tbuckley/cabot-search huggingface dataset:
Effects of the novel BET inhibitor BI 894999 on upregulation of <i>HEXIM1</i> in cancer cells and on antitumor activity in xenograft tumor models.
Authors: Ulrike Tontsch-Grunt, Fabio Savarese, Anke Baum, Dirk Scharn, Daniel Gerlach, Marco H. Hofmann, Onur Kaya, Norbert Schweifer, Harald Engelhardt, Hanny Musa, Chooi Peng Lee, Gerd Michael Munzert, Norbert Kraut
Journal: Journal of Clinical Oncology (2016)

11574 Background: BRD4 is a key epigenetic regulator facilitating transcriptional elongation of super-enhancer regulated oncogenes including MYC. BI 894999, a novel, potent and selective orally bioavailable inhibitor of the BET family has entered clinical trials (NCT02516553). Methods: The effects of BI 894999 in proliferation, cell cycle (FACS) and apoptosis (caspase 3/7 or PARP cleavage) assays were studied in vitro. In vivo potency was demonstrated in xenografts for hematological malignancies and solid tumors. ChIP-seq was performed to analyze chromatin configuration. Results: BI 894999 displayed strong anti-proliferative activity, particularly in hematological cell lines. Out of 48 hematological cell lines, all but K562 cells showed an EC50 < 100nM, mostly in the single digit nM range. When comparing BI 894999 to other epigenetic drugs targeting histone acetylation or DNA methylation, BI 894999 was found to regulate a distinct set of genes including MYC and its targets. Potent tumor growth inhibition was demonstrated in xenograft models of AML and lymphoma as a monotherapy, and combinatorial activity was observed in a range of distinct combination settings. Combination therapy of BI 894999 with a BTK inhibitor led to tumor regression in 6/7 animals in a lymphoma model. Furthermore, combination treatment with another transcriptional inhibitor resulted in excellent in vivo efficacy in an AML model with strong concomitant repression of MYC expression. In vivo potency of BI 894999 in SCLC, prostate and pancreas tumor models confirmed the potential of this BET inhibitor for treatment of solid cancers. Extended PK/PD analyses verified HEXIM1, a negative regulator of p-TEFb, as suitable PD biomarker, which was robustly induced by BI 894999 in all samples tested and is currently being utilized in clinical trials. Conclusions: These studies demonstrate that BI 894999 is a potent inhibitor of BET epigenetic regulators in models of hematologic and solid malignancies in vitro and in vivo, resulting in a robust induction of HEXIM1 transcription. For addressing the therapeutic potential of BET inhibition, BI 894999 has entered clinical studies in patients with advanced cancers.
Physicians Interrupting Patients—Reply
Authors: Larry B. Mauksch
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Prognostic significance of serum MMP-8, -9, and TIMP-1 in colorectal cancer
Authors: Camilla Böckelman, Ines Beilmann-Lehtonen, Tuomas Kaprio, Selja Koskensalo, Taina Tervahartiala, Jaana Hagström, Harri Mustonen, Timo Sorsa, Caj Haglund
Journal: Annals of Oncology (2017)
Chapter VIII: Faribault Materials and Methods
Journal: Circulation (1968)

The National Diet-Heart Study included a feasibility trial in an institution for the mentally retarded, the Faribault State School and Hospital, Faribault, Minnesota. In order to recruit 225 men from a total institutional population of 3,179, the age range had to be expanded to 40-59, and the medical criteria for eligibility relaxed. In both the First and Extended Studies, four groups were followed, B, C, and D (as in the open centers), plus a group E. (40% of calories from fat, low in saturated fat and cholesterol, very high in polyunsaturated fat). In the Extended Study, less expensive lean meats were procured locally, and fed to half the men, while the other half continued to eat D-H meats. A considerable investment had to be made to assure successful feeding of the four diets to the subjects. The Second Study at Faribault evaluated the effects on serum cholesterol of simultaneously varying amount of dietary cholesterol, and amount and type of dietary fat (for design and results, cf. Chapter XVII).
Abstract 10305: Clinical and Angiographic Characteristics of Patients Undergoing Percutaneous Coronary Intervention Following Sudden Cardiac Arrest: Insights From the NCDR(R)
Authors: Navdeep Gupta, Michael C Kontos, Aditi Gupta, George W Vetrovec, John Messenger
Journal: Circulation (2011)

