tbuckley/cabot-search huggingface dataset:
Genetic and epigenetic inactivation of <i>SESTRIN1</i> controls mTORC1 and response to EZH2 inhibition in follicular lymphoma
Authors: Elisa Oricchio, Natalya Katanayeva, Maria Christine Donaldson, Stephanie Sungalee, Joyce P. Pasion, Wendy Béguelin, Elena Battistello, Viraj R. Sanghvi, Man Jiang, Yanwen Jiang, Matt Teater, Anita Parmigiani, Andrei V. Budanov, Fong Chun Chan, Sohrab P. Shah, Robert Kridel, Ari M. Melnick, Giovanni Ciriello, Hans-Guido Wendel
Journal: Science Translational Medicine (2017)

Follicular lymphoma (FL) is an incurable form of B cell lymphoma. Genomic studies have cataloged common genetic lesions in FL such as translocation t(14;18), frequent losses of chromosome 6q, and mutations in epigenetic regulators such as EZH2 Using a focused genetic screen, we identified SESTRIN1 as a relevant target of the 6q deletion and demonstrate tumor suppression by SESTRIN1 in vivo. Moreover, SESTRIN1 is a direct target of the lymphoma-specific EZH2 gain-of-function mutation (EZH2Y641X ). SESTRIN1 inactivation disrupts p53-mediated control of mammalian target of rapamycin complex 1 (mTORC1) and enables mRNA translation under genotoxic stress. SESTRIN1 loss represents an alternative to RRAGC mutations that maintain mTORC1 activity under nutrient starvation. The antitumor efficacy of pharmacological EZH2 inhibition depends on SESTRIN1, indicating that mTORC1 control is a critical function of EZH2 in lymphoma. Conversely, EZH2Y641X mutant lymphomas show increased sensitivity to RapaLink-1, a bifunctional mTOR inhibitor. Hence, SESTRIN1 contributes to the genetic and epigenetic control of mTORC1 in lymphoma and influences responses to targeted therapies.
American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society Scientific Statement on Noninvasive Risk Stratification Techniques for Identifying Patients at Risk for Sudden Cardiac Death
Authors: Jeffrey J. Goldberger, Michael E. Cain, Stefan H. Hohnloser, Alan H. Kadish, Bradley P. Knight, Michael S. Lauer, Barry J. Maron, Richard L. Page, Rod S. Passman, David Siscovick, William G. Stevenson, Douglas P. Zipes
Journal: Circulation (2008)
Treatment Efficacy, Adherence, and Quality of Life Among Women Younger Than 35 Years in the International Breast Cancer Study Group TEXT and SOFT Adjuvant Endocrine Therapy Trials
Authors: Poornima Saha, Meredith M. Regan, Olivia Pagani, Prudence A. Francis, Barbara A. Walley, Karin Ribi, Jürg Bernhard, Weixiu Luo, Henry L. Gómez, Harold J. Burstein, Vani Parmar, Roberto Torres, Josephine Stewart, Meritxell Bellet, Antonia Perelló, Faysal Dane, Antonio Moreira, Daniel Vorobiof, Michelle Nottage, Karen N. Price, Alan S. Coates, Aron Goldhirsch, Richard D. Gelber, Marco Colleoni, Gini F. Fleming
Journal: Journal of Clinical Oncology (2017)

Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2-negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer-free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2-negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful (≥ 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. Conclusion In women younger than 35 years with hormone receptor-positive breast cancer, adjuvant OFS combined with tamoxifen or exemestane produces large improvements in BCFI compared with tamoxifen alone. Menopausal symptoms are significant but are not worse than those seen in older premenopausal women.
Impairment of drug response cascades, by DNA methylation, in platinum-resistant ovarian cancer.
Authors: Curtis Balch, Dhaval Desai, Meng Li, John Montgomery, Henry Paik, Pearlly Yan, Tim Huang, Kenneth Nephew
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

