tbuckley/cabot-search huggingface dataset:
Effect of inhibition of poly-(ADP ribose) polymerase on gemcitabine and radiation-induced cytotoxicity of pancreatic cancer cells.
Authors: R. Tuli, A. Surmak, A. Blackford, A. Leubner, E. M. Jaffee, T. L. DeWeese, J. M. Herman
Journal: Journal of Clinical Oncology (2011)

203 Background: Poly-(ADP ribose) polymerases (PARPs) are DNA-binding proteins involved in DNA repair. PARP inhibition has resulted in excellent antitumor activity when used with other cytotoxic therapies. ABT-888 is a promising PARP inhibitor with excellent potency against the PARP-1/2 enzymes and good oral bioavailability. We attempt to determine whether PARP-1/2 inhibition alone, or in combination with gemcitabine, will enhance the effects of irradiation (RT) of pancreatic cancer cells. Methods: The pancreatic carcinoma cell lines, MiaPaCa-2 and Panc02, were treated with ABT-888, gemcitabine, RT, or combinations thereof. RT was delivered with a 137-Cs Gammacell in a single fraction. Cells were pre-treated once with ABT-888 and/or gemcitabine 30 minutes prior to RT. Viability was assessed through reduction of resazurin into fluorescent resorufin. Levels of apoptosis were determined by measuring caspase-3/7 activity using a luminescent assay. PARP activity was determined using a chemiluminescent PAR elisa. Results: The half maximal inhibitory concentration (IC50) of RT was 5 Gy; IC10 for ABT-888 and gemcitabine were 10 uM and 5 nM, respectively. Treatment with ABT-888 (10 uM), gemcitabine (5 nM), or combinations of the two with RT led to increasingly higher rates of cell death 8 days after treatment (p&lt;0.001). RT dose enhancement factors were 1.5, 1.82 and 2.36 for 1, 10 and 100 uM ABT-888, respectively. Minimal cytotoxicity was noted when cells were treated with ABT-888 alone up to 100 uM. Caspase activity was not significantly increased when treated with ABT-888 (10 uM) alone (1.28 fold, p=0.077), but became significant when RT (2 Gy) was added (2.03 fold, p=0.006). This difference was further enhanced by the addition of gemcitabine (2.95 fold, p=0.004). Conclusions: ABT-888 is a potent radiosensitizer of pancreatic cancer cells with minimal cytotoxicity when used alone. Cell death is further potentiated by cotreatment with gemcitabine. Radiation-induced apoptosis was significantly enhanced by ABT-888 and gemcitabine, suggesting a synergistic mechanism of interference with DNA repair. These data are currently being validated in an orthotopic pancreatic cancer mouse model. No significant financial relationships to disclose.
Outcome in Allo- SCT in Patients with Refrectory Acute Lymphoblastic Leukemia with Non TBI Conditioning Regimens
Authors: Ajay Sharma, Velu Nair, Sataya Ranjan Das, Sanjeevan Sharma, Jasjit Singh, Rajeev Kumar, Jyoti Kotwal, Jasmit Kaur
Journal: Blood (2014)
Expected effects of adopting a 9 month regimen for multidrug-resistant tuberculosis: a population modelling analysis
Authors: Emily A Kendall, Anthony T Fojo, David W Dowdy
Journal: The Lancet Respiratory Medicine (2016)

In May, 2016, WHO endorsed a 9 month regimen for multidrug-resistant tuberculosis that is cheaper and potentially more effective than the conventional, longer (20-24 month) therapy. We aimed to investigate the population-level implications of scaling up this new regimen.In this population modelling analysis, we developed a dynamic transmission model to simulate the introduction of this short-course regimen as an instantaneous switch in 2016. We projected the corresponding percentage reduction in the incidence of multidrug-resistant tuberculosis by 2024 compared with continued use of longer therapy. In the primary analysis in a representative southeast Asian setting, we assumed that the short-course regimen would double treatment access (through savings in resources or capacity) and achieve long-term efficacy at levels seen in preliminary cohort studies. We then did extensive sensitivity analyses to explore a range of alternative scenarios.Under the optimistic assumptions in the primary analysis, the incidence of multidrug-resistant tuberculosis in 2024 would be 3·3 (95% uncertainty range 2·2-5·6) per 100 000 population with the short-course regimen and 4·3 (2·9-7·6) per 100 000 population with continued use of longer therapy-ie, the short-course