Background: Coronary artery disease is present in the majority of out-of-hospital sudden cardiac arrest (SCA) patients (pts), and acute myocardial infarction (MI) is the most common cause of sudden...
Pooled Systemic Efficacy and Safety Data from the Pivotal Phase II Studies (NP28673 and NP28761) of Alectinib in ALK -positive Non-Small Cell Lung Cancer
Authors: James Chih-Hsin Yang, Sai-Hong Ignatius Ou, Luigi De Petris, Shirish Gadgeel, Leena Gandhi, Dong-Wan Kim, Fabrice Barlesi, Ramaswamy Govindan, Anne-Marie C. Dingemans, Lucio Crino, Herve Lena, Sanjay Popat, Jin Seok Ahn, Eric Dansin, Sophie Golding, Walter Bordogna, Bogdana Balas, Peter N. Morcos, Ali Zeaiter, Alice T. Shaw
Journal: Journal of Thoracic Oncology (2017)

Alectinib demonstrated clinical efficacy and an acceptable safety profile in two phase II studies (NP28761 and NP28673). Here we report the pooled efficacy and safety data after 15 and 18 months more follow-up than in the respective primary analyses.Enrolled patients had ALK receptor tyrosine kinase gene (ALK)-positive NSCLC and had progressed while taking, or could not tolerate, crizotinib. Patients received oral alectinib, 600 mg twice daily. The primary end point in both studies was objective response rate assessed by an independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included disease control rate, duration of response, progression-free survival, overall survival, and safety.The pooled data set included 225 patients (n = 138 in NP28673 and n = 87 in NP28761). The response-evaluable population included 189 patients (84% [n = 122 in NP28673 and n = 67 in NP28761]). In the response-evaluable population, objective response rate as assessed by the IRC was 51.3% (95% confidence interval [CI]: 44.0-58.6 [all PRs]), the disease control rate was 78.8% (95% CI: 72.3-84.4), and the median duration of response was 14.9 months (95% CI: 11.1-20.4) after 58% of events. Median progression-free survival as assessed by the IRC was 8.3 months (95% CI: 7.0-11.3) and median overall survival was 26.0 months (95% CI: 21.4-not estimable). Grade 3 or higher adverse events (AEs) occurred in 40% of patients, 6% of patients had treatment withdrawn on account of AEs, and 33% had AEs leading to dose interruptions/modification.This pooled data analysis confirmed the robust systemic efficacy of alectinib in ALK-positive NSCLC with a durable response rate. Alectinib also had an acceptable safety profile with a longer duration of follow-up.
Avelumab (MSB0010718C; anti-PD-L1) ± pegylated liposomal doxorubicin vs pegylated liposomal doxorubicin alone in patients with platinum-resistant/refractory ovarian cancer: The phase III JAVELIN Ovarian 200 trial.
Authors: Eric Pujade-Lourraine, Nicoletta Colombo, Mary L. Disis, Keiichi Fujiwara, Jonathan A. Ledermann, Mansoor Raza Mirza, Gary Edward Richardson, J. Thaddeus Beck, Stephanie Gaillard, Patricia Haney, Michael Shnaidman, Alexei Morozov, Bradley J. Monk
Journal: Journal of Clinical Oncology (2016)

