tbuckley/cabot-search huggingface dataset:
Activation switch pocket inhibitors target the T315I mutant of BCR-ABL
Authors: Thomas O'Hare, Christopher Eide, Scott Wise, Bryan Smith, Peter Petillo, Daniel Flynn, Brian Druker
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

4867 

Overview: The BCR-ABLT315I mutant is highly resistant to imatinib, nilotinib and dasatinib and is frequently detected in CML patients relapsing on the newer ABL kinase inhibitors. We have developed switch pocket inhibitors of ABL kinase that are effective against BCR-ABLT315I. The switch pocket controls the activity state of ABL by binding key residues of the kinase activation loop. These inhibitors exhibit long off-rates and retain potency against gatekeeper and P-loop residues implicated in resistance. Here, we evaluated two switch pocket inhibitors, DCC-2036 and DP-2494, against native and mutant BCR-ABL. Methods: We assessed DCC-2036 and DP-2494 in cellular and biochemical assays against a panel of BCR-ABL mutants: M244V, G250E, Q252H, Y253F, Y253H, E255K, E255V, T315A, T315I, F317L, F317V, M351T, F359V, and H396P. Colony assays were performed with primary CML cells expressing BCR-ABLT315I. Results: Our results establish that both inhibitors have activity against most imatinib-resistant mutants, with minimal effect on parental cells (IC50 > 5 µM). DCC-2036 inhibited growth of cells expressing BCR-ABL (IC50: 19 nM) with ~16-fold higher potency than imatinib. Of key importance, DCC-2036 also blocked growth of cells expressing BCR-ABLT315I (IC50: 63 nM). Sensitivity to DCC-2036 segregated into 3 categories: [IC50 ≤ 50 nM: 1/14; M351T], [IC50 ≤ 100 nM: 8/14; M244V, G250E, Q252H, Y253F, T315A, T315I, F317L, H396P], and [IC50 > 100 nM: 5/14; Y253H, E255K, E255V, F317V, F359V]. By comparison, the potency of DP-2494 against cells expressing BCR-ABL (IC50: 0.06 nM) rivals that of dasatinib (IC50: 0.8 nM). Unlike dasatinib, DP-2494 also inhibited BCR-ABLT315I (IC50: 6.1 nM). All tested BCR-ABL mutants except E255V (IC50: 144 nM) were inhibited by DP-2494 with an IC50 ≤ 50 nM. Colony formation by patient-derived cells expressing BCR-ABLT315I was reduced by each of the inhibitors in a dose-dependent manner. Results from a mutagenesis screen for BCR-ABL mutants emerging in the presence of DCC-2036 or DP-2494 will be reported. Conclusions: Both inhibitors exhibited significant activity against T315I. Our results suggest that monotherapy with DCC-2036 or DP-2494 may provide a treatment option for relapsed patients with a BCR-ABLT315I mutation, but vulnerability to mutations such as E255V is predicted. However, combinations of ABL kinase inhibitors that include a T315I-targeted compound such as DCC-2036 or DP-2494 may completely pre-empt BCR-ABL-dependent resistance.
Finding the Rare Pathogenic Variants in a Human Genome
Authors: James P. Evans, Bradford C. Powell, Jonathan S. Berg
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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) 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
Mediastinal masses: A study of our cases by transthoracic needle biopsy (TTNB) versus open surgery as a diagnostic procedure
Authors: F. Gradica, L. Lisha, D. Argjiri, A. Cani, A. Leka, F. Kokici, S. Gradica, Y. Vata, F. Gradica, V. Rexha
Journal: Annals of Oncology (2017)
Abstract P261: Endothelial Differentiation Gene-1 Is Involved in Related Transcriptional Enhancer Factor-1--Induced Endothelial Cell Aggregation
Authors: Ping He, Xiaojin An, Jiaping Wu, Angela Messmer-Blust, Melissa Philbrick, Jian Li
Journal: Circulation Research (2011)