regimen could reduce incidence by 23% (10-38). Incidence would be reduced by 14% (4-28) if the new regimen affected only treatment effectiveness and by 11% (3-24) if it affected only treatment availability. Under more pessimistic assumptions, the short-course regimen would have minimal effect and even potential for harm-eg, when 30% of patients are ineligible for the new regimen because of second-line drug resistance, we projected a change in incidence of -2% (-20 to +28). The new regimen's effect was greater in settings with more ongoing transmission of multidrug-resistant tuberculosis, but results were otherwise similar across settings with different levels of tuberculosis incidence and prevalence of multidrug resistance.The short-course regimen has potential to substantially lessen the multidrug-resistant tuberculosis epidemic, but this effect depends on its long-term efficacy, its ability to expand treatment access, and the role of second-line drug resistance.US National Institutes of Health and Bill & Melinda Gates Foundation.
Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML in Vitro and in Vivo
Authors: Katia Beider, Merav Darash-Yahana, Boaz Pal, Orly Blaier, Maya Koren-Michowitz, Michal Abraham, Hanna Wald, Orly Eizenberg, Amnon Peled, Arnon Nagler
Journal: Blood (2012)
Abstract 3416: IHC assessment of PBRM1 loss in colon and lung carcinomas
Authors: Aihua Li, Yongfu Gao, Yuekai Zhang, Hongyang Pan, Jackie K. Chan, Ximing J. Yang, Taiying Chen
Journal: Cancer Research (2015)

Abstract PBRM1 (also known as BAF 180) is a chromatin remodeling polybromodomain protein recently identified as the second most frequently mutated gene in renal cell carcinoma (RCC). Loss of PBRM1 protein expression is most frequently observed in clear cell RCC and correlated with tumor progression. Approximately 40-50% of patients with RCC have mutations in PBRM1, and loss of PBRM1 was also reported in 28% of melanocytic neoplasms. However, loss of PBRM1 has not been studied in other tumors using patient tissues. The purpose of this study was to assess the protein expression of PBRM1 in a wide-ranging collection of normal and tumor tissues. Here we report our findings of PBRM1 loss in colon and lung carcinomas using a newly developed rabbit monoclonal antibody (RabMAb), Clone EP342. The antibody was generated by immunization of rabbits with PBRM1 recombinant protein. Sera collected from immunized rabbits were screened by ELISA, WB and IHC. After fusion, antibody from final hybridoma cell line was characterized using ELISA and Western blot (WB). A 180 KDa PBRM1 protein was detected by WB in A431 and MCF7 cell lysates. The antibody was further characterized by extensive IHC testing using formalin-fixed and paraffin-embedded (FFPE) human normal and tumor tissue microarray (TMA). IHC analysis on human tissue microarray (TMA) comprising seventeen types of normal tissues showed that PBRM1 antibody stained positively in the nuclei of all normal cells except cardiac muscle cells. In tumor TMAs comprising of fifteen types of tumors (2-4 cases for each type), negative staining was observed in carcinomas of the lung and colon, as well as clear cell RCC. Further analysis of specific types of tumor TMAs showed that PBRM1 was lost in 5 out of 30 colon carcinomas (17%), 8 out of 35 (14%) lung carcinomas, and 8 out of 1844%) clear cell RCC. In summary, the RabMAb PBRM1 antibody, clone EP342 specifically labels normal cells and most tumor cells. It is a useful tool in identifying cancers with loss of PBRM1 expression on FFPE tissues. The rate of PBRM1 loss in clear cell RCC (44%) detected by this clone is consistent with literature reported. Our study showed that PBRM1 protein was lost in colon and lung carcinomas, but less frequent than that of clear cell RCC. Further studies on colon and lung carcinomas are needed to clarify the role of PBRM1 in tumor progression in these tumors. Citation Format: Aihua Li, Yongfu Gao, Yuekai Zhang, Hongyang Pan, Jackie K. Chan, Ximing J. Yang, Taiying Chen. IHC assessment of PBRM1 loss in colon and lung carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3416. doi:10.1158/1538-7445.AM2015-3416
Comparison of two major prognostic models for patients with metastatic renal cell carcinoma treated in the contemporary era of targeted therapies.