TPS5600 Background: Programmed death-1 receptor ligand (PD-L1) is a key therapeutic target in the reactivation of the immune response against multiple cancers. Avelumab* is a fully human anti-PD-L1 IgG1 antibody that has shown promising efficacy and an acceptable safety profile in heavily pretreated patients (pts) with recurrent ovarian cancer. This open-label, multicenter, 3-arm, phase 3 trial (NCT02580058) compares avelumab ± pegylated liposomal doxorubicin (PLD) vs PLD alone in pts with platinum-resistant/refractory ovarian cancer, and is the first phase 3 trial of a checkpoint inhibitor in ovarian cancer. Methods: The primary objective of this global, multicenter trial is to demonstrate superiority of avelumab ± PLD vs PLD alone, defined by overall survival (OS). Key eligibility criteria include: histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer; up to 3 prior lines of chemotherapy for platinum-sensitive disease (platinum-containing regimen as most recent); and no prior therapy for platinum-resistant disease. Pts are not preselected for PD-L1 expression. Approximately 550 eligible patients will be randomized to receive either avelumab (10 mg/kg as a 1h intravenous [IV] infusion Q2W) ± PLD (40 mg/m2 as a 1h IV infusion Q4W) or PLD alone (40 mg/m2 as a 1h IV infusion Q4W). Treatment is given until disease progression, unacceptable toxicity, or withdrawal. Secondary endpoints include objective response, progression-free survival, duration of response, disease control, pharmacokinetics, immunogenicity, quality of life (assessed via EORTC QLQ-C30, EORTC QLQ-OV38, FOSI, and EQ-5D-5L), safety as per NCI-CTCAE v4.03, and tumor biomarkers, including PD-L1 expression and tumor infiltrating CD8+ T lymphocytes by IHC and tissue expression of immune regulators. Responses are evaluated according to RECIST 1.1 and adjudicated by a blinded independent review committee. Trial enrollment began in December 2015. *Proposed INN. Clinical trial information: NCT02580058.
Abstract P274: Cardiac-Specific Knockout of <i>Capn4</i> Attenuates Myocardial Remodeling and Improves Function After Myocardial Infarction in Mice
Authors: Jian Ma, Meng Wei, Hao Wang, Weihua Liu, Wei Zhu, Ying Li, James Lacefield, Peter Greer, Morris Karmazyn, Tianqing Peng
Journal: Circulation Research (2011)

Background - Calpain has been implicated in myocardial injury after myocardial infarction (MI). However, no direct evidence is available on the role of calpain in post-MI myocardial remodelling and dysfunction. The present study investigated the effects of cardiomyocyte-specific deletion of Capn4 , essential for calpain-1 and calpain-2 activities on myocardial remodelling and dysfunction following MI. Methods and Results - A novel mouse model with cardiomyocyte-specific deletion of Capn4 ( Capn4-ko ) was generated. MI was induced by left coronary artery ligation. Deficiency of Capn4 significantly reduced the protein levels and activities of calpain-1 and calpain-2 in the Capn4-ko heart. In vivo cardiac function was relatively improved in Capn4-ko mice at 7 and 30 days after MI compared with their wild-type littermates. Deletion of Capn4 reduced cardiac apoptosis, limited infarct expansion and infarct zone thinning, and prevented left ventricle dilation in Capn4-ko mice. Furthermore, myocardial collagen deposition and cardiomyocyte cross-sectional areas were significantly attenuated in Capn4-ko mice, which were accompanied by down-regulation of pro-fibrotic genes and hypertrophic genes. These effects of Capn4 knockout correlated with down-regulation of inflammatory mediators and normalization of matrix metalloproteinase (MMP)-9 activity in the non-infarct area of Capn4-ko mice after MI. In vivo mouse model of endotoxemia confirmed that calpain activation resulted in inflammatory gene expression and MMP-9 activity in the heart. Conclusions - Cardiomyocyte-specific knockout of calpain attenuates myocardial adverse remodelling and improves myocardial function after MI. These beneficial effects of calpain disruption may result from inhibition of cardiac apoptosis, inflammation and MMP-9 activity.
High Risk Familial Colorectal Cancer Clinic – a Review of HNPCC Surveillance
Authors: G Horgan, DNA Iskandar, L O'Brien, S McGovern, T Scanlon, P MacMathuna
Journal: Endoscopy (2006)

Introduction: Surveillance of high risk familial colorectal cancer is complex and requires Gastroenterology, Primary Care, Genetics, Laboratory and Specialist Nursing input.
FDA analysis of treatment beyond disease progression disease (PD) in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab vs. everolimus.
Authors: Chana Weinstock, Virginia Ellen Maher, Lijun Zhang, James Xunhai Xu, Shenghui Tang, Rajeshwari Sridhara, Amna Ibrahim, Geoffrey Kim, Richard Pazdur
Journal: Journal of Clinical Oncology (2016)

