tbuckley/cabot-search huggingface dataset:
Role of Bruton’s tyrosine kinase in B cells and malignancies
Authors: Simar Pal Singh, Floris Dammeijer, Rudi W. Hendriks
Journal: Molecular Cancer (2018)

Abstract Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR). More recently, small-molecule inhibitors of this kinase have shown excellent anti-tumor activity, first in animal models and subsequently in clinical studies. In particular, the orally administered irreversible BTK inhibitor ibrutinib is associated with high response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle-cell lymphoma (MCL), including patients with high-risk genetic lesions. Because ibrutinib is generally well tolerated and shows durable single-agent efficacy, it was rapidly approved for first-line treatment of patients with CLL in 2016. To date, evidence is accumulating for efficacy of ibrutinib in various other B cell malignancies. BTK inhibition has molecular effects beyond its classic role in BCR signaling. These involve B cell-intrinsic signaling pathways central to cellular survival, proliferation or retention in supportive lymphoid niches. Moreover, BTK functions in several myeloid cell populations representing important components of the tumor microenvironment. As a result, there is currently a considerable interest in BTK inhibition as an anti-cancer therapy, not only in B cell malignancies but also in solid tumors. Efficacy of BTK inhibition as a single agent therapy is strong, but resistance may develop, fueling the development of combination therapies that improve clinical responses. In this review, we discuss the role of BTK in B cell differentiation and B cell malignancies and highlight the importance of BTK inhibition in cancer therapy.
Three quarters of surgical trainees undertake fellowships
Authors: Helen Jaques
Journal: BMJ (2013)

Three quarters of trainee surgeons have completed a clinical fellowship or intend to do so, shows a large survey, with trainees in plastic surgery and cardiothoracic surgery most keen on the fellowships.

Clinical fellowships are optional 6-12 month training programmes. They offer trainees—and doctors who have completed training but not yet obtained a consultant post—subspecialty clinical experience beyond what they would receive in specialty training.

The 38 item electronic questionnaire was sent to core and specialty surgical trainees on royal college and specialty …
THE DURATION OF PERSISTENT ATRIAL FIBRILLATION PRIOR TO THE HYBRID (VATS MAZE + CATHETER) ABLATION PROCEDURE PREDICTS RECURRENCE RATE AT ONE YEAR
Authors: Chase Phillips, Daniel Kaiser, L. Bing Liem, Peter Chang Sing, Gansevoort Dunnington, Carrie Pierce, Shelby Burk
Journal: Journal of the American College of Cardiology (2018)
EXCELLENT DURABILITY OF HOMOGRAFT'S IN PULMONARY POSITION ANALYZED IN A PREDEFINED ADULT GROUP WITH TETRALOGY OF FALLOT
Authors: Fleur Meijer, Philippine Kies, Monique Jongbloed, Mark Hazekamp, David Koolbergen, Nico Blom, Albert De Roos, Hubert Vliegen
Journal: Journal of the American College of Cardiology (2018)
UK surgical training should learn from US model to offer more teaching and simulation, researchers say
Authors: Abi Rimmer
Journal: BMJ (2014)

Surgical training in the United Kingdom should learn from the way training is delivered in the United States to offer more teaching and better access to simulation training, researchers have argued.1

A team from the US and UK including Ara Darzi, a former UK health minister, sent a survey to surgical trainees in London and at the University of Pennsylvania. The survey asked about training programmes and was based on indicators from the Joint Committee on …
A third of paediatric trainees don’t think they will become consultants
Authors: Abi Rimmer
Journal: BMJ (2014)

A third of paediatric trainees are not confident that they will secure a consultant post, a survey by the Royal College of Paediatrics and Child Health has found.1

The college surveyed paediatricians who began their training in 2007 and received 257 responses. The survey found that 31% of respondents who intended to become consultants (67) were not confident that they would achieve a post, and overall just 13% of respondents were confident that they …
ASSOCIATIONS BETWEEN VALVE TYPE AND OUTCOMES IN WOMEN UNDERGOING TRANSCATHETER AORTIC VALVE REPLACEMENT: RESULTS FROM THE WIN-TAVI REGISTRY
Authors: A. Sonia Petronio, Alaide Chieffo, Julinda Mehilli, Jaya Chandrasekhar, Samantha Sartori, Michela Faggioni, Cristina Giannini, Usman Baber, Thierry Lefevre, Patrizia Presbitero, Piera Capranzano, Didier Tchetche, Alessandro Iadanza, Gennaro Sardella, Nicolas Van Mieghem, Emanuele Meliga, Nicolas Dumonteil, Chiara Fraccaro, Daniela Trabattoni, Ghada Mikhail, Clayton Snyder, Samin K. Sharma, Madhav Sharma, Marie Morice, Roxana Mehran
Journal: Journal of the American College of Cardiology (2018)
Diploma in Child Health (DCH)
Authors: Cyrus Fernandes
Journal: BMJ (2005)

According to the Royal College of Paediatrics and Child Health (RCPCH), the DCH is designed to give recognition of competence in the care of children to general practitioner vocational trainees, staff grade doctors and senior house officers in paediatrics, and trainees in specialties allied to paediatrics.

