tbuckley/cabot-search huggingface dataset:
Activity of dual PI3K/mTOR inhibitor, NVP-BEZ235, and mTOR inhibitor, RAD001 (everolimus), in endometrial cancer cell lines.
Authors: K. Shoji, K. Oda, S. Nakagawa, Y. Ikeda, H. Kuramoto, M. Nishida, K. Kawana, T. Yano, S. Kozuma, Y. Taketani
Journal: Journal of Clinical Oncology (2010)

5074 Background: PI3K and its downstream mTOR play a critical role in malignant phenotype in many tumors. PI3K pathway is frequently hyper-activated in endometrial cancer through various PI3K/AKT activating mutations (such as PTEN and PIK3CA). As these mutations activate not only mTOR pathway but other AKT effector pathways, dual inhibition of PI3K and mTOR might be more effective than mTOR inhibition alone in endometrial cancer. NVP-BEZ235 is a dual inhibitor of PI3K and mTOR, and is currently under phase I/II trials in solid tumors. Our aims were to compare the activity of NVP-BEZ235 with that of mTOR inhibitor, RAD001, in endometrial cancer cell lines. Methods: Using 13 endometrial cancer cell lines, 11 of which possess mutations in PTEN and/or PIK3CA, we evaluated the effects of NVP-BEZ235 and RAD001 on cell growth by MTT assay and FACS analysis. A xenograft endometrial cancer model was used to determine in vivo effects. Results: RAD001 at 50nM showed growth inhibitory effect with 30%-60% reduction against ten cell lines, all of which possess PTEN and/or PIK3CA mutations. NVP-BEZ235 at 50nM inhibited cell growth with 30%-80% in all the cell lines examined. The observed IC50-values of RAD001 were less than 100nM in two of the 13 cell lines (15%), whereas the values of NVP-BEZ235 with less than 100nM were observed in ten (77%) cell lines. All of these ‘sensitive' cells possess PTEN and/or PIK3CA mutations. FACS analysis revealed that G1 arrest was more efficiently induced by NVP-BEZ235 than RAD001. We observed in vivo anti-tumor activity of NVP-BEZ235 at a tolerated dose in mice inoculated with PTEN mutant endometrial cell line. Conclusions: Our data suggest that both NVP-BEZ235 and RAD001 suppressed cell growth in endometrial cancer cell lines, especially in cells with PIK3CA and/or PTEN mutations. More robust activity of NVP-BEZ235 than RAD001 suggested that inhibition of multiple AKT effector pathways, including the mTOR pathway, is important for sufficient suppression of the tumor growth. Considering the high frequency of mutations in both PIK3CA and PTEN, a dual PI3K/mTOR inhibitor, such as NVP-BEZ235, would be a promising molecular-targeted therapy in endometrial cancer. No significant financial relationships to disclose.
Abstract #5603: Autophagy as the predominant type of programmed cell death induced by high-LET radiation combined with oxaliplatin in a human hepatocellular carcinoma cell line
Authors: Anais Altmeyer, Mihaela Ignat, Alain Jung, Marc Wilt, Jean Marc Denis, John Gueulette, Georges Noel, Didier Mutter, Pierre Bischoff
Journal: Cancer Research (2009)

While radiochemotherapeutic protocols have improved treatment outcomes in several types of human cancers, they remain unsatisfactory as malignant cells continue to resist to their destruction by ionising radiation in many cases. Radiation therapy with high linear energy transfer (LET) accelerated particles (fast neutrons and carbon ions), called hadrontherapy, has been shown to overcome radioresistance against standard low-LET radiation. Combining these two approaches is therefore a possible strategy to increase killing of highly radioresistant cancer cells. Previously, we reported that fast neutrons (p(65)+Be) (produced at the Cyclotron Research Center, Louvain-la-Neuve, Belgium) could induce autophagy, an alternative mode of programmed cell death, when combined with oxaliplatin (Ox) in radioresistant U-87 glioblastoma cells. In the present study, we further investigated the effects of fast neutron irradiation combined with Ox in the human hepatocellular carcinoma cell line SK-Hep1, with the aim of comparing the occurrence of autophagy with the number and persistence of DNA double strand breaks (DSBs). The poly(ADP-ribose)polymerase (PARP) inhibitor PJ34 was also tested for its capacity to amplify DNA damages caused by this co-treatment. Cells were irradiated in the presence or absence of Ox (3µM) and/or PJ34 (5µM), and the incidences of apoptosis, autophagy and DSBs were determined at various times post-irradiation. The percentages of apoptotic and autophagic cells were measured by flow cytometry after propidium iodide and acridine orange staining, and foci corresponding to DSBs we scored after an anti-\#947;-H2AX labelling. Autophagic vacuoles were visualized by fluorescence microscopy after GFP-LC3 transfection. Results indicate the emergence of a large number of DSBs at 24 hr, persisting until 72 hours after irradiation, in Ox-treated, irradiated cells. At 24 hr, this number was highly elevated compared to non-irradiated untreated control cells and was further increased when PJ34 was added to the co-treatment. Interestingly, this trend was reversed at 48hr, the highest number of DSBs being obtained for cells irradiated (8 Gy) without additional drug treatment. The highest percentage of autophagic cells was also obtained at this time point under the same conditions, which strongly suggests the existence of a correlation between the persistence of DSBs and the induction of autophagy after high-LET irradiation. Next, we will investigate the induction of autophagy by the combination of Ox + high-LET radiation in cell lines derived from head and neck squamous cell carcinoma, as these are also indications for hadrontherapy.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5603.
Female gender is an independent predictor of superior perioperative survival following non-small cell lung cancer (NSCLC) resection
Authors: B. J. Park, N. Rizk, R. M. Flores, R. Downey, M. S. Bains, V. W. Rusch
Journal: Journal of Clinical Oncology (2006)