Authors: M. Crepel, B. J. Escudier, J. H. Machiels, M. D. Staehler, A. Ravaud, G. Gravis, F. Joly, C. Chevreau, L. Zini, H. Lang, L. Salomon, P. Bigot, J. Rigaud, J. Patard
Journal: Journal of Clinical Oncology (2011)

4660 Background: The 2 most popular prognostic systems for patients with metastatic renal cell carcinoma (mRCC) are MSKCC and French Group of Immunotherapy (FGI) models. Both systems have initially been established by using cohorts of patients treated with cytokines. No direct comparison of these 2 models has been published so far in the modern era of targeted therapies. Our goal was to compare their effectiveness in predicting overall survival (OS) in mRCC patients treated with anti-angiogenic drugs. Methods: Based on an international cohort of 965 mRCC patients from 18 tertiary care centers treated with systemic treatment, we assessed OS in univariate Cox regression according to both prognostic models stratification. Then, variables of each model were compared in multivariate Cox regression. Area under the curve (AUC) of both model was also calculated. Results: Median OS for the entire population was 31.8 months. Both systems were able to distinguish 3 groups with statistically significantly different survivals. Median OS in good, intermediate and poor prognostic group were 45.9, 23.5, 13.5 months and 50.9, 33.4, 13.5 months in MSKCC and FGI models, respectively. In multivariate Cox regression analysis, 3 out of the 5 variables of MSKCC model achieved independent prognostic value (haemoglobin level (HR=1.79, p=0.001), LDH elevation (HR=4.3; p=0.001) and Performance Status (HR=1.71; p=0.006). Similarly, 3 out of the 5 variables of the FGI model achieved independent prognostic status (haemoglobin level (HR=1.74; p=0.04); number of metastasis (HR=2.2; p=0.008) and performance status (HR=2.12; p=0.006). AUC of MSKCC and FGI models were 0.57 and 0.65, respectively. When focusing on 369 patients who received sunitinib as first line treatment, AUC of MSKCC and FGI models were 0.66 and 0.75, respectively. Conclusions: MSKCC and FGI are both effective prognostic models in predicting OS in mRCC patients treated in the contemporary period. However, based on our data, FGI model seems to exhibit a better predictive accuracy than MSKCC model. The prognostic role of FGI model should be therefore revisited in the era of targeted therapies.
Changes in global patterns of care for first-line advanced nonsquamous (NS) non-small cell lung cancer (NSCLC): 2007-2010.