4508 Background: Traditional measurement of disease progression by RECIST v1.1 criteria may not fully capture patient benefit from PD-1 and PD-L1 inhibitors. Contemporary immunotherapy protocols generally allow patients to continue treatment beyond investigator-assessed radiographic PD as long as there is ongoing clinical benefit. However, the frequency of responses beyond PD is unknown, and whether this strategy is beneficial to the patient remains unclear. We present a review of the data from patients with mRCC treated beyond PD with nivolumab on CheckMate 025 (a randomized, phase 3 study of nivolumab vs. everolimus in locally advanced or mRCC). Methods: Subjects on CheckMate 025 who received any treatment beyond radiographic PD were identified. Dates of progression, treatment discontinuation, and corresponding tumor measurements were analyzed. Results: Treatment beyond radiographic PD occurred in 171 of patients treated with nivolumab. Median treatment duration beyond radiographic progression was 3.2 months (range 0.1-23.4). There were 5 patients (2.9% of those treated beyond progression) with a partial response after initially meeting criteria for RECIST 1.1-defined PD. In these 5 patients, small changes in tumor burden led to assessments of progression and response. Median survival in the 171 patients on the nivolumab arm treated beyond PD was 28.1 months. Median survival was 25.0 months among the 410 patients randomized to nivolumab and 16.6 months among the 134 patients who did not receive nivolumab after PD. Conclusions: Responses beyond investigator-assessed PD in mRCC patients treated with nivolumab appear to be rare, similar to data from treatment beyond PD with nivolumab in melanoma (FDA review). However, it is possible that some patients may derive clinical benefit that is not captured by radiographic assessments, and further investigation is needed. This data may help inform future treatment decisions and/or trial design in patients treated with immune checkpoint inhibitors. Clinical trial information: NCT01668784.
Abstract 17134: Race/Ethnic Differences in Uncontrolled Hypertension in the Outpatient Setting: The Guideline Advantage
Authors: Julie K Bower, Sejal Patel, Yosef Khan, Mary A Bauman, Randi E Foraker
Journal: Circulation (2016)

Introduction: Blood pressure (BP) screening is routine practice during outpatient care, yet the prevalence of uncontrolled hypertension is 14% in the U.S. The aim of this study was to examine race/...
Activated Protein C (APC) Therapy Ameliorates Chronic Graft Versus Host Disease By Cell Signaling Mechanisms That Require Cleavage at Arg46 in PAR1 on T Cells
Authors: Ranjeet Kumar Sinha, Ryan P Flynn, Jose A. Fernandez, Xiao Xu, Greg Martin, Sergey Kupriyanov, John H. Griffin, Bruce R. Blazar
Journal: Blood (2016)
PNPLA3 gene variants and insulin resistance in patients with genotype-1 chronic hepatitis C
Authors: Chiara Rosso, S Petta, Maria Lorena Abate, Ester Vanni, Lavinia Mezzabotta, S Grimaudo, Gian Paolo Caviglia, Roberto Gambino, M Cassader, Mario Rizzetto, Antonina Smedile, Elisabetta Bugianesi
Journal: Hepatology (2013)
The role of TGF-β in the pathophysiology of peritoneal endometriosis
Authors: Vicky J. Young, S.F. Ahmad, W. Colin Duncan, Andrew W. Horne
Journal: Human Reproduction Update (2017)

