tbuckley/cabot-search huggingface dataset:
Long‐term effect of epirubicin on incidence of heart failure in women with breast cancer: insight from a randomized clinical trial
Authors: Ann Banke, Emil L. Fosbøl, Jacob E. Møller, Gunnar H. Gislason, Mads Andersen, Mogens Bernsdorf, Maj‐Britt Jensen, Morten Schou, Bent Ejlertsen
Journal: European Journal of Heart Failure (2018)
A Phase I Clinical Trial of Guadecitabine and Carboplatin in Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic, and Pharmacodynamic Analyses
Authors: Daniela Matei, Sharad Ghamande, Lynda Roman, Angeles Alvarez Secord, John Nemunaitis, Merry Jennifer Markham, Kenneth P. Nephew, Simone Jueliger, Aram Oganesian, Sue Naim, Xiang Yao Su, Harold Keer, Mohammad Azab, Gini F. Fleming
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Epigenetic changes are implicated in acquired resistance to platinum. Guadecitabine is a next-generation hypomethylating agent (HMA). Here, we report the clinical results, along with pharmacokinetic (PK) and pharmacodynamic analyses of the phase I study of guadecitabine and carboplatin in patients with recurrent, platinum-resistant high-grade serous ovarian cancer, primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC). Experimental Design: Guadecitabine was administered once daily on days 1 to 5 followed by carboplatin i.v. on day 8 of a 28-day cycle. Patients had either measurable or detectable disease. Safety assessments used CTCAE v4. Results: Twenty patients were enrolled and treated. Median age was 56 years (38–72 years). The median number of prior regimens was 7 (1–14). In the first cohort (N = 6), the starting doses were guadecitabine 45 mg/m2 and carboplatin AUC5. Four patients experienced dose-limiting toxicity (DLT; neutropenia and thrombocytopenia), leading to dose deescalation of guadecitabine to 30 mg/m2 and of carboplatin to AUC4. No DLTs were observed in the subsequent 14 patients. Grade ≥3 adverse events ≥10% were neutropenia, leukopenia, anemia, nausea, vomiting, ascites, constipation, hypokalemia, pulmonary embolism, small-intestinal obstruction, and thrombocytopenia. Three patients had a partial response (PR), and 6 patients had stable disease (SD) &amp;gt;3 months, for an overall response rate (ORR) and clinical benefit rate of 15% and 45%, respectively. LINE-1 demethylation in PBMCs and promoter demethylation/gene reexpression in paired tumor biopsies/ascites were recorded. Conclusions: Guadecitabine and carboplatin were tolerated and induced clinical responses in a heavily pretreated platinum-resistant ovarian cancer population, supporting a subsequent randomized phase II trial. Clin Cancer Res; 24(10); 2285–93. ©2018 AACR.
PROGRESSION OF AORTIC STENOSIS BY SERIAL ECHOCARDIOGRAPHY AMONG SURGICAL BICUSPID AORTIC VALVE PATIENTS
Authors: Dillon Schafer, Aakash Bavishi, Adin-Cristian Andrei, Hangzhi Shi, Jane Kruse, Erin Crawford, Patrick McCarthy, S. Chris Malaisrie, James Thomas, Jyothy Puthumana
Journal: Journal of the American College of Cardiology (2018)
Reflection of Cardioprotection by Remote Ischemic Perconditioning in Attenuated ST-Segment Elevation During Ongoing Coronary Occlusion in Pigs
Authors: Petra Kleinbongard, Georgios Amanakis, Andreas Skyschally, Gerd Heusch
Journal: Circulation Research (2018)