7150 Background: Selecting patients who will benefit from surgical resection of NSCLC, especially following induction therapy, can be challenging. We analyzed our modern experience to determine factors associated with superior operative outcomes. Methods: A retrospective review of a prospectively maintained database of consecutive NSCLC patients who underwent surgical exploration for resection from January 1999 through June 2005 was performed. Factors evaluated included age, sex, co-morbidities, use of induction therapy, previous thoracic operations, extent of lung resection, and in-hospital mortality. Associations between categorical variables were evaluated with a chi-squared test and for continuous variables with an analysis of variance. Multivariate analysis was done with a logistic regression model. Results: A total of 2,524 patients underwent attempt at surgical resection, 1,398 of whom were female (55.4%). One hundred and four (4.1%) patients had exploration only. The majority of patients underwent lobectomy (1,692/2,524, 67.1%), and 6.1% (154/2,524) had a pneumonectomy. Induction therapy was given in 492 patients (19.5%). Univariate analysis showed that male gender (2.4% vs 0.93%, respectively, p = 0.003), presence of cardiac co-morbidity (p = 0.05), poor diffusion capacity (p = 0.003), and greater extent of resection (p = 0.01) were associated with increased in-hospital mortality. Multivariate analysis controlling for gender, age, diffusion capacity, cardiac, and diabetic co-morbidity, as well as prior lung cancer operation, extent of resection and use of induction therapy demonstrated that increased age, decreased diffusion capacity and greater anatomic lung resection were risk factors for higher in-hospital mortality. However, female sex was an independent predictor of lower in-hospital mortality (OR 0.41, p = 0.01). Conclusions: In addition to other previously described predictors of poor surgical outcome, such as advanced age, poor lung function and greater extent of lung removal, we observed that female gender appears to be associated with better in-hospital survival following surgical resection of NSCLC. No significant financial relationships to disclose.
Follicular large-cell lymphoma: intermediate or low grade?
Authors: N L Bartlett, M Rizeq, R F Dorfman, J Halpern, S J Horning
Journal: Journal of Clinical Oncology (1994)

PURPOSE To evaluate the benefit of anthracycline-based chemotherapy, identify prognostic factors, and determine the value of the International Prognostic Factors Index for patients with follicular large-cell (FLC) lymphoma. PATIENTS AND METHODS This retrospective study includes 96 patients with FLC lymphoma treated at Stanford University Medical Center between 1969 and 1991. Fifty-five patients received doxorubicin plus cyclophosphamide-containing chemotherapy regimens, 21 patients received other chemotherapy regimens, 15 patients received radiotherapy only, and five patients received no initial therapy. Thirty-four patients had stage I or II disease and 62 patients had stage III or IV disease. RESULTS With a median follow-up duration of 5.2 years (range, 1 to 18), the actuarial 5- and 10-year overall survival rates were 75% and 54%, with actuarial 5- and 10-year freedom from progression (FFP) rates of 53% and 42%, respectively. Patients treated with chemotherapy regimens that contained both doxorubicin and cyclophosphamide had a superior actuarial 10-year FFP rate (55% v 25%, P = .06) and overall survival rate (65% v 42%, P = .04) compared with patients treated with other chemotherapy regimens. Only one patient treated with doxorubicin plus cyclophosphamide relapsed after 3 years. In the multivariate analysis, discordant lymphoma and treatment with chemotherapy regimens not containing both cyclophosphamide and doxorubicin predicted for worse FFP and overall survival rates. In addition, poor performance status and increasing areas of diffuse histology predicted for a worse survival, while anemia and male sex predicted for a worse FFP. The age-specific International Index was useful in predicting outcome; however, few patients with FLC lymphoma had high-risk features. CONCLUSION The plateau in FFP implies that patients with FLC lymphoma enjoy sustained remissions after standard anthracycline-based chemotherapy. FLC lymphoma should continue to be approached as an intermediate-grade lymphoma with curative intent.
Abstract 19545: The Association Between Adiposity and Mortality in Patients with Coronary Artery Disease is Modified by Time
Authors: Billie-Jean Martin, Lawrence De Koning, Danielle A Southern, Adriane M Lewin, P D Galbraith, Colleen M Norris, Merill L Knudtson, None APPROACH Investigators
Journal: Circulation (2012)

