tbuckley/cabot-search huggingface dataset:
Abstract 1674: Humanized mouse models for personalized preclinical testing of monoclonal antibodies targeting immune checkpoints
Authors: Gilson S. Baia, David Vasquez, Daniel Ciznadija, Brandy Wilkinson, David Sidransky, Amanda Katz, Keren Paz
Journal: Cancer Research (2014)

Abstract The blockade of immune checkpoints with monoclonal antibodies (mAbs) is a promising therapeutic avenue, with durable objective responses observed in patients with solid tumors, particularly melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma. Preclinical models that recapitulate a functional human immune system will therefore be essential tools for the continued investigation of immunotherapy approaches. Champions Oncology is engaged in advanced personalized solutions and our TumorGraft models have been developed and extensively characterized as a platform for use in personalizing cancer patient care, as well as pharmaceutical development. However, because TumorGrafts are established by engrafting patient tumors into immune-deficient mice, the therapeutic efficacy of immune-modulatory drugs cannot be directly examined. To circumvent this limitation, we reconstituted the human immune system by engrafting human hematopoietic cells (HLA-A2; CD34+) into immune-compromised mice (PrkdcscidIl2rgtm1Sug) carrying the scid mutation and a targeted mutation of the Il2r-gamma gene. Ten to twelve weeks later, mature CD45+ human T cells could be detected in these mice, at which time TumorGrafts were established, followed by drug-sensitivity testing with various mAbs targeting the immune system. Fifty six well-established melanoma, colorectal, breast and lung TumorGraft models were characterized and selected with regard to their HLA type and other molecular characteristics such as BRAF mutation status (in melanoma) and KRAS mutation status (in colorectal and lung cancer) as well as expression of PD-L1. With the present study, we demonstrated the potential of combining the humanized mouse with Champions TumorGraft to generate a preclinical platform for assessing the therapeutic value of mAbs targeting immune checkpoints in various solid tumors. Citation Format: Gilson S. Baia, David Vasquez, Daniel Ciznadija, Brandy Wilkinson, David Sidransky, Amanda Katz, Keren Paz. Humanized mouse models for personalized preclinical testing of monoclonal antibodies targeting immune checkpoints. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1674. doi:10.1158/1538-7445.AM2014-1674
UK scientists recommend gene testing for inherited bowel cancer
Authors: Susan Mayor
Journal: BMJ (2001)

Cancer researchers who identified the association between mutations in a human gene and an inherited form of bowel cancer are calling on governments to consider genetic screening programmes to identify people at risk.

Walter Bodmer, honorary head of the Imperial Cancer Research Fund Laboratory for Cancer and Immunogenetics at the Weatherall Institute of Molecular Medicine in Oxford, has called for the screening. Dr Bodmer is one of the scientists who discovered the APC gene mutations, which are linked to …
Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Mediated Proliferation of Tumor Cells with Receptor-Proximal Apoptosis Defects
Authors: Eva Baader, Agnieszka Toloczko, Uta Fuchs, Irene Schmid, Christian Beltinger, Harald Ehrhardt, Klaus-Michael Debatin, Irmela Jeremias
Journal: Cancer Research (2005)

Abstract Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) might represent a future cytotoxic drug to treat cancer as it induces apoptosis in tumor cells without toxicity in animal trials. We recently described that in contrast to apoptosis, TRAIL mediates tumor cell survival and proliferation in certain tumor cells. Here we studied the effect of TRAIL on 18 cell lines and 53 primary leukemia cells and classified these tumor cells into four groups: TRAIL, anti-DR4 or anti-DR5 induced apoptosis in group A cells, whereas they had no effect on group 0 cells and mediated proliferation in group P cells. To our surprise, TRAIL induced simultaneous apoptosis and proliferation in group AP cells. More than 20% of all cells tested belonged to group P and showed TRAIL-mediated proliferation even in the presence of certain cytotoxic drugs but not inhibitors of nuclear factor-κB. Transfection with B-cell leukemia/lymphoma protein 2 transformed group A cells into group 0 cells, whereas transfection with Fas-associated polypeptide with death domain (FADD)–like interleukin-1-converting enzyme–inhibitory protein (FLIP) transformed them into group AP cells. Loss of caspase-8 or transfection of dominant-negative FADD transformed group A cells into group P cells. Taken together, our data suggest that proliferation is a frequent effect of TRAIL on tumor cells, which is related to receptor-proximal apoptosis defects at the level of the death-inducing signaling complex and should be prevented during antitumor therapy with TRAIL.
Long term outcome of Ph+ CML patients achieving complete cytogenetic remission with interferon based therapy moving from interferon to imatinib era
Authors: Michele Malagola, Massimo Breccia, Cristina Skert, Valeria Cancelli, Simona Soverini, Ilaria Iacobucci, Federica Cattina, Anna Maria Liberati, Mario Tiribelli, Mario Annunziata, Elena Trabacchi, Antonio De Vivo, Fausto Castagnetti, Giovanni Martinelli, Miriam Fogli, Fabio Stagno, Gianmatteo Pica, Alessandra Iurlo, Patrizia Pregno, Elisabetta Abruzzese, Simonetta Pardini, Monica Bocchia, Sabina Russo, Ivana Pierri, Monia Lunghi, Sara Barulli, Serena Merante, Franco Mandelli, Giuliana Alimena, Gianatonio Rosti, Michele Baccarani, Domenico Russo
Journal: American Journal of Hematology (2013)

