK; Badr G

INSTITUCIÓN / INSTITUTION:  - Clinical Pathology Department, South Egypt Cancer Institute, Assiut University, Assiut 171515, Egypt.

RESUMEN / SUMMARY:  - Background. Multiple myeloma (MM), an almost incurable disease, is the second most common blood cancer. Initial chemotherapeutic treatment could be successful; however, resistance development urges the use of higher toxic doses accompanied by hematopoietic stem cell transplantation. The establishment of more effective treatments that can overcome or circumvent chemoresistance has become a priority. We recently demonstrated that venom extracted from Walterinnesia aegyptia (WEV) either alone or in combination with silica nanoparticles (WEV+NPs) mediated the growth arrest and apoptosis of prostate cancer cells. In the present study, we evaluated the impact of WEV alone and WEV+NP on proliferation and apoptosis of MM cells. Methods. The impacts of WEV alone and WEV+NP were monitored in MM cells from 70 diagnosed patients. The influences of WEV and WEV+NP were assessed with flow cytometry analysis. Results. WEV alone and WEV+NP decreased the viability of MM cells. Using a CFSE proliferation assay, we found that WEV+NP strongly inhibited MM cell proliferation. Furthermore, analysis of the cell cycle using the propidium iodide (PI) staining method indicated that WEV+NP strongly altered  the cell cycle of MM cells and enhanced the induction of apoptosis. Conclusions.  Our data reveal the biological effects of WEV and WEV+NP on MM cells that enable  these compounds to function as effective treatments for MM.

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[936]

TÍTULO / TITLE:  - Retinoic Acid Induces Apoptosis of Prostate Cancer DU145 Cells through Cdk5 Overactivation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Evid Based Complement Alternat Med. 2012;2012:580736. doi: 10.1155/2012/580736. Epub 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1155/2012/580736

AUTORES / AUTHORS:  - Chen MC; Huang CY; Hsu SL; Lin E; Ku CT; Lin H; Chen CM

INSTITUCIÓN / INSTITUTION:  - Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan.

RESUMEN / SUMMARY:  - Retinoic acid (RA) has been believed to be an anticancer drug for a long history. However, the molecular mechanisms of RA actions on cancer cells remain diverse. In this study, the dose-dependent inhibition of RA on DU145 cell proliferation was identified. Interestingly, RA treatment triggered p35 cleavage (p25 formation) and Cdk5 overactivation, and all could be blocked by Calpain inhibitor, Calpeptin (CP). Subsequently, RA-triggered DU145 apoptosis detected by sub-G1 phase accumulation and Annexin V staining could also be blocked by CP treatment. Furthermore, RA-triggered caspase 3 activation and following Cdk5 over-activation were destroyed by treatments of both CP and Cdk5 knockdown. In conclusion, we report a new mechanism in which RA could cause apoptosis of androgen-independent prostate cancer cells through p35 cleavage and Cdk5 over-activation. This finding may contribute to constructing a clearer image of RA function and bring RA as a valuable chemoprevention agent for prostate cancer  patients.

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[937]

TÍTULO / TITLE:  - (3S)-1,2,3,4-Tetrahydro-&#946;-carboline-3-carboxylic Acid from Cichorium endivia. L Induces Apoptosis of Human Colorectal Cancer HCT-8 Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Molecules. 2012 Dec 28;18(1):418-29. doi: 10.3390/molecules18010418.

            ●● Enlace al texto completo (gratuito o de pago) 3390/molecules18010418

AUTORES / AUTHORS:  - Wang FX; Deng AJ; Li M; Wei JF; Qin HL; Wang AP

INSTITUCIÓN / INSTITUTION:  - New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Xiannongtan Street, Beijing 100050, China. qinhailin@imm.ac.cn.

RESUMEN / SUMMARY:  - Cichorium endivia. L, consumed either cooked or eaten raw in salads, is a popular kind of vegetable cultivated all around the World. Its components have been widely used in folk medicine in anti-inflammatory therapy. However, the anti-cancer activity of the components has never been reported. In this study, (3S)-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (1), an amino acid isolated from C. endivia. L, was found for the first time to show cytotoxic activity in colorectal cancer cell line HCT-8. Compound 1 at concentrations of 0.5-4 muM induced apoptosis of HCT-8 cells in a dose-dependent manner. The compound 1-induced apoptosis in HCT-8 cells was accompanied by the loss of mitochondrial membrane potential, the activation of caspase-3, caspase-8 and caspase-9, the up-regulation of Bax and the down-regulation of Bcl-2. In addition, compound 1 suppressed the activation of NF-kappaB, which acts as an inhibitor of apoptosis. Taken together, these results suggested that compound 1 could significantly induce apoptosis of HCT-8 cells through the suppression of NF-kappaB signaling pathway, and thus can be considered as a potential candidate  for developing chemotherapeutic drugs against cancer.

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[938]

TÍTULO / TITLE:  - Lower salinomycin concentration increases apoptotic detachment in high-density cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2012 Oct 12;13(10):13169-82. doi: 10.3390/ijms131013169.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms131013169

AUTORES / AUTHORS:  - Kim JH; Kim TY; Kim HS; Hong S; Yoon S

INSTITUCIÓN / INSTITUTION:  - Research Institute, National Cancer Center, Ilsan-gu, Goyang-si, Gyeonggi-do 410-769, Korea. yoons@ncc.re.kr.

RESUMEN / SUMMARY:  - The present study identified a novel salinomycin (Sal) sensitization mechanism in cancer. We tested whether Sal reduced proliferation in a high-density population  by counting attached cell numbers after Sal treatment. Sal reduced proliferation  in high-density cell populations. Longer exposure to Sal further reduced proliferation. Sal concentrations of 0.1 and 5 &mu;M had similar sensitization effects, suggesting that Sal toxicity was minimal with longer exposure to a high-density cell population. The results suggest that Sal can be applied at a relatively low concentration for a longer time to overcome drug-resistant solid tumors. The 0.5 &mu;M Sal treatment resulted in fewer attached cells than that of the 5 &mu;M Sal treatment with a longer exposure. The lower Sal concentration mainly increased the number of easily detachable cells on the surface. In particular, 0.5 &mu;M Sal increased cellular detachment of newly produced daughter cells. The easily-detachable cells were undergoing apoptosis. It seems that the 0.5 &mu;M Sal treatment also increased cellular toxicity. These novel findings may contribute to the development of Sal-based therapy for patients with drug-resistant cancer or a high-density solid tumor.

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[939]

TÍTULO / TITLE:  - Synthetic miRNA-Mowers Targeting miR-183-96-182 Cluster or miR-210 Inhibit Growth and Migration and Induce Apoptosis in Bladder Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e52280. doi: 10.1371/journal.pone.0052280. Epub 2012 Dec 17.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052280

AUTORES / AUTHORS:  - Liu Y; Han Y; Zhang H; Nie L; Jiang Z; Fa P; Gui Y; Cai Z

INSTITUCIÓN / INSTITUTION:  - Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, People’s Republic of China ; Anhui Medical University,  Hefei, People’s Republic of China ; Shenzhen Key Laboratory of Genitourinary Tumor, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, People’s Republic of China.

RESUMEN / SUMMARY:  - BACKGROUND: MicroRNAs (miRNAs) function as endogenous regulators of biological behaviors of human cancers. Several natural non-coding RNAs are reported to inhibit miRNAs by base-pairing interactions. These phenomena raise questions about the ability of artificial device to regulate miRNAs. The purpose of this study is to create synthetic devices that target a single miRNA or a miRNA cluster and to ascertain their therapeutic effects on the phenotypes of bladder cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: Tandem bulged miRNA binding sites were inserted into the 3’ untranslated region (UTR) of the SV-40 promoter-driven  Renilla luciferase gene to construct two “miRNA-mowers” for suppression of miR-183-96-182 cluster or miR-210. A third device with tandem repeat sequences not complementary to any known miRNA was generated as an untargeted-control. In functional analyses, bladder cancer T24 and UM-UC-3 cells were transfected with each of the three devices, followed by assays for detection of their impacts. Luciferase assays indicated that the activities of the luciferase reporters in the miRNA-mowers were decreased to 30-50% of the untargeted-control. Using Real-Time qPCR, the expression levels of the target miRNAs were shown to be reduced 2-3-fold by the corresponding miRNA-mower. Cell growth, apoptosis, and migration were tested by MTT assay, flow cytometry assay, and in vitro scratch assay, respectively. Cell growth inhibition, increased apoptosis, and decreased motility were observed in miRNA-mowers-transfected bladder cancer cells. CONCLUSIONS/SIGNIFICANCE: Not only a single target miRNA but also the whole members of a target miRNA cluster can be blocked using this modular design strategy. Anti-cancer effects are induced by the synthetic miRNA-mowers in the bladder cancer cell lines. miR-183/96/182 cluster and miR-210 are shown to play oncogenic roles in bladder cancer. A potentially useful synthetic biology platform for miRNA loss-of-function study and cancer treatment has been established in this work.

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[940]

TÍTULO / TITLE:  - PI3K Inhibition Enhances Doxorubicin-Induced Apoptosis in Sarcoma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e52898. doi: 10.1371/journal.pone.0052898. Epub 2012 Dec 31.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052898

AUTORES / AUTHORS:  - Marklein D; Graab U; Naumann I; Yan T; Ridzewski R; Nitzki F; Rosenberger A; Dittmann K; Wienands J; Wojnowski L; Fulda S; Hahn H

INSTITUCIÓN / INSTITUTION:  - Institute of Human Genetics, University Medical Center, Goettingen, Germany.

RESUMEN / SUMMARY:  - We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX). We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis. PI103 decreased the expression of MDR1 and MRP1, which resulted in DOX accumulation. However, the enhancement of DOX-induced apoptosis was unrelated to  DOX accumulation. Neither did it involve inhibition of mTOR. Instead, the combination treatment of DOX plus PI103 activated Bax, the mitochondrial apoptosis pathway, and caspase 3. Caspase 3 activation was also observed in xenografts of sarcoma cells in nude mice upon combination of DOX with the specific PI3K inhibitor GDC-0941. Although the increase in apoptosis did not further impact on tumor growth when compared to the efficient growth inhibition by GDC-0941 alone, these findings suggest that inhibition of PI3K may improve DOX-induced proapoptotic effects in sarcoma. Taken together with similar recent studies of neuroblastoma- and glioblastoma-derived cells, PI3K inhibition seems to be a more general option to sensitize tumor cells to anthracyclines.

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[941]

TÍTULO / TITLE:  - Induction of apoptosis by chitosan/HPV16 E7 siRNA complexes in cervical cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Med Report. 2012 Dec 20. doi: 10.3892/mmr.2012.1246.

            ●● Enlace al texto completo (gratuito o de pago) 3892/mmr.2012.1246

AUTORES / AUTHORS:  - Yang J; Li S; Guo F; Zhang W; Wang Y; Pan Y

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xinxiang Medical College, Henan 453100, P.R. China.

RESUMEN / SUMMARY:  - Consecutive expression of the highrisk human papillomavirus (HPV) oncoproteins, E6 and E7, is pivotal for malignant transformation and maintenance of the malignant phenotype. These oncogenes may be potential targets of gene silencingbased molecular therapies for human cervical cancer. The aim of the present study was to evaluate the efficacy of chitosanbased HPV16 E7 siRNA delivery and the chitosan/HPV16 E7 siRNA complex in the induction of apoptosis in CaSki cells constitutively expressing HPV16 E6 and E7. Chitosan/siRNA nanoparticles were prepared by adding a chitosan solution dropwise to an equal volume of siRNA solution. Formation of the chitosan/siRNA complex was verified by gel retardation assays and the entry of siRNA into the cells was confirmed by fluorescence microscopy. Expression of HPV16 E7 was examined by western blot analysis and apoptotic cells were detected by TUNEL staining. Chitosan formed complexes with HPV16 E7 siRNA. The chitosan/siRNA nanoparticles were efficiently  delivered into CaSki cells and were observed to induce apoptosis. In conclusion,  chitosan is suitable for use as a carrier for delivery of siRNA into cancer cells. The delivery of chitosan/HPV16 E7 siRNA nanoparticles in vivo may serve as a promising therapy for cervical cancer.

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[942]

TÍTULO / TITLE:  - Vemurafenib Potently Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in BRAFV600E Melanoma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Sci Signal. 2013 Jan 29;6(260):ra7. doi: 10.1126/scisignal.2003057.

            ●● Enlace al texto completo (gratuito o de pago) 1126/scisignal.2003057

AUTORES / AUTHORS:  - Beck D; Niessner H; Smalley KS; Flaherty K; Paraiso KH; Busch C; Sinnberg T; Vasseur S; Iovanna JL; Driessen S; Stork B; Wesselborg S; Schaller M; Biedermann T; Bauer J; Lasithiotakis K; Weide B; Eberle J; Schittek B; Schadendorf D; Garbe C; Kulms D; Meier F

INSTITUCIÓN / INSTITUTION:  - 1Division of Dermatologic Oncology, Department of Dermatology, University of Tubingen, 72076 Tubingen, Germany.

RESUMEN / SUMMARY:  - The V600E mutation in the kinase BRAF is frequently detected in melanomas and results in constitutive activation of BRAF, which then promotes cell proliferation by the mitogen-activated protein kinase signaling pathway. Although the BRAFV600E kinase inhibitor vemurafenib has remarkable antitumor activity in patients with BRAFV600E-mutated melanoma, its effects are limited by the onset of drug resistance. We found that exposure of melanoma cell lines with the BRAFV600E mutation to vemurafenib decreased the abundance of antiapoptotic proteins and induced intrinsic mitochondrial apoptosis. Vemurafenib-treated melanoma cells showed increased cytosolic concentration of calcium, a potential trigger for endoplasmic reticulum (ER) stress, which can lead to apoptosis. Consistent with an ER stress-induced response, vemurafenib decreased the abundance of the ER chaperone protein glucose-regulated protein 78, increased the abundance of the spliced isoform of the transcription factor X-box binding protein 1 (XBP1) (which transcriptionally activates genes involved in ER stress responses), increased the phosphorylation of the translation initiation factor eIF2alpha (which would be expected to inhibit protein synthesis), and induced the expression of ER stress-related genes. Knockdown of the ER stress response protein activating transcription factor 4 (ATF4) significantly reduced vemurafenib-induced apoptosis. Moreover, the ER stress inducer thapsigargin prevented invasive growth of tumors formed from vemurafenib-sensitive melanoma cells in vivo. In melanoma cells with low sensitivity or resistance to vemurafenib, combination treatment with thapsigargin augmented or induced apoptosis. Thus, thapsigargin or other inducers of ER stress may be useful in combination therapies to overcome vemurafenib resistance.

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[943]

TÍTULO / TITLE:  - Quercetin enhances the effects of 5-fluorouracil-mediated growth inhibition and apoptosis of esophageal cancer cells by inhibiting NF-kappaB.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2012 Oct;4(4):775-778. Epub 2012 Jul 27.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.829

AUTORES / AUTHORS:  - Chuang-Xin L; Wen-Yu W; Yao C; Xiao-Yan L; Yun Z

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Henan People’s Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.

RESUMEN / SUMMARY:  - Despite its limited success, 5-fluorouracil (5-FU) remains the primary chemotherapy agent for the treatment of esophageal cancer. Quercetin has been demonstrated to inhibit the growth of transformed cells. The present study was conducted to examine whether quercetin combined with conventional chemotherapeutic agents would improve the therapeutic strategy for esophageal cancer. In this study, an MTT assay was used to determine the effects of quercetin on the proliferation of EC9706 and Eca109 cells. Annexin V-FITC/propidium iodide (PI)-stained fluorescence-activated cell sorter (FACS) analysis was used to detect the apoptotic fraction of treated cells, and western  blot analysis was used to examine the protein levels. The results of our study demonstrated that quercetin in combination with 5-FU significantly inhibited growth (P<0.05) and stimulated apoptosis (P<0.005) in EC9706 and Eca109 esophageal cancer cells compared with quercetin or 5-FU alone. These changes were associated with the decreased expression of a phosphorylated inhibitory molecule  of NF-kappaB (pIkappaBalpha), which was activated by exposure to 5-FU alone. We suggest that inclusion of quercetin to the conventional chemotherapeutic agent 5-FU may be an effective therapeutic strategy for esophageal cancer.

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[944]

TÍTULO / TITLE:  - Apoptosis is Induced in Cancer Cells via the Mitochondrial Pathway by the Novel Xylocydine-Derived Compound JRS-15.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2013 Jan 4;14(1):850-70. doi: 10.3390/ijms14010850.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms14010850

AUTORES / AUTHORS:  - Sun C; Guo XX; Zhu D; Xiao C; Bai X; Li Y; Zhan Z; Li XL; Song ZG; Jin YH

INSTITUCIÓN / INSTITUTION:  - Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun 130012, China. szg@jlu.edu.cn.

RESUMEN / SUMMARY:  - The novel compound JRS-15 was obtained through the chemical modification of xylocydine. JRS-15 exhibited much stronger cytotoxic and pro-apoptotic activity than its parent compound in various cancer cell lines, with IC(50) values in HeLa, HepG2, SK-HEP-1, PC-3M and A549 cells ranging from 12.42 to 28.25 microM. In addition, it is more potent for killing cancer than non-cancerous cells. Mechanistic studies showed that JRS-15 treatment arrested cell cycle at the G1/S  phase, which further triggered the translocation of Bax and Bak to the mitochondria, resulting in mitochondrial membrane potential (MMP) depolarization  and the subsequent release of cytochrome c and the second mitochondria-derived activator of caspase (Smac). The sequential activation of caspase-9 and caspase-3/7 and the cleavage of poly (ADP-ribose) polymerase (PARP) were observed following these mitochondrial events. Caspase-8, an initiator caspase that is required to activate the membrane receptor-mediated extrinsic apoptosis pathway was not activated in JRS-15-treated cells. Further analysis showed that the levels of the anti-apoptotic proteins Bcl-xL and XIAP were significantly reduced  upon JRS-15 treatment. Furthermore, the caspase-9 inhibitor z-LEHD-fmk, the pan-caspase inhibitor z-VAD-fmk, and Bcl-xL or XIAP overexpression all effectively prevented JRS-15-induced apoptosis. Taken together, these results indicate that JRS-15 induces cancer cell apoptosis by regulating multiple apoptosis-related proteins, and this compound may therefore be a good candidate reagent for anticancer therapy.

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[945]

TÍTULO / TITLE:  - The Effect of Sulfated (1&#8594;3)-&#945;-l-Fucan from the Brown Alga Saccharina  cichorioides Miyabe on Resveratrol-Induced Apoptosis in Colon Carcinoma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mar Drugs. 2013 Jan 21;11(1):194-212. doi: 10.3390/md11010194.

            ●● Enlace al texto completo (gratuito o de pago) 3390/md11010194

AUTORES / AUTHORS:  - Vishchuk OS; Ermakova SP; Zvyagintseva TN

INSTITUCIÓN / INSTITUTION:  - Laboratory of Enzyme Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159 100-Let Vladivostoku Ave., Vladivostok 690022, Russian Federation. vishchuk87@gmail.com.

RESUMEN / SUMMARY:  - Accumulating data clearly indicate that the induction of apoptosis by nontoxic natural compounds is a potent defense against the development and progression of  many malignancies, including colon cancer. Resveratrol and the fucoidans have been shown to possess potent anti-tumor activity in vitro and in vivo. The aim of the present study was to examine whether the combination of a fucoidan from the brown alga Saccharina cichorioides Miyabe and resveratrol would be an effective preventive and/or therapeutic strategy against colon cancer. Based on NMR spectroscopy and MALDI-TOF analysis, the fucoidan isolated and purified from Saccharina cichorioides Miyabe was (1-->3)-alpha-l-fucan with sulfate groups at C2 and C4 of the alpha-l-fucopyranose residues. The fucoidan enhanced the antiproliferative activity of resveratrol at nontoxic doses and facilitated resveratrol-induced apoptosis in the HCT 116 human colon cancer cell line. Apoptosis was realized by the activation of initiator caspase-9 and effector caspase-7 and -3, followed by the cleavage of PARP. Furthermore, significant inhibition of HCT 116 colony formation was associated with the sensitization of cells to resveratrol by the fucoidan. Taken together, these results demonstrate that the combination of the algal fucoidan with resveratrol may provide a potential therapy against human colon cancer.

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[946]

TÍTULO / TITLE:  - Inhibitory effect of nicardipine on rotenoneinduced apoptosis in SHSY5Y human neuroblastoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Med Report. 2013 Jan 3. doi: 10.3892/mmr.2013.1260.

            ●● Enlace al texto completo (gratuito o de pago) 3892/mmr.2013.1260

AUTORES / AUTHORS:  - Park HJ; Kim HJ

INSTITUCIÓN / INSTITUTION:  - Kohwang Medical Research Institute, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.

RESUMEN / SUMMARY:  - Previous studies have demonstrated that calcium channel blockers have protective  effects on damaged brains. In the present study, the protective effect of the calcium channel blocker nicardipine against rotenoneinduced apoptosis in SHSY5Y human neuroblastoma cells was investigated, focusing on mitogenactivated protein  kinases (MAPKs) and caspase (CASP)mediated apoptotic events. Nicardipine was found to decrease rotenoneinduced apoptosis through 4,6diamidino2phenylindole staining and the terminal deoxynucleotidyl transferasemediated dUTP nick endlabeling assay. In addition, nicardipine was identified to inhibit rotenoneinduced elevation of intracellular Ca2+ concentration measured using the  Fluo4 AM fluorescent dye. Rotenone increased phosphorylation of cJun NH2terminal  kinase (JNK) and p38 MAPK, whereas nicardipine blocked these increases. Nicardipine also prevented downregulation of Bcell CLL/lymphoma 2 and upregulation of Bcl2associated X protein by rotenone. Furthermore, nicardipine abrogated cleavage of CASP9 and 3 and poly (ADPribose) polymerase1 by rotenone and CASP3 enzyme activity in rotenonetreated cells. These results indicate that nicardipine exerts a protective effect against rotenoneinduced apoptosis in SHSY5Y cells, inhibiting phosphorylation of JNK and p38 MAPK and activation of CASPs.

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[947]

TÍTULO / TITLE:  - Induction of apoptosis by sinulariolide from soft coral through mitochondrial-related and p38MAPK pathways on human bladder carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mar Drugs. 2012 Dec 18;10(12):2893-911. doi: 10.3390/md10122893.

            ●● Enlace al texto completo (gratuito o de pago) 3390/md10122893

AUTORES / AUTHORS:  - Neoh CA; Wang RY; Din ZH; Su JH; Chen YK; Tsai FJ; Weng SH; Wu YJ

INSTITUCIÓN / INSTITUTION:  - Department of Research, Pingtung Christian Hospital, Pingtung 90059, Taiwan.

RESUMEN / SUMMARY:  - Sinulariolide, an isolated compound from the soft coral Sinularia flexibilis, possesses the anti-proliferative, anti-migratory and apoptosis-inducing activities against the TSGH bladder carcinoma cell. The anti-tumor effects of sinulariolide were determined by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, cell migration assay and flow cytometry, respectively. Sinulariolide inhibited the growth and migration of bladder carcinoma cells in a  dose-dependent manner, as well as induced both early and late apoptosis as determined by the flow cytometer. Also, the sinulariolide-induced apoptosis is related to the mitochondrial-mediated apoptosis via caspase-dependent pathways, elucidated by the loss of mitochondrial membrane potential, release of cytochrome C, activation of caspase-3/-9, Bax and Bad, as well as suppression of Bcl-2/Bcl-xL/Mcl-1. Detection of the PARP-1 cleaved product suggested the partial involvement of caspase-independent pathways. Moreover, inhibition of p38MAPK activity leads to the rescue of the cell cytotoxicity of sinulariolide-treated TSGH cells, indicating that the p38MAPK pathway is also involved in the sinulariolide-induced cell apoptosis. Altogether, these results suggest that sinulariolide induces apoptosis against bladder cancer cells through mitochondrial-related and p38MAPK pathways.

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[948]

TÍTULO / TITLE:  - Terpenoids from Zingiber officinale (Ginger) Induce Apoptosis in Endometrial Cancer Cells through the Activation of p53.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e53178. doi: 10.1371/journal.pone.0053178. Epub 2012 Dec 31.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0053178

AUTORES / AUTHORS:  - Liu Y; Whelan RJ; Pattnaik BR; Ludwig K; Subudhi E; Rowland H; Claussen N; Zucker N; Uppal S; Kushner DM; Felder M; Patankar MS; Kapur A

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, Shandong University, Qi Lu Hospital, Ji  Nan, China ; Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

RESUMEN / SUMMARY:  - Novel strategies are necessary to improve chemotherapy response in advanced and recurrent endometrial cancer. Here, we demonstrate that terpenoids present in the Steam Distilled Extract of Ginger (SDGE) are potent inhibitors of proliferation of endometrial cancer cells. SDGE, isolated from six different batches of ginger  rhizomes, consistently inhibited proliferation of the endometrial cancer cell lines Ishikawa and ECC-1 at IC(50) of 1.25 microg/ml. SDGE also enhanced the anti-proliferative effect of radiation and cisplatin. Decreased proliferation of  Ishikawa and ECC-1 cells was a direct result of SDGE-induced apoptosis as demonstrated by FITC-Annexin V staining and expression of cleaved caspase 3. GC/MS analysis identified a total of 22 different terpenoid compounds in SDGE, with the isomers neral and geranial constituting 30-40%. Citral, a mixture of neral and geranial inhibited the proliferation of Ishikawa and ECC-1 cells at an  IC(50) 10 microM (2.3 microg/ml). Phenolic compounds such as gingerol and shogaol were not detected in SDGE and 6-gingerol was a weaker inhibitor of the proliferation of the endometrial cancer cells. SDGE was more effective in inducing cancer cell death than citral, suggesting that other terpenes present in SDGE were also contributing to endometrial cancer cell death. SDGE treatment resulted in a rapid and strong increase in intracellular calcium and a 20-40% decrease in the mitochondrial membrane potential. Ser-15 of p53 was phosphorylated after 15 min treatment of the cancer cells with SDGE. This increase in p53 was associated with 90% decrease in Bcl2 whereas no effect was observed on Bax. Inhibitor of p53, pifithrin-alpha, attenuated the anti-cancer effects of SDGE and apoptosis was also not observed in the p53(neg) SKOV-3 cells. Our studies demonstrate that terpenoids from SDGE mediate apoptosis by activating p53 and should be therefore be investigated as agents for the treatment of endometrial cancer.

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[949]

TÍTULO / TITLE:  - Integrative genomics in combination with RNA interference identifies prognostic and functionally relevant gene targets for oral squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS Genet. 2013 Jan;9(1):e1003169. doi: 10.1371/journal.pgen.1003169. Epub 2013  Jan 17.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pgen.1003169

AUTORES / AUTHORS:  - Xu C; Wang P; Liu Y; Zhang Y; Fan W; Upton MP; Lohavanichbutr P; Houck JR; Doody DR; Futran ND; Zhao LP; Schwartz SM; Chen C; Mendez E

INSTITUCIÓN / INSTITUTION:  - Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, Washington, United States of America ; Clinical Research Division, Fred  Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

RESUMEN / SUMMARY:  - In oral squamous cell carcinoma (OSCC), metastasis to lymph nodes is associated with a 50% reduction in 5-year survival. To identify a metastatic gene set based  on DNA copy number abnormalities (CNAs) of differentially expressed genes, we compared DNA and RNA of OSCC cells laser-microdissected from non-metastatic primary tumors (n = 17) with those from lymph node metastases (n = 20), using Affymetrix 250K Nsp single-nucleotide polymorphism (SNP) arrays and U133 Plus 2.0 arrays, respectively. With a false discovery rate (FDR)<5%, 1988 transcripts were found to be differentially expressed between primary and metastatic OSCC. Of these, 114 were found to have a significant correlation between DNA copy number and gene expression (FDR<0.01). Among these 114 correlated transcripts, the corresponding genomic regions of each of 95 transcripts had CNAs differences between primary and metastatic OSCC (FDR<0.01). Using an independent dataset of 133 patients, multivariable analysis showed that the OSCC-specific and overall mortality hazards ratio (HR) for patients carrying the 95-transcript signature were 4.75 (95% CI: 2.03-11.11) and 3.45 (95% CI: 1.84-6.50), respectively. To determine the degree by which these genes impact cell survival, we compared the growth of five OSCC cell lines before and after knockdown of over-amplified transcripts via a high-throughput siRNA-mediated screen. The expression-knockdown of 18 of the 26 genes tested showed a growth suppression >/=30% in at least one cell line (P<0.01). In particular, cell lines derived from late-stage OSCC were more sensitive to the knockdown of G3BP1 than cell lines derived from early-stage OSCC, and the growth suppression was likely caused by increase in apoptosis. Further investigation is warranted to examine the biological role of these genes  in OSCC progression and their therapeutic potentials.

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[950]

TÍTULO / TITLE:  - Mini-Review: Bmx Kinase Inhibitors for Cancer Therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Recent Pat Anticancer Drug Discov. 2012 Nov 29.

AUTORES / AUTHORS:  - Jarboe JS; Dutta S; Velu SE; Willey CD

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, The University of Alabama at Birmingham, 619 19th St. South, HSROC 2232C, Birmingham, AL 35249, USA. cwilley@uab.edu.

RESUMEN / SUMMARY:  - Kinase inhibitors are among the fastest growing class of anti-cancer therapies. One family of kinases that has recently gained attention as a target for treating malignant disorders is the Tec kinase family. Evidence has been published that one member of this family; the Bmx kinase, may play a role in the pathogenesis of glioblastoma, prostate, breast and lung cancer. Bmx has also shown potential as an anti-vascular therapy in combination with radiation or as a sensitizer to chemotherapeutic agents. Therefore, several companies such as Pharmacyclics, Avila Therapeutics, Merck and Co., Metaproteomics, IRM, and Moerae Matrix have developed compounds or peptides that function as Bmx kinase inhibitors. These companies have subsequently been issued patents for these inhibitors. Additionally, it has been shown that current clinical stage EGFR inhibitors can irreversibly inhibit Bmx, suggesting these compounds might be rapidly moved to clinical trials for other malignancies. This review will discuss current patents  issued since 2009 that contain data specifically on inhibition of the Bmx kinase, and will also discuss the scientific literature that suggests their potential application as therapeutics in the treatment of the aforementioned malignancies.

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[951]

TÍTULO / TITLE:  - Erlotinib : A Guide to Its Use in First-Line Treatment of Non-Small-Cell Lung Cancer with Epidermal Growth Factor-Activating Mutations.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Diagn Ther. 2013 Jan 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s40291-013-0015-x

AUTORES / AUTHORS:  - Lyseng-Williamson KA

INSTITUCIÓN / INSTITUTION:  - Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, 0754, Auckland, New Zealand, MDT@adis.com.

RESUMEN / SUMMARY:  - In the EU, the approved use of erlotinib (Tarceva(®)), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has recently been expanded to include first-line treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) in patients with EGFR-activating mutations. In randomized, open-label, phase III clinical trials, oral erlotinib reduced the risk of progression, improved response rates, and was well tolerated relative to standard platinum-based doublet chemotherapy in Caucasian and Asian populations with advanced NSCLC with EGFR-activating mutations.

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[952]

TÍTULO / TITLE:  - Prognostic significance of pre-treatment latent membrane protein 1 from nasopharyngeal swabs for stage III-IVA nasopharyngeal carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Head Neck Oncol. 2012 Nov 23;4(4):81.

AUTORES / AUTHORS:  - Guo Q; Tham IW; Lin S; Su Y; Chen Z; Lin J; Han L; Lin Q; Pan J; Lu JJ

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, Fujian Provincial Cancer Hospital, Provincial Clinical College of Fujian Medical University, Fuzhou, Fujian, People’s Republic  of China. Department of Radiation Oncology, National University Cancer Institute, National University Health System, National University of Singapore, Singapore. These authors contributed equally to this study.

RESUMEN / SUMMARY:  - BACKGROUND: Previous studies have proposed that the latent membrane protein 1 (LMP1) gene is related to the pathogenesis and progression of nasopharyngeal carcinoma. However, the role of pre-treatment LMP1 as a prognostic factor has not been fully addressed, and most previous studies did not utilize polymerase chain  reaction detection techniques. We aimed to investigate whether the presence of pre-treatment LMP1 from nasopharyngeal swabs detected by polymerase chain reaction would allow prognostication and potentially treatment stratification prior to any intervention. METHODS: From June 2007 to June 2008, 87 patients with stage III-IVA nasopharyngeal carcinoma who completed radical radiation therapy were enrolled prospectively. All patients underwent nasopharyngeal swabs for LMP1 prior to treatment. RESULTS: Of the 87 swab samples, LMP1 was detected in 75 (86.2%). Overall survival rates were significantly higher in patients without LMP1 expression (LMP1-) compared with those with LMP1 (LMP1+) (100% vs. 71.6%, respectively, P = 0.034). In addition, clear trends of improved regional relapse-free, distant metastasis-free and progression-free survival rates were noted in the LMP1- group compared with the LMP1+ group (P = 0.076, P = 0.067 and  P = 0.058, respectively). Local control between the two groups was similar (P = 0.165). CONCLUSION: Pre-treatment LMP1 as detected by nasopharyngeal swabs using  polymerase chain reaction is an adverse prognostic factor for stage III-IVA nasopharyngeal carcinoma and potentially can be used as a treatment stratification tool.

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[953]

TÍTULO / TITLE:  - The dominant role of G12C over other KRAS mutation types in the negative prediction of efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Genet. 2013 Jan 9. pii: S2210-7762(12)00278-5. doi: 10.1016/j.cancergen.2012.12.003.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.cancergen.2012.12.003

AUTORES / AUTHORS:  - Fiala O; Pesek M; Finek J; Benesova L; Belsanova B; Minarik M

INSTITUCIÓN / INSTITUTION:  - Department of Oncology and Radiotherapy, Medical School and Teaching Hospital Pilsen, Charles University Prague, Czech Republic. Electronic address: fiala.o@centrum.cz.

RESUMEN / SUMMARY:  - The role of KRAS mutations in molecular targeted therapy by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) has not been fully understood. The present investigation is aimed  at an elucidation of the role of specific KRAS mutation types in predicting outcomes of patients with advanced NSCLC receiving EGFR-TKI therapy. Initially, 448 NSCLC patients were tested for the presence of KRAS mutations, to obtain frequencies of specific KRAS mutation types. Subsequently, the clinical outcome of treatment was evaluated in a subgroup of 38 KRAS-positive patients receiving EGFR-TKI therapy. KRAS mutations were detected in 69 of 448 patients (15.4%), mostly in smokers (17.86% vs. 5.8%, P = 0.0048), and appeared more frequently in  adenocarcinomas than in squamous cell NSCLC or NSCLC that is not otherwise specified (21% vs. 6.99% vs. 4.4%, P = 0.0004). The most frequent type of KRAS mutation was G12C. The progression-free survival (PFS) was doubled in a group of  non-G12C patients compared with that of the G12C group (9.0 wk vs. 4.3 wk, P = 0.009). The overall survival (OS) was not significantly different between non-G12C and G12C groups (12.1 wk vs. 9.3 wk, P = 0.068). The G12C KRAS mutation  is a strong negative predictor for EGFR-TKI treatment, whereas other KRAS mutation types have not negatively predicted treatment efficacy compared with that for the wild-type KRAS genotype.

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[954]

TÍTULO / TITLE:  - Aminoimidazole Carboxamide Ribonucleotide (AICAR) Inhibits the Growth of Retinoblastoma In Vivo by Decreasing Angiogenesis and Inducing Apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e52852. doi: 10.1371/journal.pone.0052852. Epub 2013 Jan 3.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052852

AUTORES / AUTHORS:  - Theodoropoulou S; Brodowska K; Kayama M; Morizane Y; Miller JW; Gragoudas ES; Vavvas DG

INSTITUCIÓN / INSTITUTION:  - Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Retina Service, Harvard Medical School, Boston, Massachusetts, United States of America.

RESUMEN / SUMMARY:  - 5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), an analog of AMP  is widely used as an activator of AMP-kinase (AMPK), a protein that regulates the responses of the cell to energy change. Recently, we showed that AICAR-induced AMPK activation inhibits the growth of retinoblastoma cells in vitro by decreasing cyclins and by inducing apoptosis and S-phase arrest. In this study, we investigated the effects of AMPK activator AICAR on the growth of retinoblastoma in vivo. Intraperitoneal injection of AICAR resulted in 48% growth inhibition of Y79 retinoblastoma cell tumors in mice. Tumors isolated from mice treated with AICAR had decreased expression of Ki67 and increased apoptotic cells (TUNEL positive) compared with the control. In addition, AICAR treatment suppressed significantly tumor vessel density and macrophage infiltration. We also showed that AICAR administration resulted in AMPK activation and mTOR pathway inhibition. Paradoxically observed down-regulation of p21, which indicates that p21 may have a novel function of an oncogene in retinoblastoma tumor. Our results indicate that AICAR treatment inhibited the growth of retinoblastoma tumor in vivo via AMPK/mTORC1 pathway and by apoptogenic, anti-proliferative, anti-angiogenesis mechanism. AICAR is a promising novel non-chemotherapeutic drug that may be effective as an adjuvant in treating Retinoblastoma.