Authors: A. J. Combest, J. K. Bryan, A. Moseley, D. J. Reitsma, M. Scazafave, J. M. Wood, H. A. Iocca, J. Goyo, J. S. An, M. W. Lee
Journal: Journal of Clinical Oncology (2011)

e16639 Background: Few reports have focused on global changes in cancer care. The objective of this study is to assess changes in first line therapy of NS NSCLC following publication of phase 3 data in Sept 2007 (IASLC 2007), May 2008 (Scagliotti JCO 2008) and May 2009 (ASCO 2009, 8045). Methods: Chemotherapy use in first line NS NSCLC was collected via Synovate’s Tandem Oncology Monitor, a commercial system in which oncologists in US (500), EU (783), Korea (125) and Japan (350) enter de-identified data on patterns of care for cancer patients from their practice monthly. Results: See table. Conclusions: While Plat/ Pac and Plat/ Gem use gradually declined, use of Plat/ Pem and EGFR inhibitors increased. Although results were first presented in 2007 (IASLC), increase in Plat/ Pem use in the US and EU followed publication of the manuscript (JCO, 2008) and Pem approval. The increase occurred in ’09-’10 in Asia following the Asian subgroup analysis (ASCO, 2009) and Pem approval. Jan-Jun 07 Jul-Dec 07 Jan-Jun 08 Jul-Dec 08 Jan-Jun 09 Jul-Dec 09 Jan-Jun 10 Jul-Sept 10 US (N)* 527 586 536 1,222 1,414 1,274 1,217 548 Carbo/Pac ± Bev** 40 42 43 27 28 24 24 28 Plat/Pem ± Bev 0 0 1 5 13 20 18 24 Plat/Gem ± Bev 13 13 13 11 6 6 4 4 Plat/Doc ± Bev 9 9 9 9 6 8 12 8 Single agent 15 20 15 18 18 17 15 14 Erl ± Bev 9 9 10 19 21 17 17 16 Other 8 8 6 4 5 4 5 3 Europe (N)+ 706 803 725 819 911 881 991 485 Plat/ Pac ± Bev 11 9 10 9 10 8 11 13 Plat/ Pem ± Bev 0 0 1 8 10 16 24 26 Plat/ Gem ± Bev 37 35 37 34 26 27 22 18 Plat/Doc 5 7 9 6 5 6 5 4 Plat/Vin 15 17 13 13 16 13 9 7 Single Agent 19 16 16 15 17 13 12 9 EGFR Inhibitor 4 6 6 6 8 11 11 16 Other 7 5 7 6 4 5 3 4 Japan (N) 439 378 403 354 410 362 303 174 Carbo/Pac ± Bev 31 25 33 32 28 27 16 19 Plat/Pem 0 0 0 0 0 10 21 25 Plat/Gem 15 10 14 15 14 12 10 8 Plat/Doc 7 11 6 9 7 5 7 6 Plat/Vin 9 10 6 9 6 6 6 3 Single agent 6 8 11 9 10 7 9 9 EGFR Inhibitor 19 21 20 18 25 28 27 26 Other 12 14 13 10 9 5 4 4 Korea (N) 74 82 97 102 75 98 76 36 Plat/Pac 23 32 24 20 14 23 42 16 Plat/Pem ± Bev 0 0 0 1 0 0 12 14 Plat/Gem ± Bev 37 27 31 17 45 26 28 25 Plat/Doc 17 24 26 33 12 21 7 19 Single agent 8 4 4 7 8 12 5 11 EGFR inhibitor 3 1 2 10 9 2 5 8 Other 11 12 12 13 9 15 2 6 Abbreviations: Plat: Carboplatin or cisplatin; Bev: Bevacizumab; Single agent: docetaxel/gemcitabine/pemetrexed/vinorelbine; EGFR inhibitor: erlotinib/gefitinib. * N: Unique treatments. ** All data are% use. + EU: France, Italy, Germany, UK and Spain
Abstract IA47: Epigenetic programming and therapy in germinal center derived B-cell lymphomas.