Interferon α (IFNα) prolongs survival of CML patients achieving CCyR and potentially synergizes with TKIs. We report on the molecular status and long term outcome of 121 patients who were treated in Italy between 1986 and 2000 with IFNα based therapy and who obtained CCyR. After a median follow up of 16.5 years, 74 (61%) patients were switched to standard imatinib: 48 (65%) lost the CCyR on IFNα, and 36 (75%) are alive and in CCyR; 26 (35%) were switched to imatinib when they were still in CCyR on IFNα, and all 26 are alive and in CCyR. Forty-seven patients (39%) were never switched to imatinib: 24 (51%) continued and 23 (49%) discontinued IFNα, respectively, and 39/47 (83%) are alive and in CCyR. At last follow-up, the BCR-ABL transcripts level was available in 96/101 living patients (95%) The BCR-ABL:ABL ratio was between 0.1 and 0.01% (MR(3.0) ) in 17%, and less than 0.01% (MR(4.0) ) in 81% of patients. No patient was completely molecular negative (MR(4.5) or MR(5.0) ). The OS at 10 and 20 years is 92 and 84%, respectively. This study confirms that CCyR achieved with IFNα and maintained with or without imatinib or any other therapy significantly correlates with long term survival in CML patients who mostly have MR(4.0) . Complete molecular response (MR(4.5) or MR(5.0) ) seems to be unnecessary for such a long survival. This study further supports development of studies testing the clinical effect of the combinations of TKIs with IFNα.
<i>SLCO1B1</i>Variants and Statin-Induced Myopathy — A Genomewide Study
Authors: E Link, S Parish, J Armitage, L Bowman, S Heath, F Matsuda, I Gut, M Lathrop, R Collins
Journal: New England Journal of Medicine (2008)

Lowering low-density lipoprotein cholesterol with statin therapy results in substantial reductions in cardiovascular events, and larger reductions in cholesterol may produce larger benefits. In rare cases, myopathy occurs in association with statin therapy, especially when the statins are administered at higher doses and with certain other medications.We carried out a genomewide association study using approximately 300,000 markers (and additional fine-mapping) in 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking 80 mg of simvastatin daily as part of a trial involving 12,000 participants. Replication was tested in a trial of 40 mg of simvastatin daily involving 20,000 participants.The genomewide scan yielded a single strong association of myopathy with the rs4363657 single-nucleotide polymorphism (SNP) located within SLCO1B1 on chromosome 12 (P=4x10(-9)). SLCO1B1 encodes the organic anion-transporting polypeptide OATP1B1, which has been shown to regulate the hepatic uptake of statins. The noncoding rs4363657 SNP was in nearly complete linkage disequilibrium with the nonsynonymous rs4149056 SNP (r(2)=0.97), which has been linked to statin metabolism. The prevalence of the rs4149056 C allele in the population was 15%. The odds ratio for myopathy was 4.5 (95% confidence interval [CI], 2.6 to 7.7) per copy of the C allele, and 16.9 (95% CI, 4.7 to 61.1) in CC as compared with TT homozygotes. More than 60% of these myopathy cases could be attributed to the C variant. The association of rs4149056 with myopathy was replicated in the trial of 40 mg of simvastatin daily, which also showed an association between rs4149056 and the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy.We have identified common variants in SLCO1B1 that are strongly associated with an increased risk of statin-induced myopathy. Genotyping these variants may help to achieve the benefits of statin therapy more safely and effectively. (Current Controlled Trials number, ISRCTN74348595.)
Gender-Specific Risk Stratification With B-Type Natriuretic Peptide Levels in Patients With AcuteDyspnea
Authors: Michael Christ, Kirsten Laule-Kilian, Willibald Hochholzer, Theresia Klima, Tobias Breidthardt, Andre P. Perruchoud, Christian Mueller
Journal: Journal of the American College of Cardiology (2006)
Abstract 16149: Pulse Wave Velocity and Augmentation Index as New Markers of Vasculopathy in Sickle Cell Disease: Preliminary Results of the CADRE Study
Authors: Brigitte Ranque, Aymeric Menet, Ibrahima Bara Diop, Samuel Kingue, Rolland N’Guetta, Mamadou Diarra, Pierre Boutouyrie, Xavier Jouven
Journal: Circulation (2014)