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[955]

TÍTULO / TITLE:  - Vorinostat induces apoptosis and differentiation in myeloid malignancies: genetic and molecular mechanisms.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e53766. doi: 10.1371/journal.pone.0053766. Epub 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0053766

AUTORES / AUTHORS:  - Silva G; Cardoso BA; Belo H; Almeida AM

INSTITUCIÓN / INSTITUTION:  - Unidade de Investigacao em Patobiologia Molecular, Instituto Portugues de Oncologia de Lisboa Francisco Gentil, E.P.E., Lisboa, Portugal ; CEDOC, Faculdade de Ciencias Medicas, Universidade Nova de Lisboa, Lisboa, Portugal.

RESUMEN / SUMMARY:  - BACKGROUND: Aberrant epigenetic patterns are central in the pathogenesis of haematopoietic diseases such as myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Vorinostat is a HDACi which has produced responses in these disorders. The purpose of this study was to address the functional effects of vorinostat in leukemic cell lines and primary AML and MDS myeloid cells and to dissect the genetic and molecular mechanisms by which it exerts its action. METHODOLOGY/PRINCIPAL FINDINGS: Functional assays showed vorinostat promoted cell cycle arrest, inhibited growth, and induced apoptosis and differentiation of K562, HL60 and THP-1 and of CD33(+) cells from AML and MDS patients. To explore the genetic mechanism for these effects, we quantified gene expression modulation by vorinostat in these cells. Vorinostat increased expression of genes down-regulated in MDS and/or AML (cFOS, COX2, IER3, p15, RAI3) and suppressed expression of genes over-expressed in these malignancies (AXL, c-MYC, Cyclin D1)  and modulated cell cycle and apoptosis genes in a manner which would favor cell cycle arrest, differentiation, and apoptosis of neoplastic cells, consistent with the functional assays. Reporter assays showed transcriptional effect of vorinostat on some of these genes was mediated by proximal promoter elements in GC-rich regions. Vorinostat-modulated expression of some genes was potentiated by mithramycin A, a compound that interferes with SP1 binding to GC-rich DNA sequences, and siRNA-mediated SP1 reduction. ChIP assays revealed vorinostat inhibited DNA binding of SP1 to the proximal promoter regions of these genes. These results suggest vorinostat transcriptional action in some genes is regulated by proximal promoter GC-rich DNA sequences and by SP1. CONCLUSION: This study sheds light on the effects of vorinostat in AML and MDS and supports the implementation of clinical trials to explore the use of vorinostat in the treatment of these diseases.

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[956]

TÍTULO / TITLE:  - Histone deacetylase inhibitor, 2-propylpentanoic acid, increases the chemosensitivity and radiosensitivity of human glioma cell lines in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin Med J (Engl). 2012 Dec;125(24):4338-43.

AUTORES / AUTHORS:  - Shao CJ; Wu MW; Chen FR; Li C; Xia YF; Chen ZP

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-sen University, Guangzhou, Guangdong 510060, China; Department of Neurosurgery/Neuro-oncology, Cancer Center of Sun Yat-sen University, Guangzhou,  Guangdong 510060, China.

RESUMEN / SUMMARY:  - BACKGROUND: Treatment for malignant glioma generally consists of cytoreductive surgery followed by radiotherapy and chemotherapy. In this study, we intended to  investigate the effects of 2-propylpentanoic acid (VPA), a histone deacetylase inhibitor, on chemosensitivity and radiosensitivity in human glioma cell lines. METHODS: Human glioma cell lines, T98-G, and SF295, were treated with temozolomide (TMZ) or irradiation (IR), with or without VPA (1.0 mmol/L). Then, cytotoxicity and clonogenic survival assay was performed. Cell cycle stage, apoptosis, and autophagy were also detected using flow cytometry and dansyl monocadaverin (MDC) incorporation assay. One-way analysis of variance (ANOVA) and t-test were used to analyze the differences among variant groups. RESULTS: Mild cytotoxicity of VPA was revealed in both cell lines, T98-G and SF295, with the 50% inhibiting concentration (IC50) value of (3.85 +/- 0.58) mmol/L and (2.15 +/- 0.38) mmol/L, respectively; while the IC50 value of TMZ was (0.20 +/- 0.09) mmol/L for T98-G and (0.08 +/- 0.02) mmol/L for SF295. Moreover, if combined with VPA (1.0 mmol/L) for 96 hours, the sensitivity of glioma cells to TMZ was significant increased (P < 0.05). The surviving fractions at 2 Gy (SF2) of T98-G  and SF295 cells exposed to IR alone were 0.52 and 0.58. However, when VPA was combined with IR, the SF2 of T98-G and SF295 dropped to 0.39 (P = 0.047) and 0.49 (P = 0.049), respectively. Treatment with VPA plus TMZ or IR also resulted in a significant decrease in the proportion of cells in the G2 phase and increased apoptotic rates as well as autophagy in T98-G and SF295 cell lines (P < 0.01). CONCLUSION: VPA may enhance the activities of TMZ and IR on glioma cells possibly through cell cycle block and promote autophagy, and thus could be a potential sensitizer of glioma treatment.

 

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[957]

TÍTULO / TITLE:  - Interleukin-18 and -12 synergistically enhance cytotoxic functions of tumor-infiltrating lymphocytes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin Med J (Engl). 2012 Dec;125(23):4245-8.

AUTORES / AUTHORS:  - Chen ZF; Zhou R; Xia B; Deng CS

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.

RESUMEN / SUMMARY:  - BACKGROUND: The role of tumor-infiltrating lymphocytes (TILs) in the immunopathogenesis of individual cancer is not clear and is a challenge for anti-tumor immunotherapy. This study aimed to investigate the effects of interleukin (IL)-18 and -12 on cytotoxic functions of TILs. METHODS: TILs from postoperative gastric cancer patients were costimulated with IL-18 and IL-12. SGC-7901 tumor cells were pre-incubated with TILs and subcutaneously injected into BALB/C SCID mice. The function of TILs was evaluated by measuring tumor sizes in tumor-bearing mice, T helper (Th)1 (tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma) and Th2 cytokine levels (IL-10 and IL-4) in serum and cytotoxicity of mouse natural killer (NK) and CD8(+) T cells. RESULTS: IL-18 and  IL-12 synergistically inhibited the growth of SGC-7901 cells in vivo and significantly extended the survival rate of SGC-7901-bearing mice (66.7% vs. 13.7%, P < 0.01). Moreover, TILs could promote the secretion of TNF-alpha and IFN-gamma ((130.34 +/- 7.65) vs. (210.63 +/- 12.31) pg/ml, P < 0.01; (14.23 +/- 1.97) vs. (30.52 +/- 2.12) pg/ml, P < 0.01), and downregulate IL-10 and IL-4 secretion ((103.72 +/- 11.21) vs. (61.36 +/- 5.41) pg/ml, P = 0.021; (49.36 +/- 4.67) vs. (28.48 +/- 3.86) pg/ml, P = 0.024). CONCLUSION: IL-18 and IL-12 can synergistically enhance cytotoxic functions of TILs from human gastric cancer.

 

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[958]

TÍTULO / TITLE:  - Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Front Oncol. 2012;2:186. doi: 10.3389/fonc.2012.00186. Epub 2012 Dec 5.

            ●● Enlace al texto completo (gratuito o de pago) 3389/fonc.2012.00186

AUTORES / AUTHORS:  - Yoshimoto K; Mizoguchi M; Hata N; Murata H; Hatae R; Amano T; Nakamizo A; Sasaki T

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University Fukuoka, Japan.

RESUMEN / SUMMARY:  - Many conventional chemotherapeutic drugs exert their cytotoxic function by inducing DNA damage in the tumor cell. Therefore, a cell-inherent DNA repair pathway, which reverses the DNA-damaging effect of the cytotoxic drugs, can mediate therapeutic resistance to chemotherapy. The monofunctional DNA-alkylating agent temozolomide (TMZ) is a commonly used chemotherapeutic drug and the gold standard treatment for glioblastoma (GBM). Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been described as the main modulator to determine the sensitivity of GBM to TMZ, a subset of GBM does not respond despite MGMT inactivation, suggesting that another DNA repair mechanism may also modulate the tolerance to TMZ. Considerable interest has focused on MGMT, mismatch repair (MMR), and the base excision repair (BER) pathway in the mechanism of mediating TMZ resistance, but emerging roles for the  DNA strand-break repair pathway have been demonstrated. In the first part of this review article, we briefly review the significant role of MGMT, MMR, and the BER  pathway in the tolerance to TMZ; in the last part, we review the recent publications that demonstrate possible roles of DNA strand-break repair pathways, such as single-strand break repair and double-strand break repair, as well as the Fanconi anemia pathway in the repair process after alkylating agent-based therapy. It is possible that all of these repair pathways have a potential to modulate the sensitivity to TMZ and aid in overcoming the therapeutic resistance  in the clinic.

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[959]

TÍTULO / TITLE:  - Synthesized multiple antigenic polypeptide vaccine based on B-cell epitopes of human heparanase could elicit a potent antimetastatic effect on human hepatocellular carcinoma in vivo.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e52940. doi: 10.1371/journal.pone.0052940. Epub 2013 Jan 7.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052940

AUTORES / AUTHORS:  - Zhang J; Yang JM; Wang HJ; Ru GQ; Fan DM

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shanxi Province, People’s Republic of China ; Department of Gastroenterology, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang Province, People’s Republic of China.

RESUMEN / SUMMARY:  - AIMS: The aim of this study was to investigate the antimetastatic effect of multiple antigenic polypeptide (MAP) vaccine based on B-cell epitopes of heparanase (HPSE) on human hepatocellular carcinoma (HCC) in vivo. METHODS: The antiserum against B-cell epitopes of HPSE was isolated, purified and characterized after immunizing white-hair-black-eye (WHBY) rabbit with freshly synthesized MAP vaccine. Tumor-bearing murine models of orthotopic implants using HCC-97H cell line were built in BALB/c nude mice. Anti-MAP polyclonal antibodies  induced by MAP vaccine were administrated to the models. The impact on metastasis was assessed, the expressions of VEGF/bFGF in hepatoma tissues and in murine sera were evaluated, and the micro-vessel density (MVD) was counted as well. In addition, the possible impairments of the HPSE MAP vaccine on certain HPSE positive normal organs and blood cells were investigated. RESULTS: The antiserum  was harvested, purified and identified. The antibodies induced by MAP vaccine could specifically react with the dominant epitopes of both precursor protein and large subunit monomer of HPSE, markedly decrease HPSE activity, suppress the expressions of both VEGF and bFGF, and reduce the MVD. Pulmonary metastasis was also attenuated significantly by the anti-MAP polyclonal antibodies. In addition, no obvious impairment could be observed in certain HPSE positive organs and cells. CONCLUSION: MAP vaccine based on B-cell epitopes of HPSE is capable of alleviating HCC metastasis in vivo, mainly through inhibiting the HPSE activity and tumor associated angiogenesis, by virtue of the specific anti-MAP polyclonal  antibodies. Furthermore, these HPSE-specific antibodies do not cause obvious abnormalities on certain HPSE positive blood cells and organs. Our study provides theoretical evidences for the clinical use of the synthesized MAP vaccine based on B-cell epitopes of HPSE in preventing HCC metastasis.

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[960]

TÍTULO / TITLE:  - Antitumor Activity of Antimicrobial Peptides Containing CisoDGRC in CD13 Negative Breast Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e53491. doi: 10.1371/journal.pone.0053491. Epub 2013 Jan 11.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0053491

AUTORES / AUTHORS:  - Hou L; Zhao X; Wang P; Ning Q; Meng M; Liu C

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, The First Affiliated Hospital of Medical School of Xi’an  Jiaotong University, Xi’an, Shaanxi Province, China.

RESUMEN / SUMMARY:  - BACKGROUD: isoAsp-Gly-Arg (isoDGR) is a derivative of the Asn-Gly-Arg (NGR) motif, which is used as a targeted delivery tool to aminopeptidase N (CD13) positive cells. Recent studies have shown that cyclic isoDGR (CisoDGRC) has a more efficient affinity with alpha(v)beta(3), a type of integrin that overexpresses in tumor cells. Antimicrobial peptides (AMPs) are an efficient antitumor peptide that specifically kills tumor cells. In the present study, we designed antimicrobial peptides containing the CisoDGRC motif (CDAK) and assessed its antitumor activity for CD13(-)/alpha(v)beta(3) (+) breast cancer cells (MCF-7 and MDA-MB-231) in vitro and in vivo. METHODS: IN VITRO: We assessed the cytotoxicity of CDAK for MCF-7 and MDA-MB-231 breast cancer cells, the human umbilical vein endothelial cell (HUVEC), and human foreskin fibroblasts (HFF). We performed an apoptosis assay using Annexin-V/PI, DNA ladder, mitochondrial membrane potential, and Caspase-3 and Bcl-2. The effect on cell cycles and affinity with cell were tested using flow cytometry and fluorescent microscopy and the effect on invasion was analyzed using an invasion assay. CDAK was injected intravenously into tumor-bearing athymic nude mice in vivo experiment. RESULTS: CDAK showed cytotoxic activity in MCF-7 and MDA-MB-231 cells, whereas HUVEC and HFF were less sensitive to the peptides. CDAK induced apoptosis, reduced mitochondrial membrane potential, promoted Caspase-3, and inhibited Bcl-2 expression in the two breast cancer cell lines. In addition, CDAK inhibited proliferation of cancer cell through S phase arrest, and own selective affinity with MCF-7 and MDA-MB-231cells, inhibited the invasion of MDA-MB-231 cells. In vivo, CDAK significant inhibited the progression of the tumor and the generation  of neovascularization. CONCLUSION: Antimicrobial peptides containing the CisoDGRC (CDAK) motif could efficiently exhibit the antitumor activity for CD13(-)/alpha(v)beta(3) (+) breast cancer cells.

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[961]

TÍTULO / TITLE:  - Targeting antitumor CD4 helper T cells with universal tumor-reactive helper peptides derived from telomerase for cancer vaccine.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hum Vaccin Immunother. 2013 Jan 28;9(5).

AUTORES / AUTHORS:  - Adotevi O; Dosset M; Galaine J; Beziaud L; Godet Y; Borg C

INSTITUCIÓN / INSTITUTION:  - INSERM, Unite Mixte de Recherche 1098; Besancon Cedex, France; Etablissement Francais du Sang de Bourgogne Franche-Comte; Besancon cedex, France; Universite de Franche-Comte, UMR1098, SFR IBCT; Besancon cedex, France; CHRU de Besancon; Service d’Oncologie; F-25030; Besancon cedex, France.

RESUMEN / SUMMARY:  - Current cancer immunotherapies predominantly rely on CD8 (+) T cells to fight against tumors. However accumulative evidence showed that proinflammatory CD4 (+) helper T cells are critical determinants of effective antitumor immunity. The utilization of universal tumor-reactive helper peptides from telomerase represents a powerful approach to the fully use of CD4 (+) T cell-based immunotherapy.

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[962]

TÍTULO / TITLE:  - Quantification of dynamic contrast-enhanced ultrasound in HCC: prediction of response to a new combination therapy of sorafenib and panobinostat in advanced hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - British Medical J (BMJ). Acceso gratuito al texto completo.

            ●● Enlace a la Editora de la Revista http://bmj.com/search.dtl 

            ●● Cita: British Medical J. (BMJ): <> Case Rep. 2012 Dec 17;2012. pii: bcr2012007576. doi: 10.1136/bcr-2012-007576.

            ●● Enlace al texto completo (gratuito o de pago) 1136/bcr-2012-007576

AUTORES / AUTHORS:  - Knieling F; Waldner MJ; Goertz RS; Strobel D

INSTITUCIÓN / INSTITUTION:  - Department of Medicine 1, University of Erlangen, Erlangen, Germany.

RESUMEN / SUMMARY:  - Here, we report the case of a patient, who showed an antitumour response to a new combination therapy of sorafenib and the histon deacetylase inhibitor panobinostat (LBH-589). D-CEUS (Dynamic contrast-enhanced ultrasonography) was able to predict response to the new therapy regime and may be an interesting tool in the early evaluation of response to therapy. It might be especially useful to  differentiate between responders and non-responders of new-targeted pharmaceuticals like multikinase inhibitors in hepatocellular carcinomas.

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[963]

TÍTULO / TITLE:  - Fascin-1, ezrin and paxillin contribute to the malignant progression and are predictors of clinical prognosis in laryngeal squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(11):e50710. doi: 10.1371/journal.pone.0050710. Epub 2012 Nov 27.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0050710

AUTORES / AUTHORS:  - Gao W; Zhang C; Feng Y; Chen G; Wen S; Huangfu H; Wang B

INSTITUCIÓN / INSTITUTION:  - Department of Otolaryngology, Head & Neck Surgery, No. 1 Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.

RESUMEN / SUMMARY:  - AIMS: Fascin-1, ezrin and paxillin, cytoskeleton-associated proteins, have been implicated in several human cancers, but their role in laryngeal squamous cell carcinoma (LSCC) is unknown. We investigated the association of their expression  and clinicopathologic factors and their prognostic value in LSCC. MATERIALS AND METHODS: Quantitative RT-PCR and western blot analyses were used to examine mRNA  and protein levels in 10 fresh LSCC specimens and 10 corresponding adjacent normal margin (ANM) tissues from patients undergoing surgery in 2012. We used immunohistochemistry to retrospectively study 216 paraffin blocks of LSCC samples from patients (193 men) who had undergone surgery between 2000 and 2006 and had not received special treatment before the diagnosis. Univariate analysis of patient survival involved the Kaplan-Meier method. Multivariate analyses involved the Cox proportional hazards model. RESULTS: The relative mRNA and protein levels of fascin-1, ezrin and paxillin were significantly greater in LSCC than ANM tissue (P<0.05). The high expression of fascin-1, ezrin or paxillin was positively correlated with poor tumor differentiation, cervical lymph node metastasis (N+), and advanced clinical stage (III+IV) (P<0.05) but not sex or metastasis. In addition, a high expression of fascin-1 (P = 0.007) or ezrin (P =  0.047) was associated with advanced tumor stage (T3+T4). The expression of fascin-1 was higher in smokers than non-smokers (P = 0.019). A high expression of fascin-1, ezrin or paxillin was associated with poor prognosis. CONCLUSIONS: Fascin-1, ezrin and paxillin may be prognostic of poor outcome with LSCC after surgery. Our study may lead to establishing new molecular therapeutic targets and/or prognostic biomarkers in LSCC.

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[964]

TÍTULO / TITLE:  - In vitro inhibitory and pro-apoptotic effect of stellera chamaejasme L extract on human lung cancer cell line NCI-H157.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Tradit Chin Med. 2012 Sep;32(3):404-10.

AUTORES / AUTHORS:  - Liu X; Li Y; Yang Q; Chen Y; Weng X; Wang Y; Li N; Zhu X

INSTITUCIÓN / INSTITUTION:  - Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.

RESUMEN / SUMMARY:  - OBJECTIVE: To investigate the inhibitory and pro-apoptotic effect of Stellera Chamaejasme L extract (ESC) in vitro. METHODS: ESC was first extracted with ethanol, and then washed using a polyamide column with 60% ethanol. ESC was then  decompressively recycled and vacuum dried at room temperature to obtain active fractions. Subsequently, the cytotoxic and apoptotic effects of ESC on NCI-H157 human lung cancer cells were determined. RESULTS: The results showed that ESC was rich in isomers of Chamaejasminor, neochamaejasmine and Sikokianin. ESC had significant cytotoxicity against NCI-H157 cells, with an IC50 of approximately 18.50 microg x mL(-). ESC caused significant increase in total apoptotic rate, the activity of caspase 3 and 8, CONCLUSION: The inhibitory effect of ESC on NCI-H157 tumor cells might partly be attributed to its apoptotic induction through activation of the Fas death receptor pathway.

 

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[965]

TÍTULO / TITLE:  - In Vitro Comparison of Hypericin and 5-Aminolevulinic Acid-Derived Protoporphyrin IX for Photodynamic Inactivation of Medulloblastoma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51974. doi: 10.1371/journal.pone.0051974. Epub 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051974

AUTORES / AUTHORS:  - Ritz R; Scheidle C; Noell S; Roser F; Schenk M; Dietz K; Strauss WS

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Eberhard Karls University Tubingen, Tubingen, Germany.

RESUMEN / SUMMARY:  - BACKGROUND: Hypericin (HYP) is a naturally occurring photosensitizer. Cellular uptake and photodynamic inactivation after incubation with this photosensitizer have neither been examined in medulloblastoma cells in vitro, nor compared with 5-aminolevulinic acid-derived protoporphyrin IX (5-ALA-derived PpIX). METHODS: In 3 medulloblastoma cell lines (D283 Med, Daoy, and D341 Med) the time- and concentration-dependent intracellular accumulation of HYP and 5-ALA-derived PpIX  was analyzed by fluorescence microscopy (FM) and FACS. Photocytotoxicity was measured after illumination at 595 nm (HYP) and 635 nm (5-ALA-derived PpIX) in D283 Med cells and compared to U373 MG glioma cells. RESULTS: All medulloblastoma cell lines exhibited concentration- and time-dependent uptake of HYP. Incubation  with HYP up to 10 microM resulted in a rapid increase in fluorescence intensity,  which peaked between 2 and 4 hours. 5-ALA-derived PpIX accumulation increased in  D283 Med cells by 22% over baseline after 5-ALA incubation up to 1.2 mM. Photocytotoxicity of 5-ALA-derived PpIX was higher in D283 Med medulloblastoma compared to U373MG glioma. The [Formula: see text] [lethal dose (light dose that  is required to reduce cell survival to 50% of control)] of 5-ALA-derived PpIX was 3.8 J/cm(2) in D283 Med cells versus 5.7 J/cm2 in U373MG glioma cells. Photocytotoxicity of HYP in D283 Med cells was determined at 2.5 microM after an  incubation time of 2 h and an illumination wavelength of 595 nm. The [Formula: see text] value was 0.47 J/cm(2). CONCLUSION: By its 5-fold increase in fluorescence over autofluorescence levels HYP has excellent properties for tumor  visualization in medulloblastomas. The high photocytotoxicity of HYP, compared to 5-ALA-derived PpIX, is convincingly demonstrated by its 8- to 13-fold lower [Formula: see text]. Therefore HYP might be a promising molecule for intraoperative visualization and photodynamic treatment of medulloblastomas.

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[966]

TÍTULO / TITLE:  - Expression profile and prognostic role of sex hormone receptors in gastric cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Cancer. 2012 Dec 2;12:566. doi: 10.1186/1471-2407-12-566.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2407-12-566

AUTORES / AUTHORS:  - Gan L; He J; Zhang X; Zhang YJ; Yu GZ; Chen Y; Pan J; Wang JJ; Wang X

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Changzheng Hospital, Second Military Medical University,  Shanghai, China.

RESUMEN / SUMMARY:  - BACKGROUND: Increasing interest has been devoted to the expression and possible role of sex hormone receptors in gastric cancer, but most of these findings are controversial. In the present study, the expression profile of sex hormone receptors in gastric cancer and their clinicopathological and prognostic value were determined in a large Chinese cohort. METHODS: The mRNA and protein expression of estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), progesterone receptor (PR), and androgen receptor (AR) in primary gastric tumors  and corresponding adjacent normal tissues from 60 and 866 Chinese gastric cancer  patients was detected by real-time quantitative PCR and immunohistochemistry method, respectively. The expression profile of the four receptors was compared and their associations with clinicopathological characteristics were assessed by  using Chi-square test. The prognostic value of the four receptors in gastric cancer was evaluated by using univariate and multivariate Cox regression analysis. RESULTS: The presence of ERalpha, ERbeta, PR, and AR in both gastric tumors and normal tissues was confirmed but their expression levels were extremely low except for the predominance of ERbeta. The four receptors were expressed independently and showed a decreased expression pattern in gastric tumors compared to adjacent normal tissues. The positive expression of the four receptors all correlated with high tumor grade and intestinal type, and ERalpha and AR were also associated with early TNM stage and thereby a favorable outcome. However, ERalpha and AR were not independent prognostic factors for gastric cancer when multivariate survival analysis was performed. CONCLUSIONS: Our findings indicate that the sex hormone receptors may be partly involved in gastric carcinogenesis but their clinicopathological and prognostic significance  in gastric cancer appears to be limited.

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[967]

TÍTULO / TITLE:  - 2-Deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography Demonstrates Target  Inhibition with the Potential to Predict Anti-Tumour Activity Following Treatment with the AKT Inhibitor AZD5363.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Imaging Biol. 2013 Jan 24.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11307-013-0613-3

AUTORES / AUTHORS:  - Maynard J; Ricketts SA; Gendrin C; Dudley P; Davies BR

INSTITUCIÓN / INSTITUTION:  - Personalised Healthcare and Biomarkers, AstraZeneca, Cheshire, SK10 4TG, UK, Juliana.maynard@astrazeneca.com.

RESUMEN / SUMMARY:  - PURPOSE: The phosphatidyl inositol 3 kinase, AKT and mammalian target of rapamycin are frequently deregulated in human cancer and are among one of the most promising targets for cancer therapy. AZD5363 (AstraZeneca) is an AKT inhibitor in phase 1 clinical trials. Given its utility in assessing glucose metabolism, we investigated the role of 2-Deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) positron emission tomography (PET) as a biomarker to demonstrate target inhibition and its potential to predict and demonstrate the anti-tumour activity of AZD5363. METHODS: (18)F-FDG PETscans were performed in nude mice in a number of xenograft models (U87-MG glioblastoma, BT474C breast carcinoma and Calu-6 lung). Mice were fasted prior to imaging, and either static or dynamic (18)F-FDG PET imaging was performed. RESULTS: We have shown that (18)F-FDG uptake in tumour xenografts was reduced by 39 % reduction compared to vehicle after a single dose of AZD5363, demonstrating activation of the AKT pathway after only 4  h of dosing. Multiple doses of AZD5363 showed an anti-tumour volume effect and a  reduction in (18)F-FDG uptake (28 % reduction compared to vehicle), highlighting  the potential of (18)F-FDG PET as an efficacy biomarker. Furthermore, the degree  of inhibition of (18)F-FDG uptake corresponded with the sensitivity of the tumour model to AZD5363. The use of dynamic (18)F-FDG PET and a two-compartmental analysis identified the mechanism of this change to be due to a change in cellular uptake of (18)F-FDG following administration of AZD5363. CONCLUSIONS: We conclude that (18)F-FDG PET is a promising pharmacodynamic biomarker of AKT pathway inhibition, with potential to predict and demonstrate anti-tumour activity. It is a biomarker that may stop ineffective drug schedules, helping to  make early stop decisions and identify responding subsets of patients, resulting  in improved clinical decision making both during drug development and patient management.

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[968]

TÍTULO / TITLE:  - Expression of RET finger protein predicts chemoresistance in epithelial ovarian cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Med. 2012 Oct;1(2):218-29. doi: 10.1002/cam4.32. Epub 2012 Sep 13.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cam4.32

AUTORES / AUTHORS:  - Horio M; Kato T; Mii S; Enomoto A; Asai M; Asai N; Murakumo Y; Shibata K; Kikkawa F; Takahashi M

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Nagoya University Graduate School of Medicine Nagoya, Japan ; Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine Nagoya, Japan.

RESUMEN / SUMMARY:  - Resistance to platinum- and taxane-based chemotherapy is a major cause of treatment failure in ovarian cancer. Thus, it is necessary to develop a predictive marker and molecular target for overcoming drug resistance in ovarian  cancer treatment. In a previous report, using an in vitro model, we found that the RET finger protein (RFP) (also known as tripartite motif-containing protein 27, TRIM27) confers cancer cell resistance to anticancer drugs. However, the significance of RFP expression in cancer patients remains elusive. In this study, we showed that RFP was expressed in 62% of ovarian cancer patients and its positivity significantly correlated with drug resistance. Consistent with clinical data, depletion of RFP by RNA interference (RNAi) in ovarian cancer cell lines, SKOV3 and HEY, significantly increased carboplatin- or paclitaxel-induced  apoptosis and resulted in reduced anticancer drug resistance. In a nude mouse tumor xenograft model, inoculated RFP-knockdown ovarian cancer cells exhibited lower carboplatin resistance than control cells. These findings suggest that RFP  could be a predictive marker for chemoresistance in ovarian cancer patients and also a candidate for a molecular-targeted agent.

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[969]

TÍTULO / TITLE:  - N-acetylcysteine improves antitumoural response of Interferon alpha by NF-kB downregulation in liver cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Comp Hepatol. 2012 Dec 4;11(1):4. doi: 10.1186/1476-5926-11-4.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1476-5926-11-4

AUTORES / AUTHORS:  - Kretzmann NA; Chiela E; Matte U; Marroni N; Marroni CA

INSTITUCIÓN / INSTITUTION:  - Post-Graduation Program in Medicine: Hepatology, Universidade Federal de Ciencias da Saude de Porto Alegre, Brazil, Universidade Federal de Ciencias da Saude de Porto Alegre, Porto Alegre, RS, CEP: 90050-170, Brazil. nakfilho@gmail.com.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Liver cancer is one of the most common malignancies in the  world and at the moment, there is no drug intervention effective for the treatment of liver tumours. Investigate the effect of N-acetylcysteine (NAC), which has been studied for its antitumoural properties, on the toxicity of hepatocarcinoma (HCC) cells in vitro when used with the drug interferon alpha-2A  (IFN), which is used clinically to treat HCC. RESULTS: NAC, IFN and NAC plus IFN  reduced cell viability, as determined by MTT assay. More importantly, NAC potentiates the cytotoxic effect of IFN, with the best response achieved with 10  mM of NAC and 2.5 x 104 of IFN. These results were confirmed by Annexin/PI staining through flow cytometry and morphologic analyses. Co-treatment reduced the expression of the nuclear transcription factor kappa-B (NF-kB). In a similar  way to NAC, RNAi against p65 potentiated the toxic effect of IFN, suggesting that, indeed, NAC may be enhancing the effect of IFN through inhibition of NF-kB. CONCLUSIONS: Our results support the notion that NAC may be an important drug for the treatment of liver tumours as primary or adjuvant therapy. IFN has a limited  clinical response, and therefore, the anti-proliferative properties of NAC in the liver should be explored further as an alternative for non-responders to IFN treatment.

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[970]

TÍTULO / TITLE:  - Autophagy-independent enhancing effects of Beclin 1 on cytotoxicity of ovarian cancer cells mediated by proteasome inhibitors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Cancer. 2012 Dec 27;12:622. doi: 10.1186/1471-2407-12-622.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2407-12-622

AUTORES / AUTHORS:  - Liu C; Yan X; Wang HQ; Gao YY; Liu J; Hu Z; Liu D; Gao J; Lin B

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics & Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110004, China. 892207391@qq.com.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: The ubiquitin-proteasome system and macroautophagy (hereafter referred to autophagy) are two complementary pathways for protein degradation. Emerging evidence suggests that proteasome inhibition might be a promising approach for tumor therapy. Accumulating data suggest that autophagy is activated as a compensatory mechanism upon proteasome activity is impaired. METHOD: Autophagy activation was measured using acridine orange staining and LC3  transition. Cell viability and apoptosis were measured using MTT assay and flow cytometry, respectively. Beclin 1 expression vectors or shRNA against Beclin 1 (shBeclin 1) were transfected to investigate the role of Beclin 1 in autophagy activation and cytotoxicity of ovarian cancer cells induced by proteasome inhibitors. RESULTS: Proteasome inhibitors suppressed proliferation and induced autophagy in ovarian cancer cells. Neither phosphoinositide 3-kinase (PI3K) inhibitors nor shRNA against Beclin 1 could abolish the formation of acidic vacuoles and the processing of LC3 induced by proteasome inhibitors. Moreover, Beclin 1 overexpression enhanced anti-proliferative effects of proteasome inhibitors in ovarian cancer cells. CONCLUSIONS: For the first time, the current  study demonstrated that proteasome inhibitors induced PI3K and Beclin 1-independent autophagy in ovarian cancer cells. In addition, this study revealed autophagy-independent tumor suppressive effects of Beclin 1 in ovarian cancer cells.

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[971]

TÍTULO / TITLE:  - Impact of histone deacetylase inhibitor valproic acid on the anticancer effect of etoposide on neuroblastoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Neuro Endocrinol Lett. 2012 Dec 26;33(Suppl3):16-24.

AUTORES / AUTHORS:  - Groh T; Hrabeta J; Poljakova J; Eckschlager T; Stiborova M

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.

RESUMEN / SUMMARY:  - OBJECTIVES: Etoposide (Vepesid, VP-16), an inhibitor of topoisomerase II, is a chemotherapeutic drug commonly used for treatment of different types of malignant diseases. By inhibiting the topoisomerase II enzyme activity in cancer cells, this drug leads to DNA damage and subsequently to cell death. In this study, we investigated the effect of this anticancer drug alone and in combination with a histone deacetylase (HDAC) inhibitor, valproic acid (VPA), on a human UKF-NB-4 neuroblastoma cell line. METHODS: The effects of etoposide and VPA on UKF-NB-4 cells were tested under the normoxic and also the hypoxic (1% O2) cultivation conditions. The cytotoxicity of etoposide and VPA to a UKF-NB-4 neuroblastoma cell line was evaluated with MTT assay. Apoptosis of the cells was analyzed by flow cytometry using an Annexin V and propidium iodide binding method. The effect of etoposide and VPA on the cell cycle distribution was determined by flow cytometric analysis using propidium iodide staining. RESULTS: The results of the  study demonstrate that UKF-NB-4 neuroblastoma cells are sensitive both to etoposide and to VPA. They also indicate that the impact of VPA on cytotoxicity of etoposide in these tumor cells varies depending on the sequence of cultivation of the cells with the drugs. As a suitable sequence of cultivation, with a high rate of suppression of neuroblastoma cell growth was found the preincubation of the cells with etoposide, which was followed by their cultivation with VPA. In contrast, the reversed combination (preincubation of the cells with VPA before their treating with etoposide) did not give any increase in etoposide cytotoxicity. The effect of such combined treatment can be explained by measuring the cell cycle distribution, which shows that both etoposide and VPA change the cell cycle phase distribution. CONCLUSION: Etoposide and VPA were found as cycle  phase specific drugs that are cytotoxic to human UKF-NB-4 neuroblastoma cells used either as single drugs or both together. However, whereas VPA might sensitize the cells to etoposide, inappropriate sequence of cultivation of the cells with VPA can decrease the etoposide cytotoxic efficacy. The results found here warrant further studies of combined treatment of neuroblastoma cells with etoposide with HDAC inhibitors and may help in the design of new protocols geared to the treatment of high risk neuroblastomas.

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[972]

TÍTULO / TITLE:  - Sorafenib combined with gemcitabine in EGFR-TKI-resistant human lung cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2013 Jan;5(1):68-72. Epub 2012 Oct 9.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.958

AUTORES / AUTHORS:  - Li J; Pan YY; Zhang Y

INSTITUCIÓN / INSTITUTION:  - Department of Geriatrics, The Third Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230061;

RESUMEN / SUMMARY:  - Sorafenib is a multi-targeted agent and has been reported to have potent antitumor effects against various types of tumors, including human non-small cell lung cancer (NSCLC). In this study, we explored in vitro the antitumor effects of sorafenib alone and in combination with gemcitabine in epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant human lung cancer cell lines and the related molecular mechanisms. The NSCLC cell lines A549 (mutant KRAS), H1666 (mutant BRAF) and H1975 (mutant EGFR-T790M) were treated with sorafenib and gemcitabine alone and in combination. The cytotoxicity was assessed by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathways were analyzed by western blotting. We found that sorafenib exhibited dose-dependent growth inhibition in all three EGFR-TKI-resistant NSCLC cell lines. When sorafenib was combined with gemcitabine, synergistic activity was observed in the A549 and H1666 cells and antagonistic activity was observed in the H1975 cells. Sorafenib arrested the cell cycle at the G1 phase, whereas gemcitabine arrested the cell cycle at the S  phase. Sorafenib inhibited C-RAF and p-ERK in the A549 cells and B-RAF and p-ERK  in the H1666 and H1975 cells. The molecular mechanism of this synergism is that RAF/MEK/ERK which are activated by gemcitabine are efficiently suppressed by simultaneously administered sorafenib. By contrast, the mechanism of antagonism may be due to mutual interference with the cell cycle in the H1975 cells. In conclusion, we found that sorafenib exhibits antiproliferative effects in EGFR-TKI-resistant NSCLC cell lines and when combined with gemcitabine demonstrates synergistic activity in A549 and H1666 cells but antagonistic activity in H1975 cells.