January 2004, during the second year of my general practice vocational training.

Having thoroughly enjoyed my paediatric rotation, I wanted to consolidate my knowledge and skills in paediatrics and gain a qualification at the same time.

I found that the best way to approach the written examination was initially to read about cases seen frequently on the wards. As I am not a last minute crammer, I began …
Abstract 14287: Ang II-induced Pathological Autophagy is Inhibited by IL-10 via Akt Dependent Inhibition of Beclin 1 in Mice Heart
Authors: Suresh K Verma, Prasanna Krishnamurthy, Venkata N Girikipathi, Tatiana Abramova, Anna Gumpert, Moshin Khan, Nickoloff Emily, Jennifer Johnson, Cindy Benedict, Walter Koch, Raj Kishore
Journal: Circulation (2015)

Although, autophagy is an essential cellular salvage process to maintain cellular homeostasis, pathological autophagy can lead to cardiac abnormalities and ultimately heart failure. Therefore, a tight regulation on autophagic process would be important to treat chronic heart failure. Previously, we have shown that IL-10 strongly improved cardiac function in chronic heart failure models, but the role of IL-10 in regulation of pathological autophagy is not yet investigated. We tested the hypothesis that IL-10 inhibits angiotensin II-induced pathological autophagy and thus improved cardiac function. Pathological autophagy was induced in wild type (WT) and IL10-knockout mice by angiotensin II infusion. Ang II-induced left ventricular dysfunction and hypertrophic remodeling were accentuated in IL-10 KO mice compared to WT mice. IL-10 KO mice showed exaggerated autophagy with reduced AKT phosphorylation. In neonatal rat ventricular cardiomyocytes, Ang II activated beclin1 and LC3 levels and inhibited AKT/mTORC1 and AKT-Bcl2 signaling. IL-10 inhibited Ang II-induced autophagic marker proteins. Additionally, IL-10 restored Ang II effects on AKT/mTORC1 and AKT-Bcl2 signaling. Both pharmacological/molecular inhibition of AKT via PI3K inhibitor (LY290002) or Akt siRNA, attenuated IL-10 effects on the Ang II-induced pathological autophagy, confirming that IL-10 mediated regulation of pathological autophagy is AKT dependent. Similar results were observed with mTORC1 inhibitor rapamycin. Chloroquine (a lysosome inhibitor) strongly inhibits Ang II-induced autophagic flux. However, chloroquine did not affect IL-10 effects on autophagic flux, suggesting that IL-10 inhibits stress-induced pathological autophagy. Finally, as physical interaction of Bcl2 with beclin 1 is important to inhibit autophagy and IL-10 is strong activator of Bcl2, we performed immunoprecipitation experiment. Immunoprecipitation data suggested that Ang II disrupt the physical interaction of beclin 1 with Bcl2 and IL-10 reestablished this physical interaction to reduce autophagy. Our data give a novel role of IL-10 in regulation of pathological autophagy and thus can act as a potential therapeutic molecule in treatment of chronic heart disease.
Impact on students of consultants’ seven day working must be assessed, academics say
Authors: Abi Rimmer
Journal: BMJ (2014)

The BMA must assess how a seven day working week for consultants would affect medical students, the BMA’s Medical Academic Staff Committee has said.

Delegates at the BMA’s conference of medical academic representatives in London last week voted in favour of a motion that concerned the potential problems created by consultant seven day working. The motion said, “This conference calls on the BMA to assess how …
Chitotriosidase inhibits allergic asthmatic airways via regulation of <scp>TGF</scp>‐β expression and Foxp3<sup>+</sup> Treg cells
Authors: J. Y. Hong, M. Kim, I. S. Sol, K. W. Kim, C.‐M. Lee, J. A. Elias, M. H. Sohn, C. G. Lee
Journal: Allergy (2018)

Abstract Background Chitotriosidase (chitinase 1, Chit1), a major true chitinase in humans, is induced in childhood asthma and has been implicated in the pathogenesis of a variety of inflammatory and tissue remodeling responses. However, the role and the mechanisms that underlie these contributions to the diseases have not been defined. We hypothesized that Chit1 plays a significant role in the pathogenesis of allergic asthma. Methods Wild‐type and Chit1‐deficient mice and cells in culture were used to define the roles of Chit1 in models of allergic adaptive Th2 inflammation. In addition, the levels of sputum Chit1 were evaluated in pediatric asthma patients and compared to control. Results The levels of sputum Chit1 were significantly increased in the patients with childhood asthma. Mice with Chit1 null mutation demonstrated enhanced allergic Th2 inflammatory and cytokine and IgE responses to OVA or house dust mite allergen sensitization and challenge. However, the expression levels of TGF ‐β1 were significantly decreased with a diminished number of Foxp3 + regulatory T cells (Treg) in the lungs of Chit1 −/− mice compared to WT controls. In vitro, the absence of Chit1 significantly reduced TGF ‐β‐stimulated conversion of CD 4 + CD 25 − naïve T cells to CD 4 + Foxp3 + Treg cells, suggesting Chit1 is required for optimal effect of TGF ‐β1 in Treg cell differentiation. Conclusion Chit1 plays a protective role in the pathogenesis of allergic inflammation and asthmatic airway responses via regulation of TGF ‐β expression and Foxp3 + Treg cells.
Treatment of Advanced Non–Small Cell Lung Cancer in 2018
Authors: Deborah B. Doroshow, Roy S. Herbst
Journal: JAMA Oncology (2018)