Introduction: Sickle cell disease (SCD) is now considered a vascular disease, involving many organs (pulmonary hypertension, nephropathy, stroke, leg ulcers...). We have settled a large cohort of SCD patients to estimate the incidence of cardiovascular complications in SCD and look for their predictive factors in five African countries: Cameroon, Senegal, Mali, Gabon and Ivory Coast. Methods: Subjects have undergone clinical and biological examinations, pulse wave velocity (PWV) and augmentation index (AI) measures and echocardiography. We have compared PWD and AI in healthy controls and in two main SCD phenotype groups: SS or Sβ0 (severe SCD) and SC or Sβ+ (mild SCD) and looked for the clinical and biological markers associated. Results: 3950 SCD patients (2792 SS-Sβ0 and 776 SC-Sβ+) and 800 controls of all ages have been recruited. As compared to controls, SCD patients have increased cardiac frequency, increased diameter of all cardiac cavities and decreased blood pressure (BP) (p<.001 for all) with sim...
Thrombin Generation, Inhibition and Clinical Outcomes in Patients With Acute Myocardial Infarction Treated With Thrombolytic Therapy and Heparin: Results From the GUSTO-I Trial fn1fn1This study was supported by Genentech, Inc., South San Francisco, California; Bayer Corporation, New York, New York; CIBA-Corning, Medfield, Massachusetts; ICI Pharmaceuticals, Wilmington, Delaware; and Sanofi Pharmaceuticals, Paris, France.
Authors: Christopher B. Granger, Richard Becker, Russell P. Tracy, Robert M. Califf, Eric J. Topol, Karen S. Pieper, Allan M. Ross, Sherryn Roth, Costas Lambrew, Edwin G. Bovill
Journal: Journal of the American College of Cardiology (1998)
Comparative Electromechanical and Hemodynamic Effects of Left Ventricular and Biventricular Pacing in Dyssynchronous Heart Failure
Authors: Joost Lumens, Sylvain Ploux, Marc Strik, John Gorcsan, Hubert Cochet, Nicolas Derval, Maria Strom, Charu Ramanathan, Philippe Ritter, Michel Haïssaguerre, Pierre Jaïs, Theo Arts, Tammo Delhaas, Frits W. Prinzen, Pierre Bordachar
Journal: Journal of the American College of Cardiology (2013)
Abstract 3535: Epigenetic regulation of miR-31 and miR-205 of apoptosis in prostate cancer
Authors: Qunshu Zhang
Journal: Cancer Research (2014)