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[973]

TÍTULO / TITLE:  - Altered DNA Binding and Amplification of Human Breast Cancer Suppressor Gene BRCA1 Induced by a Novel Antitumor Compound, [Ru(&eta;6-p-phenylethacrynate)Cl2(pta)].

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2012 Oct 15;13(10):13183-202. doi: 10.3390/ijms131013183.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms131013183

AUTORES / AUTHORS:  - Chakree K; Ovatlarnporn C; Dyson PJ; Ratanaphan A

INSTITUCIÓN / INSTITUTION:  - Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla 90112, Thailand. adisorn.r@psu.ac.th.

RESUMEN / SUMMARY:  - The ruthenium-based complex [Ru(&eta;6-p-phenylethacrynate)Cl(2)(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane), termed ethaRAPTA, is an interesting antitumor compound. The elucidation of the molecular mechanism of drug activity is central to the drug development program. To this end, we have characterized the ethaRAPTA interaction with DNA, including probing the sequence  specific modified DNA structural stability and DNA amplification using the breast cancer suppressor gene 1 (BRCA1) of human breast and colon adenocarcinoma cell lines as models. The preference of ethaRAPTA base binding is in the order A &gt;  G &gt; T &gt; C. Once modified, the ethaRAPTA-induced BRCA1 structure has higher  thermal stability than the modified equivalents of its related compound, RAPTA-C. EthaRAPTA exhibits a higher efficiency than RAPTA-C in inhibiting BRCA1 amplification. With respect to both compounds, the inhibition of BRCA1 amplification is more effective in an isolated system than in cell lines. These data provide evidence that will help to understand the process of elucidating the pathways involved in the response induced by ethaRAPTA.

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[974]

TÍTULO / TITLE:  - Germline DNA copy number aberrations identified as potential prognostic factors for breast cancer recurrence.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e53850. doi: 10.1371/journal.pone.0053850. Epub 2013 Jan 16.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0053850

AUTORES / AUTHORS:  - Sapkota Y; Ghosh S; Lai R; Coe BP; Cass CE; Yasui Y; Mackey JR; Damaraju S

INSTITUCIÓN / INSTITUTION:  - Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada ; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.

RESUMEN / SUMMARY:  - Breast cancer recurrence (BCR) is a common treatment outcome despite curative-intent primary treatment of non-metastatic breast cancer. Currently used prognostic and predictive factors utilize tumor-based markers, and are not optimal determinants of risk of BCR. Germline-based copy number aberrations (CNAs) have not been evaluated as determinants of predisposition to experience BCR. In this study, we accessed germline DNA from 369 female breast cancer subjects who received curative-intent primary treatment following diagnosis. Of these, 155 experienced BCR and 214 did not, after a median duration of follow up  after breast cancer diagnosis of 6.35 years (range = 0.60-21.78) and 8.60 years (range = 3.08-13.57), respectively. Whole genome CNA genotyping was performed on  the Affymetrix SNP array 6.0 platform. CNAs were identified using the SNP-Fast Adaptive States Segmentation Technique 2 algorithm implemented in Nexus Copy Number 6.0. Six samples were removed due to poor quality scores, leaving 363 samples for further analysis. We identified 18,561 CNAs with >/=1 kb as a predefined cut-off for observed aberrations. Univariate survival analyses (log-rank tests) identified seven CNAs (two copy number gains and five copy neutral-loss of heterozygosities, CN-LOHs) showing significant differences (P<2.01x10(-5)) in recurrence-free survival (RFS) probabilities with and without  CNAs.We also observed three additional but distinct CN-LOHs showing significant differences in RFS probabilities (P<2.86x10(-5)) when analyses were restricted to stratified cases (luminal A, n = 208) only. After adjusting for tumor stage and grade in multivariate analyses (Cox proportional hazards models), all the CNAs remained strongly associated with the phenotype of BCR. Of these, we confirmed three CNAs at 17q11.2, 11q13.1 and 6q24.1 in representative samples using independent genotyping platforms. Our results suggest further investigations on the potential use of germline DNA variations as prognostic markers in cancer-associated phenotypes.

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[975]

TÍTULO / TITLE:  - Clinically relevant cancer biomarkers and pharmacogenetic assays.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Oncol Pharm Pract. 2013 Jan 24.

            ●● Enlace al texto completo (gratuito o de pago) 1177/1078155212473862

AUTORES / AUTHORS:  - Patel JN; Mandock K; McLeod HL

INSTITUCIÓN / INSTITUTION:  - Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA; UNC Institute for Pharmacogenomics and Individualized Therapy, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA.

RESUMEN / SUMMARY:  - BackgroundThe number of pharmacogenetic assays available is continuously expanding as more molecularly targeted anticancer drugs are under clinical development. While the literature regarding drug-gene associations and therapeutic implications is often robust, reviews regarding clinical assay availability and profiling methodologies of commonly used cancer biomarkers are often lacking. OBJECTIVE: /st>To concisely identify and describe cancer biomarkers and their respective pharmacogenetic assays currently available in clinical practice.DiscussionAnalysis of germ-line DNA mutations can often help to predict pharmacokinetic and pharmacodynamic responses, whereas somatic DNA mutations are particularly useful in predicting tumor response. Molecular profiling and pre-emptive identification of cancer biomarkers can help to predict disease prognosis as well as response to anticancer therapy. Dozens of pharmacogenetic assays, utilizing several common methodologies, are currently available in clinical practice. It is essential for clinicians to understand the  molecular pathways for anticancer drugs, the therapeutic implications of mutations within these pathways, the clinical assay(s) available to test for pharmacogenetic differences, and the common profiling methodology employed. CONCLUSION: /st>As research continues to unveil more drug-gene and disease-gene associations, it is critical that clinicians understand which pharmacogenetic assays are available to identify inter-individual differences that predict safety and efficacy of anticancer drugs as we move toward the concept of personalized medicine.

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[976]

TÍTULO / TITLE:  - In silico prediction of tumor antigens derived from functional missense mutations of the cancer gene census.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncoimmunology. 2012 Nov 1;1(8):1281-1289.

            ●● Enlace al texto completo (gratuito o de pago) 4161/onci.21511

AUTORES / AUTHORS:  - Khalili JS; Hanson RW; Szallasi Z

INSTITUCIÓN / INSTITUTION:  - Departments of Melanoma Medical Oncology and Systems Biology; University of Texas M.D. Anderson Cancer Center; Houston, TX USA.

RESUMEN / SUMMARY:  - Antigen-specific immune responses against peptides derived from missense gene mutations have been identified in multiple cancers. The application of personalized peptide vaccines based on the tumor mutation repertoire of each cancer patient is a near-term clinical reality. These peptides can be identified  for pre-validation by leveraging the results of massive gene sequencing efforts in cancer. In this study, we utilized NetMHC 3.2 to predict nanomolar peptide binding affinity to 57 human HLA-A and B alleles. All peptides were derived from  5,685 missense mutations in 312 genes annotated as functionally relevant in the Cancer Genome Project. Of the 26,672,189 potential 8-11 mer peptide-HLA pairs evaluated, 0.4% (127,800) display binding affinities < 50 nM, predicting high affinity interactions. These peptides can be segregated into two groups based on  the binding affinity to HLA proteins relative to germline-encoded sequences: peptides for which both the mutant and wild-type forms are high affinity binders, and peptides for which only the mutant form is a high affinity binder. Current evidence directs the attention to mutations that increase HLA binding affinity, as compared with cognate wild-type peptide sequences, as these potentially are more relevant for vaccine development from a clinical perspective. Our analysis generated a database including all predicted HLA binding peptides and the corresponding change in binding affinity as a result of point mutations. Our study constitutes a broad foundation for the development of personalized peptide  vaccines that hone-in on functionally relevant targets in multiple cancers in individuals with diverse HLA haplotypes.

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[977]

TÍTULO / TITLE:  - Safety and Efficacy of Maintenance Therapy With a Nonspecific Cytochrome P17 Inhibitor (CYP17i) After Response/Stabilization to Docetaxel in Metastatic Castration-Resistant Prostate Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Genitourin Cancer. 2012 Dec 20. pii: S1558-7673(12)00236-4. doi: 10.1016/j.clgc.2012.11.003.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clgc.2012.11.003

AUTORES / AUTHORS:  - Gil-Bazo I; Arevalo E; Castillo A; Zudaire ME; Carranza OE; Fusco JP; Castanon E; Collado-Gomez V; Lopez I; Gil-Aldea I

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Clinica Universidad de Navarra, Pamplona, España;  Division of Oncology, Center for Applied Medical Research, Pamplona, España. Electronic address: igbazo@unav.es.

RESUMEN / SUMMARY:  - BACKGROUND: Frontline treatment of metastatic castration-resistant prostate cancer (mCRPC) consists of docetaxel-based chemotherapy. The median time to progression (TTP) from chemotherapy initiation is 6 to 8 months. Ketoconazole, a  nonspecific cytochrome P17 inhibitor (CYP17i), blocks adrenal androgen synthesis. Low-dose ketoconazole (LDK), (200 mg three times daily [t.d.s]) has shown activity in mCRPC after progression to androgen deprivation. The role of a CYP17i after docetaxel treatment in the maintenance setting has been unexplored. METHODS: We identified 38 patients with mCRPC who showed progression to luteinizing hormone releasing-hormone agonists (LHRHa) and who were treated with  a median of 7 cycles of frontline three-weekly docetaxel (75 mg/m(2)) plus prednisone (10 mg/d) and LHRHa. Medical charts of 20 patients who showed no progression to docetaxel were reviewed. After the last docetaxel cycle, 10 patients received LDK maintenance treatment plus prednisone (10 mg/d) and LHRHa,  whereas 10 patients received LHRHa alone. TTP was the primary endpoint. RESULTS:  After a follow-up of 27 months, disease in all patients receiving LHRHa alone progressed, whereas 8/10 patients progressed to maintenance therapy. Median TTP from docetaxel initiation was 11.5 months (95% confidence interval [CI], 6.3-16.6) for maintenance therapy and 9.2 months (95% CI, 8.5-9.9) for LHRHa alone (P = .047). The maintenance treatment was well tolerated. Only 1 patient experienced a grade 4 adverse event due to a nonsymptomatic pulmonary embolism. CONCLUSION: This is the first study evaluating a CYP17i for maintenance therapy after docetaxel therapy. We showed a 2-month significant benefit in TTP for patients with mCRPC treated with LDK maintenance therapy after docetaxel, with a  favorable toxicity profile. A large prospective randomized study using a CYP17i is warranted.

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[978]

TÍTULO / TITLE:  - HDAC Inhibitor L-Carnitine and Proteasome Inhibitor Bortezomib Synergistically Exert Anti-Tumor Activity In Vitro and In Vivo.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e52576. doi: 10.1371/journal.pone.0052576. Epub 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052576

AUTORES / AUTHORS:  - Huang H; Liu N; Yang C; Liao S; Guo H; Zhao K; Li X; Liu S; Guan L; Liu C; Xu L; Zhang C; Song W; Li B; Tang P; Dou QP; Liu J

INSTITUCIÓN / INSTITUTION:  - Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical College, Guangdong, People’s Republic of China.

RESUMEN / SUMMARY:  - Combinations of proteasome inhibitors and histone deacetylases (HDAC) inhibitors  appear to be the most potent to produce synergistic cytotoxicity in preclinical trials. We have recently confirmed that L-carnitine (LC) is an endogenous HDAC inhibitor. In the current study, the anti-tumor effect of LC plus proteasome inhibitor bortezomib (velcade, Vel) was investigated both in cultured hepatoma cancer cells and in Balb/c mice bearing HepG2 tumor. Cell death and cell viability were assayed by flow cytometry and MTS, respectively. Gene, mRNA expression and protein levels were detected by gene microarray, quantitative real-time PCR and Western blot, respectively. The effect of Vel on the acetylation of histone H3 associated with the p21(cip1) gene promoter was examined by using ChIP assay and proteasome peptidase activity was detected by cell-based chymotrypsin-like (CT-like) activity assay. Here we report that (i) the combination of LC and Vel synergistically induces cytotoxicity in vitro; (ii) the combination also synergistically inhibits tumor growth in vivo; (iii) two major pathways are involved in the synergistical effects of the combinational treatment: increased p21(cip1) expression and histone acetylation in vitro and in vivo and enhanced Vel-induced proteasome inhibition by LC. The synergistic effect of LC and Vel in cancer therapy should have great potential in the future clinical trials.

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[979]

TÍTULO / TITLE:  - Epidermal Growth Factor Receptor Mutation Status and Adjuvant Chemotherapy in Resected Advanced Non-Small-Cell Lung Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Lung Cancer. 2013 Jan 4. pii: S1525-7304(12)00260-4. doi: 10.1016/j.cllc.2012.10.008.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.cllc.2012.10.008

AUTORES / AUTHORS:  - Sun HB; Ou W; Li Y; Fang Q; Qin J; Zhang L; Wang SY

INSTITUCIÓN / INSTITUTION:  - Department of Thoracic Surgery, Henan Cancer Hospital, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.

RESUMEN / SUMMARY:  - INTRODUCTION: This study was to assess the association of epidermal growth factor receptor (EGFR) mutation status and efficacy of adjuvant chemotherapy in patients with fully resected IIIA-N2 non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Tumor samples (n = 150) from patients with IIIA-N2 NSCLC who either had  or had not received paclitaxel plus carboplatin or vinorelbine plus carboplatin doublet adjuvant chemotherapy were analyzed for EGFR mutations. The association of the presence of EGFR mutations and survival was assessed. RESULTS: Mutations were identified in 43 (28.7%) patients (n = 25 in the no chemotherapy [observation] arm and n = 18 in the chemotherapy arm). Patients with EGFR mutations had statistically significant improved disease-free survival (41 months [95% CI, 25.1-56.9 months] vs. 20 months [95% CI, 15.0-25.0 months]; 2P = .005) and overall survival (50 months [95% CI, 37.6-62.4 months] vs. 25 months [95% CI, 20.8-29.2 months]; 2P = .001), regardless of treatment. The patients with wild-type EGFR had greater overall survival with chemotherapy compared with no adjuvant therapy (hazard ratio [HR] 4.748 [95% CI, 2.844-7.928]; 2P < .001). In contrast, in patients with EGFR mutation in the observation group compared with the chemotherapy group had longer median disease-free survival (49 months [95% CI, 35.1-62.9 months] for the observation arm vs. 30 months [95% CI, 23.8-36.2 months] for the chemotherapy arm, 2P = .195) and overall survival (59 months [95% CI, 43.9-74.1 months] vs. 33 months [95% CI, 24.7-41.3 months]; 2P = .050). CONCLUSIONS: In this exploratory study, the status of EGFR mutations was associated with different clinical outcomes in patients with resected IIIA-N2 NSCLC. Further studies are required to confirm that a patient’s adjuvant treatment may be customized to their EGFR mutational status.

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[980]

TÍTULO / TITLE:  - Synergism between carnosic acid and arsenic trioxide on induction of acute myeloid leukemia cell apoptosis is associated with modulation of PTEN/Akt signaling pathway.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Integr Med. 2012 Dec;18(12):934-41. doi: 10.1007/s11655-012-1297-z. Epub 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11655-012-1297-z

AUTORES / AUTHORS:  - Wang R; Cong WH; Guo G; Li XX; Chen XL; Yu XN; Li H

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Qilu Hospital of Shandong University, Jinan 250012, China.

RESUMEN / SUMMARY:  - OBJECTIVE: To investigate the synergistic effects of carnosic acid (CA) with arsenic trioxide (As(2)O(3)) on proliferation and apoptosis in HL-60 human myeloid leukemia cells, and the major cellular signaling pathway involved in these effects. METHODS: HL-60 cellular proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis. Cell cycle distribution and apoptosis were monitored by flow cytometry. The activation of casepase-9, Bcl-2-associated agonist of cell death (BAD), p-BAD, p27, phosphatase and tensin homolog deleted on chromosome ten (PTEN), Akt, p-Akt was assessed by Western blot analysis. The expression of PTEN mRNA was tested by reverse transcription polymerase chain reaction (RT-PCR) analysis. RESULTS: CA reduced HL-60 cell viability in a dose- and time-dependent manner, and induced G1 arrest and apoptosis. Moreover, CA upregulated PTEN expression, blocked the Akt signaling pathway, subsequently inhibited phosphorylation of BAD, reactivated caspase-9, and elevated levels of p27. CA also augmented these effects of As(2)O(3). CONCLUSION: CA might be a novel candidate of the combination therapy for leukemia treatment; these effects were apparently associated with the modulation of PTEN/Akt signaling pathway.

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[981]

TÍTULO / TITLE:  - Role of macrophage polarization in tumor angiogenesis and vessel normalization: implications for new anticancer therapies.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int Rev Cell Mol Biol. 2013;301:1-35. doi: 10.1016/B978-0-12-407704-1.00001-4.

            ●● Enlace al texto completo (gratuito o de pago) 1016/B978-0-12-407704-1.00001-4

AUTORES / AUTHORS:  - Chen P; Bonaldo P

INSTITUCIÓN / INSTITUTION:  - Department of Biomedical Sciences, University of Padova, Padova, Italy.

RESUMEN / SUMMARY:  - Angiogenesis, the formation of new capillary blood vessels from preexisting vasculature, is one of the hallmarks of cancer that is pivotal for tumor growth and metastasis. Tumor vessels are known to be abnormal, with typically aberrant,  leaky and disordered vessels. Thus, the combination of angiogenesis inhibition and vessel normalization is a potential strategy for anticancer therapy. The solid tumor is composed of not only cancer cells, but also the nonmalignant resident stromal cells, such as bone-marrow-derived cells (BMDCs) and cancer-associated fibroblasts (CAFs). Tumor-associated macrophages (TAMs) are the most abundant cell components of BMDCs, which play a significant role in promoting tumor progression. Accumulating evidences from both patient biopsies and experimental animal models have shown that TAMs function in tumor angiogenesis and vessel abnormalization in a density- and phenotype-dependent manner. This chapter will discuss the evidence for the factors and signaling pathways that are involved in macrophage recruitment and polarization in the tumor microenvironment, and it summarizes the role and underlying molecular mechanisms of macrophage polarization in tumor angiogenesis and vessel normalization. In addition, an overview of the potential of targeting TAM polarization for anticancer therapy will be provided.

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[982]

TÍTULO / TITLE:  - Bevacizumab and Angiogenesis Inhibitors in the Treatment of CNS metastases: the Road less Travelled.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Mol Pharmacol. 2013 Jan 8.

AUTORES / AUTHORS:  - Veytsman I; Aragon-Ching JB; Swain SM

INSTITUCIÓN / INSTITUTION:  - Washington Cancer Institute Washington Hospital Center Washington, DC, USA. Irina.g.veytsman@medstar.net.

RESUMEN / SUMMARY:  - The incidence of central nervous system (CNS) metastases secondary to solid tumors is increasing. As more effective systemic therapy is being used in patients with solid tumors, patients with cancer live longer and are ultimately at higher risk for CNS metastases. However, CNS metastases remain challenging to  treat because of limited available therapeutic options. This article reviews mechanisms of CNS metastases, the use of bevacizumab and other angiogenesis inhibitors in the treatment of recurrent and front-line CNS metastases, as well as emerging issues of resistance to anti-angiogenic therapy.

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[983]

TÍTULO / TITLE:  - From targeted monotherapy to combined BRAF-MEK inhibitors and integrated genome analysis for melanoma treatment.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Future Oncol. 2013 Jan;9(1):5-8. doi: 10.2217/fon.12.169.

            ●● Enlace al texto completo (gratuito o de pago) 2217/fon.12.169

AUTORES / AUTHORS:  - Roukos DH; Papaloukas C; Tzaphlidou M

INSTITUCIÓN / INSTITUTION:  - Centre for Biosystems & Genomic Network Medicine, Ioannina University, 45110 Ioannina, Greece.

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[984]

TÍTULO / TITLE:  - Prognostic value of ferritin, neuron-specific enolase, lactate dehydrogenase, and urinary and plasmatic catecholamine metabolites in children with neuroblastoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Onco Targets Ther. 2012;5:417-23. doi: 10.2147/OTT.S36366. Epub 2012 Nov 30.

            ●● Enlace al texto completo (gratuito o de pago) 2147/OTT.S36366

AUTORES / AUTHORS:  - Cangemi G; Reggiardo G; Barco S; Barbagallo L; Conte M; D’Angelo P; Bianchi M; Favre C; Galleni B; Melioli G; Haupt R; Garaventa A; Corrias MV

INSTITUCIÓN / INSTITUTION:  - Clinical Pathology Laboratory Unit, Giannina Gaslini Institute, Genoa, Italy.

RESUMEN / SUMMARY:  - Different plasma and urinary parameters have been tested as valuable prognostic markers for children with neuroblastoma (NB), but conclusive results from multivariate analyses are still lacking. Samples collected at diagnosis from 505  patients diagnosed in Italy between June 1994 and November 2010 were analyzed at  the Italian reference laboratory according to standard methodologies. Patient clinical data were retrieved from the Italian NB Registry. For statistical analysis, patients were grouped according to stage, age, MYCN status, and outcome. Cumulative survival was calculated by the Kaplan-Meier procedure using the first quartile of the marker distribution as a cut-off value to stratify the  patients. Multivariate analysis was performed by the Cox regression model by considering only the significant variables. When the entire cohort of patients was considered, none of the different parameters had an independent prognostic value. However, in patients with localized disease without MYCN amplification the significant positive associations between urinary and plasmatic vanillylmandelic  acid (VMA)/homovanillic acid (HVA) ratio and a better prognosis remained significant (P < 0.05 and P < 0.01, respectively), as well as, the positive association between high lactate dehydrogenase (LDH) values and a worse prognosis (P < 0.001). Moreover, in stage 4 patients without MYCN amplification, neuron-specific enolase levels above 200 ng/mL and LDH levels above 2500 IU/mL maintained their significant association with a worse outcome (P = 0.01 and P = 0.0001, respectively). In conclusion, LDH had an independent prognostic value in  patients of all stages without MYCN amplification. Moreover, the urinary and plasmatic VMA/HVA ratio was an independent predictor of prognosis in patients with localized disease without MYCN amplification. Since LDH and catecholamine metabolites are measured in all patients at diagnosis, these findings may be helpful for an easy, cost-effective, patient risk stratification.

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[985]

TÍTULO / TITLE:  - Prognostic value of expression of molecular markers in adenoid cystic cancer of the salivary glands compared with lymph node metastasis: a retrospective study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Surg Oncol. 2012 Dec 11;10:266. doi: 10.1186/1477-7819-10-266.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1477-7819-10-266

AUTORES / AUTHORS:  - Lee SK; Kwon MS; Lee YS; Choi SH; Kim SY; Cho KJ; Nam SY

INSTITUCIÓN / INSTITUTION:  - Department of Otolaryngology, Asan Medical Center, University of Ulsan, College of Medicine, 388-1 Pungnap-2dong, Songpa-gu, Seoul, 138-736, South Korea. synam@amc.seou.kr.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Adenoid cystic cancer arising in the salivary glands has distinctive features such as perineural invasion, distant metastasis, and a variable prognosis. In salivary gland cancer, c-kit, EGFR, and VEGF are representative molecular markers that may predict remnant and recurrent tumors. In this study, the expression of c-kit, EGFR, and VEGF in adenoid cystic cancer was evaluated, and the relationships between the expression of these markers and  the clinical findings were investigated. METHODS: The medical records of 48 patients who were treated for parotid adenoid cystic cancer from January 1990 to  January 2006 were reviewed. The tumor location, size, histological subtypes, perineural invasion, the resected margin status, and lymph node metastasis were assessed. Immunohistochemical staining and semiquantitative analysis of c-kit, EGFR and VEGF were performed. The relationship between the expression of each marker and the clinicopathological factors were analyzed. RESULTS: Positive c-kit immunostaining was present in 45 patients (94%), with weak positivity (+1) in 23, moderate positivity (+2) in 19 and strong positivity (+3) in three. Positive EGFR immunostaining was observed in 27 (56%), with weak positivity (+1) in 19 and moderate positivity (+2) in eight with no strong positive staining. Positive VEGF immunostaining was present in 42 patients (88%) with weak positivity (+1) in 12,  moderate positivity (+2) in 17, and strong positivity (+3) in 13. Only the expression of VEGF was significantly higher in parotid gland tumors than in any other gland (P = 0.032). Marginal involvement was associated with strong VEGF expression (P = 0.02). No marker was significantly correlated with recurrence or  the survival rate. Lymph node status was related to the survival rate. CONCLUSIONS: The expression of c-kit, EGRF, and VEGF had no predictive value for  recurrence or the prognosis of adenoid cystic cancer. Only the lymph node status  was related to the prognosis.

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[986]

TÍTULO / TITLE:  - A 67 year old woman on tumor necrosis factor- alpha inhibitor therapy presenting  with neurological dysfunction.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Arthritis Care Res (Hoboken). 2012 Nov 30. doi: 10.1002/acr.21882.

            ●● Enlace al texto completo (gratuito o de pago) 1002/acr.21882

AUTORES / AUTHORS:  - Garg N; Woltjer R; Hamilton B; Neuwelt EA; Rosenbaum JT

INSTITUCIÓN / INSTITUTION:  - Division of Arthritis and Rheumatism, Mail Code OP-09 Oregon Health and Sciences  University 3181 Sam Jackson Park Road Portland, OR 97239. gargn@ohsu.edu.

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[987]

TÍTULO / TITLE:  - Chemotherapy refractory testicular germ cell tumor is associated with a variant in Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Front Endocrinol (Lausanne). 2012;3:163. doi: 10.3389/fendo.2012.00163. Epub 2012 Dec 13.

            ●● Enlace al texto completo (gratuito o de pago) 3389/fendo.2012.00163

AUTORES / AUTHORS:  - Fung C; Vaughn DJ; Mitra N; Ciosek SL; Vardhanabhuti S; Nathanson KL; Kanetsky PA

INSTITUCIÓN / INSTITUTION:  - Department of Hematology and Oncology, Wilmot Cancer Center, University of Rochester Medical Center Rochester, NY, USA.

RESUMEN / SUMMARY:  - Introduction: There is evidence that inherited genetic variation affects both testicular germ cell tumor (TGCT) treatment outcome and risks of late-complications arising from cisplatin-based chemotherapy. Using a candidate gene approach, we examined associations of three genes involved in the cisplatin  metabolism pathway, GSTP1, COMT, and TPMT, with TGCT outcome and cisplatin-induced neurotoxicity. Materials and Methods: Our study population includes a subset of patients (n = 137) from a genome-wide association study at the University of Pennsylvania that evaluates inherited genetic susceptibility to TGCT. All patients in our study had at least one course of cisplatin-based chemotherapy with at least 1 year of follow-up. A total of 90 markers in GSTP1, COMT, and TPMT and their adjacent genomic regions (+/-20 kb) were analyzed for associations with refractory TGCT after first course of chemotherapy, progression-free survival (PFS), overall survival (OS), peripheral neuropathy, and ototoxicity. Results: After adjustment for multiple comparisons, one Single nucleotide polymorphism (SNP), rs2073743, in the flanking region (+/-20 kb) of COMT was associated with refractory TGCT after initial chemotherapy. This SNP lies within the intron region of the Armadillo Repeat gene deleted in Velco-Cardio-Facial syndrome (ARVCF). The G allele of rs2073743 predisposed patients to refractory disease with a relative risk of 2.6 (95% CI 1.1, 6.3; P =  0.03). Assuming recessive inheritance, patients with the GG genotype had 22.7 times higher risk (95% CI 3.3, 155.8; P = 0.04) of developing refractory disease  when compared to those with the GC or CC genotypes. We found no association of our candidate genes with peripheral neuropathy, ototoxicity, PFS and OS. Discussion: This is the first study to suggest that germline genetic variants of  ARVCF may affect TGCT outcome. The result of this study is hypothesis generating  and should be validated in future studies.

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[988]

TÍTULO / TITLE:  - The Blocking of c-Met Signaling Induces Apoptosis through the Increase of p53 Protein in Lung Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. Acceso gratuito al texto completo a partir de 1 año de la fecha de publicación.

            ●● Enlace a la Editora de la Revista http://cancerres.aacrjournals.org/ 

            ●● Cita: Cancer Research: <> Treat. 2012 Dec;44(4):251-61. doi: 10.4143/crt.2012.44.4.251. Epub 2012 Dec 31.

            ●● Enlace al texto completo (gratuito o de pago) 4143/crt.2012.44.4.251

AUTORES / AUTHORS:  - Jung HY; Joo HJ; Park JK; Kim YH

INSTITUCIÓN / INSTITUTION:  - Brain Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, Korea. ; Genomic Research Center for Lung and Breast/Ovarian Cancers, Korea University College of Medicine, Seoul, Korea.

RESUMEN / SUMMARY:  - PURPOSE: c-Met is an attractive potential target for novel therapeutic inhibition of human cancer, and c-Met tyrosine kinase inhibitors (TKIs) are effective growth inhibitors of various malignancies. However, their mechanisms in anticancer effects are not clear. In the present study, we investigated the possibility that blocking c-Met signaling induces p53-mediated growth inhibition in lung cancer. MATERIALS AND METHODS: The growth inhibitory effects of c-Met TKI (SU11274) on lung cancer cells and a xenograft model were assessed using the MTT assay, flow cytometry, and terminal deoxyribonucleotide transferase-mediated nick-end labeling staining. The role of p53 protein in the sensitivity of c-Met TKI (SU11274) was examined by Western blot analysis and immunohistochemistry. RESULTS: SU11274 significantly induced apoptosis in A549 cells with wild-type p53, compared with that in Calu-1 cells with null-type p53. SU11274 increased p53 protein by enhancing the stability of p53 protein. Increased p53 protein by SU11274 induced up-regulation of Bax and PUMA expression and down-regulation of Bcl-2 expression, subsequently activating caspase 3. In p53 knock-out and knock-in systems, we confirmed that SU11274 caused apoptosis through the p53-mediated apoptotic pathway. Likewise, in the A549 xenograft model, SU11274 effectively shrank tumor volume and induced apoptosis via increased p53 protein expression. Blocking c-Met signaling increased the level of p53 protein. CONCLUSION: Our finding suggested that p53 plays an important role in SU11274-induced apoptosis, and p53 status seems to be related to the sensitivity  to SU11274 in lung cancer.

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[989]

TÍTULO / TITLE:  - Noncompetitive Modulation of the Proteasome by Imidazoline Scaffolds Overcomes Bortezomib Resistance and Delays MM Tumor Growth in Vivo.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - ACS Chem Biol. 2012 Dec 11.

            ●● Enlace al texto completo (gratuito o de pago) 1021/cb300568r

AUTORES / AUTHORS:  - Lansdell TA; Hurchla MA; Xiang J; Hovde S; Weilbaecher KN; Henry RW; Tepe JJ

INSTITUCIÓN / INSTITUTION:  - Departments of daggerChemistry and section signBiochemistry & Molecular Biology,  Michigan State University , East Lansing, Michigan, United States.

RESUMEN / SUMMARY:  - Multiple myeloma (MM) is a malignant disorder of differentiated B-cells for which standard care involves the inhibition of the proteasome. All clinically used proteasome inhibitors, including the chemotherapeutic drug bortezomib, target the catalytic active sites of the proteasome and inhibit protein proteolysis by competing with substrate binding. However, nearly all ( approximately 97%) patients become intolerant or resistant to treatments within a few years, after which the average survival time is less than 1 year. We describe herein the inhibition of the human proteasome via a noncompetitive mechanism by the imidazoline scaffold, TCH-13. Consistent with a mechanism distinct from that of competitive inhibitors, TCH-013 acts additively with and overcomes resistance to  bortezomib. Importantly, TCH-013 induces apoptosis in a panel of myeloma and leukemia cell lines, but in contrast, normal lymphocytes, primary bone marrow stromal cells (hBMSC), and macrophages are resistant to its cytotoxic effects. TCH-013 was equally effective in blocking MM cell growth in co-cultures of MM cells with hBMSC isolated from CD138 negative bone marrow (BM) samples of MM patients. The cellular activity translated well in vivo where TCH-013 delayed tumor growth in an MM xenograft model to a similar extent as bortezomib.

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[990]

TÍTULO / TITLE:  - Correlation between thymidylate synthase gene polymorphisms and efficacy of pemetrexed in advanced non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Exp Ther Med. 2012 Dec;4(6):1010-1016. Epub 2012 Sep 28.

            ●● Enlace al texto completo (gratuito o de pago) 3892/etm.2012.730

AUTORES / AUTHORS:  - Hu Q; Li X; Su C; Chen X; Gao G; Zhang J; Zhao Y; Li J; Zhou C

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine;

RESUMEN / SUMMARY:  - One of the target genes of pemetrexed (PEM), thymidylate synthase (TS), has been  shown to have a close association with its efficacy. TS gene polymorphisms have been shown to be associated with the efficacy of antifolate treatment in enteron  tumors. The purpose of this study was to investigate the clinical significance of TS gene polymorphisms in patients with advanced NSCLC receiving PEM-based treatment. The variable nucleoid tandem repeat in the 5’-UTR region was amplified and detected using fluorescently labeled multiplex short tandem repeat polymerase chain reaction. The polymorphism in the 3’-UTR region of the TS gene was detected using the Taqman probe. Efficacy of PEM was assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. None of the genotypes were associated with gender, smoking status and age. Disease control rate (DCR), objective response rate (ORR) and progression-free survival (PFS) were similar between patients harboring 2R and 3R alleles (PFS, p=0.518; DCR, p=0.631; ORR, p=0.541), as well as those with a 6-bp insertion and 6-bp deletion (PFS, p=0.776; DCR, p=0.626; ORR, p=0.330). To study the combined effect of TS polymorphisms, the study population was divided into three groups: 2R&6 del, 2R&6 ins and 3R&6 del. No significant differences were observed among the different groups according to DCR (p=0.517), ORR (p=0.611) and PFS (p=0.938). In conclusion, polymorphisms of the TS gene do not appear to be a prognostic marker for advanced NSCLC patients receiving PEM-based treatment.

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[991]

TÍTULO / TITLE:  - Study of the UTMD-Based Delivery System to Induce Cervical Cancer Cell Apoptosis  and Inhibit Proliferation with shRNA targeting Survivin.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2013 Jan 16;14(1):1763-77. doi: 10.3390/ijms14011763.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms14011763

AUTORES / AUTHORS:  - Chen ZY; Liang K; Lin Y; Yang F

INSTITUCIÓN / INSTITUTION:  - Department of Medical Ultrasound, Key Laboratory for Major Obstetric Diseases of  Guangdong Province, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China. winchen@vip.126.com.

RESUMEN / SUMMARY:  - Apoptosis induction by short hairpin RNA (shRNA) expression vectors could be an efficient and promising strategy for cancer gene therapy. Ultrasound-targeted microbubble destruction (UTMD) is an appealing technique. In this study, we investigated the apoptosis induction and suppression of cell proliferation in vivo transfected by the UTMD-based shRNA delivery system. Nude mice with transplanted tumors of cervical cancer were randomly arranged into three groups:  control group, plasmid injection and ultrasound (P + US), P + UTMD group. Expressions of Survivin and proliferating cell nuclear antigen (PCNA), Bcl-2, Bax, Caspase-3, Ki-67, nucleostemin (NS) were investigated by immunohistochemistry. Furthermore, microvessel density (MVD) was detected by CD34 protein expressions and apoptotic index (AI) was measured by TUNEL. As compared with those in the control and P + US groups, protein expressions of PCNA, Ki-67,  Bcl-2, Survivin and NS in P + UTMD groups were down-regulated markedly, while those of Bax, Caspase-3 were up-regulated significantly (p < 0.05). MVD decreased significantly, whereas AI increased remarkably (p < 0.05). We suggested that UTMD-based shRNA delivery system could induce apoptosis and inhibit proliferation significantly, without causing any apparently adverse effect, representing a new, promising technology that would be used in the future gene therapy and research.