We have previously demonstrated that Related Transcriptional Enhancer Factor-1 (RTEF-1) regulated angiogenesis through induction of vascular endothelial growth factor (VEGF) under hypoxic conditions. Recently, we discovered that RTEF-1 accelerated endothelial cell connections and enhanced endothelial cell aggregation. To investigate the mechanism of RTEF-1 in regulated endothelial aggregation, a DNA array analysis was performed in the endothelial cell (HMEC-1) lacking RTEF-1 by its siRNA and resulted in a significant decrease of endothelial differentiation gene -1 (Edg-1). RTEF-1 significantly increase Edg-1 promoter activity (4.10 Fold) and the expression levels of Edg-1 gene are concordant with the RTEF-1 gene in both mRNA and protein levels in cultured endothelial cells as well as in endothelial specific RTEF-1 transgenic mice (VE-Cad-RTEF-1) and RTEF-1 knock out mice (Tie2 Cre :RTEF-1 floxp ) . In Matrigel tube formation assay, over-expression of Edg-1 gene stimulated endothelial cell aggregation, while siRNA of Edg-1 significantly blocked RTEF-1-driven endothelial cell aggregation. Furthermore, using an Edg-1 receptor agonist Sphingosine-1-phosphate (S1P), the acceleration of the proliferation, migration and tube formation were observed, whereas Edg-1 receptor inhibitor Pertussis Toxin (PTX) could block RTEF-1-induced cell aggregation. Our data demonstrates that Edg-1 is a potential target gene of RTEF-1. It is involved in RTEF-1 regulated endothelial cell angiogenesis, specifically in endothelial cell aggregation.
The contemporary refugee crisis: an overview of mental health challenges
Authors: Derrick Silove, Peter Ventevogel, Susan Rees
Journal: World Psychiatry (2017)

There has been an unprecedented upsurge in the number of refugees worldwide, the majority being located in low‐income countries with limited resources in mental health care. This paper considers contemporary issues in the refugee mental health field, including developments in research, conceptual models, social and psychological interventions, and policy. Prevalence data yielded by cross‐sectional epidemiological studies do not allow a clear distinction to be made between situational forms of distress and frank mental disorder, a shortcoming that may be addressed by longitudinal studies. An evolving ecological model of research focuses on the dynamic inter‐relationship of past traumatic experiences, ongoing daily stressors and the background disruptions of core psychosocial systems, the scope extending beyond the individual to the conjugal couple and the family. Although brief, structured psychotherapies administered by lay counsellors have been shown to be effective in the short term for a range of traumatic stress responses, questions remain whether these interventions can be sustained in low‐resource settings and whether they meet the needs of complex cases. In the ideal circumstance, a comprehensive array of programs should be provided, including social and psychotherapeutic interventions, generic mental health services, rehabilitation, and special programs for vulnerable groups. Sustainability of services, ensuring best practice, evidence‐based approaches, and promoting equity of access must remain the goals of future developments, a daunting challenge given that most refugees reside in settings where skills and resources in mental health care are in shortest supply.
First-in-Human study of LMB763, a novel, orally-available farnesoid X receptor agonist that demonstrates modulation of the pharmacodynamic markers FGF19 and C4 in healthy subjects
Authors: K. Huttner, S. Desai, M. DeCristofaro, B. Laffitte, T. Lin, J. Chen, L. Klickstein, M.K. Badman
Journal: Journal of Hepatology (2017)
Pediatric autoimmune hepatitis shows a strong increase of intrahepatic Tregs and an IL-2 associated Treg decline under therapy
Authors: J. Diestelhorst, N. Junge, J. Schlue, C.S. Falk, M.P. Manns, U. Baumann, E. Jaeckel, R. Taubert
Journal: Journal of Hepatology (2017)
Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases
Authors: Ashwin N. Ananthakrishnan, Chengwei Luo, Vijay Yajnik, Hamed Khalili, John J. Garber, Betsy W. Stevens, Thomas Cleland, Ramnik J. Xavier
Journal: Cell Host & Microbe (2017)
SWOG S9005: Double blind phase III randomized trial of the anti-progestin agent mifepristone in the treatment of unresectable meningioma.
Authors: Yongli Ji, Cathryn J Rankin, Steven M. Grunberg, Andy Sherrod, Jamshid Ahmadi, Lynn G. Feun, Ruth Fredericks, Christy Ann Russell, Fairooz F. Kabbinavar, Keith Stelzer, Anne F. Schott, Claire F. Verschraegen
Journal: Journal of Clinical Oncology (2015)