2867 

To examine mechanisms of ovarian cancer development of platinum resistance, we developed a model culture system demonstrating stepwise adaptation of increasingly chemoresistant clones of the initially drug-sensitive cell line A2780. Specifically, DNA was isolated for genome-wide assessment of promoter DNA methylation, using a microarray approach known as differential methylation hybridization (DMH), to determine the relationship of this epigenetic phenomenon to drug resistance. Using DMH, global methylation of A2780 genomic DNA, following each selection cycle, was compared to DNA methylation of initially untreated (and chemosensitive) single clones. The total number of methylated (defined by a 1.5-fold hybridization difference) loci was found to increase following 1, 3, and 5 cycles of cisplatin treatment (590, 870, and 1176 loci, respectively). Moreover, a linear correlation between those increases in methylated loci and cisplatin resistance (as determined by IC50 dose) was also observed (R=0.98; P<0.001, Spearman analysis). Using the bioinformatics tool Pathway Express (Onto-Tools), we identified specific cascades altered by DNA methylation following 1, 3, and 5 cycles of cisplatin treatment. Notably, methylation of apoptosis (0, 2, and 7 genes, respectively, after 1, 3, and 5 cycles) and cell cycle (5, 7, and 11 genes) pathway components increased linearly with drug resistance, strongly suggesting that DNA methylation, and subsequent disruption, of those signaling cascades plays a prominent role in the development of insensitivity to platinum drugs. Finally, based on sequence information of chemoresistance-associated methylated loci, we used additional bioinformatics approaches to identify transcription factor-binding sites associated with those loci, examining the possibility of methylation-induced direct obstruction of transcription machinery as a means of gene silencing. In summary, we believe that these computational approaches will allow the generation of “epigenetic models” of ovarian cancer drug resistance that could provide for novel strategies for managing this devastating clinical phenomenon.
Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): Pooled analyses after long-term follow-up in KEYNOTE-012.
Authors: Ranee Mehra, Tanguy Y. Seiwert, Amit Mahipal, Jared Weiss, Raanan Berger, Joseph Paul Eder, Barbara Burtness, Makoto Tahara, Bhumsuk Keam, Dung T. Le, Kei Muro, Ravit Geva, Hyun Cheol Chung, Chia-Chi Lin, Amy Meister, Darcy Hille, Jonathan D. Cheng, Laura Quan Man Chow, Robert I. Haddad
Journal: Journal of Clinical Oncology (2016)