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[992]

TÍTULO / TITLE:  - Therapeutic targeting of cancer cell cycle using proteasome inhibitors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Div. 2012 Dec 26;7(1):26.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1747-1028-7-26

AUTORES / AUTHORS:  - Rastogi N; Mishra DP

RESUMEN / SUMMARY:  - ABSTRACT: Proteasomes are multicatalytic protease complexes in the cell, involved in the non-lysosomal recycling of intra-cellular proteins. Proteasomes play a critical role in regulation of cell division in both normal as well as cancer cells. In cancer cells this homeostatic function is deregulated leading to the hyperactivation of the proteasomes. Proteasome inhibitors (PIs) are a class of compounds, which either reversibly or irreversibly block the activity of proteasomes and induce cancer cell death. Interference of PIs with the ubiquitin  proteasome pathway (UPP) involved in protein turnover in the cell leads to the accumulation of proteins engaged in cell cycle progression, which ultimately put  a halt to cancer cell division and induce apoptosis. Upregulation of many tumor suppressor proteins involved in cell cycle arrest are known to play a role in PI  induced cell cycle arrest in a variety of cancer cells. Although many PIs target  the proteasomes, not all of them are effective in cancer therapy. Some cancers develop resistance against proteasome inhibition by possibly activating compensatory signaling pathways. However, the details of the activation of these  pathways and their contribution to resistance to PI therapy remain obscure. Delineation of these pathways may help in checking resistance against PIs and deducing effective combinational approaches for improved treatment strategies. This review will discuss some of the signaling pathways related to proteasome inhibition and cell division that may help explain the basis of resistance of some cancers to proteasome inhibitors and underline the need for usage of PIs in  combination with traditional chemotherapy.

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[993]

TÍTULO / TITLE:  - Elevation in inflammatory serum biomarkers predicts response to trastuzumab-containing therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51379. doi: 10.1371/journal.pone.0051379. Epub 2012 Dec 26.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051379

AUTORES / AUTHORS:  - Alkhateeb AA; Leitzel K; Ali SM; Campbell-Baird C; Evans M; Fuchs EM; Kostler WJ; Lipton A; Connor J

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, The Pennsylvania State University Hershey Medical Center, Hershey, Pennsylvania, United States of America.

RESUMEN / SUMMARY:  - Approximately half of all HER2/neu-overexpressing breast cancer patients do not respond to trastuzumab-containing therapy. Therefore, there remains an urgent and unmet clinical need for the development of predictive biomarkers for trastuzumab  response. Recently, several lines of evidence have demonstrated that the inflammatory tumor microenvironment is a major contributor to therapy resistance  in breast cancer. In order to explore the predictive value of inflammation in breast cancer patients, we measured the inflammatory biomarkers serum ferritin and C-reactive protein (CRP) in 66 patients immediately before undergoing trastuzumab-containing therapy and evaluated their progression-free and overall survival. The elevation in pre-treatment serum ferritin (>250 ng/ml) or CRP (>7.25 mg/l) was a significant predictor of reduced progression-free survival and shorter overall survival. When patients were stratified based on their serum ferritin and CRP levels, patients with elevation in both inflammatory biomarkers  had a markedly poorer response to trastuzumab-containing therapy. Therefore, the  elevation in inflammatory serum biomarkers may reflect a pathological state that  decreases the clinical efficacy of this therapy. Anti-inflammatory drugs and life-style changes to decrease inflammation in cancer patients should be explored as possible strategies to sensitize patients to anti-cancer therapeutics.

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[994]

TÍTULO / TITLE:  - Hyperthermia enhances the antitumor effect of photodynamic therapy with ALA hexyl ester in a squamous cell carcinoma tumor model.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Photodiagnosis Photodyn Ther. 2012 Dec;9(4):369-75. doi: 10.1016/j.pdpdt.2012.04.003. Epub 2012 Jun 12.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.pdpdt.2012.04.003

AUTORES / AUTHORS:  - Yanase S; Nomura J; Matsumura Y; Kato H; Tagawa T

INSTITUCIÓN / INSTITUTION:  - Department of Dentistry and Oral Surgery, Mie-chuo Medical Center, National Hospital Organization, 2158-5 Hisaimyojin-cho, Tsu, Mie 514-1101, Japan. shigeaki@clin.medic.mie-u.ac.jp

RESUMEN / SUMMARY:  - BACKGROUND: Photodynamic therapy (PDT) using 5-aminolevulinic acid is considered  to be ineffective in the treatment of tumors with progression to the deep layer.  Therefore, for such tumors, a method is required which can enhance the effectiveness of this therapy. We examined the anti tumor effect of the combination of PDT with 5-aminolevulinic acid hexyl ester (hALA) and hyperthermia (HT) in a squamous cell carcinoma (SCC) tumor model. METHODS: A tumor model was prepared by subcutaneously implanting SCC into nude mice, and treated with HT, PDT with hALA (hALA-PDT), or hALA-PDT combined with HT (PDT+HT). The treatment was performed by remodeled near infra-red irradiator which allows the generation  of two types of rays for PDT and HT. With HT, the tumor was irradiated for raising the temperature with a light dose of 437.5 J/cm(2). With hALA-PDT, the tumor treated with 250 mg/kg hALA was irradiated with a light dose of 50 J/cm(2). With PDT+HT, the tumor was treated as for hALA-PDT except that the temperature was raised during irradiation with a light dose of 437.5 J/cm(2) (including light dose of 50 J/cm(2) for PDT). RESULTS: The tumor growth rates on Day 12 were 97.10% in HT, 67.55% in hALA-PDT and 33.90% in PDT+HT, and PDT+HT showed significant inhibitory effects on tumor growth, although the anti-tumoral effects of HT and hALA-PDT were not seen. CONCLUSION: hALA-PDT combined with HT demonstrated a significant inhibitory effect on the tumor growth of squamous cell carcinoma showing a progression in the deep layer. This suggests that this therapy is useful for tumors showing progression to the deep layer, which hALA-PDT alone is generally ineffective in treating.

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[995]

TÍTULO / TITLE:  - Lung adenocarcinoma in the era of targeted therapies: histological classification, sample prioritization, and predictive biomarkers.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Transl Oncol. 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12094-012-0983-z

AUTORES / AUTHORS:  - Conde E; Angulo B; Izquierdo E; Paz-Ares L; Belda-Iniesta C; Hidalgo M; Lopez-Rios F

INSTITUCIÓN / INSTITUTION:  - Laboratorio de Dianas Terapeuticas, Centro Integral Oncologico Clara Campal, Hospital Universitario Madrid Sanchinarro, Faculty of Medicine, Universidad San Pablo-CEU, Madrid, España.

RESUMEN / SUMMARY:  - The arrival of targeted therapies has presented both a conceptual and a practical challenge in the treatment of patients with advanced non-small cell lung carcinomas (NSCLCs). The relationship of these treatments with specific histologies and predictive biomarkers has made the handling of biopsies the key factor for success. In this study, we highlight the balance between precise histological diagnosis and the practice of conducting multiple predictive assays  simultaneously. This can only be achieved where there is a commitment to multidisciplinary working by the tumor board to ensure that a sensible protocol is applied. This proposal for prioritizing samples includes both recent technological advances and the some of the latest discoveries in the molecular classification of NSCLCs.

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[996]

TÍTULO / TITLE:  - Short hairpin RNA-mediated MDR1 gene silencing increases apoptosis of human ovarian cancer cell line A2780/Taxol.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Cancer Res. 2012 Jun;24(2):138-42. doi: 10.1007/s11670-012-0138-3.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11670-012-0138-3

AUTORES / AUTHORS:  - Xu H; Hong FZ; Li S; Zhang P; Zhu L

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, the SecondHospital of ShandongUniversity, Jinan 250033, China.

RESUMEN / SUMMARY:  - OBJECTIVE: Recurrent ovarian cancer is often resistant to drugs such as paclitaxel. Short hairpin RNA (shRNA) targeting MDR1, a gene involved in the process of drug resistance, may be a promising strategy to overcome drug resistance. METHODS: Construction and identification of eukaryotic expression plasmid of shRNA targeting on MDR1 gene. The plasmid was transiently transfected  into human ovarian cancer cell line A2780/Taxol. Apoptosis was determined by flow cytometry using annexin V-FITC/PI double labeling. Expression of MDR1 mRNA was detected by quantitative polymerase chain reaction (qPCR) and P-glycoprotein expression was detected using Western blot. RESULTS: The IC50 of paclitaxel in MDR1shRNA-transfected group was significantly reduced (1.986+/-0.153) mumol/ml as compared with that in negative control (5.246+/-0.107) mumol/ml and empty vector-transfected group (5.212+/-0.075) mumol/ml (P<0.05). The percent of the relative reverse sensitivity to paclitaxel on A2780/Taxol cells was 67.1%, and the apoptotic rate was significantly increased [(6.977+/-0.333)%] compared with control [(1.637+/-0.111)%] and empty vector-transfected group [(1.663+/-0.114)%]  (P<0.05). Expressions of MDR1 mRNA and P-glycoprotein were significantly reduced  compared with control (P<0.05). CONCLUSION: The present study demonstrated that the eukaryotic expression plasmid of shRNA targeting on MDR1 inhibited the expression of MDR1 effectively, thus enhance the sensitivity of A2780/Taxol cells to paclitaxel.

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[997]

TÍTULO / TITLE:  - Gynaecological cancer: CLOVAR validates prognostic gene-expression signature.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Nat Rev Clin Oncol. 2013 Feb;10(2):68. doi: 10.1038/nrclinonc.2013.2. Epub 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1038/nrclinonc.2013.2

AUTORES / AUTHORS:  - Hutchinson L

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[998]

TÍTULO / TITLE:  - Toll-like receptor 3 in Epstein-Barr virus-associated nasopharyngeal carcinomas:  consistent expression and cytotoxic effects of its synthetic ligand poly(A:U) combined to a Smac-mimetic.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Infect Agent Cancer. 2012 Dec 3;7(1):36.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1750-9378-7-36

AUTORES / AUTHORS:  - Verillaud B; Gressette M; Morel Y; Paturel C; Herman P; Lo KW; Tsao SW; Wassef M; Jimenez-Pailhes AS; Busson P

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Nasopharyngeal carcinomas (NPC) are consistently associated with the Epstein-Barr virus (EBV). Though NPCs are more radiosensitive and chemosensitive than other tumors of the upper aero-digestive tract, many therapeutic challenges remain. In a previous report, we have presented data supporting a possible therapeutic strategy based on artificial TLR3 stimulation combined to the inhibition of the IAP protein family (Inhibitor of Apoptosis Proteins). The present study was designed to progress towards practical applications of this strategy pursuing 2 main objectives: 1) to formally demonstrate expression of the TLR3 protein by malignant NPC cells; 2) to investigate the effect of poly(A:U) as a novel TLR3-agonist more specific than poly(I:C) which was used in our previous study. METHODS: TLR3 expression was investigated in a series of NPC cell lines and clinical specimens by Western blot analysis and immunohistochemistry, respectively. The effects on NPC cells growth  of the TLR3 ligand poly(A:U) used either alone or in combination with RMT5265, an IAP inhibitor based on Smac-mimicry, were assessed using MTT assays and clonogenic assays. RESULTS: TLR3 was detected at a high level in all NPC cell lines and clinical specimens. Low concentrations of poly(A:U) were applied to several types of NPC cells including cells from the C17 xenograft which for the first time have been adapted to permanent propagation in vitro. As a single agent, poly(A:U) had no significant effects on cell growth and cell survival. In  contrast, dramatic effects were obtained when it was combined with the IAP inhibitor RMT5265. These effects were obtained using concentrations as low as 0.5 mug/ml (poly(A:U)) and 50 nM (RMT5265). CONCLUSION: These data confirm that TLR3  expression is a factor of vulnerability for NPC cells. They suggest that in some  specific pathological and pharmacological contexts, it might be worth to use Smac-mimetics at very low doses, allowing a better management of secondary effects. In light of our observations, combined use of both types of compounds should be considered for treatment of nasopharyngeal carcinomas.

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[999]

TÍTULO / TITLE:  - The value of molecular expression of KIT and KIT ligand analysed using real-time  polymerase chain reaction and immunohistochemistry as a prognostic indicator for  canine cutaneous mast cell tumours.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Vet Comp Oncol. 2013 Jan 7. doi: 10.1111/vco.12010.

            ●● Enlace al texto completo (gratuito o de pago) 1111/vco.12010

AUTORES / AUTHORS:  - Costa Casagrande TA; de Oliveira Barros LM; Fukumasu H; Cogliati B; Chaible LM; Dagli ML; Matera JM

INSTITUCIÓN / INSTITUTION:  - Biotechnology Master Program, Positivo University, Curitiba, Parana, Brazil.

RESUMEN / SUMMARY:  - This study investigated the correlation between KIT gene expression determined by immunohistochemistry and real-time polymerase chain reaction (RT-PCR) and the rate of tumour recurrence and tumour-related deaths in dogs affected with mast cell tumour (MCT). Kaplan-Meier curves were constructed to compare tumour recurrence and tumour-related death between patients. The log-rank test was used  to check for significant differences between curves. KIT-I, KIT-II and KIT-III staining patterns were observed in 9 (11.11%), 50 (61.73%) and 22 (27.16%) tumours, respectively. Tumour recurrence rates and tumour-related deaths were not associated with KIT staining patterns (P = 0278, P > 0.05), KIT (P = 0.289, P > 0.05) or KIT ligand (P = 0.106, P > 0.05) gene expression. Despite the lack of association between KIT staining pattern and patient survival time, the results suggest a correlation between aberrant KIT localization and increased proliferative activity of MCTs. RT-PCR seems to be a sensible method for quantitative detection of KIT gene expression in canine MCT, although expressions levels are not correlated with prognosis.

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[1000]

TÍTULO / TITLE:  - Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Discov. 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 1158/2159-8290.CD-12-0386

AUTORES / AUTHORS:  - Girotti MR; Pedersen M; Sanchez-Laorden B; Viros A; Turajlic S; Niculescu-Duvaz D; Zambon A; Sinclair J; Hayes A; Gore M; Lorigan P; Springer CJ; Larkin J; Jorgensen C; Marais R

INSTITUCIÓN / INSTITUTION:  - 1.

RESUMEN / SUMMARY:  - We generated cell lines resistant to BRAF inhibitors and show that the EGF receptor (EGFR)-SRC family kinase (SFK)-STAT3 signaling pathway was upregulated in these cells. In addition to driving proliferation of resistant cells, this pathway also stimulated invasion and metastasis. EGFR inhibitors cooperated with  BRAF inhibitors to block the growth of the resistant cells in vitro and in vivo,  and monotherapy with the broad specificity tyrosine kinase inhibitor dasatinib blocked growth and metastasis in vivo. We analyzed tumors from patients with intrinsic or acquired resistance to vemurafenib and observed increased EGFR and SFK activity. Furthermore, dasatinib blocked the growth and metastasis of one of  the resistant tumors in immunocompromised mice. Our data shows that BRAF inhibitor-mediated activation of EFGR/SFK/STAT3 signaling can mediate resistance  in BRAF mutant melanoma patients. We describe two treatments that appear to overcome this resistance and could deliver therapeutic efficacy in drug-resistant BRAF mutant melanoma patients.

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[1001]

TÍTULO / TITLE:  - Combined Inhibition of IGF-1R/IR and Src Family Kinases Enhances Antitumor Effects in Prostate Cancer by Decreasing Activated Survival Pathways.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51189. doi: 10.1371/journal.pone.0051189. Epub 2012 Dec 26.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051189

AUTORES / AUTHORS:  - Dayyani F; Parikh NU; Varkaris AS; Song JH; Moorthy S; Chatterji T; Maity SN; Wolfe AR; Carboni JM; Gottardis MM; Logothetis CJ; Gallick GE

INSTITUCIÓN / INSTITUTION:  - Department of Genitourinary Medical Oncology and David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

RESUMEN / SUMMARY:  - BACKGROUND: Treatment of metastatic prostate cancer (PCa) with single agents has  shown only modest efficacy. We hypothesized dual inhibition of different pathways in PCa results in improved tumor inhibition. The Src family kinases (SFK) and insulin-like growth factor-1 (IGF-1) signaling axes are aberrantly activated in both primary PCa and bone metastases and regulate distinct and overlapping functions in PCa progression. We examined the antitumor effects of combined inhibition of these pathways. MATERIALS AND METHODS: Src andIGF-1 receptor (IGF-1R) inhibition was achieved in vitro by short hairpin (sh)RNA and in vitro and in vivo by small molecule inhibitors (dasatinib and BMS-754807, against SFK and IGF-1R/Insulin Receptor(IR), respectively). RESULTS: In vitro, inhibition of  IGF-1 signaling affected cell survival and proliferation. SFK blockade alone had  modest effects on proliferation, but significantly enhanced the IGF-1R blockade.  These findings correlated with a robust inhibition of IGF-1-induced Akt1 phophorylation by dasatinib, whereas Akt2 phosphorylation was SFK independent and only inhibited by BMS-754807. Thus, complete inhibition of both Akt genes, not seen by either drug alone, is likely a major mechanism for the decreased survival of PCa cells. Furthermore, dasatinib and BMS-754807 inhibited in vivo growth of the primary human xenograft MDA PCa 133, with corresponding inhibition of Akt in  tumors. Also, both orthotopic and intratibial tumor growth of PC-3 cells were more potently inhibited by dual SFK and IGF-1R/IR blockade compared to either pathway alone, with a corresponding decrease in bone turnover markers. CONCLUSIONS: Dual IGF-1R/IR and SFK inhibition may be a rational therapeutic approach in PCa by blocking both independent and complementary processes critical to tumor growth.

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[1002]

TÍTULO / TITLE:  - Antagonism of Inhibitor of Apoptosis Proteins Increases Bone Metastasis via Unexpected Osteoclast Activation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Discov. 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1158/2159-8290.CD-12-0271

AUTORES / AUTHORS:  - Yang C; Davis JL; Zeng R; Vora P; Su X; Collins LI; Vangveravong S; Mach RH; Piwnica-Worms D; Weilbaecher KN; Faccio R; Veis Novack D

INSTITUCIÓN / INSTITUTION:  - Divisions of 1Bone and Mineral Diseases and 2Molecular Oncology, Department of Medicine; 3Mallinckrodt Institute of Radiology; Departments of 4Cell Biology and  Physiology/BRIGHT Institute, 5Orthopedic Surgery, and 6Pathology and Immunology,  Washington University School of Medicine, St. Louis, Missouri.

RESUMEN / SUMMARY:  - Inhibitor of apoptosis (IAP) proteins play a central role in many types of cancer, and IAP antagonists are in development as anticancer agents. IAP antagonists cause apoptosis in many cells, but they also activate alternative NF-kappaB signaling through NF-kappaB-inducing kinase (NIK), which regulates osteoclasts. In bone metastasis, a positive feedback loop between tumors and osteoclasts promotes tumor growth and osteolysis. We therefore tested the effect  of IAP antagonists on the bone microenvironment for metastasis. In both drug-sensitive and drug-resistant tumors, growth in bone was favored, as compared with other sites during IAP antagonist treatment. These drugs also caused osteoporosis and increased osteoclastogenesis, mediated by NIK, and enhanced tumor-associated osteolysis. Cotreatment with zoledronic acid, a potent osteoclast inhibitor, reduced IAP antagonist-enhanced tumor growth in bone and osteolysis. Thus, IAP antagonist-based cancer treatment may be compromised by osteoporosis and enhanced skeletal metastasis, which may be prevented by antiresorptive agents.

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[1003]

TÍTULO / TITLE:  - Thymoquinone induces apoptosis in malignant T-cells via generation of ROS .

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Front Biosci (Elite Ed). 2013 Jan 1;5:706-19.

AUTORES / AUTHORS:  - Dergarabetian EM; Ghattass KI; El-Sitt SB; Al-Mismar RM; El-Baba CO; Itani WS; Melhem NM; El-Hajj HA; Bazarbachi AA; Schneider-Stock R; Gali-Muhtasib HU

INSTITUCIÓN / INSTITUTION:  - Department of Biology, American University of Beirut, Beirut, Lebanon.

RESUMEN / SUMMARY:  - We show that HTLV-1 negative leukemia cells are more sensitive to TQ due to higher levels of drug-induced reactive oxygen species (ROS). PreG1 population in  HTLV-1 negative Jurkat and CEM was higher than HTLV-1 transformed HuT-102 and MT-2 cells. Peripheral blood mononuclear cells were more resistant. Hoechst staining indicated more features of apoptosis, namely nuclear blebs and shrunken  nuclei in HuT-102 than Jurkat. A greater depletion of the antioxidant enzyme glutathione occurred in Jurkat, which consequently led to an increase in ROS, loss of mitochondrial membrane potential, cytochrome c release, activation of caspases 3 and 9, and cleavage of PARP. Treatment with z-VAD-fmk partially reversed TQ-induced apoptosis, suggesting a caspase-dependent mechanism. N-acetyl cysteine prevented apoptosis providing evidence that cell death is ROS-dependent. Catalase prevented apoptosis to a lesser extent than NAC. In summary, TQ induces  apoptosis in adult T cell leukemia/lymphoma by decreasing glutathione and increasing ROS, and levels of ROS underlie the differential cellular response to  TQ. Our data suggest a potential therapeutic role for TQ in sensitizing HTLV-I-negative T-cell lymphomas.

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[1004]

TÍTULO / TITLE:  - TNF-&#945; Gene Knockout in Triple Negative Breast Cancer Cell Line Induces Apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2012 Dec 24;14(1):411-20. doi: 10.3390/ijms14010411.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms14010411

AUTORES / AUTHORS:  - Pileczki V; Braicu C; Gherman CD; Berindan-Neagoe I

INSTITUCIÓN / INSTITUTION:  - Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, 4 Pasteur Street, Cluj-Napoca 400349, Romania. ghermanclaudia@yahoo.com.

RESUMEN / SUMMARY:  - Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine involved in the promotion and progression of cancer, including triple negative breast cancer cells. Thus, there is significant interest in understanding the molecular  signaling pathways that connect TNF-alpha with the survival of tumor cells. In our experiments, we used as an in vitro model for triple negative breast cancer the cell line Hs578T. The purpose of this study is to determine the gene expression profiling of apoptotic signaling networks after blocking TNF-alpha formation by using specially designed siRNA molecules to target TNF-alpha messenger RNA. Knockdown of TNF-alpha gene was associated with cell proliferation inhibition and apoptosis, as observed by monitoring the cell index using the xCELLigence RTCA System and flow cytometry. PCR array technology was used to examine the transcript levels of 84 genes involved in apoptosis. 15 genes were found to be relevant after comparing the treated group with the untreated one of  which 3 were down-regulated and 12 up-regulated. The down-regulated genes are all involved in cell survival, whereas the up-regulated ones are involved in and interact with pro-apoptotic pathways. The results described here indicate that the direct target of TNF-alpha in the Hs578T breast cancer cell line increases the level of certain pro-apoptotic factors that modulate different cellular networks that direct the cells towards death.

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[1005]

TÍTULO / TITLE:  - Epigenetic regulation of multiple tumor-related genes leads to suppression of breast tumorigenesis by dietary genistein.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e54369. doi: 10.1371/journal.pone.0054369. Epub 2013 Jan 14.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0054369

AUTORES / AUTHORS:  - Li Y; Chen H; Hardy TM; Tollefsbol TO

INSTITUCIÓN / INSTITUTION:  - Department of Biology, University of Alabama at Birmingham, Birmingham, Alabama,  United States of America ; Comprehensive Cancer Center, University of Alabama at  Birmingham, Birmingham, Alabama, United States of America.

RESUMEN / SUMMARY:  - Breast cancer is one of the most lethal diseases in women; however, the precise etiological factors are still not clear. Genistein (GE), a natural isoflavone found in soybean products, is believed to be a potent chemopreventive agent for breast cancer. One of the most important mechanisms for GE inhibition of breast cancer may involve its potential in impacting epigenetic processes allowing reversal of aberrant epigenetic events during breast tumorigenesis. To investigate epigenetic regulation for GE impedance of breast tumorigenesis, we monitored epigenetic alterations of several key tumor-related genes in an established breast cancer transformation system. Our results show that GE significantly inhibited cell growth in a dose-dependent manner in precancerous breast cells and breast cancer cells, whereas it exhibited little effect on normal human mammary epithelial cells. Furthermore, GE treatment increased expression of two crucial tumor suppressor genes, p21(WAF1) (p21) and p16(INK4a)  (p16), although it decreased expression of two tumor promoting genes, BMI1 and c-MYC. GE treatment led to alterations of histone modifications in the promoters  of p21 and p16 as well as the binding ability of the c-MYC-BMI1 complex to the p16 promoter contributing to GE-induced epigenetic activation of these tumor suppressor genes. In addition, an orally-fed GE diet prevented breast tumorigenesis and inhibited breast cancer development in breast cancer mice xenografts. Our results suggest that genistein may repress early breast tumorigenesis by epigenetic regulation of p21 and p16 by impacting histone modifications as well as the BMI1-c-MYC complex recruitment to the regulatory region in the promoters of these genes. These studies will facilitate more effective use of soybean product in breast cancer prevention and also help elucidate the mechanisms during the process of early breast tumorigenesis.

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[1006]

TÍTULO / TITLE:  - Comparison of different methods for detecting epidermal growth factor receptor mutations in peripheral blood and tumor tissue of non-small cell lung cancer as a predictor of response to gefitinib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Onco Targets Ther. 2012;5:439-47. doi: 10.2147/OTT.S37289. Epub 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 2147/OTT.S37289

AUTORES / AUTHORS:  - Xu F; Wu J; Xue C; Zhao Y; Jiang W; Lin L; Wu X; Lu Y; Bai H; Xu J; Zhu G; Zhang L

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Oncology in South China, Department of Medical Oncology,  Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of  China.

RESUMEN / SUMMARY:  - BACKGROUND: Previous studies have reported that epidermal growth factor receptor  (EGFR) mutation in tumor tissue and peripheral blood can predict the response to  EGFR tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC). However, the heterogeneity of the sample sources makes it difficult to evaluate the detecting methodologies. The goal of this study is to compare different methods for analyzing EGFR mutation in blood and tumor tissue. MATERIALS AND METHODS: Fifty-one advanced NSCLC patients treated with gefitinib were included in the study. The EGFR mutation status of each patients’ blood was analyzed by denaturing high-performance liquid chromatography (DHPLC), mutant-enriched liquidchip (ME-Liquidchip), and Scorpion Amplification Refractory Mutation System (Scorpion-ARMS) kits. EGFR mutation information in paired tumor samples detected  by Scorpion-ARMS served as a reference. Comparative analyses were performed on mutation status results obtained from different methods and on the association between the clinical outcome of TKI treatment and EGFR mutation status. RESULTS:  The response rate (RR) in the whole group was 33.3%. EGFR mutation rates were identified as 15.7%, 27.5%, and 29.4% by DHPLC, ME-Liquidchip, and Scorpion-ARMS  in blood, respectively. In 34 cases that had paired tumor samples, the mutation rate in tissue was 41.2%. The RRs of patients with mutation detected by different methods were 71.4% (tumor), 62.5% (blood, DHPLC), 50.0% (blood, ME-Liquidchip), and 66.7% (blood, Scorpion-ARMS). EGFR mutation detected by Scorpion-ARMS in blood and tumor tissues had better prediction of RR to EGFR-TKI (P = 0.002 and P  = 0.001) than mutation detected with DHPLC and ME-Liquidchip. CONCLUSION: Tumor tissue sample is the best source for EGFR mutation analysis in NSCLC patients. Peripheral blood samples may be used as an alternative source only in special conditions. Scorpion-ARMS, DHPLC, or ME-Liquidchip methods are all optional for detecting tumor EGFR mutation from blood.

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[1007]

TÍTULO / TITLE:  - Targeted approach to metastatic colorectal cancer: what comes beyond epidermal growth factor receptor antibodies and bevacizumab?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ther Adv Med Oncol. 2013 Jan;5(1):51-72. doi: 10.1177/1758834012462462.

            ●● Enlace al texto completo (gratuito o de pago) 1177_1758834012462462 [pii

            ●● Enlace al texto completo (gratuito o de pago) 1177/1758834012462462

AUTORES / AUTHORS:  - Troiani T; Martinelli E; Morgillo F; Capasso A; Nappi A; Sforza V; Ciardiello F

INSTITUCIÓN / INSTITUTION:  - Oncologia Medica and Immunologia Clinica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale F. Magrassi e A. Lanzara, Seconda Universita  degli Studi di Napoli, Napoli, Italy.

RESUMEN / SUMMARY:  - The prognosis of patients with cancer remains poor in spite of the advances obtained in recent years with new therapeutic agents, new approaches in surgical  procedures and new diagnostic methods. The discovery of a plethora of cellular targets and the rational generation of selective targeting agents has opened an era of new opportunities and extraordinary challenges. The specificity of these agents renders them capable of specifically targeting the inherent abnormalities  of cancer cells, potentially resulting in less toxicity than traditional nonselective cytotoxics. Among the many new types of rationally designed agents are therapeutics targeting various strategic facets of growth signal transduction, malignant angiogenesis, survival, metastasis and cell-cycle regulation. The evaluation of these agents is likely to require some changes from the traditional drug development paradigms to realize their full potential. Inhibition of the epidermal growth factor receptor and the vascular endothelial growth factor have provided proof of principle that disruption of signal cascades in patients with colorectal cancer has therapeutic potential. This experience has also taught us that resistance to such rationally developed targeted therapeutic  strategies is common. In this article, we review the role of signal transduction  in colorectal cancer, introduce promising molecular targets, and outline therapeutic approaches under development.

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[1008]

TÍTULO / TITLE:  - Prognostic Value of Promoter Hypermethylation of Retinoic Acid Receptor Beta (RARB) and CDKN2 (p16/MTS1) in Prostate Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Cancer Res. 2011 Dec;23(4):306-11. doi: 10.1007/s11670-011-0306-x.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11670-011-0306-x

AUTORES / AUTHORS:  - Ameri A; Alidoosti A; Hosseini SY; Parvin M; Emranpour MH; Taslimi F; Salehi E; Fadavip P

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran;

RESUMEN / SUMMARY:  - OBJECTIVE: The molecular mechanism of prostate cancer is poorly understood. The aim of the study was to investigate the prevalence and prognostic value of promoter hypermethylation of retinoic acid receptor beta (RARB) and p16 among benign prostatic hyperplasia (BPH) and prostate cancer patients. METHODS: In this case-control study, 63 patients were included in three groups; 21 with BPH as the control group, 21 with prostate cancer and good prognostic factors (based on prostate-specific antigen, Gleason score and stage) as good prognosis group, and  21 with prostate cancer and poor prognostic features as poor prognosis group. The prostate biopsy specimen of each individual was examined for hypermethylation of  RARB and p16 promoters by methylation specific PCR (MSPCR). RESULTS: Seven (33.3%) patients with good prognosis and 15 (71.4%) patients with poor prognosis  were positive for RARB methylation, which were significantly higher than controls (P<0.0001). p16 promoter methylation was shown in 19.0% and 47.6% patients with good and poor prognosis, respectively. The RARB and p16 promoter methylation in the poor prognosis group was significantly higher than that in the good prognosis group (P =0.02 for RARB and P<0.0001 for p16). CONCLUSION: Hypermethylation of RARB and p16 promoters may predict prognosis in prostate cancer.

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[1009]

TÍTULO / TITLE:  - Combination of a selective activator of the glucocorticoid receptor Compound A with a proteasome inhibitor as a novel strategy for chemotherapy of hematologic malignancies.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Cycle. 2013 Jan 1;12(1):133-44. doi: 10.4161/cc.23048. Epub 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 4161/cc.23048

AUTORES / AUTHORS:  - Lesovaya E; Yemelyanov A; Kirsanov K; Popa A; Belitsky G; Yakubovskaya M; Gordon LI; Rosen ST; Budunova I

INSTITUCIÓN / INSTITUTION:  - Department of Chemical Carcinogenesis; Institute of Carcinogenesis; Blokhin Cancer Research Center; RAMS; Moscow, Russia.

RESUMEN / SUMMARY:  - Glucocorticoids are widely used for the treatment of hematological malignancies;  however, their chronic use results in numerous metabolic side effects. Thus, the  development of selective glucocorticoid receptor (GR) activators (SEGRA) with improved therapeutic index is important. GR regulates gene expression via (1) transactivation that requires GR homodimer binding to gene promoters and is linked to side effects and (2) transrepression-mediated via negative GR interaction with other transcription factors. Novel GR modulator Compound A (CpdA) prevents GR dimerization, retains glucocorticoid anti-inflammatory activity and has fewer side effects compared with glucocorticoids in vivo. Here we tested CpdA anticancer activity in human T- and B-lymphoma and multiple myeloma cells expressing GR and their counterparts with silenced GR. We found that CpdA in GR-dependent manner strongly inhibited growth and viability of human T-, B-lymphoma and multiple myeloma cells. Furthermore, primary leukemia cell cultures from T-ALL patients appeared to be equally sensitive to glucocorticoid dexamethasone and CpdA. It is known that GR expression is controlled by proteasome. We showed that pretreatment of lymphoma CEM and NCEB cells with proteasome-inhibitor Bortezomib resulted in GR accumulation and enhanced ligand properties of CpdA, shifting GR activity toward transrepression evaluated by inhibition of NFsmall ka, CyrillicB and AP-1 transcription factors. We also revealed remarkable GR-dependent cooperation between CpdA and Bortezomib in suppressing growth and survival of T- and B-lymphoma and multiple myeloma MM.1S cells. Overall, our data provide the rationale for novel GR-based therapy for hematological malignancies based on combination of SEGRA with proteasome inhibitors.

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[1010]

TÍTULO / TITLE:  - Molecular phenotype predicts sensitivity of squamous cell carcinoma of the head and neck to epidermal growth factor receptor inhibition.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Oncol. 2012 Nov 14. pii: S1574-7891(12)00121-4. doi: 10.1016/j.molonc.2012.11.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.molonc.2012.11.001

AUTORES / AUTHORS:  - Young NR; Liu J; Pierce C; Wei TF; Grushko T; Olopade OI; Liu W; Shen C; Seiwert TY; Cohen EE

INSTITUCIÓN / INSTITUTION:  - Department of Medicine and Comprehensive Cancer Center, University of Chicago, 900 East 57th Street, Chicago, IL 60637, USA. Electronic address: nyoung@medicine.bsd.uchicago.edu.

RESUMEN / SUMMARY:  - Despite nearly universal expression of the wild-type epidermal growth factor receptor (EGFR) and reproducible activity of EGFR inhibitors in patients with squamous cell carcinoma of the head and neck (SCCHN), the majority of patients will not have objective responses. The mechanisms of this intrinsic resistance are not well established. We hypothesized that sensitivity to EGFR inhibitors can be predicted based on the inhibitors’ effects on downstream signaling. Cell viability assays were used to assess sensitivity to the EGFR inhibitor gefitinib  (ZD1839) in 8 SCCHN cell lines. Fluorescence in-situ hybridization showed the two most sensitive lines to be highly gene-amplified for EGFR. Western blotting confirmed that phosphoEGFR was inhibited at low concentrations of gefitinib in all lines tested. Phosphorylation of downstream signaling protein AKT was inhibited in sensitive lines while inhibition of phosphoERK displayed no relationship to gefitinib efficacy. Phosphatase and tensin homolog (PTEN) expression was evident in all cell lines. Activating PIK3CA mutations were found  in two resistant cell lines where pAKT was not inhibited by gefitinib. In resistant cell lines harboring PIK3CA mutations, a PI3K inhibitor, LY294002, or AKT siRNA reduced cell viability with an additive effect demonstrated in combination with gefitinib. Additionally, LY294002 alone and in combination with  gefitinib, was effective at treating PIK3CA mutated tumors xenografted into nude  mice. Taken together this suggests that constitutively active AKT is a mechanism  of intrinsic gefitinib resistance in SCCHN. This resistance can be overcome through targeting of the PI3K/AKT pathway in combination with EGFR inhibition.

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[1011]

TÍTULO / TITLE:  - Effects of the proapoptotic regulator Bcl-2/adenovirus EIB 19-kDa-interacting protein 3 on the chemosensitivity of human colon cancer cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2012 Dec;4(6):1195-1202. Epub 2012 Sep 21.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.933

AUTORES / AUTHORS:  - Wang Z; Huang C; Zeng J; Deng Q; Zeng H; Liu Z; Peng X; Bi F; Tang Q; Li Z

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041;

RESUMEN / SUMMARY:  - In the clinical setting, drug resistance remains a significant obstacle for successful chemotherapy. Bcl-2/adenovirus EIB 19-kDa-interacting protein 3 (BNIP3) is a proapoptotic member of the Bcl-2 family. To address its potential as a therapeutic target for chemosensitisation, this study investigated the effect of BNIP3 expression on chemosensitivity and reversal of oxaliplatin (L-OHP) resistance in human colon cancer cell lines. A plasmid expressing the BNIP3 gene  was transfected into human parental colon cancer cell lines (SW620 and colo320) and L-OHP-resistant colon cancer cell lines (SW620/L-OHP and colo320/L-OHP) using Lipofectamine 2000, and the transfection efficiency was determined using fluorescence optics. Western blot analysis identified that SW620/L-OHP and colo320/L-OHP cells expressed lower levels of BNIP3 protein compared with the SW620 and colo320 cells. Transfection with the recombinant BNIP3 plasmid revealed an increase in BNIP3 expression in tumour cells. Following transfection with pDsRed-BNIP3, the chemosensitivity of parental and L-OHP-resistant cell lines to  L-OHP was increased (P<0.01), as detected by the Cell Counting Kit-8 (CCK8) assay. Hoechst 33342 staining and flow cytometry revealed that the effects on L-OHP-induced apoptosis were enhanced by the overexpression of BNIP3. Chemosensitisation in human colon cancer cells was observed following treatment with the recombinant BNIP3 plasmid in vitro. The results of this study suggest that BNIP3 is a potential therapeutic target for reversing the resistance of L-OHP-resistant colon cancer cells to L-OHP.