Authors: Ari M. Melnick
Journal: Clinical Cancer Research (2015)

Abstract Diffuse Large B-cell Lymphomas (DLBCLs) are a heterogeneous group of diseases initiating from germinal center (GC) B cells. GC B cells are uniquely specialized to tolerate rapid proliferation, and physiological genomic instability in order to generate a diverse set of clones of cells encoding high affinity antibodies. This accelerated micro-evolutionary process requires the concerted action of transcription and epigenetic factors that collectively reprogram B cells to overcome many of their normal checkpoint restraints and tolerate the various stresses associated with affinity maturation. The GC phenotype poses a significant risk of malignant transformation to B cells, which must accordingly balance suppression of checkpoints with suppression of pro-oncogenic genes. Epigenetic regulatory complexes play a critical role in lymphomagenesis. EZH2, which epigenetically silences genes through histone 3 lysine 27 methylation is upregulated in normal and malignant GC B cells. EZH2 is often affected by gain of function mutations in lymphomas that alter its enzymatic specificity. EZH2 mediates GC formation by transiently suppressing checkpoint genes and terminal differentiation genes through formation of bivalent chromatin domains. EZH2 somatic mutations induce germinal center hyperplasia and malignant transformation, and cooperate with other oncogenes such as BCL2. EZH2 specific inhibitors can suppress the growth of GC derived lymphoma cells in vitro and in vivo, and are currently being evaluated in early phase clinical trials. DNA methyltransferase 1 (DNMT1) is required for B cells to form GCs, and GC B cells display cytosine methylation redistribution as compared to resting or naïve B cells. DLBCLs in turn exhibit prominent and heterogeneous disruption of cytosine methylation distribution, with specific and distinct DNA methylation profiles occurring in different lymphoma subtypes. Epigenetic heterogeneity is associated with unfavorable outcome in B-cell lymphomas, suggesting that epigenetic diversity may provide a survival advantage to lymphoma cell populations. DNA methyltransferase inhibitors can reprogram lymphoma cells to develop a form of incomplete senescence that sensitizes lymphoma cells to more readily respond to chemotherapy. DNA methyltransferase inhibitors can be safely combined with standard lymphoma therapies for the up-front treatment of patients with high-risk lymphomas. Citation Format: Ari M. Melnick. Epigenetic programming and therapy in germinal center derived B-cell lymphomas. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA47.
Obesity and kidney disease: hidden consequences of the epidemic
Authors: Csaba P. Kovesdy, Susan L. Furth, Carmine Zoccali, Philip Kam Tao Li, Guillermo Garcia-Garcia, Mohammed Benghanem-Gharbi, Rik Bollaert, Sophie Dupuis, Timur Erk, Kamyar Kalantar-Zadeh, Csaba Kovesdy, Charlotte Osafo, Miguel C. Riella, Elena Zakharova
Journal: Kidney International (2016)
Superiority of Double over Single Autologous Stem-Cell Transplantation for Newly Diagnosed Multiple Myeloma and Prognostic Impact of Complete Response: Final Analysis of “Bologna 96” Study.
Authors: Michele Cavo, Giulia Perrone, Michela Ceccolini, Vito Michele Lauta, Massimo Offidani, Filippo Ballerini, Lucia Pantani, Annamaria Brioli, Silvana Pasini, Fausto Dore, Domenico Vertone, Paola Tacchetti, Elena Zamagni, Patrizia Tosi, Sante Tura, Michele Baccarani
Journal: Blood (2007)
Abstract CT313: Phase Ib trial of dodecafluoropentane as a radiation sensitizer during chemoradiation for glioblastoma
Authors: Jason Lickliter, Jeremy Ruben, Olivia Longacre, David Wilson, Evan Unger
Journal: Cancer Research (2015)