e17084 Background: Progesterone receptors are expressed on approximately 70 percent of meningiomas. Mifepristone is an oral anti-progestational agent that was reported to have modest activity in a phase II study. This multi-center, prospective, randomized, placebo-controlled, phase III trial conducted by SWOG was planned to define the role of Mifepristone as treatment of unresectable meningioma. Methods: Eligible patients were randomized to receive either Mifepristone or placebo for 2 years unless disease progressed. Patients who were stable or responding to protocol therapy after 2 years had the option to continue with the same blinded therapy. Serial follow-up allowed assessment of efficacy and toxicity. Time to treatment failure and overall survival was ascertained for all randomized patients. Upon progression, patients receiving placebo could crossover and receive active drug. Results: Among 164 eligible patients, 80 were randomized to Mifepristone and 84 to placebo arm. Twenty-four (30%) and 28 (33%) patients were able to complete the 2 years of Mifepristone or placebo, respectively, without disease progression, side effects, or other reasons for discontinuation. There was no statistical difference between the arms in terms of failure-free and overall survivals. None of the 41 patients who cross-over to Mifepristone, responded. Conclusions: Long term administration of Mifepristone is well tolerated but fails to improve survival in patients with unresectable meningioma. Clinical trial information: E-S9005.
Safety and efficacy of glecaprevir/pibrentasvir in adults with chronic hepatitis C virus infection genotype 1–6 and chronic kidney disease: an integrated analysis
Authors: S. Pol, P. Pockros, D. Pugatch, N. Brau, C. Landis, M. Elkhashab, J. Sasadeusz, A. Tran, Y. Hu, M. Kosloski, F. Mensa
Journal: Journal of Hepatology (2017)
Early onset of endocrine alterations during PD-1 blockade in advanced NSCLC patients
Authors: C.E. Onesti, A. Botticelli, M. Occhipinti, F.R. Di Pietro, I. Zizzari, C. Napoletano, M. Nuti, S. Lauro, F. Mazzuca, P. Marchetti
Journal: Annals of Oncology (2017)
Polymorphisms in the cyclooxygenase-2 (COX-2) gene, vascular endothelial growth factor (VEGF) and methylenetetrahydrofolate reductase (MTHFR) gene in patients with hepatocellular carcinoma and hepatitis C virus infection
Authors: S.C.R.D. Carvalho, L.R.S. Vasconcelos, R.F. Carmo, D.C.B.L. Aroucha, M.T. Tomitão, U. Ribeiro-Jr, L.M.M.B. Pereira, C.P. Oliveira, F.J. Carrilho
Journal: Journal of Hepatology (2017)
Antibiotic Prescribing for Nonbacterial Acute Upper Respiratory Infections in Elderly Persons
Authors: Michael Silverman, Marcus Povitz, Jessica M. Sontrop, Lihua Li, Lucie Richard, Sonny Cejic, Salimah Z. Shariff
Journal: Annals of Internal Medicine (2017)