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[1012]

TÍTULO / TITLE:  - Using the Theory of Coevolution to predict protein- interactions in non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Cancer. 2012 Dec 14. doi: 10.5732/cjc.012.10100.

            ●● Enlace al texto completo (gratuito o de pago) 5732/cjc.012.10100

AUTORES / AUTHORS:  - Zhang M; Chan M; Tu W; He L; Lee C; He M

INSTITUCIÓN / INSTITUTION:  - Life Sciences School, Sun Yat-sen University, Guangzhou, Guangdong 510275, P.R. China lsshem@mail.sysu.edu.cn.

RESUMEN / SUMMARY:  - Systems biology has become an effective approach for understanding the molecular  mechanisms underlying the development of lung cancer. In this study, sequences of 100 non-small cell lung cancer (NSCLC)-related proteins were downloaded from NCBI databases. The Theory of Coevolution was then used to construct a protein-protein interaction (PPI) network of NSCLC. Adopting the reverse thinking approach, we analyzed the NSCLC proteins one at a time. Fifteen key proteins were identified and categorized into a special protein family F(K), which included CCND1, CDH1, CDKN2A, CSCL12, EGF, EGFR, FAS, FRAP1, MGMT, PARK2, PTEN, CACNA2D2, TUBB, SMARCA2, and WNT7A. Seven key nodes of the sub-network were identified, which included PARK2, WNT7A, SMARCA2, FRAP1, CDKN2A, CCND1, and EGFR. The PPI predictions of EGFR-EGF, PARK2-FAS, PTEN-FAS, and CACNA2D2-CDH1 were confirmed experimentally by retrieving BioGRID and Pubmed databases. We proposed that the proteins, which included PARK2, WNT7A, SMARCA2, FRAP1, CDKN2A, CCND1, and EGFR, could serve as potential diagnostic molecular markers for NSCLC. In accordance with the developmental mode of lung cancer established by Minna et al., we assumed that the occurrence and development of lung cancer was linked not only to gene loss in the 3p region (WNT7A, 3p25) and genetic mutations in the 9p region but also to similar events in the regions of 1p36.2 (FRAP1), 6q25.2-q27 (PARK2),  and 11q13 (CCND1). Lastly, it might lead to the invasion or metastasis of lung cancer.

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[1013]

TÍTULO / TITLE:  - Gene Variants in Predicting BCG Response to Urinary Bladder Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Indian J Clin Biochem. 2012 Jan;27(1):1-5. doi: 10.1007/s12291-012-0191-1. Epub 2012 Feb 11.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12291-012-0191-1

AUTORES / AUTHORS:  - Mittal RD

INSTITUCIÓN / INSTITUTION:  - Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226014 Uttar Pradesh India.

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[1014]

TÍTULO / TITLE:  - Influence of human MIF promoter polymorphism on hepatocellular carcinoma prognosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Genet Mol Res. 2013 Jan 4;12(AOP).

            ●● Enlace al texto completo (gratuito o de pago) 4238/2013.Janruary.4.3

AUTORES / AUTHORS:  - Yuan T; Tang C; Chen M; Deng S; Chen P

INSTITUCIÓN / INSTITUTION:  - Department of Hepatobiliary Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.

RESUMEN / SUMMARY:  - Hepatocellular carcinoma (HCC) is one of the most common worldwide malignancies.  A relative complete diagnosis system for primary carcinoma of liver has already been established, but the surgical prognosis for HCC, which depends mainly on postoperative pathological classification and data of recurrence and metastasis lacks valid experimental indicators. Macrophage migration inhibition factor (MIF) relates to many cancers; hence, the polymorphism of MIF genes may be associated with the surgical prognosis of HCC. The purpose of this study was to investigate  the relationship between polymorphisms of MIF gene promoter 794CATT (MIF-794CATT) microsatellite repeats and HCC surgical prognosis and evaluate the contribution of polymorphism to the prognosis of hepatectomy. Sequencing was used to identify  the MIF-794CATT of 241 patients who had HCC surgery. These patients were classified into 2 groups: one with MIF-794CATT high-repetitive-sequence genotypes (7/X+8/X) and one with low-repetitive-sequence genotypes (5/5+5/6+6/6). Five indictors were analyzed: average survival times were compared using t-test, and tumor-node-metastasis staging, recurrence and metastasis, differentiation grade,  and survival rate were compared using the chi-square test. The (7/x+8/x) CATT group had 139 patients, and the (5/5+5/6+6/6) CATT group had 102. Significant differences were found in the 5 factors (P = 0.000, P = 0.008, P = 0.002, P = 0.000, and P = 0.003, respectively). Patients with MIF-794CATT(5-8) low-repetitive-sequence genotypes had better prognosis than those with high-repetitive-sequence genotypes. The polymorphism detection of MIF- 794CATT microsatellite repeats is valuable for HCC surgical prognosis.

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[1015]

TÍTULO / TITLE:  - Increased MiR-221 expression in hepatocellular carcinoma tissues and its role in  enhancing cell growth and inhibiting apoptosis in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Cancer. 2013 Jan 16;13:21. doi: 10.1186/1471-2407-13-21.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2407-13-21

AUTORES / AUTHORS:  - Rong M; Chen G; Dang Y

INSTITUCIÓN / INSTITUTION:  - Research Department, Affiliated Cancer Hospital, Guangxi Medical University, 71 Hedi Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, P,R, China. tourtair@163.com.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: MiR-221 is over-expressed in human hepatocellular carcinoma (HCC), but its clinical significance and function in HCC remains uncertain. The aim of the study was to investigate the relationship between miR-221 overexpression and clinicopathological parameters in HCC formalin-fixed paraffin-embedded (FFPE) tissues, and the effect of miR-221 inhibitor and mimic on different HCC cell lines in vitro. METHODS: MiR-221 expression was detected using real time RT-qPCR in FFPE HCC and the adjacent noncancerous liver tissues.  The relationship between miR-221 level and clinicopathological features was also  analyzed. Furthermore, miR-221 inhibitor and mimic were transfected into HCC cell lines HepB3, HepG2 and SNU449. The effects of miR-221 on cell growth, cell cycle, caspase activity and apoptosis were also investigated by spectrophotometry, fluorimetry, fluorescence microscopy and flow cytometry, respectively. RESULTS: The relative expression of miR-221 in clinical TNM stages III and IV was significantly higher than that in the stages I and II. The miR-221 level was also upregulated in the metastatic group compared to the nonmetastatic group. Furthermore, miR-221 over-expression was related to the status of tumor capsular  infiltration in HCC clinical samples. Functionally, cell growth was inhibited, cell cycle was arrested in G1/S-phase and apoptosis was increased by miR-221 inhibitor in vitro. Likewise, miR-221 mimic accelerated the cell growth. CONCLUSIONS: Expression of miR-221 in FFPE tissues could provide predictive significance for prognosis of HCC patients. Moreover, miR-221 inhibitor could be  useful to suppress proliferation and induce apoptosis in HCC cells. Thus miR-221  might be a critical targeted therapy strategy for HCC.

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[1016]

TÍTULO / TITLE:  - Expressions of Osteopontin (OPN), alphanubeta3 and Pim-1 Associated with Poor Prognosis in Non-small Cell Lung Cancer (NSCLC).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Cancer Res. 2012 Jun;24(2):103-8. doi: 10.1007/s11670-012-0103-1.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11670-012-0103-1

AUTORES / AUTHORS:  - Jin Y; Tong DY; Tang LY; Chen JN; Zhou J; Feng ZY; Shao CK

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.

RESUMEN / SUMMARY:  - OBJECTIVE: To examine the expressions of osteopontin (OPN), (alpha) (nu) (beta) (3) and Pim-1 in non-small cell lung cancer (NSCLC), and investigate their potential pathogenic roles in the development of NSCLC. METHODS: Immunohistochemistry was used to examine the expressions of OPN, (alpha) (nu) (beta) (3) and Pim-1 in cohort (136 cases) of NSCLC samples and their adjacent normal lung tissue specimens. Statistical analysis was performed to evaluate the  relationships among expressions of OPN, (alpha) (nu) (beta) (3) and Pim-1 and their associations with patients clinico- pathological parameters. RESULTS: The expressions of OPN and Pim-1 were predominantly observed in cytoplasm. The expression of (alpha) (nu) (beta) (3) was mostly detected in cytoplasm and/or membrane. In NSCLC samples, the positive rates of OPN, (alpha) (nu) (beta) (3) and Pim-1 expressions were 68.4% (93/136), 77.2% (105/136) and 57.4% (78/136), respectively. In normal lung tissues, in contrast, the positive rates of OPN, (alpha) (nu) (beta) (3) and Pim-1 were 24.0% (12/50), 26.0% (13/50) and 16.0% (8/50), respectively. There were significant differences of the positive expression rates of OPN, (alpha) (nu) (beta) (3) and Pim-1 between NSCLCs samples and normal lung tissues (P<0.01). In addition, the positive expression of OPN, (alpha) (nu) (beta) (3) and Pim-1 in NSCLCs samples was significantly associated  with increased pathological grade, lymph node metastasis and advanced clinical stage (P<0.01), and they were independent of other clinicopathological parameters (P>0.05). Furthermore, a significantly positive correlation between the expression of OPN and (alpha) (nu) (beta) (3) (r=0.38, P<0.01), OPN and Pim-1 (r=0.37, P<0.01), or (alpha) (nu) (beta) (3) and Pim-1 (r=0.20, P<0.05) was evaluated in our NSCLC cohort. CONCLUSION: OPN, (alpha) (nu) (beta) (3) and Pim-1 proteins are frequently overexpressed in NSCLC, and they may play important roles in the development and/or progression of NSCLC.

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[1017]

TÍTULO / TITLE:  - The pan-deacetylase inhibitor panobinostat modulates the expression of epithelial-mesenchymal transition markers in hepatocellular carcinoma models.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2013 Jan;5(1):127-134. Epub 2012 Oct 1.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.951

AUTORES / AUTHORS:  - DI Fazio P; Montalbano R; Quint K; Alinger B; Kemmerling R; Kiesslich T; Ocker M; Neureiter D

INSTITUCIÓN / INSTITUTION:  - Institute for Surgical Research, Philipps-University Marburg, Baldingerstrasse, Marburg 35043, Germany ;

RESUMEN / SUMMARY:  - Deacetylase inhibitors (DACis) represent a novel therapeutic option for human cancers by classically affecting proliferation or apoptosis. Since transdifferentiation and dedifferentiation play a key role in carcinogenesis, we  investigated the epigenetic influence on the molecular differentiation status in  human hepatocellular carcinoma (HCC) models. Markers of differentiation, including cytokeratin (Ck) 7, Ck8, Ck18, Ck19, Ck20, vimentin, sonic hedgehog homolog (SHH), smoothened (Smo), patched (Ptc), glioma-associated oncogene homolog 1 (Gli1), CD133, octamer-binding transcription factor 4 (Oct4) and beta-catenin, were examined in the human HCC cell lines HepG2 and Hep3B in vitro  and in vivo (xenograft model) using quantitative real-time PCR and immunohistochemistry following treatment with the pan-DACi panobinostat (LBH589). Compared to untreated controls, treated HepG2 xenografts, and to a lesser extent  cell lines, demonstrated a significant increase of differentiation markers Ck7 and Ck19 (classical cholangiocellular type) and Ck8 and Ck18 (classical HCC type), and a decreased level of dedifferentiation markers vimentin (mesenchymal)  and SHH/Ptc (embryonic), paralleled with a more membranous expression of beta-catenin. These findings were dose-dependently correlated with tumor size, necrosis rate, microvessel density and mitosis/Ki-67-associated proliferation rate. Our results demonstrate that the differentiation status of human HCC cells  is influenced by the pan-DACi panobinostat, indicating that this treatment may influence the epithelial-mesenchymal transition (EMT) status related to metastasis and aggressiveness.

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[1018]

TÍTULO / TITLE:  - Blocking the Proliferation of Human Tumor Cell Lines by Peptidase Inhibitors from Bauhinia Seeds.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Planta Med. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1055/s-0032-1328156

AUTORES / AUTHORS:  - Nakahata AM; Mayer B; Neth P; Hansen D; Sampaio MU; Oliva ML

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry, Universidade Federal de Sao Paulo-Escola Paulista de  Medicina, Sao Paulo, Brazil.

RESUMEN / SUMMARY:  - In cancer tumors, growth, invasion, and formation of metastasis at a secondary site play a pivotal role, participating in diverse processes in the development of the pathology, such as degradation of extracellular matrix. Bauhinia seeds contain relatively large quantities of peptidase inhibitors, and two Bauhinia inhibitors were obtained in a recombinant form from the Bauhinia bauhinioides species, B. bauhinoides cruzipain inhibitor, which is a cysteine and serine peptidase inhibitor, and B. bauhinioides kallikrein inhibitor, which is a serine  peptidase inhibitor. While recombinant B. bauhinoides cruzipain inhibitor inhibits human neutrophil elastase cathepsin G and the cysteine proteinase cathepsin L, recombinant B. bauhinioides kallikrein inhibitor inhibits plasma kallikrein and plasmin. The effects of recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor on the viability of tumor cell lines with a distinct potential of growth from the same tissue were compared to those of the clinical cytotoxic drug 5-fluorouracil. At 12.5 microM concentration, recombinant B. bauhinoides cruzipain inhibitor and recombinant B.  bauhinioides kallikrein inhibitor were more efficient than 5-fluorouracil in inhibiting MKN-28 and Hs746T (gastric), HCT116 and HT29 (colorectal), SkBr-3 and  MCF-7 (breast), and THP-1 and K562 (leukemia) cell lines. Additionally, recombinant B. bauhinoides cruzipain inhibitor inhibited 40 % of the migration of Hs746T, the most invasive gastric cell line, while recombinant B. bauhinioides kallikrein inhibitor did not affect cell migration. Recombinant B. bauhinioides kallikrein inhibitor and recombinant B. bauhinoides cruzipain inhibitor, even at  high doses, did not affect hMSC proliferation while 5-fluorouracil greatly reduced the proliferation rates of hMSCs. Therefore, both recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor might be considered for further studies to block peptidase activities in order to target specific peptidase-mediated growth and invasion characteristics of individual tumors, mainly in patients resistant to 5-fluorouracil chemotherapy.

 

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[1019]

TÍTULO / TITLE:  - Virtual Screening of Specific Insulin-Like Growth Factor 1 Receptor (IGF1R) Inhibitors from the National Cancer Institute (NCI) Molecular Database.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2012 Dec 14;13(12):17185-209. doi: 10.3390/ijms131217185.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms131217185

AUTORES / AUTHORS:  - Fan C; Huang YX; Bao YL; Sun LG; Wu Y; Yu CL; Zhang Y; Song ZB; Zheng LH; Sun Y; Wang GN; Li YX

INSTITUCIÓN / INSTITUTION:  - National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China. huangyx356@nenu.edu.cn.

RESUMEN / SUMMARY:  - Insulin-like growth factor 1 receptor (IGF1R) is an attractive drug target for cancer therapy and research on IGF1R inhibitors has had success in clinical trials. A particular challenge in the development of specific IGF1R inhibitors is interference from insulin receptor (IR), which has a nearly identical sequence. A few potent inhibitors that are selective for IGF1R have been discovered experimentally with the aid of computational methods. However, studies on the rapid identification of IGF1R-selective inhibitors using virtual screening and confidence-level inspections of ligands that show different interactions with IGF1R and IR in docking analysis are rare. In this study, we established virtual  screening and binding-mode prediction workflows based on benchmark results of IGF1R and several kinase receptors with IGF1R-like structures. We used comprehensive analysis of the known complexes of IGF1R and IR with their binding  ligands to screen specific IGF1R inhibitors. Using these workflows, 17 of 139,735 compounds in the NCI (National Cancer Institute) database were identified as potential specific inhibitors of IGF1R. Calculations of the potential of mean force (PMF) with GROMACS were further conducted for three of the identified compounds to assess their binding affinity differences towards IGF1R and IR.

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[1020]

TÍTULO / TITLE:  - Effectiveness of aromatase inhibitors and tamoxifen in reducing subsequent breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Med. 2012 Dec;1(3):318-27. doi: 10.1002/cam4.37. Epub 2012 Sep 26.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cam4.37

AUTORES / AUTHORS:  - Haque R; Ahmed SA; Fisher A; Avila CC; Shi J; Guo A; Craig Cheetham T; Schottinger JE

INSTITUCIÓN / INSTITUTION:  - Kaiser Permanente Southern California Pasadena, California, 91101.

RESUMEN / SUMMARY:  - Tamoxifen (TAM) has been prescribed for decades and aromatase inhibitors (AIs) have been used since the early 2000s in preventing subsequent breast cancer. However, outside of clinical trials, the effectiveness of AIs is not established. We examined the long-term risk of subsequent breast cancer among survivors treated with TAM and AIs in a large health plan. The study included 22,850 survivors, diagnosed with initial breast cancer (stages 0-IV) from 1996 to 2006,  and followed 13 years maximum. We compared the risk of subsequent breast cancer in those who used TAM and/or AIs versus nonusers (the reference group). Hazard ratios (HR) adjusted for patient, tumor, treatment, and health-care characteristics were estimated using Cox models with time-dependent drug use status. Women who used TAM/AIs had a large reduction in risk of subsequent breast cancer compared with nonusers. While confidence intervals (CI) for all hormone treatment groups overlapped, women with high adherence (medication possession ratio >/=80%) who used AIs exclusively and had positive ER or PR receptor status  had the greatest risk reduction (HR = 0.34, 95% CI: 0.28-0.41), followed by those who switched from TAM to AIs (HR = 0.39, 95% CI: 0.30-0.49), and those who used TAM exclusively (HR = 0.42, 95% CI: 0.36-0.47). Women with high adherence had the greatest risk reduction in subsequent breast cancer, but the results were not substantially different from women who took the drugs less regularly. Compared with nonusers, the reduction in subsequent breast cancer risk ranged from 58% to  66% across the hormone treatment groups and degree of adherence.

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[1021]

TÍTULO / TITLE:  - Are race-specific ERCC1 haplotypes in melanoma cases versus controls related to the predictive and prognostic value of ERCC1 N118N?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - British Medical J (BMJ). Acceso gratuito al texto completo.

            ●● Enlace a la Editora de la Revista http://bmj.com/search.dtl 

            ●● Cita: British Medical J. (BMJ): <> Open. 2013 Jan 3;3(1). pii: e002030. doi: 10.1136/bmjopen-2012-002030. Print  2013.

            ●● Enlace al texto completo (gratuito o de pago) 1136/bmjopen-2012-002030

AUTORES / AUTHORS:  - Gao R; Reece KM; Sissung T; Fu SH; Venzon DJ; Reed E; Spencer SD; Price DK; Figg WD

INSTITUCIÓN / INSTITUTION:  - Molecular Pharmacology Section, Medical Oncology Branch, Center for Cancer Research, Bethesda, Maryland, USA.

RESUMEN / SUMMARY:  - OBJECTIVES: Although it does not alter the ERCC1 phenotype, the ERCC1 500C>T (rs11615) polymorphism has undergone a myriad of investigations into its role as  a marker for nucleotide excision repair (NER) function in different races, diseases and treatment outcomes. The goal of our study was to test the hypothesis that 500C>T is in linkage disequilibrium (LD) with causative alleles, and that these haplotypes are more frequent in Caucasians with melanoma than in healthy Caucasians or African Americans. DESIGN: In this case-control study, we selected  race-specific ERCC1 single-nucleotide polymorphism (SNPs), conducted LD analysis  with ERCC1 500C>T and compared the frequency of ERCC1 diplotypes in Caucasians with melanoma (n=165), healthy Caucasians (n=150) and healthy African Americans (n=159). The haplotype was further studied using a fusion gene containing multiple ERCC1 SNPs. SETTING: Large cancer institute in the USA. PARTICIPANTS: A  total of 165 Caucasian melanoma patients, 159 healthy Caucasian controls and 159  African American healthy controls. Men and women were enrolled in the clinical trial; however, since the screening trial included prostate cancer screening in addition to screening for other cancers, only male controls were available. OUTCOME MEASURES: The outcome measures were melanoma risk in Caucasians, and LD between ERCC1 SNP, N118N and other race-specific allelic variants. RESULTS: When  compared to ERCC1 500C>T alone, a race-specific three-SNP variant haplotype in ERCC1 (comprised of rs11615, rs3212950 and rs3212948) was even more frequent in Caucasians with melanoma than in healthy Caucasians (p=0.0034) or African Americans (p<0.0001). A plasmid containing the variant haplotype was not differentially expressed. CONCLUSIONS: We demonstrate that ERCC1 500C>T participates in a previously characterised cancer-risk haplotype found more frequently in Caucasians, while LD is weak in African Americans; this haplotype appears to also be related to melanoma. It is therefore likely that ERCC1 500C>T  is only a valid NER, disease or treatment outcome marker in Caucasians.

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[1022]

TÍTULO / TITLE:  - The roles of epidermal growth factor receptor (EGFR) inhibitors in the management of lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Infect Public Health. 2012 Dec;5 Suppl 1:S50-60. doi: 10.1016/j.jiph.2012.09.004. Epub 2012 Nov 6.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jiph.2012.09.004

AUTORES / AUTHORS:  - Al Olayan A; Al Hussaini H; Rahman Jazieh A

INSTITUCIÓN / INSTITUTION:  - King Abdulaziz Medical City for National Guard - King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. Electronic address: alolayanas@ngha.med.sa.

RESUMEN / SUMMARY:  - Targeting epidermal growth factor receptor (EGFR) is an important treatment option for non-small cell lung cancer (NSCLC). These targeted therapies have been studied extensively in NSCLC in first line and subsequent lines, including maintenance in empiric fashion or in patients with tumors harboring the EGFR mutations. In this manuscript, we will review in details the evolutions of these  targeted therapy in the management of NSCLC.

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[1023]

TÍTULO / TITLE:  - Serum interleukin - 4 and tumor necrosis factor alpha concentrations in children  with primary acid gastroesophageal reflux and acid gastroesophageal reflux secondary to cow’s milk allergy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Adv Med Sci. 2012 Oct 24:1-9. doi: 10.2478/v10039-012-0037-3.

            ●● Enlace al texto completo (gratuito o de pago) 2478/v10039-012-0037-3

AUTORES / AUTHORS:  - Semeniuk J; Wasilewska J; Kaczmarski M

RESUMEN / SUMMARY:  - ABSTRACT Aim: The possible role of serum interleukin 4 (IL-4) and tumor necrosis  factor alpha (TNF- alpha) in pathogenesis of the reflux symptoms in children with primary acid gastroesophageal reflux (GER) and acid GER secondary to cow’s milk allergy (CMA). Material and methods. Out of 264 children, 76 (28.8%) patients with primary GER and 62 (23.5%) patients with GER secondary to CMA (pH - monitoring) serum IL-4 and TNF- alpha concentrations were assessed before treatment, 1 and 2 years after the initiation of the periodically administered pharmacotherapy. Results. Children with primary GER had mean IL-4 concentrations  0.17 +/- 0.06 pg/ml before treatment, 0.08 +/- 0.07 pg/ ml after 1-year and 0.07  +/- 0.06 pg/ml after 2-years of treatment. The mean IL-4 concentrations were 1.07 +/- 0.24, 0.5 +/- 0.22 and 0.44 +/- 0.19 pg/ml respectively in children with GER  secondary to CMA. The mean serum TNF- alpha concentrations was 3.62 +/- 1.30 pg/ml before treatment , 2.16 +/- 1,35 pg/ ml after 1 year and 1.65 +/- 1.16 pg/ml after 2 years of treatment in children with primary GER. In group with GER  secondary to CMA mean serum TNF- alpha concentrations were 4.95 +/- 1.88, 2.53 +/- 0.80 and 2.02 +/- 0.78 pg/ml respectively. Statistical analysis of the concentration of both cytokines showed their differentiation between them and in  the study groups. Conclusions. The highest mean serum IL-4 and TNF-alpha concentrations were observed in children with GER secondary to CMA and in children in control group (with cow’s milk allergy and/or other food allergy diagnosed - CMA/FA) before the treatment administration.

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[1024]

TÍTULO / TITLE:  - Expression of EGFR, Her2 predict lymph node metastasis (LNM)-associated metastasis in colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Biomark. 2012;11(5):219-26. doi: 10.3233/CBM-2012-00282.

            ●● Enlace al texto completo (gratuito o de pago) 3233/CBM-2012-00282

AUTORES / AUTHORS:  - Lu Y; Jingyan G; Baorong S; Peng J; Xu Y; Cai S

INSTITUCIÓN / INSTITUTION:  - Fudan University Shanghai Cancer Center, Department of Colorectal Cancer and Oncology, Shanghai Medical College Fudan University, Shanghai, China.

RESUMEN / SUMMARY:  - BACKGROUND: As key molecules that drive progression and chemoresistance in gastrointestinal cancers, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (Her2) have become efficacious drug targets in this setting. But until now, although above studies suggested that EGFR and Her2  may serve as effective biomarkers for targeted therapy in cancer patients with primary tumor, the information on these biomarkers in colorectal cancer is still  limited in metastases. OBJECTIVE: The purpose of this study is to evaluate the expression of epidermal growth factor receptor (EGFR) and human epidermal growth  factor receptor 2 (Her2) on the lymph node metastasis (LNM) of colorectal cancer  (CRC), develop LNM-associated biomarkers for CRC. METHODS: Differences in EGFR and Her2 expression between primary CRC with LNM (LNM CRC) and without LNM (non-LNM CRC) were assessed in a total of 126 Chinese colorectal carcinoma samples using quantitative real-time PCR analysis and western blot. Confirmation  assay with immunohistochemistry (IHC) study was applied in the same samples. The  relationship to clinicopathological parameters and prognosis of candidate biomarkers was also examined in the same samples. RESULTS: EGFR and Her2 were significantly upregulated in LNM CRC compared to non-LNM CRC, which was confirmed by real-time quantitative polymerase chain reaction, western blot. Similar results were confirmed in the immunohistochemistry (IHC) assay. Overexpression of EGFR and Her2 were significantly associated with LNM (P < 0.001), advanced TNM stage (P < 0.001), increased 5-year recurrence rate (P < 0.001) and decreased 5-year overall survival rate (P < 0.001). Univariate and multivariate analyses indicated that EGFR and Her2 expression were useful independent prognostic factor for recurrence and survival of CRC patients (P < 0.05). CONCLUSIONS: EGFR and Her2 might serve as a potential biomarker for LNM and a prognostic factor in CRC. Over-expression of EGFR or Her2 is a potential predict factor to the poor outcome in clinical colorectal cancer.

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[1025]

TÍTULO / TITLE:  - Heterogeneity of the EGFR mutation status between the primary tumor and metastatic lymph node and the sensitivity to EGFR tyrosine kinase inhibitor in non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Target Oncol. 2012 Dec 5.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11523-012-0241-x

AUTORES / AUTHORS:  - Shimizu K; Yukawa T; Hirami Y; Okita R; Saisho S; Maeda A; Yasuda K; Nakata M

INSTITUCIÓN / INSTITUTION:  - Department of General Thoracic Surgery, Kawasaki Medical School, 577 Matsushima,  Kurashiki, Okayama, 701-0192, Japan, kshimizu@med.kawasaki-m.ac.jp.

RESUMEN / SUMMARY:  - The purpose of this study was to clarify the distribution of epidermal growth factor receptor (EGFR) mutations between primary tumors (PT) and metastatic lymph node (MLN) in patients with resected non-small cell lung cancer (NSCLC) and to identify a better predictive marker of the response to EGFR tyrosine kinase inhibitor (EGFR-TKI). We conducted a retrospective review of the data of 70 lung  cancer patients with lymph node metastasis who underwent surgical resection. Analysis to detect EGFR mutations was performed by a peptide nucleic acid-locked  nucleic acid polymerase chain reaction clamp method. EGFR mutations were detected in 15.7 % of both the PT and MLN and in 14.3 % of the PT only. The response rate  to EGFR-TKI tended to be higher in patients with EGFR mutations in the MLN, as all patients with EGFR mutations in the MLN showed disease control to treatment with EGFR-TKI. Our results demonstrated that the EGFR mutation status of MLN is a predictive marker of the response to EGFR-TKI therapy in patients with recurrent  NSCLC after surgical resection.

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[1026]

TÍTULO / TITLE:  - Detection of Low-Abundance KRAS Mutations in Colorectal Cancer Using Microfluidic Capillary Electrophoresis-Based Restriction Fragment Length Polymorphism Method with Optimized Assay Conditions.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e54510. doi: 10.1371/journal.pone.0054510. Epub 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0054510

AUTORES / AUTHORS:  - Zhang H; Song J; Ren H; Xu Z; Wang X; Shan L; Fang J

INSTITUCIÓN / INSTITUTION:  - Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China  Medical University, Shenyang, China.

RESUMEN / SUMMARY:  - Constitutively active KRAS mutations have been found to be involved in various processes of cancer development, and render tumor cells resistant to EGFR-targeted therapies. Mutation detection methods with higher sensitivity will  increase the possibility of choosing the correct individual therapy. Here, we established a highly sensitive and efficient microfluidic capillary electrophoresis-based restriction fragment length polymorphism (microCE-based RFLP) platform for low-abundance KRAS genotyping with the combination of microCE  and RFLP techniques. By using our self-built sensitive laser induced fluorescence (LIF) detector and a new DNA intercalating dye YOYO-1, the separation conditions  of microCE for PhiX174 HaeIII DNA marker were first optimized. Then, a Mav I digested 107-bp KRAS gene fragment was directly introduced into the microfluidic  device and analyzed by microCE, in which field amplified sample stacking (FASS) technique was employed to obtain the enrichment of the RFLP digestion products and extremely improved the sensitivity. The accurate analysis of KRAS statuses in HT29, LS174T, CCL187, SW480, Clone A, and CX-1 colorectal cancer (CRC) cell lines by microCE-based RFLP were achieved in 5 min with picoliter-scale sample consumption, and as low as 0.01% of mutant KRAS could be identified from a large  excess of wild-type genomic DNA (gDNA). In 98 paraffin-embedded CRC tissues, KRAS codon 12 mutations were discovered in 28 (28.6%), significantly higher than that  obtained by direct sequencing (13, 13.3%). Clone sequencing confirmed these results and showed this system could detect at least 0.4% of the mutant KRAS in CRC tissue slides. Compared with direct sequencing, the new finding of the microCE-based RFLP platform was that KRAS mutations in codon 12 were correlated with the patient’s age. In conclusion, we established a sensitive, fast, and cost-effective screening method for KRAS mutations, and successfully detected low-abundance KRAS mutations in clinical samples, which will allow provision of more precise individualized cancer therapy.

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[1027]

TÍTULO / TITLE:  - Tumor-associated autoantibodies as diagnostic and prognostic biomarkers.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMB Rep. 2012 Dec;45(12):677-85.

AUTORES / AUTHORS:  - Heo CK; Bahk YY; Cho EW

INSTITUCIÓN / INSTITUTION:  - Cancer Biomarkers Development Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea ewcho@kribb.re.kr.

RESUMEN / SUMMARY:  - In the process of tumorigenesis, normal cells are remodeled to cancer cells and protein expression patterns are changed to those of tumor cells. A newly formed tumor microenvironment elicits the immune system and, as a result, a humoral immune response takes place. Although the tumor antigens are undetectable in sera at the early stage of tumorigenesis, the nature of an antibody amplification response to antigens makes tumor-associated autoantibodies as promising early biomarkers in cancer diagnosis. Moreover, the recent development of proteomic techniques that make neo-epitopes of tumor-associated autoantigens discovered concomitantly has opened a new area of ‘immuno-proteomics’, which presents tumor-associated autoantibody signatures and confers information to redefine the  process of tumorigenesis. In this article, the strategies recently used to identify and validate serum autoantibodies are outlined and tumor-associated antigens suggested until now as diagnostic/prognostic biomarkers in various tumor types are reviewed. Also, the meaning of autoantibody signatures and their clinical utility in personalized medicine are discussed. [BMB Reports 2012; 45(12): 677-685].

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[1028]

TÍTULO / TITLE:  - Prognostic and Predictive Roles of KRAS Mutation in Colorectal Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2012 Sep 25;13(10):12153-68. doi: 10.3390/ijms131012153.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms131012153

AUTORES / AUTHORS:  - Arrington AK; Heinrich EL; Lee W; Duldulao M; Patel S; Sanchez J; Garcia-Aguilar J; Kim J

INSTITUCIÓN / INSTITUTION:  - Division of Surgical Oncology, City of Hope Comprehensive Cancer Center, Duarte,  CA 91010, USA. aarrington@coh.org.

RESUMEN / SUMMARY:  - The RAS gene family is among the most studied and best characterized of the known cancer-related genes. Of the three human ras isoforms, KRAS is the most frequently altered gene, with mutations occurring in 17%-25% of all cancers. In particular, approximately 30%-40% of colon cancers harbor a KRAS mutation. KRAS mutations in colon cancers have been associated with poorer survival and increased tumor aggressiveness. Additionally, KRAS mutations in colorectal cancer lead to resistance to select treatment strategies. In this review we examine the  history of KRAS, its prognostic value in patients with colorectal cancer, and evidence supporting its predictive value in determining appropriate therapies for patients with colorectal cancer.

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[1029]

TÍTULO / TITLE:  - Individualized chemotherapy for colorectal cancer based on the collagen gel droplet-embedded drug sensitivity test.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2012 Oct;4(4):621-624. Epub 2012 Jul 25.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.823

AUTORES / AUTHORS:  - Ochiai T; Nishimura K; Watanabe T; Kitajima M; Nakatani A; Inou T; Washio M; Sakuyama N; Sato T; Kishine K; Ochi T; Okubo S; Futagawa S; Mashiko S; Nagaoka I

INSTITUCIÓN / INSTITUTION:  - Departments of Surgery and.

RESUMEN / SUMMARY:  - The leucovorin (FOL) and fluorouracil (5-FU) plus oxaliplatin (l-OHP; FOLFOX) or  FOL and 5-FU plus irinotecan (SN-38; FOLFIRI) regimens with or without molecularly-targeted drugs are widely used as first-line chemotherapy in the treatment of advanced colorectal cancer (CRC). Whether FOLFOX or FOLFIRI is administered first is not significant, however, it is essential that full administration of the targeted dosages of all 3 drugs, 5-FU, l-OHP and SN-38, is  achieved. However, this is not always possible and second-line chemotherapy must  be abandoned in certain cases. Where possible, the most effective regimen should  be selected as the first line of treatment. The aim of this study was to determine whether first-line chemotherapy may be individualized using the collagen gel droplet-embedded drug sensitivity test (CD-DST). Specimens of primary tumors were obtained from 43 CRC patients who had received no preoperative chemotherapy. Informed consent to measure drug sensitivity was obtained from all patients. The CD-DST allows evaluation of drug sensitivity using isolated, 3-dimensionally cultured tumor cells in a small collagen gel droplet. The CD-DST was performed and the growth inhibition rate (IR) was obtained under incubation conditions (5-FU with l-OHP at 6.0 and 3.0 mug/ml, or 5-FU with SN-38 at 6.0 and 0.2 mug/ml, respectively, for 24 h). The cumulative distributions of the growth IRs under each condition were evaluated based on the  evidence that the clinical response rates to FOLFOX and FOLFIRI were almost the same. Individualization of first-line treatment was possible in all patients, with FOLFOX and FOLFIRI showing higher efficacy in 26 and 15 patients, respectively, and equal efficacy in 2 cases. This method has the potential to facilitate the establishment of individualized first-line chemotherapy for CRC and improve the prognosis in such patients.

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[1030]

TÍTULO / TITLE:  - Extended adjuvant temozolomide with cis-retinoic acid for adult glioblastoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Oncol. 2012 Dec;19(6):308-14. doi: 10.3747/co.19.1151.

            ●● Enlace al texto completo (gratuito o de pago) 3747/co.19.1151

AUTORES / AUTHORS:  - Pitz MW; Lipson M; Hosseini B; Lambert P; Guilbert K; Lister D; Schroeder G; Jones K; Mihalicioiu C; Eisenstat DD

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, University of Manitoba, Winnipeg, MB. ; Department of Haematology/Medical Oncology, CancerCare Manitoba, Winnipeg, MB.