6012 Background: The PD-1 pathway is a key mechanism by which R/M HNSCC tumors evade immune surveillance. Pembrolizumab (pembro), an anti–PD-1 antibody, showed promising antitumor activity in R/M HNSCC in KEYNOTE-012 (NCT01848834). We present a pooled analysis of efficacy and safety of pembro after long-term follow-up in R/M HNSCC pts in this study. Methods: Pts had R/M HNSCC, measurable disease by RECIST v1.1, and ECOG PS 0-1. The initial (I) cohort enrolled PD-L1+ pts; expansion (E) cohort enrolled pts regardless of PD-L1 status. Pembro 10 mg/kg Q2W (I) or 200 mg Q3W (E) was given for 24 mo or until disease progression, unacceptable safety, or investigator/pt decision. Response was assessed every 8 wk. AEs were graded using CTCAE v4.0. Primary end point was ORR (RECIST v1.1) per central imaging vendor review. Secondary end points included PFS, OS, and duration of response (DOR). Pts who received ≥ 1 dose of pembro were included in these pooled analyses. Results: 192 R/M HNSCC pts were enrolled and received pembro (I = 60; E = 132); the last pt was enrolled on Oct 8, 2014. 32 (17%) pts (I = 6; E = 26) were still on treatment as of Sept 1, 2015. Median age was 60 y; 83% were male; 70% had ECOG PS 1; 61% received ≥ 2 therapies for recurrent disease. ORR (confirmed) was 17.7% (95% CI, 12.6%-23.9%; 7 CRs, 27 PRs). Median follow-up duration in responders was 12.5 mo (range, 8.4-24.4). At data cutoff, median DOR was not yet reached (range, 1.8+ to 21.8+ mo); responses were ongoing in 22 (76%) pts. Responses of ≥ 6 mo and ≥ 12 mo were noted in 25 pts and 4 pts. 33 (17%) pts achieved stable disease. ORR was 21.9% (95% CI, 12.5%-34.0%) in HPV+ pts and 15.9% (95% CI, 10.0%-23.4%) in HPV- pts. Median OS was 8.5 mo (95% CI, 6.5-10.5). The 6-mo PFS rate was 24.9%. Treatment-related AEs (TRAEs) occurred in 122 (64%) pts; 23 (12%) pts had a grade 3-4 TRAE. No pts died because of a TRAE. ALT and AST increases were the only grade 3-4 TRAEs in > 2 pts. Conclusions: Robust antitumor activity, with durable responses up to ~2 y and promising survival during long-term follow-up, suggests pembro given as 200 mg Q3W or 10 mg/kg Q2W is an active treatment for R/M HNSCC regardless of PD-L1 status. Pembro was well tolerated in R/M HNSCC pts. Clinical trial information: NCT01848834.
Efficacy, tolerability and impact on quality of life of selective internal radiation therapy (with yttrium-90 resin microspheres) or sorafenib in patients with locally advanced hepatocellular carcinoma: The SARAH trial
Authors: Mohamed Bouattour, Eric Assenat, Boris Guiu, Diana Ilonca Alina, Georges-Philippe Pageaux, Annie Sibert, Rachida Lebtahi, Wassim Allaham, Hélène Barraud, Valérie Laurent, Elodie Mathias, Jean-Pierre Bronowicki, Jean-Pierre Tasu, Rémy Perdrisot, Christine Silvain, René Gerolami, Olivier Mundler, Jean-Francois Seitz, Vincent Vidal, Christophe Aubé, Frédéric Oberti, Olivier Couturier, Isabelle Brenot-Rossi, Jean-Luc Raoul, Anthony Sarran, Charlotte Costentin, Emmanuel Itti, Alain Luciani, René Adam, Maïté Lewin, Didier Samuel, Maxime Ronot, Aurelia Dinut, Helena Pereira, Laurent Castera, Gilles Chatellier, Valérie Vilgrain
Journal: Annals of Oncology (2017)
A phase II study of neoadjuvant FOLFOXIRI followed by concurrent capecitabine and radiotherapy for high risk rectal cancer
Authors: Brigette Ma, Janet Lee, Michael Cheung, Simon Chu, Dennis Ng, Leung Li, Carmen Cho, Esther Hung, William Yeung, Macy Tong, Wing Ho, Edwin Hui, Wai Tsang, Sophie Hon, Tony Mak, Simon Ng, Joyce Suen
Journal: Annals of Oncology (2017)
My Child Is Islet Autoantibody Positive: Impact on Parental Anxiety
Authors: Suzanne Bennett Johnson, Kristian F. Lynch, Roswith Roth, Desmond Schatz
Journal: Diabetes Care (2017)

To assess parent anxiety in response to genetic and islet autoantibody (IA) testing in children at increased genetic risk for type 1 diabetes followed from birth in The Environmental Determinants of Diabetes in the Young (TEDDY) study.
Antitumoral action of melatonin in Ewing Sarcoma cells: possible EWS-FLI1 implication
Authors: Guillermo Garcia-Santos, Jezabel Rodriguez-Blanco, Isaac Antolin, Federico Herrera, Vanesa Martin, Sara Casado-Zapico, Jeffrey Toretsky, Carmen Rodriguez
Journal: Cancer Research (2008)