Endometriosis is estimated to affect 6–10% of women of reproductive age and it is associated with chronic pelvic pain, dysmenorrhoea and subfertility. It is currently managed surgically or medically but symptoms recur in up to 75% of cases and available medical treatments have undesirable side effects. Endometriosis is defined as the presence of endometrial tissue outside the uterus with lesions typically found on the peritoneum. The aetiology of endometriosis is uncertain but there is increasing evidence that transforming growth factor (TGF)-β plays a major role. A descriptive review was undertaken of the published literature on the expression pattern of TGF-β ligands and signalling molecules in women with and without endometriosis, and on the potential roles of TGF-β signalling in the development and progression of peritoneal endometriosis. The current understanding of the TGF-β signalling pathway is summarized. We searched the Pubmed database using the terms 'transforming growth factor beta' and 'endometriosis' for studies published between 1995 and 2016. The initial search identified 99 studies and these were used as the basic material for this review. We also extended our remit for important older publications. In addition, we searched the reference lists of studies used in this review for additional studies we judged as relevant. Studies which were included in the review focused on peritoneal endometriosis only as increasing evidence suggests that ovarian and deep endometriosis may have a differing pathophysiology. Thus, a final 95 studies were included in the review. TGF-β1 is reported to be increased in the peritoneal fluid, serum, ectopic endometrium and peritoneum of women with endometriosis compared to women without endometriosis, and TGF-β1-null mice have reduced endometriosis lesion growth when compared to their wild-type controls. Studies in mice and women have indicated that increasing levels of TGF-β ligands are associated with decreased immune cell activity within the peritoneum, together with an increase in ectopic endometrial cell survival, attachment, invasion and proliferation, during endometriosis lesion development. TGF-β1 has been associated with changes in ectopic endometrial and peritoneal cell metabolism and the initiation of neoangiogenesis, further fuelling endometriosis lesion development. Together these studies suggest that TGF-β1 plays a major role in the development of peritoneal endometriosis lesions and that targeting this pathway may be of therapeutic potential.
Genomic mutation profiling (GMP) and clinical outcome in patients (pts) treated with ribociclib (CDK4/6 inhibitor) in the Signature program.
Authors: Julio Antonio Peguero, Bert H. O'Neil, Davendra Sohal, Todd Michael Bauer, Vivek Subbiah, Karen Kelly, Juneko E. Grilley-Olson, Lincoln Nadauld, Howard Safran, Eric Daniel Slosberg, Rajinder Sidhu, Erica Stealey, Sudha Parasuraman, Barinder Kang, Joseph Paul Eder
Journal: Journal of Clinical Oncology (2016)

2528 Background: The Signature program comprises a series of 8 tissue-agnostic, mutation-specific, signal-seeking protocols without predetermined study sites, thereby bringing the protocol to the pt. Pts included in the ribociclib (LEE011) protocol had CDK4/6 pathway aberrations, identified via standard-of-care physician-directed profiling. Separate ribociclib phase 3 studies in breast cancer are ongoing. Methods: Pts with measurable advanced malignancies and no established standard therapy options were eligible. The primary objective was assessment of clinical benefit (CB; CR + PR + SD) at wk 16 by local investigator. Ribociclib was given orally (600 mg QD; 3 wk on, 1 wk off). Statistical design adaptively clustered pts into cohorts for independent analysis of early futility or efficacy. GMP of pt tumors was performed centrally for post hoc eligibility confirmation. Results: As of 28 Aug 2015, 106 pts were enrolled across 31 tumor types. Median age was 63 years (range, 19-86 years), 53% were women, and median number of prior antineoplastic therapies was 3 (range, 0-19). Baseline actionable alterations included 73 p16 (CDKN2A) mutations (mut; 68.9%); 10 cyclin D1 (CCND1) amplifications (amp; 9.4%); 9 CDK6 amp (8.5%); 7 CDK4 amp (6.6%); 5 each of CDK4 mut and cyclin D3 (CCND3) amp (4.7%); and 2 CDK6 mut (1.9%). 5 pts had > 1 eligible aberration. Major tumor types (in ≥ 4 pts) included sarcoma (13 [12%]) and bladder, triple-negative breast, and HNSCC (7 each [7%]). Rare tumors included mesothelioma (5 [5%]) and thyroid, penile, and adrenal (1 each [1%]). 12 analyzable cohorts were formed. Neutropenia (17% grade 3/4; 29% all grades) was the most frequent grade 3/4 drug-related AE seen in ≥ 10% of pts. At wk 16, CB was seen in 19 pts; 11 (58%) had p16 mut/loss. Preliminary antitumor activity was observed in 4 pts: 1 pt with urothelial cancer (CCND1 amp), 1 pt with sarcoma (CDK4 amp), 1 pt with unknown primary tumor (CDK6 amp), and 1 pt with ovarian cancer (CDK6 mut; reported after data cutoff). Conclusions: Ribociclib showed clinical activity in some pts. Correlation of CB and GMP is ongoing and will help to determine the significance of these mutations and potential for combination with other agents. Clinical trial information: NCT02187783.