RESUMEN / SUMMARY:  - OBJECTIVE: To determine the toxicity and effectiveness of 24 months of adjuvant temozolomide (tmz) with cis-retinoic acid (cra) for patients with glioblastoma. METHODS: This retrospective population-based review considered the charts of all  patients diagnosed with glioblastoma in Manitoba and referred to a provincial cancer centre during 2002-2008. Consecutive patients came from a population-based referral centre and provincial cancer registry. All patients were treated according to the local standard of care with surgical resection followed by concurrent radiotherapy and tmz 75 mg/m(2) daily, followed by tmz 150-200 mg/m(2) for days 1-5, repeated every 28 days for up to 24 cycles, and cra 50 mg/m(2) twice daily for days 1-21, repeated every 28 days. The main outcome measures were safety, tolerability, and effectiveness of long-term tmz and cra. RESULTS: Of 247 patients diagnosed with glioblastoma in Manitoba during the study period, 116 started concurrent chemoradiotherapy, and 80 received adjuvant tmz. Of the patients who started concurrent chemoradiotherapy, 80 began adjuvant chemotherapy. Patients completed a median of 5.5 cycles of tmz and 3 cycles of cra. Grade 3 or 4 hematologic toxicity was noted in 16% of patients. Median overall survival was 15.1 months, and 26.7% of patients remained alive at 2 years. CONCLUSIONS: Extended adjuvant tmz and cra is well tolerated. However, the population-based effectiveness of this regimen is similar to the clinical trial efficacy of 6 months of adjuvant tmz. Future studies in glioblastoma should incorporate duration of adjuvant chemotherapy into the study design.

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[1031]

TÍTULO / TITLE:  - Finding a new prognostic biomarker for metastatic colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Korean Soc Coloproctol. 2012 Dec;28(6):284-5. doi: 10.3393/jksc.2012.28.6.284.  Epub 2012 Dec 31.

            ●● Enlace al texto completo (gratuito o de pago) 3393/jksc.2012.28.6.284

AUTORES / AUTHORS:  - Kim H

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.

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[1032]

TÍTULO / TITLE:  - Genome-Wide Analysis of miRNA Signature Differentially Expressed in Doxorubicin-Resistant and Parental Human Hepatocellular Carcinoma Cell Lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e54111. doi: 10.1371/journal.pone.0054111. Epub 2013 Jan 24.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0054111

AUTORES / AUTHORS:  - Zhang J; Wang Y; Zhen P; Luo X; Zhang C; Zhou L; Lu Y; Yang Y; Zhang W; Wan J

INSTITUCIÓN / INSTITUTION:  - Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Shenzhen, China ; School of Life Science, Guangdong Pharmaceutical University, Guangzhou, China.

RESUMEN / SUMMARY:  - Chemotherapy regiments have been widely used in the treatment of a variety of human malignancies including hepatocellular carcinoma (HCC). A major cause of failure in chemotherapy is drug resistance of cancer cells. Resistance to doxorubicin (DOX) is a common and representative obstacle to treat cancer effectively. Individual microRNA (miRNA) has been introduced in the evolution of  DOX resistance in HCC in recent studies. However, a global and systematic assessment of the miRNA expression profiles contributing to DOX resistance is still lacking. In the present study, we applied high-throughput Illumina sequencing to comprehensively characterize miRNA expression profiles in both human HCC cell line (HepG2) and its DOX-resistant counterpart (HepG2/DOX). A total of 269 known miRNAs were significantly differentially expressed, of which 23 were up-regulated and 246 were down-regulated in HepG2/DOX cells, indicating that part of them might be involved in the development of DOX resistance. In addition, we have identified 9 and 13 novel miRNAs up- and down-expressed significantly in HepG2/DOX cells, respectively. miRNA profiling was then validated by quantitative real-time PCR for selected miRNAs, including 22 known miRNAs and 6 novel miRNAs. Furthermore, we predicted the putative target genes for the deregulated miRNAs in the samples. Function annotation implied that these selected miRNAs affected many target genes mainly involved in MAPK signaling pathway. This study provides us a general description of miRNA expression profiling, which is helpful to find potential miRNAs for adjunct treatment to overcome DOX resistance in future HCC chemotherapy.

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[1033]

TÍTULO / TITLE:  - Combination of a Proteomics Approach and Reengineering of Meso Scale Network Models for Prediction of Mode-of-Action for Tyrosine Kinase Inhibitors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e53668. doi: 10.1371/journal.pone.0053668. Epub 2013 Jan 9.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0053668

AUTORES / AUTHORS:  - Balabanov S; Wilhelm T; Venz S; Keller G; Scharf C; Pospisil H; Braig M; Barett C; Bokemeyer C; Walther R; Brummendorf TH; Schuppert A

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Haematology and Bone Marrow Transplantation with Section  Pneumology, Hubertus Wald-Tumor Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany ; Division of Hematology, University Hospital Zurich, Zurich, Switzerland.

RESUMEN / SUMMARY:  - In drug discovery, the characterisation of the precise modes of action (MoA) and  of unwanted off-target effects of novel molecularly targeted compounds is of highest relevance. Recent approaches for identification of MoA have employed various techniques for modeling of well defined signaling pathways including structural information, changes in phenotypic behavior of cells and gene expression patterns after drug treatment. However, efficient approaches focusing  on proteome wide data for the identification of MoA including interference with mutations are underrepresented. As mutations are key drivers of drug resistance in molecularly targeted tumor therapies, efficient analysis and modeling of downstream effects of mutations on drug MoA is a key to efficient development of  improved targeted anti-cancer drugs. Here we present a combination of a global proteome analysis, reengineering of network models and integration of apoptosis data used to infer the mode-of-action of various tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) cell lines expressing wild type as well  as TKI resistance conferring mutants of BCR-ABL. The inferred network models provide a tool to predict the main MoA of drugs as well as to grouping of drugs with known similar kinase inhibitory activity patterns in comparison to drugs with an additional MoA. We believe that our direct network reconstruction approach, demonstrated on proteomics data, can provide a complementary method to  the established network reconstruction approaches for the preclinical modeling of the MoA of various types of targeted drugs in cancer treatment. Hence it may contribute to the more precise prediction of clinically relevant on- and off-target effects of TKIs.

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[1034]

TÍTULO / TITLE:  - Functional DNA repair signature of cancer cell lines exposed to a set of cytotoxic anticancer drugs using a multiplexed enzymatic repair assay on biochip.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51754. doi: 10.1371/journal.pone.0051754. Epub 2012 Dec 31.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051754

AUTORES / AUTHORS:  - Forestier A; Sarrazy F; Caillat S; Vandenbrouck Y; Sauvaigo S

INSTITUCIÓN / INSTITUTION:  - Laboratoire Lesions des Acides Nucleiques, CEA, DSM, INAC, SCIB, UMR-E3 CEA/UJF-Grenoble 1, Grenoble, France.

RESUMEN / SUMMARY:  - The development of resistances to conventional anticancer drugs compromises the efficacy of cancer treatments. In the case of DNA-targeting chemotherapeutic agents, cancer cells may display tolerance to the drug-induced DNA lesions and/or enhanced DNA repair. However, the role of DNA damage response (DDR) and DNA repair in this chemoresistance has yet to be defined. To provide insights in this challenging area, we analyzed the DNA repair signature of 7 cancer cell lines treated by 5 cytotoxic drugs using a recently developed multiplexed functional DNA repair assay. This comprehensive approach considered the complexity and redundancy of the different DNA repair pathways. Data was analyzed using clustering methods and statistical tests. This DNA repair profiling method defined relevant groups based on similarities between different drugs, thus providing information relating to their dominant mechanism of action at the DNA level. Similarly, similarities between different cell lines presumably identified identical functional DDR despite a high level of genetic heterogeneity between cell lines. Our strategy has shed new light on the contribution of specific repair sub-pathways to drug-induced cytotoxicity. Although further molecular characterisations are needed to fully unravel the mechanisms underlying our findings, our approach proved to be very promising to interrogate the complexity  of the DNA repair response. Indeed, it could be used to predict the efficacy of a given drug and the chemosensitivity of individual patients, and thus to choose the right treatment for individualised cancer care.

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[1035]

TÍTULO / TITLE:  - Circulating IL-6, IL-17 and vitamin D in hepatocellular carcinoma: Potential biomarkers for a more favorable prognosis?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Immunotoxicol. 2013 Jan 25.

            ●● Enlace al texto completo (gratuito o de pago) 3109/1547691X.2012.758198

AUTORES / AUTHORS:  - Hammad LN; Abdelraouf SM; Hassanein FS; Mohamed WA; Schaalan MF

INSTITUCIÓN / INSTITUTION:  - Biochemistry Department .

RESUMEN / SUMMARY:  - Abstract Hepatitis C virus (HCV) infects primarily hepatocytes, leads to development of fibrosis and/or cirrhosis of the liver and is a significant factor for developing hepatocellular carcinoma (HCC). Evidence indicates that liver fibrosis contains uncontrolled inflammation as a part of its etiology. Normal cell-mediated immunity plays a central role in the mechanisms involved in viral clearance/persistence in the liver. In this context, cytokines modulate the immune system and exert direct anti-viral activity. To this end, this study investigated potential associations of serum IL-17 and IL-6 with exacerbation of  hepatic damage in chronic HCV patients to determine their utility as prognostic markers for potential development of HCC. Chronic HCV-patients were recruited, divided into groups according to degree of liver damage, i.e. patients with peri-hepatic fibrosis, hepatic cirrhosis, or HCC, and had their blood collected for analysis of liver function and serum IL-6 and IL-17 levels. Interestingly, increases in serum IL-17 levels in the study groups were associated with aggravation of the clinical state from HCV to cirrhosis and then to HCC. Serum IL-6 levels followed a similar pattern. The association of both cytokines with progressive exacerbation of the initial HCV-induced liver damage was further confirmed by correlation analysis that revealed positive correlations between HCV RNA titer and IL-17 (+0.951, p < 0.05) and IL-6 (+0.85, p < 0.05). A receiver operating characteristics (ROC) analysis revealed their beneficial addition as promising biomarkers for a better prognostic profile of HCC. Interestingly, a significant progressive decline in the active vitamin D status was noted in all three clinical states, and these too were associated with progressive liver disease. This study confirms the necessity of adding screening for IL-6 and IL-17 and vitamin D to that of the classic marker AFP for patients with HCV and cirrhosis to hopefully permit clinicians to initiate measures that ultimately might mitigate/delay development of HCC in these infected patients.

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[1036]

TÍTULO / TITLE:  - MicroRNAs at the human 14q32 locus have prognostic significance in osteosarcoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Orphanet J Rare Dis. 2013 Jan 11;8(1):7.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1750-1172-8-7

AUTORES / AUTHORS:  - Sarver AL; Thayanithy V; Scott MC; Cleton-Jansen AM; Hogendoorn PC; Modiano JF; Subramanian S

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Deregulation of microRNA (miRNA) transcript levels has been observed in many types of tumors including osteosarcoma. Molecular pathways regulated by differentially expressed miRNAs may contribute to the heterogeneous  tumor behaviors observed in naturally occurring cancers. Thus, tumor-associated miRNA expression may provide informative biomarkers for disease outcome and metastatic potential in osteosarcoma patients. We showed previously that clusters of miRNAs at the 14q32 locus are downregulated in human osteosarcoma. METHODS: Human and canine osteosarcoma patient’s samples with clinical follow-up data were used in this study. We used bioinformatics and comparative genomics approaches to identify miRNA based prognostic biomarkers in osteosarcoma. Kaplan-Meier survival curves and Whitney Mann U tests were conducted for validating the statistical significance. RESULTS: Here we show that an inverse correlation exists between aggressive tumor behavior (increased metastatic potential and accelerated time to death) and the residual expression of 14q32 miRNAs (using miR-382 as a representative of 14q32 miRNAs) in a series of clinically annotated samples from  human osteosarcoma patients. We also show a comparable decrease in expression of  orthologous 14q32 miRNAs in canine osteosarcoma samples, with conservation of the inverse correlation between aggressive behavior and expression of orthologous miRNA miR-134 and miR-544. CONCLUSIONS: We conclude that downregulation of 14q32  miRNA expression is an evolutionarily conserved mechanism that contributes to the biological behavior of osteosarcoma, and that quantification of representative transcripts from this family, such as miR-382, miR-134, and miR-544, provide prognostic and predictive markers that can assist in the management of patients with this disease.

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[1037]

TÍTULO / TITLE:  - Brain Metastases from Renal Cell Carcinoma in the Era of Tyrosine Kinase Inhibitors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Genitourin Cancer. 2012 Dec 19. pii: S1558-7673(12)00233-9. doi: 10.1016/j.clgc.2012.11.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clgc.2012.11.001

AUTORES / AUTHORS:  - Dudek AZ; Raza A; Chi M; Singhal M; Oberoi R; Mittapalli RK; Agarwal S; Elmquist WF

INSTITUCIÓN / INSTITUTION:  - Masonic Cancer Center, University of Minnesota, Minneapolis, MN. Electronic address: dudek002@umn.edu.

RESUMEN / SUMMARY:  - BACKGROUND: The effectiveness of tyrosine kinase inhibitors (TKI) in preventing brain metastases in patients with renal cell carcinoma is unclear. METHODS: Preclinical studies were conducted to determine the steady-state brain and plasma concentrations of sorafenib and sunitinib in mice deficient in the drug efflux transporters; p-glycoprotein, and breast cancer resistance protein. A single-institution retrospective analysis of patients treated from 2008 to 2010 was conducted to assess the incidence of brain metastases before and during TKI treatment. RESULTS: Transport of sorafenib and sunitinib across the blood-brain barrier was restricted. Retrospective analysis revealed that the median time to develop metastatic brain disease was 28 months (range, 1-108 months) while on TKI therapy and 11.5 months (range, 0-64 months) in patients who did not receive TKI  therapy. The incidence of brain metastases per month in patients not treated with TKI therapy was 1.6 higher than the incidence in patients treated with TKI therapy. CONCLUSIONS: Penetration of sorafenib or sunitinib through an intact blood-brain barrier to brain tissue is limited; however, the incidence of brain metastases per unit time is decreased in patients on TKI therapy in comparison with the “cytokine” era.

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[1038]

TÍTULO / TITLE:  - Prediction of response to anti-EGFR antibodies in metastatic colorectal cancer: looking beyond EGFR inhibition.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Front Immunol. 2012;3:409. doi: 10.3389/fimmu.2012.00409. Epub 2013 Jan 7.

            ●● Enlace al texto completo (gratuito o de pago) 3389/fimmu.2012.00409

AUTORES / AUTHORS:  - Ottaiano A; Capuozzo M; Nasti G; Maiolino P; De Angelis V; Scala S; Iaffaioli RV

INSTITUCIÓN / INSTITUTION:  - Department of Colorectal Oncology at the National Cancer Institute, “G. Pascale”  foundation, via M. Semmola Naples, Italy.

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[1039]

TÍTULO / TITLE:  - Target-specific delivery of doxorubicin to retinoblastoma using epithelial cell adhesion molecule aptamer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Vis. 2012;18:2783-95. Epub 2012 Nov 22.

AUTORES / AUTHORS:  - Subramanian N; Raghunathan V; Kanwar JR; Kanwar RK; Elchuri SV; Khetan V; Krishnakumar S

INSTITUCIÓN / INSTITUTION:  - Larsen & Toubro Department of Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, India.

RESUMEN / SUMMARY:  - PURPOSE: To study target-specific delivery of doxorubicin (Dox) using an RNA aptamer against epithelial cell adhesion molecule (EpCAM) in retinoblastoma (RB)  cells. METHODS: The binding affinity of the EpCAM aptamer to RB primary tumor cells, Y79 and WERI-Rb1 cells, and Muller glial cell lines were evaluated with flow cytometry. Formation of physical conjugates of aptamer and Dox was monitored with spectrofluorimetry. Cellular uptake of aptamer-Dox conjugates was monitored  through fluorescent microscopy. Drug efficacy was monitored with cell proliferation assay. RESULTS: The EpCAM aptamer (EpDT3) but not the scrambled aptamer (Scr-EpDT3) bound to RB tumor cells, the Y79 and WERI-Rb1 cells. However, the EpCAM aptamer and the scrambled aptamer did not bind to the noncancerous Muller glial cells. The chimeric EpCAM aptamer Dox conjugate (EpDT3-Dox) and the  scrambled aptamer Dox conjugate (Scr-EpDT3-Dox) were synthesized and tested on the Y79, WERI-Rb1, and Muller glial cells. The targeted uptake of the EpDT3-Dox aptamer caused cytotoxicity in the Y79 and WERI-Rb1 cells but not in the Muller glial cells. There was no significant binding or consequent cytotoxicity by the Scr-EpDT3-Dox in either cell line. The EpCAM aptamer alone did not cause cytotoxicity in either cell line. CONCLUSIONS: The results show that the EpCAM aptamer-Dox conjugate can selectively deliver the drug to the RB cells there by inhibiting cellular proliferation and not to the noncancerous Muller glial cells. As EpCAM is a cancer stem cell marker, this aptamer-based targeted drug delivery  will prevent the undesired effects of non-specific drug activity and will kill cancer stem cells precisely in RB.

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[1040]

TÍTULO / TITLE:  - Overexpression of GPC3 inhibits hepatocellular carcinoma cell proliferation and invasion through induction of apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Med Report. 2013 Jan 18. doi: 10.3892/mmr.2013.1279.

            ●● Enlace al texto completo (gratuito o de pago) 3892/mmr.2013.1279

AUTORES / AUTHORS:  - Pan Z; Chen C; Long H; Lei C; Tang G; Li L; Feng J; Chen F

INSTITUCIÓN / INSTITUTION:  - Second Department of General Surgery, Fifth Hospital of Wuhan, Hubei 430050, P.R. China.

RESUMEN / SUMMARY:  - Glypican3 (GPC3) is a membrane heparan sulfate proteoglycan involved in cell proliferation, differentiation, adhesion, migration and the development of the majority of mesodermal tissues and organs. GPC3 has been found to be important for the occurrence and development of hepatocellular carcinoma (HCC). Therefore,  it may be suitable for use as a novel molecular marker for the diagnosis of primary liver cancer. In the present study, the role of GPC3 in the occurrence and development of HCC was determined. GPC3 recombinant vector was transfected into two HCC cell lines, Huh7 and SKHEP1, to upregulate the expression of GPC3 and examine changes in the biological behavior of the cells. Results indicate that overexpression of GPC3 in Huh7 and SKHEP1 cells effectively inhibited cell proliferation and cell invasion through induction of apoptosis. However, cotreatment of the cells with insulinlike growth factor 2 (IGF2) and fibroblast growth factor 2 (FGF2) was found by Annexin VPI flow cytometric analysis to significantly inhibit the apoptotic cell death induced by GPC3 overexpression. These observations indicate that GPC3 may act as a negative regulator of IGF2 and FGF2 pathways. Taken together, these results demonstrate that overexpression of GPC3 inhibits the occurrence and development of HCC.

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[1041]

TÍTULO / TITLE:  - PROGmiR: a tool for identifying prognostic miRNA biomarkers in multiple cancers using publicly available data.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Bioinforma. 2012 Dec 28;2(1):23.

            ●● Enlace al texto completo (gratuito o de pago) 1186/2043-9113-2-23

AUTORES / AUTHORS:  - Goswami CP; Nakshatri H

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Identification of prognostic biomarkers is hallmark of cancer genomics. Since miRNAs regulate the expression of multiple genes, they act as potent biomarkers in several cancers. Identification of miRNAs that are prognostically important has been done sporadically, but no resource is available till date that allows users to study prognostics of miRNAs of interest, utilizing the wealth of available data, in major cancer types.Description: In this paper, we present a web based tool that allows users to study prognostic properties of miRNAs in a several cancer types, using publicly available data. We have compiled data from Gene Expression Omnibus (GEO), and recently developed “The Cancer Genome Atlas (TCGA)”, to create this tool. The tool is called “PROGmiR” and it is available at www.compbio.iupui.edu/progmir. Currently, our tool can be used to study overall survival implications for approximately 1050 human miRNAs in 16 major cancer types. CONCLUSIONS: We believe this resource, as a hypothesis generation tool, will be helpful for researchers to link miRNA expression with cancer outcome and to design mechanistic studies. We studied performance of our tool using identified miRNA biomarkers from published studies. The prognostic plots created using our tool for specific miRNAs in specific cancer types corroborated with the findings in the studies.

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[1042]

TÍTULO / TITLE:  - Notch3 and HEY-1 as prognostic biomarkers in pancreatic adenocarcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51119. doi: 10.1371/journal.pone.0051119. Epub 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051119

AUTORES / AUTHORS:  - Mann CD; Bastianpillai C; Neal CP; Masood MM; Jones DJ; Teichert F; Singh R; Karpova E; Berry DP; Manson MM

INSTITUCIÓN / INSTITUTION:  - Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, Leicestershire, United Kingdom.

RESUMEN / SUMMARY:  - In order to achieve a better outcome for pancreatic cancer patients, reliable biomarkers are required which allow for improved diagnosis. These may emanate from a more detailed molecular understanding of the aggressive nature of this disease. Having previously reported that Notch3 activation appeared to be associated with more aggressive disease, we have now examined components of this  pathway (Notch1, Notch3, Notch4, HES-1, HEY-1) in more detail in resectable (n =  42) and non-resectable (n = 50) tumours compared to uninvolved pancreas. All three Notch family members were significantly elevated in tumour tissue, compared to uninvolved pancreas, with expression maintained within matched lymph node metastases. Furthermore, significantly higher nuclear expression of Notch1, -3 and -4, HES-1, and HEY-1 (all p </= 0.001) was noted in locally advanced and metastatic tumours compared to resectable cancers. In survival analyses, nuclear  Notch3 and HEY-1 expression were significantly associated with reduced overall and disease-free survival following tumour resection with curative intent, with nuclear HEY-1 maintaining independent prognostic significance for both outcomes on multivariate analysis. These data further support a central role for Notch signalling in pancreatic cancer and suggest that nuclear expression of Notch3 and its target gene, HEY-1, merit validation in biomarker panels for diagnosis, prognosis and treatment efficacy. A peptide fragment of Notch3 was detected in plasma from patients with inoperable pancreatic cancer, but due to wide inter-individual variation, mean levels were not significantly different compared to age-matched controls.

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[1043]

TÍTULO / TITLE:  - Oxidative stress and redox state-regulating enzymes have prognostic relevance in  diffuse large B-cell lymphoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Exp Hematol. Acceso gratuito al texto completo.

            ●● Enlace a la Editora de la Revista http://www.medicinedirect.com/journal 

            ●● Cita: Experimental Hematology: <> Oncol. 2012 Mar 26;1(1):2. doi: 10.1186/2162-3619-1-2.

            ●● Enlace al texto completo (gratuito o de pago) 1186/2162-3619-1-2

AUTORES / AUTHORS:  - Peroja P; Pasanen AK; Haapasaari KM; Jantunen E; Soini Y; Turpeenniemi-Hujanen T; Bloigu R; Lilja L; Kuittinen O; Karihtala P

INSTITUCIÓN / INSTITUTION:  - Department of Oncology and Radiotherapy, University of Oulu and Oulu University Hospital, Oulu, Finland. peeter.karihtala@oulu.fi.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Oxidative stress and redox-regulating enzymes may have roles both in lymphomagenesis and resistance to lymphoma therapy. Previous studies from the pre-rituximab era suggest that antioxidant enzyme expression is  related to prognosis in diffuse large B-cell lymphoma (DLBCL), although these results cannot be extrapolated to patient populations undergoing modern treatment modalities. In this study we assessed expression of the oxidative stress markers  8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine and the antioxidant enzymes thioredoxin (Trx), manganese superoxide dismutase (MnSOD) and glutamate-cysteine  ligase (GCL) via immunohistochemistry in 106 patients with DLBCL. All patients were treated with CHOP-like therapy combined with rituximab. Immunostaining results were correlated with progression-free survival, disease-specific survival and traditional prognostic factors of DLBCL. RESULTS: Strong 8-OHdG immunostaining intensity was associated with extranodal involvement (p = 0.00002), a high International Prognostic Index (p = 0.002) and strong Trx (p = 0.011) and GCL (p = 0.0003) expression. Strong Trx staining intensity was associated with poor progression-free survival (p = 0.046) and poor disease-specific survival (p = 0.015). Strong GCL immunostaining intensity predicted poor progression-free survival (p = 0.049). Patients with either strong Trx or strong nitrotyrosine expression showed significantly poorer progression-free survival (p = 0.003) and disease-specific survival (p = 0.031) compared with the other patients. CONCLUSIONS: The redox state-regulating enzymes GCL and Trx are promising markers in the evaluation of DLBCL prognosis in the era of modern immunochemotherapy.

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[1044]

TÍTULO / TITLE:  - Over-Expression of Semaphorin4D, Hypoxia-Inducible Factor-1&alpha; and Vascular Endothelial Growth Factor Is Related to Poor Prognosis in Ovarian Epithelial Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2012 Oct 16;13(10):13264-74. doi: 10.3390/ijms131013264.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms131013264

AUTORES / AUTHORS:  - Chen Y; Zhang L; Pan Y; Ren X; Hao Q

INSTITUCIÓN / INSTITUTION:  - Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. renxiubao@hotmail.com.

RESUMEN / SUMMARY:  - Semaphorin4D (SEMA4D) has been regarded as an important protein in tumor angiogenesis, though originally identified in neurodevelopment. SEMA4D is extensively expressed in several malignant solid tumors. Nevertheless, the function and expression of SEMA4D in epithelial ovarian cancer (EOC) is as yet not well understood. The aim of this study was to investigate SEMA4D expression in EOC and evaluate its clinical&ndash;pathological and prognostic significance.  Immunohistochemistry was used to analyze SEMA4D expression and tumor angiogenesis-related proteins (HIF-1&alpha; and VEGF) in tissues from 40 patients with normal ovarian epithelia and 124 EOC patients. SEMA4D was found to be expressed in 61.3% of the 124 EOC tissues, which was significantly higher than in the normal ovarian epithelia (p &lt; 0.001). SEMA4D expression correlated with HIF-1&alpha; and VEGF closely (&rho; = 0.349 and 0.263, p &lt; 0.001). Positive SEMA4D staining was significantly higher in tissues from patients with low histological grade, FIGO stage III-IV, lymph node metastasis and residual disease &ge;1 cm (p &lt; 0.05). In the Cox proportional hazard mode, SEMA4D expression and histologic grade were independent indicators of overall survival (OS) and progress-free survival (PFS) for EOC patients. These findings suggest that the cooperation of SEMA4D, HIF-1&alpha;, and VEGF may indicate poor prognosis for patients with EOC, thereby demonstrating that SEMA4D and its role in angiogenesis in EOC warrants further study.

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[1045]

TÍTULO / TITLE:  - Synergistic Role between p53 and JWA: Prognostic and Predictive Biomarkers in Gastric Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e52348. doi: 10.1371/journal.pone.0052348. Epub 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052348

AUTORES / AUTHORS:  - Liu X; Wang S; Xia X; Chen Y; Zhou Y; Wu X; Zhang J; He S; Tan Y; Qiang F; Roe OD; Li G; Zhou J

INSTITUCIÓN / INSTITUTION:  - Department of Molecular Cell Biology and Toxicology, Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China.

RESUMEN / SUMMARY:  - Expression of p53 appears to be correlated to prognosis in patients with malignancy, but its role in gastric carcinoma has remained controversial. Recently we reported that JWA, an ADP-ribosylation-like factor 6 interacting protein 5 (ARL6ip5), was both prognostic for overall survival and predictive for  platinum-based treatment of gastric cancer. In this study, we aimed to investigate p53 expression as a prognostic and predictive marker in resectable gastric cancer, alone and in combination with JWA. Expression of p53 was examined in three large patient cohorts (total n = 1155) of gastric cancer. High expression of p53 was significantly correlated with unfavorable clinicopathologic parameters and decreased overall patient survival. Furthermore, patients with high p53 expression in tumors acquired remarkable survival benefit from adjuvant  first-line platinum-based-chemotherapy. The synergy between p53 and JWA in predicting patient outcome was demonstrated, while no significantly elevated predictive value concerning chemotherapy was observed. Thus, p53 expression is a  potent prognostic and predictive factor for resectable gastric cancer with adjuvant platinum-based chemotherapy. A combined effect of p53 with JWA as efficient prognostic indicators was found for the first time.

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[1046]

TÍTULO / TITLE:  - Centrosome amplification in bladder washing cytology specimens is a useful prognostic biomarker for non-muscle invasive bladder cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Genet. 2013 Jan 2. pii: S2210-7762(12)00275-X. doi: 10.1016/j.cancergen.2012.11.004.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.cancergen.2012.11.004

AUTORES / AUTHORS:  - Miyachika Y; Yamamoto Y; Matsumoto H; Nishijima J; Kawai Y; Nagao K; Hara T; Sakano S; Matsuyama H

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan.

RESUMEN / SUMMARY:  - We investigated whether centrosome amplification (CA) obtained from bladder washing cytology (BWC) specimens may be a useful prognostic biomarker for patients with non-muscle invasive bladder cancer (NMIBC). The study cohort included 78 patients with pathologically confirmed NMIBC. BWC specimens were obtained from all patients during transurethral resection of bladder tumor (TURBT), and CA was evaluated by immunofluorescence staining using a pericentrin  polyclonal antibody. A positive case of CA was defined as a specimen in which >5% of cells contained >/=3 centrosomes per cell. CA was detected in 26.9% (21 of 78) of BWC specimens obtained from NMIBC patients. Disease progression was observed in 11.5% (9 of 78) of patients, with a median follow-up of 32 months. In univariate analyses, CA obtained from BWC specimens, initial or recurrent, and washing cytology were significantly associated with progression-free survival (P  = 0.009, 0.02, and 0.03, respectively). Multivariate Cox model analyses revealed  that CA was the most significant prognostic factor for disease progression (hazard ratio: 2.22, 95% confidence interval: 1.13-4.90, P = 0.022). These data suggest that analysis of CA using bladder washing cytological specimens may provide crucial predictive information regarding disease progression in NMIBC.

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[1047]

TÍTULO / TITLE:  - Nectin-2 and DDX3 are biomarkers for metastasis and poor prognosis of squamous cell/adenosquamous carcinomas and adenocarcinoma of gallbladder.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Clin Exp Pathol. 2013;6(2):179-90. Epub 2013 Jan 15.

AUTORES / AUTHORS:  - Miao X; Yang ZL; Xiong L; Zou Q; Yuan Y; Li J; Liang L; Chen M; Chen S

INSTITUCIÓN / INSTITUTION:  - Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University Changsha, Hunan 410011, PR China.

RESUMEN / SUMMARY:  - The clinicopathological and biological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) of gallbladder have not been well documented because it is a rare subtype of gallbladder cancer. In this study, the protein expression of Nectin-2 and DDX3 in 46 SC/ASCs and 80 adenocarcinomas was  measured using immunohistochemistry. We demonstrated that positive Nectin-2 and DDX3 expression was significantly associated with large tumor size, high TNM stage, and lymph node metastasis of SC/ASC and AC. Positive Nectin-2 and DDX3 expression was significantly associated with invasion and surgical curability of  AC. Univariate Kaplan-Meier analysis showed that positive Nectin-2 and DDX3 expression, degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and surgical curability were significantly associated with post-operative survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive Nectin-2 and DDX3 expression, degree of  differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and no surgical curability are independent poor-prognostic factors in both SC/ASC and AC patients. Our study suggested that positive Nectin-2 and DDx3 expression is closely correlated with clinical, pathological, and biological behaviors as well  as poor-prognosis of gallbladder cancer.

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[1048]

TÍTULO / TITLE:  - A “Game of Thrones” in Metastatic Renal Cell Carcinoma: Vascular Endothelial Growth Factor-Tyrosine Kinase Inhibitors and Mammalian Target of Rapamycin Inhibitors Battling for Position.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Genitourin Cancer. 2012 Dec 28. pii: S1558-7673(12)00239-X. doi: 10.1016/j.clgc.2012.11.006.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clgc.2012.11.006

AUTORES / AUTHORS:  - Pal SK; Vogelzang NJ

INSTITUCIÓN / INSTITUTION:  - Division of Genitourinary Malignancies, Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA.  Electronic address: spal@coh.org.

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[1049]

TÍTULO / TITLE:  - Cationic liposomes as non-viral vector for RNA delivery in cancer immunotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Recent Pat Drug Deliv Formul. 2012 Dec 31.

AUTORES / AUTHORS:  - Vitor MT; Bergami-Santos PC; Barbuto JA; De La Torre LG

INSTITUCIÓN / INSTITUTION:  - School of Chemical Engineering, Department of Materials and Bioprocess Engineering, University of Campinas (Unicamp) Current address: Av. Albert Einstein, 500, Campinas, SP, 13083-852, Brazil. latorre@feq.unicamp.br.

RESUMEN / SUMMARY:  - This review presents the current status in the use of liposomes as non-viral vector for nucleic acid delivery in cancer immunotherapy. Currently, cancer treatment uses surgery, radiotherapy and/or chemotherapy. The search for new strategies to improve the efficiency of conventional treatments is a challenge, and biological therapy has emerged as a promising technique. Immunotherapy is a branch of biological therapy that uses the body’s immune system to detect and destroy cancer cells. One immunotherapy approach is the activation of T lymphocytes from cancer patients by dendritic cells (DCs) loaded with tumor antigens. Among different antigens, mRNA coding the tumor antigens is advantageous due to its capability to be amplified from small amounts of tumor tissue, its safety because it is easily degraded without integrating into the host genome, and it does not need to cross the nuclear barrier to exert its biological activity. Nanotechnology is an approach to deliver tumor antigens into DCs. Specially, we review the use of nanoliposomes in the field of cancer therapy because cationic liposomes can be used as non-viral vectors for mRNA delivery. Aside from the promise of liposomes, the development of scalable processes and facilities to the use this individualized therapy is still a challenge. Thus, we  also present the recent techniques used for liposome production. In this context, the integration between technological knowledge in the production of cationic liposomes and immunotherapy using mRNA may contribute to the development of new strategies for cancer therapy.

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[1050]

TÍTULO / TITLE:  - Alterations in glutathione levels and apoptotic regulators are associated with acquisition of arsenic trioxide resistance in multiple myeloma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e52662. doi: 10.1371/journal.pone.0052662. Epub 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052662

AUTORES / AUTHORS:  - Matulis SM; Morales AA; Yehiayan L; Lee KP; Cai Y; Boise LH

INSTITUCIÓN / INSTITUTION:  - Departments of Hematology and Medical Oncology and Cell Biology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, United States  of America.

RESUMEN / SUMMARY:  - Arsenic trioxide (ATO) has been tested in relapsed/refractory multiple myeloma with limited success. In order to better understand drug mechanism and resistance pathways in myeloma we generated an ATO-resistant cell line, 8226/S-ATOR05, with  an IC50 that is 2-3-fold higher than control cell lines and significantly higher  than clinically achievable concentrations. Interestingly we found two parallel pathways governing resistance to ATO in 8226/S-ATOR05, and the relevance of these pathways appears to be linked to the concentration of ATO used. We found changes  in the expression of Bcl-2 family proteins Bfl-1 and Noxa as well as an increase  in cellular glutathione (GSH) levels. At low, clinically achievable concentrations, resistance was primarily associated with an increase in expression of the anti-apoptotic protein Bfl-1 and a decrease in expression of the pro-apoptotic protein Noxa. However, as the concentration of ATO increased, elevated levels of intracellular GSH in 8226/S-ATOR05 became the primary mechanism of ATO resistance. Removal of arsenic selection resulted in a loss of the resistance phenotype, with cells becoming sensitive to high concentrations of ATO within 7 days following drug removal, indicating changes associated with high level resistance (elevated GSH) are dependent upon the presence of arsenic. Conversely, not until 50 days without arsenic did cells once again become sensitive to clinically relevant doses of ATO, coinciding with a decrease in the  expression of Bfl-1. In addition we found cross-resistance to melphalan and doxorubicin in 8226/S-ATOR05, suggesting ATO-resistance pathways may also be involved in resistance to other chemotherapeutic agents used in the treatment of  multiple myeloma.

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[1051]

TÍTULO / TITLE:  - Isolation and Purification of a Peptide from Bullacta exarata and Its Impaction of Apoptosis on Prostate Cancer Cell.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mar Drugs. 2013 Jan 23;11(1):266-73. doi: 10.3390/md11010266.