Introduction: Obese Coronary Artery Disease (CAD) patients have improved short and intermediate term outcomes compared to those of normal weight. However excess mass may be associated with poor long-term outcomes. The objective of this study was to assess the association between weight and mortality in a population with CAD in different time frames. Methods: We used the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) database. Subjects were classified by BMI as normal weight (18.5 - 24.9kg/m2), overweight (25 - 29.9kg/m2), obese class I (30 - 34.9kg/m2), obese class II (35 - 39.9kg/m2), or obese class III (≥40 kg/m2). Mortality was considered over the entire follow-up, within 2 years of catheterization (short-term) or more than 2 years post-catheterization (long-term). Cox models were used to determine the association between weight and mortality. Models were adjusted for all clinical risk factors and initial treatment strategy. Results: There were 45494 subjects with ≥ one vessel CAD (overweight: 41.9%, obese class I: 23.8%, obese class II: 7.8%, obese class III: 3.5%; 23.9% female; mean age 64.0 years). There were 7904 deaths over a median of 5.6 years of follow-up (61% after 2 years). In the complete follow-up period, compared to normal weight, the hazard ratio (HR) for mortality among overweight subjects was 0.84 (p&lt;0.0001), obesity class I was 0.91 (p=0.004), obesity class II 0.98 (p=0.61), obesity class III 1.15 (p=0.038). There was a significant interaction between time and each weight class (p&lt;0.0001). In short-term follow-up, the HR for overweight was 0.80 (p&lt;0.001), for obese class I was 0.77 (p&lt;0.001), for obese class II 0.80 (p=0.006) and for obese class III was 0.92 (p=0.434). With deaths in the first two years excluded, only overweight status was associated with reduced mortality, while obese class III was associated with increased mortality (HR 1.31 (95% CI 1.12, 1.54). Conclusion: The association of adiposity with mortality in CAD patients varies by time, with the protective effect of excess weight diminishing over time. Conditions that decrease mass may result in early deaths.
Outcome of patients with recurrent hepatocellular carcinoma after liver transplantation.
Authors: A. Finkenstedt, I. W. Graziadei, H. Zoller, K. Nachbaur, W. Mark, W. Vogel
Journal: Journal of Clinical Oncology (2010)

4087 Background: Although current selection criteria have led to a significant decrease in HCC recurrence rates after liver transplantation (LT), recent studies have still reported rates around 10%-15%. Only few studies have addressed therapeutic options and outcome of patients with recurrent HCC. In this study we aimed to evaluate the survival of patients with HCC recurrence and to identify specific risk factors. Methods: We analyzed the data of 202 HCC patients (26 f/176 m) who underwent LT at our institution. Their median age was 60 (31-75) ys. The main underlying liver diseases were viral in 51% and (non) alcoholic fatty liver disease in 33%. Regarding Child-Pugh, 40% had stage A, 46% B and 14% C. PreLT TACE was performed in 138 patients, RFA in 8 and both in 10 cases. The mean follow-up was 6.1 years. Results: The actuarial patient survival rates at 1-, 5- and 10-years were 85%, 65% and 55%, respectively. HCC recurrence was found in 36 patients (18%) after a median time of 1.2 (0.2-7.4) years after LT. Patients survival at 5 and 10 years was considerably lower for patients with recurrent disease (27%, 0%) than for patients without (73% and 68%). Recurrence was limited to the liver or lymph nodes in 6 and 4 patients, 26 patients presented with metastatic disease. 24 (67%) patients died due to recurrent HCC leading to a median survival after recurrence of 0.8 (0.1–5.5) ys. The outcome of patients with recurrent HCC was significantly better if surgical or local ablative treatment options (n = 9) were possible compared to experimental systemic chemotherapy (n = 9) or best supportive care (n = 18) with median survival rates of 42.6 vs. 11.9 vs. 4.2 months (p = 0.005). In multivariate analysis preLT therapy did not influence HCC recurrence, but complete response to pre LT treatment was associated with a significantly lower risk of recurrence compared to partial or no response. Risk of recurrence correlated significantly with poorly differentiated tumors, vascular invasion, UICC stage I/II vs. III/IVa and tumor size. Conclusions: Patients suitable for surgical or loco ablative therapy have an excellent prognosis despite recurrent HCC. This warrants an intensive post-transplant surveillance program to diagnose HCC recurrence at an early stage. No significant financial relationships to disclose.
Phase II study of bevacizumab (BEV), weekly (wkly) intermittent capecitabine (Cap), and oxaliplatin (Ox) on an every-2-week schedule for patients (Pts) with untreated advanced colorectal cancer (CRC)
Authors: B. C. Lembersky, R. Sehgal, K. K. Rajasenan, T. L. Crandall, E. P. Balaban, R. A. Pinkerton, P. Kane, D. M. Potter, C. Kinney, R. K. Ramanathan
Journal: Journal of Clinical Oncology (2008)