Reduction of infarct size by remote ischemic perconditioning (perRIC) is evident only after several hours reperfusion.To develop a potential real-time estimate of cardioprotection by perRIC, we have analyzed the time course of ST-segment elevation.Anesthetized open-chest pigs were subjected to 60-minute coronary occlusion and 180-minute reperfusion (placebo; n=19). PerRIC (n=18; 4×5 min/5 min hindlimb occlusion/reperfusion) was induced 20 minutes after coronary occlusion. Regional myocardial blood flow was measured with microspheres, areas of no-reflow with thioflavin-S, area at risk with blue dye, and infarct size with triphenyl tetrazolium chloride staining. Phosphorylation of protein kinase B α/β/γ, extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription 3 was determined by Western blot. ST-segment elevation was analyzed in a V2-like ECG-lead at baseline, 5- and 55-minute coronary occlusion, and 10-, 30-, 60-, and 120-minute reperfusion. Transmural blood flow at 5-minute coronary occlusion was not different between perRIC (0.029±0.015 mL/min per gram; mean±SD) and placebo (0.024±0.018 mL/min per gram) as was area at risk (perRIC: 24±6% of the left ventricle; placebo: 21±4%). Areas of no-reflow tended to be smaller with perRIC (9±12% of area at risk versus 15±14% with placebo; P=0.13). Infarct size with perRIC was 23±12% of area at risk versus 40±11% with placebo (P<0.001). PerRIC increased phosphorylation of signal transducer and activator of transcription 3 at 120-minute reperfusion by 196±142% versus 109±120% with placebo (P=0.047). The time courses of ST-segment elevation in perRIC and placebo protocols, respectively, were different (P=0.017). With similar ST-segment elevation at 5-minute coronary occlusion (perRIC 282±34 µV; placebo 259±28 µV), partial recovery of ST-segment elevation between 5- and 55-minute coronary occlusion was more pronounced with perRIC than placebo (by 111±84 versus 15±94 µV; P=0.028).Infarct size reduction by perRIC is reflected in the ST-segment elevation during coronary occlusion in pigs, supporting the notion of protection from ischemic injury.
THE LONGEVITY GENE MINDY (I'M NOT DEAD, YET) AFFECTS BLOOD PRESSURE THROUGH SYMPATHOADRENAL MECHANISMS
Authors: Diana M. Willmes, Tina Schumann, Christine Henke, Anica Kurzbach, Friedrich Luft, Henning Morawietz, Stephen Helfand, Ali El-Armouche, Dominik Mueller, Stefan R. Bornstein, Jens Tank, Graeme Eisenhofer, Martin Daniels, Jens Jordan, Andreas Birkenfeld
Journal: Journal of the American College of Cardiology (2018)
RELATION OF STROKE AND BLEEDING RISK PROFILES TO EFFICACY AND SAFETY OF DABIGATRAN IN ATRIAL FIBRILLATION AFTER PCI: AN ANCILLARY ANALYSIS FROM THE RE-DUAL PCI TRIAL
Authors: Gregory Lip, Laura Mauri, Gilles Montalescot, Mick Ozkor, Panagiotis Vardas, Philippe Gabriel Steg, Deepak Bhatt, Stefan Hohnloser, Eva Kleine, Matias Nordaby, Takeshi Kimura, Jonas Oldgren, Jurrien Ten Berg, Christopher Cannon
Journal: Journal of the American College of Cardiology (2018)
Notice of Retraction and Replacement. Karalunas et al. Subtyping attention-deficit/hyperactivity disorder using temperament dimensions: toward biologically based nosologic criteria. <i>JAMA Psychiatry.</i> 2014;71(9):1015-1024
Authors: Sarah L. Karalunas, Damien Fair, Erica D. Musser, Kamari Aykes, Swathi P. Iyer, Joel T. Nigg
Journal: JAMA Psychiatry (2018)

Notice of Retraction and Replacement. Karalunas et al. Subtyping attention-deficit/hyperactivity disorder using temperament dimensions toward biologically based nosologic criteria. JAMA Psychiatry. 2014;71(9):1015-1024
Left Ventricle Replacement Fibrosis Detected by CMR Associated With Cardiovascular Events in Systemic Sclerosis Patients
Authors: Elie Mousseaux, Lucia Agoston-Coldea, Zora Marjanovic, Rica Stanciu, Christophe Deligny, Ludivine Perdrix, Pierre Boutouyrie, Arshid Azarine, Gilles Soulat, Dominique Farge
Journal: Journal of the American College of Cardiology (2018)
GPs in England get 1% pay increase and £60m towards indemnity fees
Authors: Abi Rimmer
Journal: BMJ (2018)

GPs in England will receive a 1% increase to their pay and £60m (€68m; $84m) towards indemnity fees, under changes to the general medical services contract announced by NHS England on 20 March.

It said that the contract would deliver £256.3m of investment in primary care next year, 3.4% higher than in 2017-18.

GPs will receive an initial 1% pay uplift, as well as an inflationary uplift to expenses, which is expected to be increased further when the Review Body on Doctors’ and Dentists’ Remuneration (DDRB) makes its recommendations later this year. Any further increase will be backdated to 1 …
Female doctors fight back against stereotypes
Authors: Serena Waters
Journal: BMJ (2015)

Female doctors from across the world have taken part in a campaign aimed at promoting women who work in traditionally male dominated fields.