            ●● Enlace al texto completo (gratuito o de pago) 3390/md11010266

AUTORES / AUTHORS:  - Ma J; Huang F; Lin H; Wang X

INSTITUCIÓN / INSTITUTION:  - School of Food Science and Pharmacy, Zhejiang Provincial Key Engineering Technology Research Center of Marine Biomedical Products, Zhejiang Ocean University, Zhoushan 316000, China. majyin2012@gmail.com.

RESUMEN / SUMMARY:  - Bullacta exarata was hydrolyzed with trypsin to prepare peptides; Hydrolysates were isolated by ultrafiltration and purified using G-25 gel filtration. The purity of the Bullacta exarata was demonstrated by HPLC and its peptide sequence  analysis was detected. The effects of BEPT II and BEPT II-1 on the proliferation  of PC-3 cells were examined using a MTT assay. BEPT II and BEPT II-1 significantly inhibited the proliferation of PC-3 cells in a time- and dose-dependent manner. Annexin V/PI double staining studies showed exposing PC-3  cells to 5, or 15 mg/mL BEPT II-1 for 24 h increased the percentage of the early  stage of apoptotic cells from 11.22% to 22.09%. In addition, typical morphologic  changes were observed in the cells with acridine orange/ethidium bromide staining. These data support that BEPT II-1 has anticancer properties and merits  further investigation to understand the mechanisms of BEPT II-1-induced apoptosis in PC-3 cells.

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[1052]

TÍTULO / TITLE:  - Inhibition effects and induction of apoptosis of flavonoids on the prostate cancer cell line PC-3 in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Food Chem. 2013 May 1;138(1):48-53. doi: 10.1016/j.foodchem.2012.09.102. Epub 2012 Nov 7.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.foodchem.2012.09.102

AUTORES / AUTHORS:  - Xu R; Zhang Y; Ye X; Xue S; Shi J; Pan J; Chen Q

INSTITUCIÓN / INSTITUTION:  - Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310029, PR China.

RESUMEN / SUMMARY:  - Myricetin and myricitrin are naturally occurring flavonoids have been suggested to play a role in inhibition of proliferation and transformation of carcinogenic  cell. However, the underlying molecular mechanisms of their activity have not yet to be revealed. The aim of the present study was to clarify the molecular mechanisms of apoptosis cell on the prostate cancer induced by myricetin, myricitrin, quercetin and quercitrin. The MTT assay confirmed that myricetin had  the strongest inhibitory effect on human prostate cancer cell line PC-3, myricitrin was second, and quercitrin was the weakest. A noticeable synergistic effect was observed with the inhibition of cell proliferation when myricetin was  used in combination with myricitrin. In the concentration range of 37.5-300mumol/L, the inhibitory effects of these flavonoids were enhanced with increasing dose and treatment time. The acridine orange analysis and annexin V-FITC/PI double-staining results confirmed that myricetin and myricitrin were effective in inducing PC-3 cell apoptosis. The results showed that myricetin was  more effective than myricitrin in inducing cell apoptosis. The apoptosis rate increased with increasing flavonoid concentration in a dose dependent manner. A synergistic effect was observed on the apoptosis rate when myricetin was used in  combination with myricitrin.

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[1053]

TÍTULO / TITLE:  - Vav1 Fine Tunes p53 Control of Apoptosis versus Proliferation in Breast Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e54321. doi: 10.1371/journal.pone.0054321. Epub 2013 Jan 14.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0054321

AUTORES / AUTHORS:  - Sebban S; Farago M; Gashai D; Ilan L; Pikarsky E; Ben-Porath I; Katzav S

INSTITUCIÓN / INSTITUTION:  - Departement of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hadassah Medical School - Hebrew University, Jerusalem, Israel.

RESUMEN / SUMMARY:  - Vav1 functions as a signal transducer protein in the hematopoietic system, where  it is exclusively expressed. Vav1 was recently implicated in several human cancers, including lung, pancreatic and neuroblasoma. In this study, we analyzed  the expression and function of Vav1 in human breast tumors and breast cancer cell lines. Immunohistochemical analysis of primary human breast carcinomas indicated  that Vav1 is expressed in 62% of 65 tumors tested and is correlated positively with estrogen receptor expression. Based on published gene profiling of 50 breast cancer cell lines, several Vav1-expressing cell lines were identified. RT-PCR confirmed Vav1 mRNA expression in several of these cell lines, yet no detectable  levels of Vav1 protein were observed due to cbl-c proteasomal degradation. We used two of these lines, MCF-7 (Vav1 mRNA negative) and AU565 (Vav1 mRNA positive), to explore the effect of Vav1 expression on breast cell phenotype and  function. Vav1 expression had opposite effects on function in these two lines: it reduced proliferation and enhanced cell death in MCF-7 cells but enhanced proliferation in AU565 cells. Consistent with these findings, transcriptome analysis revealed an increase in expression of proliferation-related genes in Vav1-expressing AU565 cells compared to controls, and an increase in apoptosis-related genes in Vav1-expressing MCF-7 cells compared with controls. TUNEL and gamma-H2AX foci assays confirmed that expression of Vav1 increased apoptosis in MCF-7 cells but not AU565 cells and shRNA experiments revealed that  p53 is required for this pro-apoptotic effect of Vav1 in these cells. These results highlight for the first time the potential role of Vav1 as an oncogenic stress activator in cancer and the p53 dependence of its pro-apoptotic effect in  breast cells.

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[1054]

TÍTULO / TITLE:  - CDK-associated Cullin 1 can promote cell proliferation and inhibit cisplatin-induced apoptosis in the AGS gastric cancer cell line.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Surg Oncol. 2013 Jan 13;11(1):5.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1477-7819-11-5

AUTORES / AUTHORS:  - Zheng Q; Zhao LY; Kong Y; Nan KJ; Yao Y; Liao ZJ

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Gastric cancer is a common and highly lethal malignancy in  the world, but its pathogenesis remains elusive. In this study, we focus on the biological functions of CDK-associated Cullin1 (CAC1), a novel gene of the cullin family, in gastric cancer, which may help us to further understand the origin of  this malignancy. METHODS: The AGS and MGC803 gastric cancer cell lines and the GES-1 gastric mucosa cell line were selected for study. At first, CAC1 expressions of those cell lines were examined by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and western blot examinations,  then CAC1 small interfering RNA (CAC1-siRNA) were designed and transfected into the AGS cell line with a relatively high level of CAC1. Once CAC1 was silenced, a series of biological characteristics of AGS cells such as cell proliferation, cell cycle, apoptosis, and expressions of apoptosis-related genes (P53, BCL2 and  BAX) were determined by MTT, flow cytometry, qRT-PCR and western blot, respectively. RESULTS: CAC1 expression of AGS or MGC803 was much higher than that of GES-1. After CAC1 expression was effectively depressed by RNA interference in  AGS cells, significant cell growth inhibition occurred. Furthermore, the proportion of cells treated with CAC1-siRNA increased in the G1 phase and decreased in the S phase, indicative of G1 cell cycle arrest. More importantly, the proportions of early/late apoptosis in AGS cells were enhanced with cis-diaminedichloroplatinum (cisplatin, CDDP) treatment, but to a higher extent with cisplatin plus CAC1-siRNA. Interestingly, BCL2 mRNA copies showed about a 30% decrease in the cisplatin group, but dropped by around 60% in the cisplatin plus CAC1-siRNA group. Conversely, the P53 mRNA expressions obtained nearly a two-fold increase in the cisplatin group, in addition to a five-fold increase in  the cisplatin plus CAC1-siRNA group, and the BAX mRNA levels had almost a two- and four-fold augmentation, respectively. Meanwhile, P53, BAX and BCL2 showed the same alteration patterns in western blot examinations. CONCLUSIONS: CAC1 can promote cell proliferation in the AGS gastric cancer cell line. Moreover, it can  prevent AGS cells from experiencing cisplatin-induced apoptosis via modulating expressions of P53, BCL2 and BAX.

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[1055]

TÍTULO / TITLE:  - Chamaejasmine Arrests Cell Cycle, Induces Apoptosis and Inhibits Nuclear NF-&#954;B Translocation in the Human Breast Cancer Cell Line MDA-MB-231.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Molecules. 2013 Jan 11;18(1):845-58. doi: 10.3390/molecules18010845.

            ●● Enlace al texto completo (gratuito o de pago) 3390/molecules18010845

AUTORES / AUTHORS:  - Zhang T; Yu H; Dong G; Cai L; Bai Y

INSTITUCIÓN / INSTITUTION:  - Oncology Department of Internal Medicine, the Third Affiliated Hospital of Harbin Medical University, Harbin 150040, China. caiwenxin76@yahoo.com.cn.

RESUMEN / SUMMARY:  - In this study, the anticancer activity of chamaejasmine was characterized in the  human breast cancer cell line, MDA-MB-231. Cell viability and cell cycle distribution were determined by MTT assay and flow cytometry, respectively. Western blotting was performed to determine changes in levels of various proteins. Results showed that treatment with chamaejasmine (4-16 muM) inhibited cell proliferation, which correlated with G2/M phase arrest and apoptosis in MDA-MB-231 cells. Chamaejasmine treatment of MDA-MB-231 cells resulted in induction of WAF1/p21 and KIP1/p27, decrease in cyclins A and cyclins B1. Cyclin-dependent kinase (cdk) 2 and cdc2 was also decreased after chamaejasmine treatment. Moreover, inhibition of nuclear translocation, phosphorylation of NF-kappaB, activation of IKKalpha and IKKbeta, inhibition of phosphorylation and  degradation of IkappaBalpha were also detected in this work. Our findings suggested that chamaejasmine could be explored as a preventive and perhaps as a chemotherapeutic agent in the management of breast cancer.

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[1056]

TÍTULO / TITLE:  - EGFR targeting monoclonal antibody combines with an mTOR inhibitor and potentiates tumor inhibition by acting on complementary signaling hubs.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Med. 2012 Oct;1(2):114-27. doi: 10.1002/cam4.21. Epub 2012 Aug 1.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cam4.21

AUTORES / AUTHORS:  - James R; Vishwakarma S; Chivukula IV; Basavaraj C; Melarkode R; Montero E; Nair P

INSTITUCIÓN / INSTITUTION:  - Biocon Ltd, R&D, Drug Development Group Bangalore, 560100, India.

RESUMEN / SUMMARY:  - Nimotuzumab, an anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, has been used extensively in many solid tumors and confers significant  survival advantage. The antibody has limited skin toxicity and is generally well  tolerated. Similar to other anti-EGFR therapies, patients may relapse a few months after treatment. In this study we show for the first time, the use of Nimotuzumab along with Sirolimus has synergistic effect on tumor inhibition as compared with the drugs used individually, in Nimotuzumab responsive and nonresponsive cell lines. In vitro studies prove that while Sirolimus (25 nmol/L) affects the signal downstream to mammalian target of rapamycin (mTOR), Nimotuzumab (83 nmol/L) downregulates pTYR, pMAPK and pSTAT3 by 40%, 20% and 30%, respectively. The combination, targeting these two different signaling hubs, may  be associated with the synergistic inhibition observed. In vivo, the use of half  human therapeutic equivalent doses for both the drugs substantially reduces tumors established in nude as well as severe combined immunodeficiency (SCID) mice by EGFR overexpressing A-431 cells. The drug combination reduces cell proliferation and the expression of signal transduction molecules. Treated tumors are better differentiated as compared with those established in the control mice. Tumor microarray demonstrates that Nimotuzumab and the combination groups segregate independently to the Sirolimus and the control treatment. The combination uniquely downregulated 55% of the altered tumor genes, extending beyond the typical pathways associated with Nimotuzumab and Sirolimus downstream  pathways inhibition. These results would suggest that this nontoxic drug combination improves therapeutic benefit even in patients with low-EGFR expression and severely immunocompromised because of their current medication.

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[1057]

TÍTULO / TITLE:  - CLPTM1L Is Overexpressed in Lung Cancer and Associated with Apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e52598. doi: 10.1371/journal.pone.0052598. Epub 2012 Dec 26.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0052598

AUTORES / AUTHORS:  - Ni Z; Tao K; Chen G; Chen Q; Tang J; Luo X; Yin P; Tang J; Wang X

INSTITUCIÓN / INSTITUTION:  - Central Lab, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

RESUMEN / SUMMARY:  - CLPTM1L is believed to be associated with lung cancer. However, there is little information regarding its expression and function. Here using immunohistochemistry, we found that CLPTM1L expression was markedly increased in  lung cancer tissues relative to normal tissues, especially in lung adenocarcinoma. CLPTM1L expression was not found to be associated with stages, smoking status, lymph node metastasis, or T lymphocyte infiltration but with differentiation stage. We found CLPTM1L to be enriched in the mitochondrial compared with plasma membrane protein extracts. CLPTM1L-EGFP transfection showed  that the molecule product was expressed in cytoplasm and indicated the mitochondrial localization stained with mitochondrial marker MitoTracker. CLPTM1L transferred lung cancer cell line 95-D showed no growth inhibition or cell apoptosis, but it did show inhibited sensitivity to cis-diamminedichloroplatinum(II) (cisplatin, CDDP). Knockdown of CLPTM1L by RNAi  did not interfere with cell proliferation but it did increase cell sensitivity to CDDP and activation of caspase-9 and caspase-3/7. These data indicate CLPTM1L is  a mitochondria protein and that it may be associated with anti-apoptotic mechanism which affects drug-resistance in turn.

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[1058]

TÍTULO / TITLE:  - Evaluation of apoptosis in classical Hodgkin’s lymphoma comparing different methods.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J BUON. 2012 Oct-Dec;17(4):746-52.

AUTORES / AUTHORS:  - Georgiadi EC; Sachinis N; Dimtsas G; Vassilakopoulos TP; Kittas C; Doussis-Anagnostopoulou IA

INSTITUCIÓN / INSTITUTION:  - Laboratory of Histology and Embryology, National and Kapodistrian University of Athens, Medical School, Athens, Greece.

RESUMEN / SUMMARY:  - Purpose: Apoptosis is a type of programmed cell death (PCD) with specific morphologic changes in the dying cell. Since classical Hodgkin’s lymphoma (cHL) is characterised by abnormalities in the apoptotic pathways, apoptosis may play a central role in its pathogenesis. Our purpose was to estimate the apoptotic process in cases of cHL using 3 different, widely accepted methods, comparing their results as well as with those found in the literature. Methods: Detection of apoptosis was performed in 76 cases of cHL, using morphological criteria, TUNEL assay (TUNEL apoptotic index; T-AI) and immunohistochemical detection of active caspase 3 (casp3-AI) on paraffin embedded sections. Results: When both apoptotic (MA) and mummified (mummi-I) cells were evaluated by morphological apoptotic index (morph-AI), the median value was 10.3%, while for MA and mummi-I  the results were 3.4% and 6%, respectively. T-AI and casp3-AI values were 10.9% and 1.9%, respectively. Morph-AI was significantly higher in the mixed cellularity (MC) subtype (p7equals;0.047rpar;, while MA was significantly higher  in the male subgroup (p7equals;0.03). MA was strongly correlated with casp37horbar;AI (p=0.01). Conclusion: Detection of apoptosis has become an important parameter in understanding tumor pathology and in designing antitumor treatment. A combination of methods is proposed in order to estimate accurately this form of cell death.

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[1059]

TÍTULO / TITLE:  - Vitamin C Induces Apoptosis in Human Colon Cancer Cell Line, HCT-8 Via the Modulation of Calcium Influx in Endoplasmic Reticulum and the Dissociation of Bad from 14-3-3beta.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Immune Netw. 2012 Oct;12(5):189-95. doi: 10.4110/in.2012.12.5.189. Epub 2012 Oct  31.

            ●● Enlace al texto completo (gratuito o de pago) 4110/in.2012.12.5.189

AUTORES / AUTHORS:  - Kim JE; Kang JS; Lee WJ

INSTITUCIÓN / INSTITUTION:  - Department of Anatomy, Chung-Ang University College of Medicine, Seoul 156-756, Korea.

RESUMEN / SUMMARY:  - It has been reported that vitamin C plays an effective role in the treatment and  prevention of cancer, but its specific mechanisms are still largely unknown. The  incidence of colon cancer is now increasing in Korea. Therefore, we have examined here the effect of vitamin C on the induction of the apoptosis on colon cancer and its related mechanisms. We have found that remarkable increase of the apoptosis and the calcium influx in endoplasmic reticulum (ER) in human colon cancer cell line, HCT-8. However, vitamin C-induced apoptosis was effectively inhibited by the pre-treatment of BAPTA-AM (1,2-bis(o-aminophenoxy) ethane-N,N,N’,N’-tetraacetic acid), which is well-known as a calcium specific chelator. During the apoptosis, we found the increase of the translocation of Bad to mitochondria from cytosol, after releasing from 14-3-3beta. In this process, the expression of Bax, a well-known pro-apoptotic protein, was also increased. Taken together, vitamin C induces apoptosis of colon cancer cell line, HCT-8 through the increase of 1) the calcium influx in endoplasmic reticulum (ER), 2) the translocation of Bad to mitochondria, and 3) the expression of Bax.

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[1060]

TÍTULO / TITLE:  - Temperature-dependent activation of differential apoptotic pathways during cryoablation in a human prostate cancer model.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Prostate Cancer Prostatic Dis. 2012 Dec 11. doi: 10.1038/pcan.2012.48.

            ●● Enlace al texto completo (gratuito o de pago) 1038/pcan.2012.48

AUTORES / AUTHORS:  - Robilotto AT; Baust JM; Van Buskirk RG; Gage AA; Baust JG

INSTITUCIÓN / INSTITUTION:  - 1] Institute of Biomedical Technology, State University of New York at Binghamton, Binghamton, NY, USA [2] Department of Biological Sciences, Institute  of Biomedical Technology, Binghamton University, Binghamton, NY, USA [3] CPSI Biotech, Owego, NY, USA.

RESUMEN / SUMMARY:  - Background:Critical to the continual improvement of cryoablation efficacy is deciphering the biochemical responses of cells to low-temperature exposure. The identification of delayed-onset cell death has allowed for the manipulation of cellular responses through the regulation of apoptosis. We hypothesized that in addition to delayed apoptotic events associated with mild subfreezing temperatures (10 to -25 degrees C), cells exposed to ultra-low temperatures (<-30 degrees C) may undergo rapid, early-onset apoptosis.Methods:Human prostate cancer model and cells (PC-3) were exposed to temperatures of -60, -30 and -15 degrees C to simulate a cryoablative procedure. Using a combination of flow-cytometry, fluorescent microscopy and western blot analyses, samples were assessed at various times post thaw to identify the presence, levels and the pathways involved in cell death.Results:Exposure to temperatures <-30 degrees C yielded a  significant apoptotic population within 30 min of thawing, peaking at 90 min ( approximately 40%), and by 6 h, only necrosis was observed. In samples only reaching temperatures >-30 degrees C, apoptosis was not noted until 6-24 h post thaw, with the levels of apoptosis reaching approximately 10% (-15 degrees C) and approximately 25% (-30 degrees C) at 6 h post thaw. Further, it was found that early-onset apoptosis progressed through a membrane-mediated mechanism, whereas delayed apoptosis progressed through a mitochondrial path.Conclusions:These data  demonstrate the impact of apoptotic continuum, whereby the more severe cryogenic  stress activated the extrinsic, membrane-regulated pathway, whereas less severe freezing activated the intrinsic, mitochondrial-mediated path. The rapid induction and progression of apoptosis at ultra-low temperatures provides an explanation as to why such results have not previously been identified following  freezing. Ultimately, an understanding of the events and signaling pathways involved in triggering apoptosis following freezing may provide a path for selective induction of the rapid-onset and delayed programmed cell death pathways in an effort to improve the overall cryoablation efficacy.Prostate Cancer and Prostatic Disease advance online publication, 11 December 2012; doi:10.1038/pcan.2012.48.

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[1061]

TÍTULO / TITLE:  - ROS Production Is Essential for the Apoptotic Function of E2F1 in Pheochromocytoma and Neuroblastoma Cell Lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51544. doi: 10.1371/journal.pone.0051544. Epub 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051544

AUTORES / AUTHORS:  - Espada L; Meo-Evoli N; Sancho P; Real S; Fabregat I; Ambrosio S; Tauler A

INSTITUCIÓN / INSTITUTION:  - Departament de Bioquimica i Biologia Molecular, Facultat de Farmacia. Universitat de Barcelona, Barcelona, Catalunya, España.

RESUMEN / SUMMARY:  - In this study we demonstrate that accumulation of reactive oxygen species (ROS) is essential for E2F1 mediated apoptosis in ER-E2F1 PC12 pheochromocytoma, and SH-SY5Y and SK-N-JD neuroblastoma stable cell lines. In these cells, the ER-E2F1  fusion protein is expressed in the cytosol; the addition of 4-hydroxytamoxifen (OHT) induces its translocation to the nucleus and activation of E2F1target genes. Previously we demonstrated that, in ER-E2F1 PC12 cells, OHT treatment induced apoptosis through activation of caspase-3. Here we show that caspase-8 activity did not change upon treatment with OHT. Moreover, over-expression of Bcl-xL arrested OHT-induced apoptosis; by contrast, over-expression of c-FLIP, did not have any effect on OHT-induced apoptosis. OHT addition induces BimL expression, its translocation to mitochondria and activation of Bax, which is paralleled by diminished mitochondrial enrichment of Bcl-xL. Treatment with a Bax-inhibitory peptide reduced OHT-induced apoptosis. These results point out the essential role of mitochondria on the apoptotic process driven by E2F1. ROS accumulation followed E2F1 induction and treatment with the antioxidant N-acetylcysteine, inhibited E2F1-induced Bax translocation to mitochondria and subsequent apoptosis. The role of ROS in mediating OHT-induced apoptosis was also studied in two neuroblastoma cell lines, SH-SY5Y and SK-N-JD. In SH-SY5Y cells, activation of E2F1 by the addition of OHT induced ROS production and apoptosis, whereas over-expression of E2F1 in SK-N-JD cells failed to induce either response. Transcriptional profiling revealed that many of the genes responsible for scavenging ROS were down-regulated following E2F1-induction in SH-SY5Y, but not in SK-N-JD cells. Finally, inhibition of GSK3beta blocked ROS production, Bax activation and the down regulation of ROS scavenging genes. These findings provide an explanation for the apparent contradictory role of E2F1 as an apoptotic agent versus a cell cycle activator.

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[1062]

TÍTULO / TITLE:  - Large-scale screening identifies a novel microRNA, miR-15a-3p, which induces apoptosis in human cancer cell lines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - RNA Biol. 2013 Jan 25;10(2).

AUTORES / AUTHORS:  - Druz A; Chen YC; Guha R; Betenbaugh M; Martin SE; Shiloach J

INSTITUCIÓN / INSTITUTION:  - Biotechnology Core Laboratory; The National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health; Bethesda, MD USA; Department  of Chemical and Biomolecular Engineering; Johns Hopkins University; Baltimore, MD USA.

RESUMEN / SUMMARY:  - MicroRNAs (miRNAs) have been found to be involved in cancer initiation, progression and metastasis and, as such, have been suggested as tools for cancer  detection and therapy. In this work, a large-scale screening of the complete miRNA mimics library demonstrated that hsa-miR-15a-3p had a pro-apoptotic role in the following human cancer cells: HeLa, AsPc-1, MDA-MB-231, KB3, ME180, HCT-116 and A549. MiR-15a-3p is a novel member of the pro-apoptotic miRNA cluster, miR-15a/16, which was found to activate Caspase-3/7 and to cause viability loss in B/CMBA.Ov cells during preliminary screening. Subsequent microarrays and bioinformatics analyses identified the following four anti-apoptotic genes: bcl2l1, naip5, fgfr2 and mybl2 as possible targets for the mmu-miR-15a-3p in B/CMBA.Ov cells. Follow-up studies confirmed the pro-apoptotic role of hsa-miR-15a-3p in human cells by its ability to activate Caspase-3/7, to reduce cell viability and to inhibit the expression of bcl2l1 (bcl-xL) in HeLa and AsPc-1 cells. MiR-15-3p was also found to reduce viability in HEK293, MDA-MB-231, KB3, ME180, HCT-116 and A549 cell lines and, therefore, may be considered for apoptosis modulating therapies in cancers associated with high Bcl-xL expression  (cervical, pancreatic, breast, lung and colorectal carcinomas). The capability of hsa-miR-15a-3p to induce apoptosis in these carcinomas may be dependent on the levels of Bcl-xL expression. The use of endogenous inhibitors of bcl-xL and other anti-apoptotic genes such as hsa-miR-15a-3p may provide improved options for apoptosis-modulating therapies in cancer treatment compared with the use of artificial antisense oligonucleotides.

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[1063]

TÍTULO / TITLE:  - Increase of cyclooxygenase-2 inhibition with celecoxib combined with 5-FU enhances tumor cell apoptosis and antitumor efficacy in a subcutaneous implantation tumor model of human colon cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Surg Oncol. 2013 Jan 24;11(1):16.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1477-7819-11-16

AUTORES / AUTHORS:  - Zhang DQ; Guo Q; Zhu JH; Chen WC

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: The purpose of this study was to investigate the anti-tumor effect and explore the mechanisms of celecoxib (a selective cyclooxygenase-2 inhibitor) combined with 5-fluorouracil (5-FU) on the treatment of human colorectal cancer in a BALB/C nude mouse subcutaneous xenograft model. METHODS: Effects of celecoxib combined with 5-FU on the proliferation of xenograft carcinoma induced by HT-29 were investigated. The apoptotic cells were detected by electron microscope and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay. Immunohistochemistry and Western blot were used to estimate  the expression of cytochrome C, caspase-3 and caspase-9. RESULTS: Compared with the control group, treatment groups showed significant inhibition of tumor growth. More apoptotic cells existed after treatment with celecoxib combined with 5-FU. Cytochrome C, caspase-3 and caspase-9 were increased in treated groups, and more obviously in the drug combination group. Cyclooxygenase-2 (COX-2) were decreased after treatment with celecoxib only or combined with 5-FU. And the combined group showed a greater decrease. CONCLUSIONS: Celecoxib combined with 5-FU could inhibit the growth of tumors in vivo by inducing apoptosis and activation of the cytochrome C dependency apoptosis signal pathway. A decrease of COX-2 and an increase of cytochrome C[ideographic comma]caspase-3 and caspase-9 may be involved in this process.

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[1064]

TÍTULO / TITLE:  - Involvement of the phosphoinositide 3-kinase/Akt pathway in apoptosis induced by  capsaicin in the human pancreatic cancer cell line PANC-1.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2013 Jan;5(1):43-48. Epub 2012 Oct 24.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.991

AUTORES / AUTHORS:  - Zhang JH; Lai FJ; Chen H; Luo J; Zhang RY; Bu HQ; Wang ZH; Lin HH; Lin SZ

INSTITUCIÓN / INSTITUTION:  - Department of Hepatobiliary-Pancreatic Surgery, The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang 325027;

RESUMEN / SUMMARY:  - Capsaicin, one of the major pungent ingredients found in red peppers, has been recently demonstrated to induce apoptosis in various malignant cell lines through an unclear mechanism. In this study, the effect of capsaicin on proliferation and apoptosis in the human pancreatic cancer cell line PANC-1 and its possible mechanism(s) of action were investigated. The results of a Cell Counting Kit-8 (CCK-8) assay revealed that capsaicin significantly decreased the viability of PANC-1 cells in a dose-dependent manner. Capsaicin induced G0/G1 phase cell cycle arrest and apoptosis in PANC-1 cells as demonstrated by a flow cytometric assessment. Caspase-3 expression at both the protein and mRNA level was promoted  following capsaicin treatment. Furthermore, we revealed that phospho-PI3 Kinase p85 (Tyr458) and phospho-Akt (Ser473) in PANC-1 cells were downregulated in response to capsaicin. Moreover, capsaicin gavage significantly inhibited the growth of pancreatic cancer PANC-1 cell xenografts in athymic nude mice. An increased number of TUNEL-positive cells and cleaved caspase-3 were observed in capsaicin-treated mice. In vivo, capsaicin downregulated the expression of phospho-PI3 Kinase p85 (Tyr458) and phospho-Akt (Ser473). In conclusion, we have  demonstrated that capsaicin is an inhibitor of growth of PANC-1 cells, and downregulation of the phosphoinositide 3-kinase/Akt pathway may be involved in capsaicin-induced apoptosis in vitro and in vivo.

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[1065]

TÍTULO / TITLE:  - Alternative Pathways of Cancer Cell Death by Rottlerin: Apoptosis versus Autophagy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Evid Based Complement Alternat Med. 2012;2012:980658. doi: 10.1155/2012/980658. Epub 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1155/2012/980658

AUTORES / AUTHORS:  - Torricelli C; Salvadori S; Valacchi G; Soucek K; Slabakova E; Muscettola M; Volpi N; Maioli E

INSTITUCIÓN / INSTITUTION:  - Department of Physiology, University of Siena, Via Aldo Moro, 7-53100 Siena, Italy.

RESUMEN / SUMMARY:  - Since the ability of cancer cells to evade apoptosis often limits the efficacy of radiotherapy and chemotherapy, autophagy is emerging as an alternative target to  promote cell death. Therefore, we wondered whether Rottlerin, a natural polyphenolic compound with antiproliferative effects in several cell types, can induce cell death in MCF-7 breast cancer cells. The MCF-7 cell line is a good model of chemo/radio resistance, being both apoptosis and autophagy resistant, due to deletion of caspase 3 gene, high expression of the antiapoptotic protein Bcl-2, and low expression of the autophagic Beclin-1 protein. The contribution of autophagy and apoptosis to the cytotoxic effects of Rottlerin was examined by light, fluorescence, and electron microscopic examination and by western blotting analysis of apoptotic and autophagic markers. By comparing caspases-3-deficient (MCF-7(3def)) and caspases-3-transfected MCF-7 cells (MCF-7(3trans)), we found that Rottlerin induced a noncanonical, Bcl-2-, Beclin 1-, Akt-, and ERK-independent autophagic death in the former- and the caspases-mediated apoptosis in the latter, in not starved conditions and in the absence of any other treatment. These findings suggest that Rottlerin could be cytotoxic for different cancer cell types, both apoptosis competent and apoptosis resistant.

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[1066]

TÍTULO / TITLE:  - Targeting Tumor Stroma: Exploiting Apoptotic Priming.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncotarget. 2012 Jan 19.

AUTORES / AUTHORS:  - Mertens JC; Gores GJ

INSTITUCIÓN / INSTITUTION:  - Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, Division of Gastroenterology and Hepatology, University Hospital Zurich.

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[1067]

TÍTULO / TITLE:  - The triterpenoid pristimerin induces U87 glioma cell apoptosis through reactive oxygen species-mediated mitochondrial dysfunction.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2013 Jan;5(1):242-248. Epub 2012 Oct 22.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.982

AUTORES / AUTHORS:  - Yan YY; Bai JP; Xie Y; Yu JZ; Ma CG

INSTITUCIÓN / INSTITUTION:  - Institute of Brain Science, Shanxi Datong University, Datong, Shanxi 037009, P.R. China.

RESUMEN / SUMMARY:  - It has become evident that some of the natural or synthetic triterpenoids are natural proteasome inhibitors that have great potential for use in cancer prevention and treatment. However, the mechanisms for the antitumor activity of triterpenoids remain to be elucidated. In the present study, we investigated the  anticancer activities of a natural triterpenoid, pristimerin, and the signaling pathways affected. Pristimerin was found to possess potent cytotoxic effects, inducing apoptosis and inhibiting proliferation in U87 human glioma cells. Hoechst 33258 staining and Annexin V/PI double staining exhibited the typical nuclear features of apoptosis and increased the proportion of apoptotic Annexin V-positive cells in a dose-dependent manner, respectively. Moreover, western blotting assay revealed that this apoptotic induction was associated with activated caspase-9, caspase-3, PARP cleavage and downregulation of Bcl-xl/Bax in a concentration-dependent manner. Pristimerin also increased the generation of reactive oxygen species and induced the subsequent release of cytochrome c from the mitochondria into the cytosol. Additionally, pristimerin downregulated EGFR protein expression and inhibited downstream signaling pathways in U87 cells. Our  results suggest that pristimerin may have potential as a new targeting therapeutic strategy in the treatment of EGFR-overexpressing gliomas.

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[1068]

TÍTULO / TITLE:  - 1-Benzyl-2-Phenylbenzimidazole (BPB), a Benzimidazole Derivative, Induces Cell Apoptosis in Human Chondrosarcoma through Intrinsic and Extrinsic Pathways.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Sci. 2012 Dec 4;13(12):16472-88. doi: 10.3390/ijms131216472.

            ●● Enlace al texto completo (gratuito o de pago) 3390/ijms131216472

AUTORES / AUTHORS:  - Liu JF; Huang YL; Yang WH; Chang CS; Tang CH

INSTITUCIÓN / INSTITUTION:  - Central Laboratory, Shin Kong Wu Ho-Su Memorial Hospital, No.95, Wunchang Road, Shihlin District, Taipei City 111, Taiwan. chtang@mail.cmu.edu.tw.

RESUMEN / SUMMARY:  - In this study, we investigated the anticancer effects of a new benzimidazole derivative, 1-benzyl-2-phenyl -benzimidazole (BPB), in human chondrosarcoma cells. BPB-mediated apoptosis was assessed by the MTT assay and flow cytometry analysis. The in vivo efficacy was examined in a JJ012 xenograft model. Here we found that BPB induced apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353) but not in primary chondrocytes. BPB induced upregulation of Bax, Bad and Bak, downregulation of Bcl-2, Bid and Bcl-XL and dysfunction of mitochondria in chondrosarcoma. In addition, BPB also promoted cytosolic releases AIF and Endo G. Furthermore, it triggered extrinsic death receptor-dependent pathway, which was characterized by activating Fas, FADD and caspase-8. Most importantly, animal studies revealed a dramatic 40% reduction in tumor volume after 21 days of treatment. Thus, BPB may be a novel anticancer agent for the treatment of chondrosarcoma.

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[1069]

TÍTULO / TITLE:  - Efficient simultaneous tumor targeting delivery of all-trans retinoid acid and paclitaxel based on hyaluronic acid-based multifunctional nanocarrier.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Pharm. 2013 Jan 15.

            ●● Enlace al texto completo (gratuito o de pago) 1021/mp3005808

AUTORES / AUTHORS:  - Jing Y; Zhang L; Zhou J; Liu H; Zhang Q

RESUMEN / SUMMARY:  - An amphiphilic hyaluronic acid (HA)-g-all-trans retinoid acid (HRA) conjugate was successfully developed as a tumor targeting nanocarrier for potentially synergistic combination chemotherapy of all-trans retinoid acid (ATRA) and paclitaxel (PTX). The HRA conjugate was synthesized by an imine reaction between  HA-COOH and ATRA-NH2. PTX-loaded HRA nanoparticles possessed a high loading capacity, nano-scale particle sizes, and good biocompatible characteristics. Cell viability assays indicated that PTX-loaded HRA nanoparticles exhibited concentration- and time-dependent cytotoxicity. Moreover, they displayed obvious  superiority in inducing the apoptosis of tumor cells. Cellular uptake analysis suggested that HRA nanoparticles could be efficiently taken up by cells via endocytic pathway and transport into the nucleus, contributing to HA receptor-mediated endocytosis and ATRA-induced nuclear translocation, respectively. Moreover, In vivo imaging analysis indicated that the accumulation  of DiR-loaded HRA nanoparticle in tumor was increased obviously after i.v. administration as compared to free DiR solution, which confirmed that the HRA nanoparticles could assist the drugs targeting to the tumor. Furthermore, PTX-loaded HRA nanoparticles exhibited greater tumor growth inhibition effect in  vivo with reducing the toxicity. Therefore, HRA nanoparticles can be considered as a promising targeted co-delivery system for combination cancer chemotherapy.

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[1070]

TÍTULO / TITLE:  - Basal/HER2 breast carcinomas: Integrating molecular taxonomy with cancer stem cell dynamics to predict primary resistance to trastuzumab (Herceptin).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Cycle. 2013 Jan 15;12(2):225-45. doi: 10.4161/cc.23274. Epub 2012 Jan 15.

            ●● Enlace al texto completo (gratuito o de pago) 4161/cc.23274

AUTORES / AUTHORS:  - Martin-Castillo B; Oliveras-Ferraros C; Vazquez-Martin A; Cufi S; Moreno JM; Corominas-Faja B; Urruticoechea A; Martin AG; Lopez-Bonet E; Menendez JA

INSTITUCIÓN / INSTITUTION:  - Unit of Clinical Research; Catalan Institute of Oncology-Girona (ICO-Girona); Catalonia, España; Girona Biomedical Research Institute (IDIBGi); Catalonia, España.