Background: Reducing inappropriate antibiotic prescribing for acute upper respiratory tract infections (AURIs) requires a better understanding of the factors associated with this practice. Objective: To determine the prevalence of antibiotic prescribing for nonbacterial AURIs and whether prescribing rates varied by physician characteristics. Design: Retrospective analysis of linked administrative health care data. Setting: Primary care physician practices in Ontario, Canada (January–December 2012). Patients: Patients aged 66 years or older with nonbacterial AURIs. Patients with cancer or immunosuppressive conditions and residents of long-term care homes were excluded. Measurements: Antibiotic prescriptions for physician-diagnosed AURIs. A multivariable logistic regression model with generalized estimating equations was used to examine whether prescribing rates varied by physician characteristics, accounting for clustering of patients among physicians and adjusting for patient-level covariates. Results: The cohort included 8990 primary care physicians and 185 014 patients who presented with a nonbacterial AURI, including the common cold (53.4%), acute bronchitis (31.3%), acute sinusitis (13.6%), or acute laryngitis (1.6%). Forty-six percent of patients received an antibiotic prescription; most prescriptions were for broad-spectrum agents (69.9% [95% CI, 69.6% to 70.2%]). Patients were more likely to receive prescriptions from mid- and late-career physicians than early-career physicians (rate difference, 5.1 percentage points [CI, 3.9 to 6.4 percentage points] and 4.6 percentage points [CI, 3.3 to 5.8 percentage points], respectively), from physicians trained outside of Canada or the United States (3.6 percentage points [CI, 2.5 to 4.6 percentage points]), and from physicians who saw 25 to 44 patients per day or 45 or more patients per day than those who saw fewer than 25 patients per day (3.1 percentage points [CI, 2.1 to 4.0 percentage points] and 4.1 percentage points [CI, 2.7 to 5.5 percentage points], respectively). Limitation: Physician rationale for prescribing was unknown. Conclusion: In this low-risk elderly cohort, 46% of patients with a nonbacterial AURI were prescribed antibiotics. Patients were more likely to receive prescriptions from mid- or late-career physicians with high patient volumes and from physicians who were trained outside of Canada or the United States. Primary Funding Source: Ontario Ministry of Health and Long-term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine and Dentistry, Western University, and Lawson Health Research Institute.
Hepatic expression of oncogenes Bmi1 and Dkk1 can be induced by treatment with hepatitis B virus particles or Lipopolysaccharide in vitro and is up-regulated in liver biopsies of patients with chronic HBV infection
Authors: R. Zhang, C.I. Real, C. Liu, B.A. Hideo, G. Gerken, M. Lu, R. Broering
Journal: Journal of Hepatology (2017)
No change in hepatitis C virus-specific T cell functionality after successful DAA treatment in chronic hepatitis C patients
Authors: F. Stelma, M.H. van der Ree, M.J. Sinnige, A. Brown, L. Swadling, S.B. Willemse, M. van der Valk, J.M. de Vree, P. Klenerman, E. Barnes, N.A. Kootstra, H.W. Reesink
Journal: Journal of Hepatology (2017)
Effect of interferon free antiviral therapy on glomerular and tubular kidney involvement in hepatitis C virus child-A cirrhosis
Authors: D. Palazzo, E. Biliotti, F. Tinti, A. Bachetoni, A. Cappoli, M. Subic, M.D. D’Alessandro, R. Labriola, S. Grieco, P. Perinelli, I. Umbro, L. Volpicelli, P. Rucci, A.P. Mitterhofer, G. Taliani
Journal: Journal of Hepatology (2017)
TAM Receptor Tyrosine Kinases in Cancer Drug Resistance
Authors: Mikaella Vouri, Sassan Hafizi
Journal: Cancer Research (2017)

Abstract Receptor tyrosine kinases (RTK) are major regulators of key biological processes, including cell growth, survival, and differentiation, and were established early on as proto-oncogenes, with aberrant expression linked to tumor progression in many cancers. Therefore, RTKs have emerged as major targets for selective therapy with small-molecule inhibitors. However, despite improvements in survival rates, it is now apparent that the targeting of RTKs with selective inhibitors is only transiently effective, as the majority of patients eventually become resistant to therapy. As chemoresistance is the leading cause of cancer spread, progression, and mortality, there is an increasing need for understanding the mechanisms by which cancer cells can evade therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily of RTKs in particular feature in a variety of cancer types that have developed resistance to a broad range of therapeutic agents, including both targeted as well as conventional chemotherapeutics. This article reviews the roles of TAMs as tumor drivers and as mediators of chemoresistance, and the potential effectiveness of targeting them as part of therapeutic strategies to delay or combat resistance. Cancer Res; 77(11); 2775–8. ©2017 AACR.
A novel role for BMP9 as a negative regulator of oval cell-mediated regeneration in response to liver damage
Authors: A. Addante, C. Roncero, L. Almalé, N. Lazcanoiturburu, M.G. Álvaro, M. Fernández, J. Sanz, P. Saperas, S.-J. Lee, I. Fabregat, P. ten Dijke, S. Dooley, B. Herrera, A. Sánchez
Journal: Journal of Hepatology (2017)
Annexin subcellular expression in laryngeal squamous cell carcinoma
Authors: Venancio Alves, Suely Nonogaki, Patricia Cury, Victor Wunsch-Filho, Marcos de Carvalho, Pedro Michaluart, Raquel Moyses, Otavio Curioni, David Figueiredo, Cristovam Scapulatempo-Neto, Edwin Parra, Wilson da Silva, Francisco Nobrega, Eloiza Tajara, Marco Zago
Journal: Clinical Cancer Research (2007)