Using the social networking site Tumblr the “This is what we look like” campaign encourages women who work in traditionally male dominated fields to purchase T shirts inscribed with the campaign’s slogan and to upload pictures of themselves wearing the T shirts (http://thisiswhatwelooklikecampaign.tumblr.com). The aim, the group says, …
Training will be at heart of new junior doctor contract, says BMA
Authors: Abi Rimmer
Journal: BMJ (2014)

Education and training will be at the heart of the new contract for junior doctors if plans for “work schedules” go ahead, the BMA has said.

Andrew Collier, co-chair of the BMA’s Junior Doctors Committee, said that the group had been developing “work schedules,” which it hoped would become part of the new junior doctor contract. Contract negotiations between the BMA and NHS Employers began last October.1

Collier …
Abstract ES9-3: Androgen, progesterone and glucocorticoid receptors: Drivers of breast tumor progression or reprogramming of steroid receptors during breast tumor progression
Authors: SD Conzen
Journal: Cancer Research (2018)

Abstract In normal physiology, glucocorticoid receptor (GR) activity regulates thousand of genes whose products modulate metabolism, inflammation, cell cycle and apoptosis/cell survival pathways. Synthetic GR agonists, or glucocorticoids (GCs), are often used to treat hematologic malignancies because of GR's ability to induce proapoptotic gene expression, inhibit nuclear factor – κB, and induce cell cycle arrest. In contrast, recent examination of GR expression and activity in human breast cancer models and clinical specimens has suggested that GR expression has remarkably diverse roles in breast cancer subtypes. In ER+ breast cancer, GR appears to modulate ER-regulated transcriptional activity through ER/GR receptor crosstalk resulting in antagonism of ER-associated proliferation. However, in ER-negative breast cancer (including TNBC), high tumor GR expression is associated with poor prognosis, anti-apoptotic signaling, and chemotherapy resistance. In addition, high GR activity in the tumor microenvironment is predicted to be immunosuppressive. Recently described selective GR modulators are expected to help dissect divergent GR mechanisms present in breast cancer subtypes. Citation Format: Conzen SD. Androgen, progesterone and glucocorticoid receptors: Drivers of breast tumor progression or reprogramming of steroid receptors during breast tumor progression [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES9-3.
Stable incorporation of GM-CSF into dissolvable microneedle patch improves skin vaccination against influenza
Authors: Elizabeth Q. Littauer, Lisa K. Mills, Nicole Brock, E. Stein Esser, Andrey Romanyuk, Joanna A. Pulit-Penaloza, Elena V. Vassilieva, Jacob T. Beaver, Olivia Antao, Florian Krammer, Richard W. Compans, Mark R. Prausnitz, Ioanna Skountzou
Journal: Journal of Controlled Release (2018)

The widely used influenza subunit vaccine would benefit from increased protection rates in vulnerable populations. Skin immunization by microneedle (MN) patch can increase vaccine immunogenicity, as well as increase vaccination coverage due to simplified administration. To further increase immunogenicity, we used granulocyte-macrophage colony stimulating factor (GM-CSF), an immunomodulatory cytokine already approved for skin cancer therapy and cancer support treatment. GM-CSF has been shown to be upregulated in skin following MN insertion. The GM-CSF-adjuvanted vaccine induced robust and long-lived antibody responses cross-reactive to homosubtypic and heterosubtypic influenza viruses. Addition of GM-CSF resulted in increased memory B cell persistence relative to groups given influenza vaccine alone and led to rapid lung viral clearance following lethal infection with homologous virus in the mouse model. Here we demonstrate that successful incorporation of the thermolabile cytokine GM-CSF into MN resulted in improved vaccine-induced protective immunity holding promise as a novel approach to improved influenza vaccination. To our knowledge, this is the first successful incorporation of a cytokine adjuvant into dissolvable MNs, thus advancing and diversifying the rapidly developing field of MN vaccination technology.
Government will hear independent advice on pay for GPs but not for consultants
Authors: Abi Rimmer
Journal: BMJ (2014)

The government has said that it will take recommendations on GPs’ pay, but not on consultants’ pay, from the Review Body on Doctors’ and Dentists’ Remuneration (DDRB) next year.