RESUMEN / SUMMARY:  - High rates of inherent primary resistance to the humanized monoclonal antibody trastuzumab (Herceptin) are frequent among HER2 gene-amplified breast carcinomas  in both metastatic and adjuvant settings. The clinical efficacy of trastuzumab is highly correlated with its ability to specifically and efficiently target HER2-driven populations of breast cancer stem cells (CSCs). Intriguingly, many of the possible mechanisms by which cancer cells escape trastuzumab involve many of  the same biomarkers that have been implicated in the biology of CS-like tumor-initiating cells. In the traditional, one-way hierarchy of CSCs in which all cancer cells descend from special self-renewing CSCs, HER2-positive CSCs can  occur solely by self-renewal. Therefore, by targeting CSC self-renewal and resistance, trastuzumab is expected to induce tumor shrinkage and further reduce  breast cancer recurrence rates when used alongside traditional therapies. In a new, alternate model, more differentiated non-stem cancer cells can revert to trastuzumab-refractory, CS-like cells via the activation of intrinsic or microenvironmental paths-to-stemness, such as the epithelial-to-mesenchymal transition (EMT). Alternatively, stochastic transitions of trastuzumab-responsive CSCs might also give rise to non-CSC cellular states that lack major attributes of CSCs and, therefore, can remain “hidden” from trastuzumab activity. Here, we hypothesize that a better understanding of the CSC/non-CSC social structure within HER2-overexpressing breast carcinomas is critical for trastuzumab-based treatment decisions in the clinic. First, we decipher the biological significance of CSC features and the EMT on the molecular effects and efficacy of trastuzumab  in HER2-positive breast cancer cells. Second, we reinterpret the genetic heterogeneity that differentiates trastuzumab-responders from non-responders in terms of CSC cellular states. Finally, we propose that novel predictive approaches aimed at better forecasting early tumor responses to trastuzumab should identify biological determinants that causally underlie the intrinsic flexibility of HER2-positive CSCs to “enter” into or “exit” from trastuzumab-sensitive states. An accurate integration of CSC cellular states and  EMT-related biomarkers with the currently available breast cancer molecular taxonomy may significantly improve our ability to make a priori decisions about whether patients belonging to HER2 subtypes differentially enriched with a “mesenchymal transition signature” (e.g., luminal/HER2 vs. basal/HER2) would distinctly benefit from trastuzumab-based therapy ab initio.

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[1071]

TÍTULO / TITLE:  - Two Panels of Plasma MicroRNAs as Non-Invasive Biomarkers for Prediction of Recurrence in Resectable NSCLC.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e54596. doi: 10.1371/journal.pone.0054596. Epub 2013 Jan 16.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0054596

AUTORES / AUTHORS:  - Sanfiorenzo C; Ilie MI; Belaid A; Barlesi F; Mouroux J; Marquette CH; Brest P; Hofman P

INSTITUCIÓN / INSTITUTION:  - Institute for Research on Cancer and Ageing in Nice IRCAN, INSERM U1081 - CNRS UMR 7284, Team 3, Nice, France ; University Hospital Center of Nice, Pasteur Hospital, Department of Pneumology, Nice, France ; University of Nice Sophia Antipolis, Faculty of Medicine, Team 3, Nice, France.

RESUMEN / SUMMARY:  - The diagnosis of non-small cell lung carcinoma (NSCLC) at an early stage, as well as better prediction of outcome remains clinically challenging due to the lack of specific and robust non-invasive markers. The discovery of microRNAs (miRNAs), particularly those found in the bloodstream, has opened up new perspectives for tumor diagnosis and prognosis. The aim of our study was to determine whether expression profiles of specific miRNAs in plasma could accurately discriminate between NSCLC patients and controls, and whether they are able to predict the prognosis of resectable NSCLC patients. We therefore evaluated a series of seventeen NSCLC-related miRNAs by quantitative real-time (qRT)-PCR in plasma from 52 patients with I-IIIA stages NSCLC, 10 patients with chronic obstructive pulmonary disease (COPD) and 20-age, sex and smoking status-matched healthy individuals. We identified an eleven-plasma miRNA panel that could distinguish NSCLC patients from healthy subjects (AUC = 0.879). A six-plasma miRNA panel was  able to discriminate between NSCLC patients and COPD patients (AUC = 0.944). Furthermore, we identified a three-miRNA plasma signature (high miR-155-5p, high  miR-223-3p, and low miR-126-3p) that significantly associated with a higher risk  for progression in adenocarcinoma patients. In addition, a three-miRNA plasma panel (high miR-20a-5p, low miR-152-3p, and low miR-199a-5p) significantly predicted survival of squamous cell carcinoma patients. In conclusion, we identified two plasma miRNA expression profiles that may be useful for predicting the outcome of patients with resectable NSCLC.

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[1072]

TÍTULO / TITLE:  - Cyst fluid carcinoembryonic antigen concentration and cytology by endosonography-guided fine needle aspiration in predicting maglinant pancreatic mucinous cystic neoplasms.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Dig Dis. 2012 Dec 25. doi: 10.1111/1751-2980.12027.

            ●● Enlace al texto completo (gratuito o de pago) 1111/1751-2980.12027

AUTORES / AUTHORS:  - Zhan XB; Wang B; Liu F; Ye XF; Jin ZD; Li ZS

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology, Changhai Hospital.

RESUMEN / SUMMARY:  - OBJECTIVE: To assess the value of CEA level and cytology examination obtained by  endosonography-guided fine needle aspiration (EUS-FNA) in predicting the malignancy of pancreatic mucinous cystic neoplasms (MCNs). METHODS: The data of patients with pancreatic MCNs who underwent EUS-FNA in Changhai Hospital, Second  Military Medical Univesrity (Shanghai, China) from November 2005 to April 2010 were collected and analyzed. The area under the receiver operating characteristics curve, sensitivity, specificity, positive predictive value (PPV)  and negative predictive value (NPV) of the cytology as well as cyst fluid CEA were determined. RESULTS: Of the total 20 MCNs confirmed by surgical pathology, 10 were malignant and the other 10 were premalignant. Cytology had some value in  differentiating malignant from premalignant MCNs with a sensitivity of 60%, specificity of 100%, PPV of 100%, and NPV of 71.4%. CEA with a cut-off value of 692.8 ng/mL was able to predict malignancy (P = 0.007) with sensitivity of 80.0%, specificity of 90.0%, PPV of 88.9% and NPV of 81.8%. CONCLUSION: Cyst fluid CEA levels and cytology obtained by EUS-FNA are useful to predict the malignancy of pancreatic MCNs.

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[1073]

TÍTULO / TITLE:  - Carfilzomib: A new proteasome inhibitor for relapsed or refractory multiple myeloma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Oncol Pharm Pract. 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1177/1078155212470388

AUTORES / AUTHORS:  - Steele JM

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacy, Roswell Park Cancer Institute, Buffalo, NY, USA.

RESUMEN / SUMMARY:  - PurposeThe pharmacology, pharmacokinetics, clinical trials, adverse effects, dosage recommendations, and economic considerations of carfilzomib are reviewed.SummaryMultiple myeloma accounts for approximately 10-15% of all hematologic malignancies and 20% of blood-related cancer deaths. Despite recent advances in the treatment of multiple myeloma, most patients will eventually relapse, requiring further treatment. Carfilzomib is a new proteasome inhibitor that primarily targets the chymotrypsin-like activity of the 20S proteasome. The  safety and efficacy of carfilzomib was demonstrated in the PX-171-003-A1 trial, a prospective phase II trial in patients with relapsed or refractory multiple myeloma who had received at least 2 prior therapies including a proteasome inhibitor and an immunomodulatory agent. Common adverse effects included fatigue  (55.5%), anemia (46.8%), nausea (44.9%), and thrombocytopenia (36.3%). The recommended dose of carfilzomib for the first cycle is 20 mg/m(2) on 2 consecutive days each week for 3 weeks in a 4-week cycle escalating to 27 mg/m(2) for subsequent cycles. It is recommended that patients receive premedication with dexamethasone during cycle 1 and cycle 2 to minimize risk of infusion reactions.  CONCLUSION: /st>Carfilzomib provides a clinical benefit to patients with relapsed or refractory multiple myeloma who have been previously treated with a proteasome inhibitor and an immunomodulatory agent.

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[1074]

TÍTULO / TITLE:  - Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Sci Rep. 2013;3:1035. doi: 10.1038/srep01035. Epub 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 1038/srep01035

AUTORES / AUTHORS:  - Realini N; Solorzano C; Pagliuca C; Pizzirani D; Armirotti A; Luciani R; Costi MP; Bandiera T; Piomelli D

INSTITUCIÓN / INSTITUTION:  - Department of Anatomy and Neurobiology, University of California , Irvine, California 92697-4625 ; Unit of Drug Discovery and Development, Italian Institute of Technology , Genoa, Italy 16163.

RESUMEN / SUMMARY:  - The expression of acid ceramidase (AC) - a cysteine amidase that hydrolyses the proapoptotic lipid ceramide - is abnormally high in several human tumors, which is suggestive of a role in chemoresistance. Available AC inhibitors lack, however, the potency and drug-likeness necessary to test this idea. Here we show  that the antineoplastic drug carmofur, which is used in the clinic to treat colorectal cancers, is a potent AC inhibitor and that this property is essential  to its anti-proliferative effects. Modifications in the chemical scaffold of carmofur yield new AC inhibitors that act synergistically with standard antitumoral drugs to prevent cancer cell proliferation. These findings identify AC as an unexpected target for carmofur, and suggest that this molecule can be used as starting point for the design of novel chemosensitizing agents.

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[1075]

TÍTULO / TITLE:  - Reduced proficiency in homologous recombination underlies the high sensitivity of embryonal carcinoma testicular germ cell tumors to Cisplatin and poly (adp-ribose) polymerase inhibition.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51563. doi: 10.1371/journal.pone.0051563. Epub 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051563

AUTORES / AUTHORS:  - Cavallo F; Graziani G; Antinozzi C; Feldman DR; Houldsworth J; Bosl GJ; Chaganti RS; Moynahan ME; Jasin M; Barchi M

INSTITUCIÓN / INSTITUTION:  - Department of Biomedicine and Prevention, Section of Anatomy, University of Rome  Tor Vergata, Rome, Italy ; Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

RESUMEN / SUMMARY:  - Testicular Germ Cell Tumors (TGCT) and patient-derived cell lines are extremely sensitive to cisplatin and other interstrand cross-link (ICL) inducing agents. Nevertheless, a subset of TGCTs are either innately resistant or acquire resistance to cisplatin during treatment. Understanding the mechanisms underlying TGCT sensitivity/resistance to cisplatin as well as the identification of novel strategies to target cisplatin-resistant TGCTs have major clinical implications.  Herein, we have examined the proficiency of five embryonal carcinoma (EC) cell lines to repair cisplatin-induced ICLs. Using gammaH2AX staining as a marker of double strand break formation, we found that EC cell lines were either incapable  of or had a reduced ability to repair ICL-induced damage. The defect correlated with reduced Homologous Recombination (HR) repair, as demonstrated by the reduction of RAD51 foci formation and by direct evaluation of HR efficiency using a GFP-reporter substrate. HR-defective tumors cells are known to be sensitive to  the treatment with poly(ADP-ribose) polymerase (PARP) inhibitor. In line with this observation, we found that EC cell lines were also sensitive to PARP inhibitor monotherapy. The magnitude of sensitivity correlated with HR-repair reduced proficiency and with the expression levels and activity of PARP1 protein. In addition, we found that PARP inhibition strongly enhanced the response of the  most resistant EC cells to cisplatin, by reducing their ability to overcome the damage. These results point to a reduced proficiency of HR repair as a source of  sensitivity of ECs to ICL-inducing agents and PARP inhibitor monotherapy, and suggest that pharmacological inhibition of PARP can be exploited to target the stem cell component of the TGCTs (namely ECs) and to enhance the sensitivity of cisplatin-resistant TGCTs to standard treatments.

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[1076]

TÍTULO / TITLE:  - Superior efficacy of co-treatment with dual PI3K/mTOR inhibitor NVP-BEZ235 and pan-histone deacetylase inhibitor against human pancreatic cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncotarget. 2012 Nov;3(11):1416-27.

AUTORES / AUTHORS:  - Venkannagari S; Fiskus W; Peth K; Atadja P; Hidalgo M; Maitra A; Bhalla KN

INSTITUCIÓN / INSTITUTION:  - The University of Kansas Cancer Center, Kansas City, KS, USA.

RESUMEN / SUMMARY:  - Genetic alterations activating K-RAS and PI3K/AKT signaling are also known to induce the activity of mTOR kinase through TORC1 and TORC2 complexes in human pancreatic ductal adenocarcinoma (PDAC). Here, we determined the effects of the dual PI3K and mTOR inhibitor, NVP-BEZ235 (BEZ235), and the pan-histone deacetylase inhibitor panobinostat (PS) against human PDAC cells. Treatment with  BEZ235 or PS inhibited cell cycle progression with induction of the cell cycle inhibitory proteins, p21waf1 and p27kip1. BEZ235 and PS also dose dependently induced loss of cell viability of the cultured PDAC cells, associated with depletion of phosphorylated (p) AKT, as well as of the TORC1 substrates 4EBP1 and p70S6 kinase. While inhibiting p-AKT, treatment with PS induced the levels of the pro-apoptotic proteins BIM and BAK. Co-treatment with BEZ235 and PS synergistically induced apoptosis of the cultured PDAC cells. This was accompanied by marked attenuation of the levels of p-AKT and Bcl-xL but induction of BIM. Although in vivo treatment with BEZ235 or PS reduced tumor growth, co-treatment with BEZ235 and PS was significantly more effective in controlling the xenograft growth of Panc1 PDAC cells in the nude mice. Furthermore, co-treatment with BEZ235 and PS more effectively blocked tumor growth of primary  PDAC heterotransplants (possessing K-RAS mutation and AKT2 amplification) subcutaneously implanted in the nude mice than each agent alone. These findings demonstrate superior activity and support further in vivo evaluation of combined  treatment with BEZ235 and PS against PDAC that possess heightened activity of RAS-RAF-ERK1/2 and PI3K-AKT-mTOR pathways.

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[1077]

TÍTULO / TITLE:  - A Core-Shell Albumin Copolymer Nanotransporter for High Capacity Loading and Two-Step Release of Doxorubicin with Enhanced Anti-Leukemia Activity.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Adv Healthc Mater. 2012 Dec 7. doi: 10.1002/adhm.201200296.

            ●● Enlace al texto completo (gratuito o de pago) 1002/adhm.201200296

AUTORES / AUTHORS:  - Wu Y; Ihme S; Feuring-Buske M; Kuan SL; Eisele K; Lamla M; Wang Y; Buske C; Weil T

INSTITUCIÓN / INSTITUTION:  - Institute of Organic Chemistry III, Macromolecular Chemistry, Albert-Einstein-Allee 11, 89081 Ulm, Germany; Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.

RESUMEN / SUMMARY:  - The native transportation protein serum albumin represents an attractive nano-sized transporter for drug delivery applications due to its beneficial safety profile. Existing albumin-based drug delivery systems are often limited by their low drug loading capacity as well as noticeable drug leakage into the blood circulation. Therefore, a unique albumin-derived core-shell doxorubicin (DOX) delivery system based on the protein denaturing-backfolding strategy was developed. 28 DOX molecules were covalently conjugated to the albumin polypeptide backbone via an acid sensitive hydrazone linker. Polycationic and pegylated human serum albumin formed two non-toxic and enzymatically degradable protection shells around the encapsulated DOX molecules. This core-shell delivery system possesses  notable advantages, including a high drug loading capacity critical for low administration doses, a two-step drug release mechanism based on pH and the presence of proteases, an attractive biocompatibility and narrow size distribution inherited from the albumin backbone, as well as fast cellular uptake and masking of epitopes due to a high degree of pegylation. The IC(50) of these nanoscopic onion-type micelles was found in the low nanomolar range for Hela cells as well as leukemia cell lines. In vivo data indicate its attractive potential as anti-leukemia treatment suggesting its promising profile as nanomedicine drug delivery system.

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[1078]

TÍTULO / TITLE:  - Fighting cancer from different signalling pathways: Effects of the proteasome inhibitor Bortezomib in combination with the polo-like-kinase-1-inhibitor BI2536  in SCCHN.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Lett. 2012 Dec;4(6):1305-1308. Epub 2012 Sep 20.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ol.2012.927

AUTORES / AUTHORS:  - Leinung M; Hirth D; Tahtali A; Diensthuber M; Stover T; Wagenblast J

INSTITUCIÓN / INSTITUTION:  - ENT Department, Medical School, Goethe University, Frankfurt am Main, Germany.

RESUMEN / SUMMARY:  - Inhibition of the proteasome with Bortezomib as well as inhibition of Polo-like-kinase-1 (PLK-1) has been shown to be effective in many solid tumour models and also in squamous cell carcinoma of the head and neck (SCCHN) cell lines. For the first time, we systematically examined the antitumour effect of Bortezomib in combination with BI2536 in SCCHN in an in vitro study. Dose escalation studies were performed with nine SCCHN cell lines using Bortezomib and BI2536 as single agent and combination treatments. Growth-inhibitory and pro-apoptotic effects were measured quantitatively using cytohistology and Human  Apoptose Array kit. The combination of Bortezomib and BI2536 showed significant anti-proliferative and apoptotic activity in all SCCHN cell lines investigated (P=0.008) compared to both the untreated control group and Bortezomib alone. A combination treatment regime consisting of the proteasome inhibitor, Bortezomib,  and the inhibitor of PLK-1, BI2536, leads to an enhanced anti-proliferative and apoptotic effect in SCCHN cell lines, compared to single agent treatment with Bortezomib alone.

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[1079]

TÍTULO / TITLE:  - Development of predictive quantitative structure-activity relationship model and  its application in the discovery of human leukotriene A4 hydrolase inhibitors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Future Med Chem. 2013 Jan;5(1):27-40. doi: 10.4155/fmc.12.184.

            ●● Enlace al texto completo (gratuito o de pago) 4155/fmc.12.184

AUTORES / AUTHORS:  - Thangapandian S; John S; Son M; Arulalapperumal V; Lee KW

INSTITUCIÓN / INSTITUTION:  - Division of Applied Life Science (BK21 Program), Systems & Synthetic Agrobiotech  Center, Research Institute of Natural Science, Plant Molecular Biology & Biotechnology Research Center, Gyeongsang National University, 501 Jinju-daero, Gazwa-dong, Jinju 660-701, Republic of Korea.

RESUMEN / SUMMARY:  - Background: Human LTA4H catalyzes the conversion of LTA4 to LTB4 and plays a key  role in innate immune responses. Inhibition of this enzyme can be a valid method  in the treatment of inflammatory response exhibited through LTB4. Results & discussion: The quantitative structure-activity relationship (QSAR) models were developed using genetic function approximation and validated. A training set of 26 diverse compounds and their molecular descriptors were used to develop highly  correlating QSAR models. A six-descriptor model explaining the biological activity of the training and test sets with correlation values of 0.846 and 0.502, respectively, was selected as the best model and used in a database screening of drug-like Maybridge database followed by molecular docking. Conclusion: Based on the predicted potent inhibitory activities, expected binding mode and molecular interactions at the active site of hLTA4H final leads were selected as to be utilized in designing future hLTA4H inhibitors.

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[1080]

TÍTULO / TITLE:  - Antiproliferative effects of zinc-citrate compound on hormone refractory prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chin J Cancer Res. 2012 Jun;24(2):124-9. doi: 10.1007/s11670-012-0124-9.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11670-012-0124-9

AUTORES / AUTHORS:  - Hong SH; Choi YS; Cho HJ; Lee JY; Kim JC; Hwang TK; Kim SW

INSTITUCIÓN / INSTITUTION:  - Department of Urology, College of Medicine, the Catholic University of Korea, Seoul 137701, Korea.

RESUMEN / SUMMARY:  - OBJECTIVE: To investigate the antiproliferative effects of zinc-citrate compound  on hormone refractory prostate cancer (HRPC). METHODS: HRPC cell line (DU145) and normal prostate cell line (RWPE-1) were treated with zinc, citrate and zinc-citrate compound at different time intervals and concentrations to investigate the effect of zinc-citrate compound. Mitochondrial (m)-aconitase activity was determined using aconitase assay. DNA laddering analysis was performed to investigate apoptosis of DU145 cells. Molecular mechanism of apoptosis was investigated by Western blot analysis of P53, P21(waf1), Bcl-2, Bcl-xL and Bax, and also caspase-3 activity analysis. RESULTS: Treatment with zinc-citrate compound resulted in a time- and dose-dependent decrease in cell number of DU145 cells in comparison with RWPE-1. M-aconitase activity was significantly decreased. DNA laddering analysis indicated apoptosis of DU145 cells. Zinc-citrate compound increased the expression of P21(waf1) and P53, and reduced the expression of Bcl-2 and Bcl-xL proteins but induced the expression of Bax protein. Zinc-citrate compound induced apoptosis of DU145 cells by activation of the caspase-3 pathway. CONCLUSION: Zinc-citrate compound can induce apoptotic  cell death in DU145, by caspase-3 activation through up-regulation of apoptotic proteins and down-regulation of antiapoptotic proteins.

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[1081]

TÍTULO / TITLE:  - An efficient piecewise linear model for predicting activity of caspase-3 inhibitors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Daru. 2012 Sep 10;20(1):31. doi: 10.1186/2008-2231-20-31.

            ●● Enlace al texto completo (gratuito o de pago) 1186/2008-2231-20-31

AUTORES / AUTHORS:  - Firoozpour L; Sadatnezhad K; Dehghani S; Pourbasheer E; Foroumadi A; Shafiee A; Amanlou M

INSTITUCIÓN / INSTITUTION:  - Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran. amanlou@tums.ac.ir.

RESUMEN / SUMMARY:  - ABSTRACT: METHODS: The linear (Multiple linear regression; MLR), non-linear (Artificial neural network; ANN), and an approach based on “Extended Classifier System in Function approximation” (XCSF) were applied herein to model the biological activity of 658 caspase-3 inhibitors. RESULTS: Various kinds of molecular descriptors were calculated to represent the molecular structures of the compounds. The original data set was partitioned into the training and test sets by the K-means classification method. Prediction error on the test data set  indicated that the XCSF as a local model estimates caspase-3 inhibition activity, better than the global models such as MLR and ANN. The atom-centered fragment type CR2X2, electronegativity, polarizability, and atomic radius and also the lipophilicity of the molecule, were the main independent factors contributing to  the caspase-3 inhibition activity. CONCLUSIONS: The results of this study may be  exploited for further design of novel caspase-3 inhibitors.

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[1082]

TÍTULO / TITLE:  - The effectiveness of interferon-alpha subtypes alternation for metastasis from renal cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biomed Res. 2012;33(6):323-8.

AUTORES / AUTHORS:  - Kadono Y; Miwa S; Shima T; Konaka H; Mizokami A; Yotsuyanagi S; Hirata A; Takase Y; Sugata T; Shimamura M; Namiki M

INSTITUCIÓN / INSTITUTION:  - Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa.

RESUMEN / SUMMARY:  - Interferon-alpha (IFN-alpha) has been used in systemic treatment for metastatic renal cell carcinoma (mRCC). IFN-alpha has at least 14 subtypes, each of which has different biological activity. There have been reports that mRCC resistant to an IFN-alpha treatment responded to another IFN-alpha subtype. This study was performed to evaluate the effectiveness of alternation of different IFN-alpha subtypes for mRCC that did not respond to initial IFN-alpha treatment. In our department and associated institutions, alternating therapy of IFN-alpha was provided for 15 initial IFN-alpha refractory mRCC cases from June 2005 to September 2008. Among the 15 patients, the effects of alternating IFN-alpha therapy were as follows: complete response (CR), 0 cases; partial response (PR),  1 case; stable disease (SD), 3 cases; progressive disease (PD), 11 cases. The response rate (CR+PR) was 7% and disease control rate (CR+PR+SD) was 27%. No severe side effects were observed in any of these cases. The PR case is still in  PR 21 months after alternating IFN-alpha therapy. Among the three SD cases, one has continued SD for 14 months and the other for 12 months. Alternating IFN-alpha therapy for mRCC can be attempted even if other cytokines are not effective.

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[1083]

TÍTULO / TITLE:  - Acquired differential regulation of caspase-8 in cisplatin-resistant non-small-cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Death Dis. 2012 Dec 20;3:e449. doi: 10.1038/cddis.2012.186.

            ●● Enlace al texto completo (gratuito o de pago) 1038/cddis.2012.186

AUTORES / AUTHORS:  - Paul I; Chacko AD; Stasik I; Busacca S; Crawford N; McCoy F; McTavish N; Wilson B; Barr M; O’Byrne KJ; Longley DB; Fennell DA

INSTITUCIÓN / INSTITUTION:  - Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Northern Ireland, UK.

RESUMEN / SUMMARY:  - Failure to efficiently induce apoptosis contributes to cisplatin resistance in non-small-cell lung cancer (NSCLC). Although BCL-2-associated X protein (BAX) and BCL-2 antagonist killer (BAK) are critical regulators of the mitochondrial apoptosis pathway, their requirement has not been robustly established in relation to cisplatin. Here, we show that cisplatin can efficiently bypass mitochondrial apoptosis block caused by loss of BAX and BAK, via activation of the extrinsic death receptor pathway in some model cell lines. Apoptosis resistance following cisplatin can only be observed when both extrinsic and intrinsic pathways are blocked, consistent with redundancy between mitochondrial  and death receptor pathways in cisplatin-induced apoptosis. In H460 NSCLC cells,  caspase-8 cleavage was shown to be induced by cisplatin and is dependent on death receptor 4, death receptor 5, Fas-associated protein with death domain, acid sphingomyelinase and ceramide synthesis. In contrast, cisplatin-resistant cells fail to activate caspase-8 via this pathway despite conserving sensitivity to death ligand-driven activation. Accordingly, caspase-8 activation block acquired  during cisplatin resistance, can be bypassed by death receptor agonism.

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[1084]

TÍTULO / TITLE:  - Triptorelin in the management of prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Future Oncol. 2013 Jan;9(1):93-102. doi: 10.2217/fon.12.158.

            ●● Enlace al texto completo (gratuito o de pago) 2217/fon.12.158

AUTORES / AUTHORS:  - Ploussard G; Mongiat-Artus P

INSTITUCIÓN / INSTITUTION:  - Department of Urology & Paris 7 University, APHP, Saint-Louis Hospital, Paris, France.

RESUMEN / SUMMARY:  - Among the therapies to achieve medical castration, gonadotropin-releasing hormone (GnRH) agonists have better safety profiles than estrogens and anti-androgens. In addition, slow-release formulations of GnRH agonists offer patients flexibility,  improve quality of life and eventually reduce cost. To illustrate the role of medical castration in prostate cancer, this paper reviews data on the GnRH agonist triptorelin long-duration and shorter-duration formulations. A similar proportion of patients achieved and maintained castration levels of serum testosterone (</=50 ng/dl) with all triptorelin formulations. Moreover, using a stricter definition of medical castration (serum testosterone <20 ng/dl), castration was maintained in >90% of patients with the 6-month triptorelin formulation. The new formulation was also well-tolerated, whilst being more convenient for patients. This short review assesses the role of this GnRH agonist in the treatment of prostate cancer.

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[1085]

TÍTULO / TITLE:  - Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants, Prolactin and Breast Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Front Oncol. 2012;2:177. doi: 10.3389/fonc.2012.00177. Epub 2012 Dec 5.

            ●● Enlace al texto completo (gratuito o de pago) 3389/fonc.2012.00177

AUTORES / AUTHORS:  - Ashbury JE; Levesque LE; Beck PA; Aronson KJ

INSTITUCIÓN / INSTITUTION:  - Department of Community Health and Epidemiology, Carruthers Hall, Queen’s University Kingston, ON, Canada.

RESUMEN / SUMMARY:  - Selective serotonin reuptake inhibitors (SSRIs) are a widely prescribed class of  antidepressants. Laboratory and epidemiologic evidence suggests that a prolactin-mediated mechanism secondary to increased serotonin levels at neuronal  synapses could lead to a potentially carcinogenic effect of SSRIs. In this population-based case-control study, we evaluated the association between SSRI use and breast cancer risk as a function of their relative degree of inhibition of serotonin reuptake as a proxy for their impact on prolactin levels. Cases were 2,129 women with primary invasive breast cancer diagnosed from 2003 to 2007, and  controls were 21,297 women randomly selected from the population registry. Detailed information for each SSRI prescription dispensed was compiled using the  Saskatchewan prescription database. Logistic regression was used to evaluate the  impact of use of high and lower inhibitors of serotonin reuptake and duration of  use, as well as to assess the effect of individual high inhibitors on the risk of breast cancer. Exclusive users of high or lower inhibitors of serotonin reuptake  were not at increased risk for breast cancer compared with non-users of SSRIs (OR = 1.01, CI = 0.88-1.17 and OR = 0.91, CI = 0.67-1.25 respectively), regardless of their duration of use or menopausal status. While we cannot rule out the possibility of a clinically important risk increase (OR = 1.83, CI = 0.99-3.40) for long-term users of sertraline (>/=24 prescriptions), given the small number of exposed cases (n = 12), the borderline statistical significance, and the wide  confidence interval, these results need to be interpreted cautiously. In this large population-based case-control study, we found no conclusive evidence of breast cancer risk associated with the use of SSRIs even after assessing the degree of serotonin reuptake inhibition and duration of use. Our results do not support the serotonin-mediated pathway for the prolactin-breast cancer hypothesis.

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[1086]

TÍTULO / TITLE:  - Arresten, a collagen-derived angiogenesis inhibitor, suppresses invasion of squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2012;7(12):e51044. doi: 10.1371/journal.pone.0051044. Epub 2012 Dec 5.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0051044

AUTORES / AUTHORS:  - Aikio M; Alahuhta I; Nurmenniemi S; Suojanen J; Palovuori R; Teppo S; Sorsa T; Lopez-Otin C; Pihlajaniemi T; Salo T; Heljasvaara R; Nyberg P

INSTITUCIÓN / INSTITUTION:  - Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.

RESUMEN / SUMMARY:  - The turnover of extracellular matrix liberates various cryptic molecules with novel biological activity. Among these are the collagen-derived anti-angiogenic fragments, some of which are suggested to affect carcinoma cells also directly. Arresten is an endogenous angiogenesis inhibitor that is derived from the non-collagenous domain of the basement membrane collagen IV alpha1 chain. As the  mere prevention of tumor angiogenesis leads to hypoxia that can result in selection of more aggressive cell types and reduces the efficacy of chemotherapy, we aimed here to elucidate how arresten influences the aggressive human carcinoma cells. Arresten efficiently inhibited migration and invasion of HSC-3 tongue carcinoma cells in culture and in an organotypic model. Subcutaneous Arr-HSC xenografts grew markedly more slowly in nude mice and showed reduced tumor cell proliferation, vessel density and local invasiveness. In the organotypic assay, HSC-3 cells overproducing arresten (Arr-HSC) showed induction of cell death. In monolayer culture the Arr-HSC cells grew in aggregated cobblestone-like clusters  and, relative to the control cells, showed increased expression and localization  of epithelial marker E-cadherin in cell-cell contacts. Application of electric cell-substrate impedance sensing (ECIS) further supported our observations on altered morphology and motility of the Arr-HSC cells. Administration of a function-blocking alpha1 integrin antibody abolished the impedance difference between the Arr-HSC and control cells suggesting that the effect of arresten on promotion of HSC-3 cell-cell contacts and cell spreading is at least partly mediated by alpha1beta1 integrin. Collectively, our data suggest novel roles for  arresten in the regulation of oral squamous carcinoma cell proliferation, survival, motility and invasion through the modulation of cell differentiation state and integrin signaling.

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[1087]

TÍTULO / TITLE:  - ERCC1 mRNA levels can predict the response to cisplatin-based concurrent chemoradiotherapy of locally advanced cervical squamous cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Radiat Oncol. 2012 Dec 23;7:221. doi: 10.1186/1748-717X-7-221.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1748-717X-7-221

AUTORES / AUTHORS:  - Bai ZL; Wang YY; Zhe H; He JL; Hai P

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, General Hospital of Ningxia Medical University, No,804 Shengli Str, Yinchuan, Ningxia, 750004, China. nxzh1961@hotmail.com.

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: The purpose of this study was to investigate whether the excision repair cross-complementation group 1 (ERCC1) mRNA expression could predict treatment response of patients with locally advanced cervical squamous cell carcinoma (LACSCC) who underwent cisplatin-based concurrent chemoradiotherapy (CCCRT). METHODS: A total of sixty LACSCC patients, treated with radical CCCRT from a single institution were evaluated. ERCC1 mRNA expression was determined by quantitative real-time RT-PCR in pre-treatment tumor tissues. The association of ERCC1 status with clinicopathological characteristics (age, histological grade, tumor size, parametrial invasion, lymph node metastasis and FIGO stage) and treatment response were analyzed. RESULTS: No significant association between ERCC1 mRNA expression and clinicopathological characteristics were observed. Patients with low ERCC1 mRNA level had a significantly higher rate of complete response (86.21%) than patients with high level of ERCC1 expression (19.36%; p < 0.001). In the logistic regression analysis, low ERCC1 mRNA level retained an independent role in predicting complete response to CCCRT (P < 0.001). An ERCC1 expression level of 0.0901 was determined as an optimal cutoff value to identify complete response patients to CCCRT treatment. The sensitivity  for detection of a complete response was 81.48% with a specificity of 96.97% (area under the curve, 0.893; 95% confidence interval, 0.804-0.983). CONCLUSIONS: This is the first analysis of the association between ERCC1 mRNA levels and treatment response in patients with LACSCC. Low ERCC1 mRNA level appears to be a  highly specific predictor of response to CCCRT in LACSCC.

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[1088]

TÍTULO / TITLE:  - Malignant hyperthermia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Korean J Anesthesiol. 2012 Nov;63(5):391-401. doi: 10.4097/kjae.2012.63.5.391. Epub 2012 Nov 16.

            ●● Enlace al texto completo (gratuito o de pago) 4097/kjae.2012.63.5.391

AUTORES / AUTHORS:  - Kim DC

INSTITUCIÓN / INSTITUTION:  - Department of Anesthesiology and Pain Medicine, Chonbuk National University Medical School, Jeonju, Korea.

RESUMEN / SUMMARY:  - Malignant hyperthermia (MH) is an uncommon, life-threatening pharmacogenetic disorder of the skeletal muscle. It presents as a hypermetabolic response in susceptible individuals to potent volatile anesthetics with/without depolarizing  muscle relaxants; in rare cases, to stress from exertion or heat stress. Susceptibility to malignant hyperthermia (MHS) is inherited as an autosomally dominant trait with variable expression and incomplete penetrance. It is known that the pathophysiology of MH is related to an uncontrolled rise of myoplasmic calcium, which activates biochemical processes resulting in hypermetabolism of the skeletal muscle. In most cases, defects in the ryanodine receptor are responsible for the functional changes of calcium regulation in MH, and more than 300 mutations have been identified in the RYR1 gene, located on chromosome 19q13.1. The classic signs of MH include increase of end-tidal carbon dioxide, tachycardia, skeletal muscle rigidity, tachycardia, hyperthermia and acidosis. Up to now, muscle contracture test is regarded as the gold standard for the diagnosis of MHS though molecular genetic test is used, on a limited basis so far to diagnose MHS. The mortality of MH is dramatically decreased from 70-80% to less than 5%, due to an introduction of dantrolene sodium for treatment of MH, early detection of MH episode using capnography, and the introduction of diagnostic testing for MHS. This review summarizes the clinically essential and important knowledge of MH, and presents new developments in the field.

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[1089]

TÍTULO / TITLE:  - Drug targets and predictive biomarkers in the management of metastatic melanoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pharmgenomics Pers Med. 2012;5:139-48. doi: 10.2147/PGPM.S25100. Epub 2012 Sep 28.

            ●● Enlace al texto completo (gratuito o de pago) 2147/PGPM.S25100

AUTORES / AUTHORS:  - Thumar J; Giesen E; Kluger HM

INSTITUCIÓN / INSTITUTION:  - Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.

RESUMEN / SUMMARY:  - Melanoma is the leading cause of fatal skin cancer, and in the past few decades,  there has been an increase in the incidence of and mortality from metastatic melanoma. Until recently, the therapeutic options for treatment of metastatic melanoma were limited. The approval of ipilimumab (an anti-CTLA-4 antibody) and vemurafenib (mutant B-RAF(V600E) kinase inhibitor) by the Federal Drug Administration has led to a new era in melanoma treatment, and additional promising drugs and drug combinations are currently being investigated. As the choices of treatment for melanoma have expanded, the need to identify predictive  biomarkers to tailor treatment strategies to individual tumor or immune system characteristics has become necessary. Such strategies have the potential of maximizing antitumor effect while minimizing toxicity and improving clinical benefit. In this article, we review the currently approved targeted therapies in  melanoma and discuss the future of personalized therapy for this disease.

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