4061 Background: CapOx and Bev is becoming a standard regimen for advanced CRC utilizing Cap on a d 1–14 schedule every 3 wks. However optimal doses and schedules of Cap with Ox and Bev needs continued evaluation. Intermittent wkly Cap (3,500 mg/m2, d 1–7) with Ox (85 mg/m2) every 2 wks compared to the standard CapOx regimen in untreated advanced CRC has shown superior response and progression free survival (PFS) in Europe (JCO 21,1307; 2003). Methods: This phase II trial was designed to evaluate weekly intermittent Cap with Ox and Bev (A-ICOX regimen) in US pts with CRC. The primary endpoint was to detect a 50% improvement in median PFS from 8 to 12 months. Study required 40 patients, with 81% power (1-sided level 0.1 log-rank test). Cap was initially administered at dose of 2,500 mg/m2 in two divided doses on d 1–7 (n=11) and was increased to 3,000 mg/m2 dose (n=29), based on tolerability of the lower dose. The dose of Ox was 85 mg/m2 and Bev 5 mg/kg. Cycles were repeated every 2 wks. Preliminary data reported previously (A4092, ASCO 2007). Results: Study is completed with accrual of 40 pts. Patient characteristics: Male (n=25, 40%); ECOG performance status 0 (n=24), 1 (n=14); median age 62 (range 38–80 years). Median cycles administered 8 (range 1–25). Pertinent Grade 3/4 toxicities were: Hand Foot syndrome in 10%, diarrhea 18% and peripheral neuropathy in 10% of pts. Bowel perforation in 1 pt (3%) and one death due to a cerebral hemorrhage (3%). Response rate was 38% with one complete and 14 partial responses. Metastasectomy was performed in 11 pts (28%). PFS is 10 months (mo)(7.1–13.9 mo, 95% CI). Overall survival is not available. Conclusions: The first US experience of the A-ICOX regimen shows it to be well tolerated, and Cap (3,000 mg/m2, d 1–7) in combination with Ox and Bev therapy every 2 wks can be safely administered. The incidence of subsequent metastasectomy, a marker of activity, is encouraging. The PFS of 10 mo did not meet study endpoint of 12 mo, but compares favorably with PFS of 9.4 mo for XELOX/FOLFOX/Bev in the NO16966 study (A4028,ASCO2007). A phase III trial of the A-ICOX regimen compared to the standard Q-3 weekly CapOx/Bev regimen is nearing completion. Supported by Genentech and Roche Pharmaceuticals Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech, sanofi-aventis
Evolution of a Catalytic Mechanism
Authors: Alissa Rauwerdink, Mark Lunzer, Titu Devamani, Bryan Jones, Joanna Mooney, Zhi-Jun Zhang, Jian-He Xu, Romas J. Kazlauskas, Antony M. Dean
Journal: Molecular Biology and Evolution (2015)