Abstract Prostate cancer is the second leading cause of cancer-related mortality among men in the United States. However, our understanding of the cause of prostate cancer remains elusive. Recent studies have implicated that epigenetics, heritable changes in gene expression caused by mechanisms other than classical genetic alterations, is an important mechanism in tumorigenesis. MicroRNAs function as epigenetic regulators to alter gene expression, and very limited information is available regarding the roles of microRNAs in prostate cancer. Evasion of apoptosis is the hallmark of cancer, and it plays an important role in the growth and development of prostate cancer. We have recently demonstrated that miR-31 and miR-205 are downregulated in advanced prostate cancer. In addition, anti-apoptotic protein E2F6 was identified as the target of miR-31 and contributed resistance to chemotherapy-induced apoptosis. While we found that miR-205 is silenced by gene promoter methylation, the mechanism of the downregulation of miR-31 in prostate cancer remains poorly defined. In this study, we report that EZH2 (Enhancer of zeste 2), a histone methyltransferase and component of the polycomb repressive complex 2 (PRC2), is responsible for miR-31 silencing in prostate cancer. EZH2 plays an essential role in the epigenetic maintenance of the H3K27me3 repressive chromatin mark. Our results have shown that siRNA knockdown of EZH2 and DZNep (3-deazaneplanocin) treatment (an EZH2 inhibitor) in prostate cancer cells increased miR-31 expression. Furthermore, EZH2 is responsible for histone methylation at the promoter of miR-31 gene. In addition, siRNA knockdown of EZH2 and the treatment with DZNep sensitized prostate cancer cells to apoptosis. In contrast, EZH2 overexpression confers resistance to chemotherapy-induced apoptosis in prostate cancer cells. Thus, polycomb protein EZH2 suppresses the expression of miR-31 and consequently contributes to apoptosis resistance in prostate cancer. The results will improve our understanding of the mechanism of drug resistance in prostate cancer cells. Novel strategies targeting EZH2 and miR-31 can be developed to increase drug-induced apoptosis and improve cancer response to chemotherapy. Citation Format: Qunshu Zhang. Epigenetic regulation of miR-31 and miR-205 of apoptosis in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3535. doi:10.1158/1538-7445.AM2014-3535
Abstract 17369: Telomere Length Predicts Post-Operative Atrial Fibrillation in Patients Undergoing CABG Independently of Chronological Age
Authors: Marios Margaritis, Sheena Patel, Alexios S Antonopoulos, Laura Herdman, Mario Petrou, Rana Sayeed, George Krasopoulos, Keith M Channon, Barbara Casadei, Charalambos Antoniades
Journal: Circulation (2014)

Background:  Telomere shortening is a marker of cellular senescence, and is associated with cardiovascular disease. Systemic oxidative stress was proposed to reduced telomere length (TL). Paroxysmal atrial fibrillation (PAF) is a redox-sensitive, early clinical complication of CABG, so we hypothesize that telomere length might be a more robust predictor of PAF than chronological age.   Methods:  We recruited 475 patients on sinus rhythm and no prior history of PAF undergoing CABG. Blood samples were obtained preoperatively and used to extract DNA and measure relative TL using qPCR, by calculating the Telomere /Single copy gene ratio against albumin (T/S). Systemic oxidative stress was evaluated by measuring plasma malonyldialdehyde (MDA) levels. Patients were monitored for in-hospital post-operative AF events until discharge.   Results:  A total of 159 (33.5% of study population) PAF events were recorded. T/S was inversely associated with plasma MDA levels (A). In cox-regression that included T/S, MDA and all the clinical variables related with PAF in univariate analysis, T/S was a strong independent predictor of PAF (RR: 0.566 [95%CI: 0.378-0.848], P=0.006) in addition to (and independently of) chronological age (RR: 1.031 [95%CI: 1.013-1.050], P   Conclusions:  We demonstrate for the first time that telomere length is a strong predictor of post-operative AF in patients undergoing following CABG, independently of chronological age and systemic oxidative stress status. These novel findings highlight the importance of cellular senescence in cardiovascular disease processes and reveal a potential role of telomere length measurement in clinical predictive models.
Unbiased Cell-Based Models to Identify GeneticVariants Associated with Chemotherapeutic Induced Toxicity
Authors: R. Stephanie Huang, Wei Zhang, Sunita Shukla, Shiwei Duan, Wasim Bleibel, Christine Hartford, M. Eileen Dolan
Journal: Clinical Cancer Research (2007)