3757  Background: The Ewing’s Sarcoma Family Tumours (ESFT) is an aggressive group of poorly differentiated pedriatic and young adult cancers of bone and soft tissue. It is characterized by the presence of a chromosomal translocation that produces a fusion protein. The 85 % of this tumours have the fusion protein EWS-FLI-1 t(11;22)(q24;q12), that acts as an aberrant transcription factor and modulate specific genes involved in oncogenesis. Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous indoleamine derived from the tryptophan that has been know to exerts wide range of physiological and pathophysiological effects including antitumoral actions. Methods: cell lines used were: Ewing Sarcoma SK-N-MC, TC-71, TC-32, A673 (EWS-FLI1 type 1), SK-ES1 (type 2), A4573 (type 3); neuroblastoma SK-N-SH, SH-SY5Y, SK-N-AS and EWS-FLI1 transformed murine embryonic fibroblasts (MEF). Cell proliferation and cytotoxicity was measured by MTT and LDH assays. Apoptosis was evaluated using DAPI staining and caspase-3 activity. The direct interaction of melatonin with recombinant EWS-FLI1 was measured using surface plasmon resonance (SPR) (Biacore T100, GE) on the surface of a dextran coated surface (CM5 chip) and levels of phospho and total proteins were evaluated by western blot. Results: Melatonin induces apoptotic cell death in all the Ewing Sarcoma cell lines in spite of the primary origin or the type of the fusion protein present, with the same efficiency as we had previously shown in SK-N-MC cells. During the apoptotic process we also observed an associated decrease of the intracellular glucogen accumulations that do not correspond with an activation of the GSK3B, furthermore, there is an increase of the inactive form of the enzyme (P-GSK3B). On the other hand, melatonin doesn’t induce apoptosis in the neuroblastoma cells but inhibits the cellular growth in a significant way. The analysis of the direct interaction between EWS-FLI1 and melatonin by the SPR technology shows a specific binding affinity between EWS-FLI1 and melatonin with a Kd around 85 µM, very close to the melatonin’s range of action (100µM-1mM). Unfortunately melatonin was not able to kill EWS-FLI1 transformed MEF cells, even at the highest concentration (1mM), and only inhibits cell growth. Conclusions: The present work extends our previous observations in the human SK-N-MC cell line and demonstrated a specific pro-apoptotic effect of melatonin in the ESFT that is not shared in other similar cancer types like neuroblastoma. Despite that melatonin don’t induces apoptosis in transformed fibroblast, probably due to a not suitable cellular model, the protein interaction data between melatonin and EWS-FLI1 led us to think that melatonin could target the fusion protein in some critical way that leads to a cellular disbalance and induction of the apoptotic process.
Integrating occupational health with the NHS will not improve access
Authors: Paul J Nicholson
Journal: BMJ (2017)

The proposal from Torrance and Heron—who are both members of the board of the Faculty of Occupational Medicine—that occupational health services be integrated into the NHS1 won’t remedy lack of access to comprehensive services. An effective solution requires consultation with faculty members, professional colleagues, and stakeholders; a systematic approach to problem solving to agree best solutions; and benchmarking against other models. …
Emerging roles for conjugated sterols in plants
Authors: Albert Ferrer, Teresa Altabella, Montserrat Arró, Albert Boronat
Journal: Progress in Lipid Research (2017)

In plants, sterols are found in free form (free sterols, FSs) and conjugated as steryl esters (SEs), steryl glycosides (SGs) and acyl steryl glycosides (ASGs). Conjugated sterols are ubiquitously found in plants but their relative contents highly differ among species and their profile may change in response to developmental and environmental cues. SEs play a central role in membrane sterol homeostasis and also represent a storage pool of sterols in particular plant tissues. SGs and ASGs are main components of the plant plasma membrane (PM) that specifically accumulate in lipid rafts, PM microdomains known to mediate many relevant cellular processes. There are increasing evidences supporting the involvement of conjugated sterols in plant stress responses. In spite of this, very little is known about their metabolism. At present, only a limited number of genes encoding enzymes participating in conjugated sterol metabolism have been cloned and characterized in plants. The aim of this review is to update the current knowledge about the tissue and cellular distribution of conjugated sterols in plants and the enzymes involved in their biosynthesis. We also discuss novel aspects on the role of conjugated sterols in plant development and stress responses recently unveiled using forward- and reverse-genetic approaches.
Environmental Determinants of Cardiovascular Disease
Authors: Aruni Bhatnagar
Journal: Circulation Research (2017)