Abstract Purpose: Using post-resected glioblastoma multiforme (GMB) patients to evaluate the pharmacokinetics, safety and potential survival benefit of Dodecafluoropentane emulsion (DDFPe) in combination with the current standard of care; radiation therapy (RT) and temozolomide (TMZ). Glioblastoma multiforme (GBM) is known to be a hypoxic tumor. Tumor hypoxia limits response to RT. DDFPe is an oxygen therapeutic (OT) which transports more than 100x more oxygen as other tested fluorocarbons OT’s. Studies in tumor xenografts show that DDFPe increases tumor pO2 by up to 400% and mitigates radiation resistance. Methods: Previously untreated GBM patients with post-resected residual tumor visible on MRI post surgery were enrolled. Patients received standard RT (60 Gray in 30 fractions over 6 weeks) with concurrent and adjuvant TMZ. In addition, DDFPe was infused intravenously over 30 minutes immediately prior to each fraction of RT while patients simultaneously breathed carbogen (98%O2:2% CO2). DDFPe was dosed using an accelerated titration design with 1 patient per dose level. Blood samples were drawn to evaluate DDFP pharmacokinetics. Objective tumor responses were assessed with gadolinium-enhanced MRI scans and RANO criteria, and tissue oxygen level dependent (TOLD) MRI was employed as an exploratory biomarker of tumor oxygenation. Results: Two patients have been enrolled to date. The first patient received DDFPe at 0.05 cc/kg and completed chemoradiation and 2 cycles of adjuvant TMZ with dose reduction or delay. Therapy was well tolerated except for transient grade 3 ALT elevation during recovery from chemoradiation. A post-radiation MRI scan showed stable disease. The second patient has completed a regimen of chemoradiation in combination with DDFPe at 0.1 cc/kg. Conclusions: DDFPe administration prior to each radiation fraction during standard chemoradiation of GBM is feasible. Further dose escalation od DDFPe is planned to establish a maximum tolerated dose and recommended dose for an envisioned Phase IIb multi-center GBM trial of DDFPe in combination with the accepted standard of care. Citation Format: Jason Lickliter, Jeremy Ruben, Olivia Longacre, David Wilson, Evan Unger. Phase Ib trial of dodecafluoropentane as a radiation sensitizer during chemoradiation for glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT313. doi:10.1158/1538-7445.AM2015-CT313
S67 Mortality in copd patients following community acquired pneumonia: a population database analysis of linked healthcare records
Authors: N Williams, NA Coombs, M Johnson, L Josephs, LA Rigge, DM Thomas, TMA Wilkinson
Journal: Thorax (2016)

<h3>Introduction</h3> Community acquired pneumonia (CAP) is a common occurrence in patients with chronic obstructive pulmonary disease (COPD), yet controversy still remains about its affect on outcome. We therefore investigated the impact of CAP on mortality in a cohort of COPD patients identified from the Hampshire Health Record analytical database, a local NHS database containing linked, anonymised primary and secondary care records. <h3>Methods</h3> Patients were defined as having COPD if they had a diagnostic Read code in their primary care record at any time prior to the 1<sup>st</sup> January 2010 and were aged ≥40 years at the start of the study. CAP episodes occurring over a 5-year period from 1<sup>st</sup> January 2010 were identified using Read and ICD-10 codes. The outcome measure was all-cause mortality following a CAP diagnosis. Cox proportional hazard modelling was used to estimate hazard ratios (HR) and confidence intervals (CI), adjusting for age, sex, GOLD stage, smoking status and inhaled corticosteroid use (ICS)). <h3>Results</h3> The cohort comprised 14506 COPD patients. The mean age was 70.3 (±10.8) years and 53.6% were male. 1931 (13.3%) patients had at least one CAP and 2870 (19.8%) deaths occurred over the study period. 28.2% of patients diagnosed with CAP died compared to only 9.7% of those without a CAP diagnosis (p &lt; 0.001). Logistic regression analysis, controlling for potential confounders identified CAP as an independent risk factor for future mortality (odds ratio 2.72; CI 2.37–3.12, p &lt; 0.001). Compared to younger individuals (40–59 years) those aged 60–79 and &gt;80 years had the highest mortality risk following CAP (HR 2.65; CI 1.61–4.34, HR 7.03; CI 4.27–11.57 respectively, both p &lt; 0.001). Concurrent use of inhaled Fluticasone or Budesonide were associated with reduced mortality risk following CAP (HR 0.82; CI: 0.68–0.98 p = 0.029, HR 0.55; CI: 0.39–0.76 p &lt; 0.001, respectively) (Figure 1). <h3>Conclusion</h3> CAP in COPD is associated with increased risk of mortality, especially in older individuals. Although known to increase CAP risk, ICS use appears to reduce risk of mortality following CAP. Further research to understand the mechanisms underlying CAP risk in COPD and modulating effects of ICS is key, to guide development of future, targeted preventative strategies.