CN01-01   The International HapMap Project provides a key resource of genotypic data in human lymphoblastoid cell lines (LCLs) derived from populations of European, African, Chinese and Japanese ancestry to associate with various phenotypic data to find genes affecting disease and response to drugs. These cell lines have allowed for the exploration of quantitative variation in complex traits such as gene expression and dug response in human populations. To identify genetic variants that contribute to gene expression and chemotherapy-induced cytotoxicity, we developed unbiased, whole genome cell based models. By integrating genotype, gene expression and sensitivity of HapMap cell lines to chemotherapeutic drugs, we built predictive models to identify genetic signatures for susceptibility to chemotherapy-induced cytotoxicity. Cell lines derived from 30 trios of European descent (CEU) and 30 trios of African descent (YRI) were utilized. Cell growth inhibition at increasing concentrations of chemotherapeutic agents (etoposide, daunorubicin, AraC, cisplatin or carboplatin) was evaluated. Gene expression of 176 HapMap cell lines (87 CEU and 89 YRI) was determined using the Affymetrix GeneChip ®  Human exon 1.0 ST Array. SNP genotype and the IC 50  (concentration required to inhibit 50% cell growth) of each agent were linked through whole genome association in cell lines from combined and independent CEU and YRI populations. A second association test was performed between SNP genotype and gene expression, and linear regression was then utilized to evaluate the correlation between gene expression and drug IC 50 . We identified genetic variants that significantly associate with sensitivity to the cytotoxic effects of these chemotherapeutic agents through differences in gene expression in the combined CEU and YRI populations, as well as each population individually. A multivariate model indicated that these limited numbers of genetic variants explained approximately 20-65% of the observed human variation in cellular sensitivity to chemotherapy. There are advantages and limitations in the use of LCLs in pharmacogenomic discovery that will be discussed as well as the wide range of cellular phenotypes that can be studied in these cell lines to ultimately gain insight as to how genetic variation contributes to phenotypic variation. These cell lines provide a novel means to answer important pharmacogenomic questions. This Pharmacogenetics of Anticancer Agents Research (PAAR) Group (http://pharmacogenetics.org) study was supported by NIH/NIGMS grant UO1GM61393.
Treatment Duration for Pulmonary Embolism
Authors: Jill Jin
Journal: JAMA (2015)

Francis Couturaud, MD, PhD; Olivier Sanchez, MD, PhD; Gilles Pernod, MD, PhD; Patrick Mismetti, MD, PhD; Patrick Jego, MD, PhD; Elisabeth Duhamel, MD; Karine Provost, MD; Claire Bal dit Sollier, MB; Emilie Presles, MS; Philippe Castellant, MD; Florence Parent, MD; Pierre-Yves Salaun, MD, PhD; Luc Bressollette, MD, PhD; Michel Nonent, MD, PhD; Philippe Lorillon, PharmD; Philippe Girard, MD; Karine Lacut, MD, PhD; Marie Guégan, MS; Jean-Luc Bosson, MD, PhD; Silvy Laporte, MS, PhD; Christophe Leroyer, MD, PhD; Hervé Décousus, MD; Guy Meyer, MD; Dominique Mottier, MD; for the PADIS-PE Investigators
Nightly variability of obstructive sleep apnoea/hypopnoea syndrome measured over 2 nights
Authors: Meriem Mjid, Yassine Ouahchi, Sonia Toujani, Salma Mokkadem, Nozha Ben Salah, Abdelmajid Ben Hmida, Bechir Louzir, Nadia Mhiri, Jouda Cherif, Majed Beji
Journal: European Respiratory Journal (2014)

Apnoea/hypopnoea index (AHI) is the primary measurement used to characterize obstructive sleep apnoea/hypopnoea (OSAHS). Despite its popularity, there are limiting factors to its application as night-to-night variability. This study aims to evaluate variability of AHI and to determine its possible relationship with other clinical features. A prospective study was designed in a University Hospital9s sleep unit. Adults with clinical suspicion of OSAHS underwent 2 consecutive nights of polygraphic recording. Then, population was divided in 2 groups (P1=AHI variation>10, P2=AHI variation 2 ±9,051. Clinical manifestations were dominated by snoring and day time sleepiness. AHI values weren9t significantly altered throughout the 2 recording nights (33.20event/h vs 31.85event/h). On the first night, 4 patients were classified as having light OSAHS, 6 were moderate and 8 presented severe apnea. AHI was lower than 5 in 2 patients. In the second night, classification has changed in 8 patients (40%). Among them, 4 changed to a more severe stage. Moreover, comparison between P1(n=7) and P2(n=10) showed no differences in regard to age and BMI ( p ). Our study demonstrates that AHI in OSAHS patients presented a good correlation among the 2 nights. However, a significant individual variability should be considered, especially when AHI is applied in OSAHS classification or as a criterion of therapeutic success.
Aspirin and Salicylate Induce Apoptosis and Activation of Caspases in B-Cell Chronic Lymphocytic Leukemia Cells
Authors: Beatriz Bellosillo, Maria Piqué, Montserrat Barragán, Esther Castaño, Neus Villamor, Dolors Colomer, Emilio Montserrat, Gabriel Pons, Joan Gil
Journal: Blood (1998)