Many features of the environment have been found to exert an important influence on cardiovascular disease (CVD) risk, progression, and severity. Changes in the environment because of migration to different geographic locations, modifications in lifestyle choices, and shifts in social policies and cultural practices alter CVD risk, even in the absence of genetic changes. Nevertheless, the cumulative impact of the environment on CVD risk has been difficult to assess and the mechanisms by which some environment factors influence CVD remain obscure. Human environments are complex, and their natural, social, and personal domains are highly variable because of diversity in human ecosystems, evolutionary histories, social structures, and individual choices. Accumulating evidence supports the notion that ecological features such as the diurnal cycles of light and day, sunlight exposure, seasons, and geographic characteristics of the natural environment such as altitude, latitude, and greenspaces are important determinants of cardiovascular health and CVD risk. In highly developed societies, the influence of the natural environment is moderated by the physical characteristics of the social environments such as the built environment and pollution, as well as by socioeconomic status and social networks. These attributes of the social environment shape lifestyle choices that significantly modify CVD risk. An understanding of how different domains of the environment, individually and collectively, affect CVD risk could lead to a better appraisal of CVD and aid in the development of new preventive and therapeutic strategies to limit the increasingly high global burden of heart disease and stroke.
Evaluation of Chest Pain in the Emergency Department
Authors: Frank N. Finkelstein
Journal: Annals of Internal Medicine (1995)

Letters15 August 1995Evaluation of Chest Pain in the Emergency DepartmentFrank N. FinkelsteinFrank N. FinkelsteinSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-123-4-199508150-00017 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:The authors of the recent editorial [1] do not support their allegation that without specialized testing, a cardiologist can sort out atypical and bizarre chest pain. Straightforward cases do not require the service or care of a cardiologist. The absence of an acute myocardial infarction does not rule out significant coronary artery disease. The natural history of coronary artery disease is that often, symptoms disappear during rest. Hence, patients who are not hospitalized or who are discharged early are not necessarily healthy. They may go home and have an infarction.We appear to be competing to see ...REFERENCE1. Kaul S, Abbott RD. Evaluation of chest pain in the emergency department (Editorial). Ann Intern Med. 1994; 121:976-8. Google Scholar Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 August 1995Volume 123, Issue 4Page: 314-318KeywordsAcute myocardial infarctionAnginaEmergency departmentInfarctionIschemiaPopulation statisticsStable coronary artery diseaseSudden cardiac death ePublished: 15 August 2000 Issue Published: 15 August 1995 Copyright & PermissionsCopyright © 1995 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Gene Expression Profiles of the Colonic Mucosa in Normal, Cancer and Polyp Subjects and the Influence of Synbiotic Consumption on Gene Expression
Authors: Y Clune, M O'Riordan, G O'Sullivan, J Collins
Journal: Endoscopy (2006)

Aims: The aim of this study was to determine the gene expression profile in rectal biopsies from normal, cancer and polyp subjects and to identify genes which are constitutively expressed in the colonic mucosa. We also investigated the subsequent effect of synbiotic consumption on gene expression in cancer and polyp subjects. Using cDNA array analysis of 588 cancer associated genes we have identified 14 genes which are constitutively expressed in the colonic mucosa of normal, cancer and polyp subjects as well as genes which are constitutively expressed in subsets of subjects. We have also identified 30 genes, which are expressed at significantly different levels in cancer, polyp and normal subjects. Synbiotic consumption modulated the expression of genes associated with differentiation and tight junction integrity and may indicate potential mechanisms by which synbiotics reduce cancer risk by modulating intestinal barrier integrity and cytoprotective gene expression. Further analysis of expression profiles of these genes in a larger number of subjects over a number of time-points are needed to confirm the expression of constitutive and differentially expressed genes identified in this study as well as the influence of synbiotic consumption on gene expression.
Emerging role of interleukin‐31 and interleukin‐31 receptor in pruritus in atopic dermatitis
Authors: M. Furue, K. Yamamura, M. Kido‐Nakahara, T. Nakahara, Y. Fukui
Journal: Allergy (2017)

Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder associated with skin barrier dysfunction. The lesional skin of AD exhibits T helper 2 (TH 2)-deviated immune reactions. Interleukin-31 (IL-31), preferentially produced from TH 2 cells, is a potent pruritogenic cytokine, and its systemic and local administration induces scratching behavior in rodents, dogs and monkeys. Recent clinical trials have revealed that administration of an anti-IL-31 receptor antibody significantly alleviates pruritus in patients with AD. In this review, we summarize recent topics related to IL-31 and its receptor with special references to atopic itch.