In July the chief secretary to the Treasury, Danny Alexander, told the DDRB that the government would not be taking recommendations from it on employed doctors’ pay in the 2015-16 pay round. …
Immune-related adverse events requiring inpatient management: Spectrum of toxicity, treatment, and outcomes.
Authors: Aanika Balaji, Jiajia Zhang, Kristen Marrone, Hany Elmariah, Mark Yarchoan, Matthias Holdhoff, Jacquelyn W. Zimmerman, Khalid Hajjir, Deborah Kay Armstrong, Daniel A. Laheru, Ranee Mehra, Won Jin Ho, Joshua E. Reuss, Joseph Heng, Paz Vellanki, Jarushka Naidoo
Journal: Journal of Clinical Oncology (2018)

138 Background: Immune checkpoint inhibitors (ICIs) are anti-cancer agents now in routine clinical practice, and may cause immune-related adverse events (irAEs). The proportion of inpatient admissions for irAEs, spectrum of toxicities, management and outcomes are not well described. Methods: Patients with solid tumors admitted to the inpatient oncology service at a tertiary academic center over 3 months, were identified. Patient demographics, treatment details, irAE event and management data, were collected for those who received ICIs, in an IRB-approved database. The diagnosis of irAEs was confirmed by the treating physician and oncologist. Associations between clinical details and irAEs were evaluated using Fisher's exact test. Results: We identified 240 inpatient oncology patients: 53 (22.1%) had received ICIs, and 25% (13/53) were admitted for irAEs. The majority of irAEs requiring admission were high grade (CTCAE grade 1-2: 6/13, 46%; grade 3+: 7/13, 54%), and included: colitis (31%), pneumonitis (23%), skin rash (8%), fever (8%), pancreatitis (8%), fatigue (8%), and renal transplant rejection (8%). Treatment for irAEs included: ICI withhold (2/13, 15%), oral/IV corticosteroids (10/13, 76%), and infliximab (1/13, 8%); with 85% of patients requiring subspecialty consultations. Those with irAEs had a shorter median length of stay vs. other inpatients (5 vs. 6 days). Most irAEs resolved/improved (11/13, 85%), while 15% worsened (1/13) or resulted in patient death (1/13). There was a numerically higher risk of any/grade3+ irAEs for those: treated with combination vs monotherapy (33% vs 23%; 100% vs 40%), age &gt; 65 vs &lt; 65 (33% vs 15%; 56% vs 50%), and former/current vs. never smokers (31% vs 19%; 63% vs 40%), however differences were not statistically significant. Conclusions: Patients with irAEs constitute a notable proportion of inpatient oncology admissions, with a higher incidence than in reported clinical trials. Initial data suggest that patients treated with combination ICIs, aged &gt; 65, and former/current smokers may be more likely to be admitted for irAEs. The majority of irAE admissions require subspecialty consultations, signifying a growing need for multidisciplinary irAE management.
USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia
Authors: Qi Jin, Carlos A. Martinez, Kelly M. Arcipowski, Yixing Zhu, Blanca T. Gutierrez-Diaz, Kenneth K. Wang, Megan R. Johnson, Andrew G. Volk, Feng Wang, Jian Wu, Charles Grove, Hui Wang, Ivan Sokirniy, Paul M. Thomas, Young Ah Goo, Nebiyu A. Abshiru, Nobuko Hijiya, Sofie Peirs, Niels Vandamme, Geert Berx, Steven Goosens, Stacy A. Marshall, Emily J. Rendleman, Yoh-hei Takahashi, Lu Wang, Radhika Rawat, Elizabeth T. Bartom, Clayton K. Collings, Pieter Van Vlierberghe, Alexandros Strikoudis, Stephen Kelly, Beatrix Ueberheide, Christine Mantis, Irawati Kandela, Jean-Pierre Bourquin, Beat Bornhauser, Valentina Serafin, Silvia Bresolin, Maddalena Paganin, Benedetta Accordi, Giuseppe Basso, Neil L. Kelleher, Joseph Weinstock, Suresh Kumar, John D. Crispino, Ali Shilatifard, Panagiotis Ntziachristos
Journal: Clinical Cancer Research (2018)

Abstract Purpose: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes. Experimental Design: To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models. Results: We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo. Conclusions: These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.
Treatment, Platelet Count Pattern and Comorbidities Among Primary Immune Thrombocytopenia (ITP) Patients Seen in Routine Clinical Practice: Data from the United Kingdom Immune Thrombocytopenia (UK ITP) Registry
Authors: Umesh Doobaree, Lara Wyatt, Raghava Nandigam, Adrian Newland, Andrew Provan
Journal: Blood (2017)
RCOG launches online tool to help doctors deal with bullying
Authors: Abi Rimmer
Journal: BMJ (2015)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following RCOG launches online tool to help doctors deal with bullying Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Opioid Analgesic Use and Risk for Invasive Pneumococcal Diseases
Authors: Andrew D. Wiese, Marie R. Griffin, William Schaffner, C. Michael Stein, Robert A. Greevy, Edward F. Mitchel, Carlos G. Grijalva
Journal: Annals of Internal Medicine (2018)