A49   Annexin 1 is a soluble cytoplasmic protein, moving to membranes when calcium levels are elevated. Annexin 1 is also shown to move to nucleus or outside the cells, depending on tysosine-kinase signaling, thus interfering in cytoskeletal organization, ion fluxes and cell differentiation, mostly in inflammatory and neoplastic processes. In the present study, Sequencing Analysis of Gene Expression experiments detected a reduced expression of  ANXA1  gene in laryngeal squamous cell carcinomas as compared to the corresponding non-neoplastic margins. Real time polymerase chain reaction confirmed  ANXA1  low expression in another random subset of 15 larynx squamous cell carcinomas and 8 matched normal samples. Based on these data, we investigated subcellular patterns of immunohistochemical expression of annexin 1 in 259 paraffin-embedded samples from 95 patients with laryngeal squamous cell carcinomas, including non-tumoral, dysplastic, primary tumoral and lymphnode metastases areas, searching for evidences for the role of annexin 1 in laryngeal carcinogenesis. The results showed annexin 1 down-regulation in dysplastic, tumoral and metastatic lesions and provided preliminary evidence for the progressive migration of annexin 1 from the nucleus towards the membrane along the sequence of laryngeal carcinogenesis. Since this dysregulation was observed very early in carcinogenesis, already in intra-epithelial neoplasms, it was not found related to prognostic markers, such as nodal metastases.
Development and Validation of the PREMM<sub>5</sub> Model for Comprehensive Risk Assessment of Lynch Syndrome
Authors: Fay Kastrinos, Hajime Uno, Chinedu Ukaegbu, Carmelita Alvero, Ashley McFarland, Matthew B. Yurgelun, Matthew H. Kulke, Deborah Schrag, Jeffrey A. Meyerhardt, Charles S. Fuchs, Robert J. Mayer, Kimmie Ng, Ewout W. Steyerberg, Sapna Syngal
Journal: Journal of Clinical Oncology (2017)

Purpose Current Lynch syndrome (LS) prediction models quantify the risk to an individual of carrying a pathogenic germline mutation in three mismatch repair (MMR) genes: MLH1, MSH2, and MSH6. We developed a new prediction model, PREMM5, that incorporates the genes PMS2 and EPCAM to provide comprehensive LS risk assessment. Patients and Methods PREMM5 was developed to predict the likelihood of a mutation in any of the LS genes by using polytomous logistic regression analysis of clinical and germline data from 18,734 individuals who were tested for all five genes. Predictors of mutation status included sex, age at genetic testing, and proband and family cancer histories. Discrimination was evaluated by the area under the receiver operating characteristic curve (AUC), and clinical impact was determined by decision curve analysis; comparisons were made to the existing PREMM1,2,6 model. External validation of PREMM5 was performed in a clinic-based cohort of 1,058 patients with colorectal cancer. Results Pathogenic mutations were detected in 1,000 (5%) of 18,734 patients in the development cohort; mutations included MLH1 (n = 306), MSH2 (n = 354), MSH6 (n = 177), PMS2 (n = 141), and EPCAM (n = 22). PREMM5 distinguished carriers from noncarriers with an AUC of 0.81 (95% CI, 0.79 to 0.82), and performance was similar in the validation cohort (AUC, 0.83; 95% CI, 0.75 to 0.92). Prediction was more difficult for PMS2 mutations (AUC, 0.64; 95% CI, 0.60 to 0.68) than for other genes. Performance characteristics of PREMM5 exceeded those of PREMM1,2,6. Decision curve analysis supported germline LS testing for PREMM5 scores ≥ 2.5%. Conclusion PREMM5 provides comprehensive risk estimation of all five LS genes and supports LS genetic testing for individuals with scores ≥ 2.5%. At this threshold, PREMM5 provides performance that is superior to the existing PREMM1,2,6 model in the identification of carriers of LS, including those with weaker phenotypes and individuals unaffected by cancer.
Safety and efficacy of elbasvir and grazoprevir with or without ribavirin for the treatment of hepatitis C virus genotype 1: results of the hepatitis C virus-TARGET study
Authors: B.L. Pearlman, G. Lutchman, M.L. Shiffman, J. Patel, L.M. Frazier, J.S. Galati, J.E. Gallant, A. Ramani, M. Vainorius, D.R. Nelson, M.W. Fried, M. Khalili, Z. Ben-Ari
Journal: Journal of Hepatology (2017)