The means by which superfamilies of specialized enzymes arise by gene duplication and functional divergence are poorly understood. The escape from adaptive conflict hypothesis, which posits multiple copies of a gene encoding a primitive inefficient and highly promiscuous generalist ancestor, receives support from experiments showing that resurrected ancestral enzymes are indeed more substrate-promiscuous than their modern descendants. Here, we provide evidence in support of an alternative model, the innovation–amplification–divergence hypothesis, which posits a single-copied ancestor as efficient and specific as any modern enzyme. We argue that the catalytic mechanisms of plant esterases and descendent acetone cyanohydrin lyases are incompatible with each other (e.g., the reactive substrate carbonyl must bind in opposite orientations in the active site). We then show that resurrected ancestral plant esterases are as catalytically specific as modern esterases, that the ancestor of modern acetone cyanohydrin lyases was itself only very weakly promiscuous, and that improvements in lyase activity came at the expense of esterase activity. These observations support the innovation–amplification–divergence hypothesis, in which an ancestor gains a weak promiscuous activity that is improved by selection at the expense of the ancestral activity, and not the escape from adaptive conflict in which an inefficient generalist ancestral enzyme steadily loses promiscuity throughout the transition to a highly active specialized modern enzyme.
Tensin2 with growth suppression and apoptosis induction activities is underexpressed in hepatocellular carcinoma
Authors: Judy Yam, Edith Tse, Frankie Ko, Lo Kong Chan, Karen Sze, Irene Ng
Journal: Cancer Research (2008)

1770   Tensin is a family of focal adhesion proteins that strategically located among the extracellular matrix, actin cytoskeleton and signal transduction. Dysregulation of tensin members has been implicated in various human cancers. Accumulating evidence has shown that different members of tensin family are interacting partners of tumor suppressor, Deleted in liver cancer (DLC). Our recent study has identified tensin2 as the interacting partner of DLC1 and tensin2 itself exerted pronounced growth suppressive activity in hepatocellular carcinoma (HCC) cells. In the present study, we aimed to elucidate the role of tensin2 in hepatocarcinogenesis by determining the expression of tensin2 in human HCC tissues and ectopically expressing tensin2 in HCC cell line. Quantitative analysis of tensin2 expression revealed that it was underexpressed in 40% of human HCC. HCC cells stably expressing tensin2 displayed lower proliferation rate, decreased anchorage-independent growth, inhibited motility and invasiveness as compared with the vector transfectants. In addition, ectopic expression of tensin2 in HCC cells caused a dramatic suppression of colony formation and triggered apoptosis. The regulatory PTEN and SH2 domains were responsible for the biological activity of tensin2. In conclusion, our study showed that tensin2 was underexpressed in HCC and suggested the potential negative regulatory role of tensin2 in hepatocarcinogenesis.
Abstract 362: Proteomic Analysis of Low Oxygen Tension-Induced Secretome of Adipose Tissue-Derived Stem Cells
Authors: Zeljko Bosnjak, Bassam Wakim, Yasheng Yan, Scott Canfield, Chika Kikuchi, Xiaowen Bai
Journal: Circulation Research (2012)

Growing evidence from animal studies shows that adipose tissue-derived stem cells (ASCs) improve cardiac function of infarcted hearts. It is commonly accepted that therapeutic potential of ASCs may depend more on their paracrine effects than differentiation potential. The underlying mechanisms remain unclear. However, most data regarding paracrine factors were obtained from ASCs cultured in normoxic condition (20%). The present study investigated how in vivo physiological oxygen (4%) tension influenced the secretome of ASCs. ASCs were isolated from three 8-week-old BALB/c mice. ASCs were confirmed by the expression of stem cell markers (CD44 and CD90) and their capacity to differentiate into adipocytes and osteocytes. ASCs at passage 5 were cultured in normoxic (20%) and lower oxygen (4%) incubators and conditioned for 24 h (3 cultures/group). The conditioned media (CM) from ASCs were subjected to trypsin digestion followed by analysis using automated nano-flow liquid chromatography tandem mass spectrometry. The collected LC/MS/MS data were searched against the rodent subset of the Uniprot database and the total proteomes were identified. The data were from 6 technical replicates. A total of 28 proteins were identified and 7 proteins were unique to normoxic CM. Of the 21 common proteins detected in both normoxic and lower oxygen CM, 9 were extracellular matrix proteins. The abundance of 6 of these proteins (e.g., collagen I and laminin) differed noticeably between normoxic and lower oxygen CM. In addition, a greater amount of cytokine CXCL5 and matrix metalloproteinase (MMP)-2 was detected in lower oxygen CM than in normoxic CM while tissue inhibitor of metalloproteinase (TIMP)-1 was only detected in normoxic CM. These results indicate that lower oxygen tension differentially regulates the secretome of ASCs. Extrapolating the results of this study to the in vivo setting, it would appear that injected ASCs may exert their anti-fibrotic and trophic effect by 1) directly regulating the balance of MMP/TIMP production and preventing collagen accumulation in ischemic hearts to decrease fibrosis, and 2) secreting trophic factors including CXCL5. These data suggest that proteomic analysis of CM is useful for elucidation of the paracrine effect of ASCs in vivo.