Background: Although certain opioid analgesics have immunosuppressive properties and increase the risk for infections in animals, the clinical effects of prescription opioid use on infection risk among humans are unknown. Objective: To test the hypothesis that prescription opioid use is an independent risk factor for invasive pneumococcal disease (IPD). Design: Nested case–control study. Setting: Tennessee Medicaid database linked to Medicare and Active Bacterial Core surveillance system databases (1995 to 2014). Patients: 1233 case patients with IPD aged 5 years and older matched to 24 399 control participants by diagnosis date, age, and county of residence. Measurements: Opioid use was measured on the basis of pharmacy prescription fills. Invasive pneumococcal disease was defined by the isolation of Streptococcus pneumoniae from a normally sterile site. The odds of current opioid use were compared between the case and control groups, accounting for known IPD risk factors. Secondary analyses categorized opioid use by opioid characteristics, applied an IPD risk score to assure comparability between exposure groups, and analyzed pneumonia and nonpneumonia IPD cases separately. Results: Persons in the case group had greater odds than control participants of being current opioid users (adjusted odds ratio [aOR], 1.62 [95% CI, 1.36 to 1.92]). Associations were strongest for opioids that were long acting (aOR, 1.87 [CI, 1.24 to 2.82]), of high potency (aOR, 1.72 [CI, 1.32 to 2.25]), or were used at high dosages (50 to 90 morphine milligram equivalents [MME]/d: aOR, 1.71 [CI, 1.22 to 2.39]; ≥90 MME/d: aOR, 1.75 [CI, 1.33 to 2.29]). Results were consistent when the IPD risk score was taken into account and pneumonia and nonpneumonia IPD were analyzed separately. Limitations: Unmeasured confounding and measurement error, although sensitivity analyses suggested that neither was likely to affect results. Actual opioid use and other nonprescription use (such as illicit opioid use) were not measured. Conclusion: Opioid use is associated with an increased risk for IPD and represents a novel risk factor for these diseases. Primary Funding Source: National Institutes of Health.
Department of Health spells out details of practice boundary pilots
Authors: Ingrid Torjesen
Journal: BMJ (2012)

General practices that take part in the Department of Health’s pilot of loosening practice boundaries will be paid £12.93 a patient and will not be responsible for out of hours care and home visits for out of area patients, new guidance has specified.

The one year pilot, starting this April, will allow patients in areas of London, Manchester and Salford, and Nottingham to register with a practice remote from their home or choose to see a GP at a practice where they are not registered on an ad hoc basis.

In the first of the two mechanisms being tested, people who …
The details of past actions on a smartphone touchscreen are reflected by intrinsic sensorimotor dynamics
Authors: Myriam Balerna, Arko Ghosh
Journal: npj Digital Medicine (2018)

Unconstrained day-to-day activities are difficult to quantify and how the corresponding movements shape the brain remain unclear. Here, we recorded all touchscreen smartphone interactions at a sub-second precision and show that the unconstrained day-to-day behavior captured on the phone reflects in the simple sensorimotor computations measured in the laboratory. The behavioral diversity on the phone, the speed of interactions, the amount of social & non-social interactions, all uniquely influenced the trial-to-trial motor variability used to measure the amount of intrinsic neuronal noise. Surprisingly, both the motor performance and the early somatosensory cortical signals (assessed using EEG in passive conditions) became noisier with increased social interactions. Inter-individual differences in how people use the smartphone can help thus decompose the structure of low-level sensorimotor computations.
Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids
Authors: Michael C. Peters, Sheena Kerr, Eleanor M. Dunican, Prescott G. Woodruff, Merritt L. Fajt, Bruce D. Levy, Elliot Israel, Brenda R. Phillips, David T. Mauger, Suzy A. Comhair, Serpil C. Erzurum, Mats W. Johansson, Nizar N. Jarjour, Andrea M. Coverstone, Mario Castro, Annette T. Hastie, Eugene R. Bleecker, Sally E. Wenzel, John V. Fahy
Journal: Journal of Allergy and Clinical Immunology (2018)