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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast 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 Oncology journal
Refractory testicular pure seminoma (PS) and non-seminomatous(NS) germ cell tumors (GCT): A comprehensive genomic profiling (CGP) study.
Authors: Joseph M Jacob, Elizabeth Kate Ferry, Oleg Shapiro, Sherri Z. Millis, Jon Chung, Julia Andrea Elvin, Jo-Anne Vergilio, Shakti Ramkissoon, James Suh, Eric Allan Severson, Sugganth Daniel, Siraj Mahamed Ali, Alexa Betzig Schrock, Vincent A. Miller, Philip J. Stephens, Laurie M. Gay, Gennady Bratslavsky, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2018)

565 Background: Although PSand NS testicular GCT have a favorable prognosis, on occasion these tumors can be refractory to conventional systemic treatments. Methods: FFPE tissues from 22 PS and 86 NSunderwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations (mut) per megabase (Mb) and microsatellite instability (MSI) was determined on 114 loci. Results: PS patients were older than NS (P=0.007). The primary tumor was sequenced in 41% of PS and 18% of NS with a metastasis sample in 59% of PS and 82% of NS.Four (18%) of PS had syncytial trophoblast cells identified. The mean GA frequency at 4.1 mut/case for NS was higher than that seen in PS and this difference reached near significance (P=0.08). The KRAS, TP53, CCND2 and FGF6/23 GA frequencies were similar in both tumor types (Table). GA in KIT, PIK3CA/ MTOR, PTEN and BRCA2 were more frequent in PS than NS whereas BRAF and ERBB2 GA were more frequent in NS (Table). MSI-High status was absent in in PS (0%) and identified in 2% of NS. Higher levels of TMB were not encountered in PS (0% TMB ≥10 mut/Mb), but higher TMB levels were more frequent in NS (5% ≥ 10 mut/B and 1% ≥ 20 mut/Mb). Conclusions: The GA found in refractory PS and NS differ significantly. PS features a lower GA frequency with slightly higher potential for targeted therapies in kinase (KIT) and MTOR pathways but, has very low TMB predicting limited opportunities for immunotherapy for these patients. For NS targeted therapy biomarkers appear even more uncommon than seen in PS with only extremely rare kinase inhibitor opportunities. However, based on rare high TMB and MSI-High status, immunotherapies may be of benefit in a small subset of NS patients. Further study of genomic findings in relapsed and clinically aggressive PS and NS appears warranted. [Table: see text]
Parkinson’s disease masterclass
Authors: Gopalakrishnan Deivasikamani
Journal: BMJ (2012)

The Parkinson’s disease masterclasses are run by the movement disorders section of the British Geriatrics Society. The classes aim to provide advanced training for senior healthcare professionals involved in treating patients with Parkinson’s disease and related disorders. 

Three types of masterclass are run by the British Geriatrics Society. The classic masterclass is for consultants, neurologists, final year specialty registrars, pharmacists, clinical fellows, clinical lecturers, and general practitioners. The registrar masterclass is for specialty trainees who are not in their final year, and the nurse masterclass is for Parkinson’s disease nurse specialists, nurse consultants, and community matrons. 

I took the registrar masterclass during the second …
Lack of hospital beds is affecting staff retention in emergency medicine, college says
Authors: Abi Rimmer
Journal: BMJ (2014)

A shortage of inpatient beds is exacerbating recruitment problems in emergency medicine, the College of Emergency Medicine has warned.

Cliff Mann, the college’s president, said that retention of doctors in emergency medicine was being undermined by delays in patients leaving emergency departments because of a lack of beds elsewhere, a situation known as “exit block.”

The college said that exit block created problems for the emergency medicine workforce by lowering morale and causing burnout and fatigue. Speaking to BMJ Careers , Mann said, “The main problem is that it saps the morale of all the people in the department, whether they’re doctors, …
A Genetic Polymorphism in <i>CTLA-4</i> Is Associated with Overall Survival in Sunitinib-Treated Patients with Clear Cell Metastatic Renal Cell Carcinoma
Authors: Xiaoyan Liu, Jesse J. Swen, Meta H.M. Diekstra, Epie Boven, Daniel Castellano, Hans Gelderblom, Ron H.J. Mathijssen, Sita H. Vermeulen, Egbert Oosterwijk, Kerstin Junker, Max Roessler, Kristin Alexiusdottir, Asgerdur Sverrisdottir, Marius T. Radu, Valentin Ambert, Tim Eisen, Anne Warren, Cristina Rodríguez-Antona, Jesus García-Donas, Stefan Böhringer, Karel K.M. Koudijs, Lambertus A.L.M. Kiemeney, Brian I. Rini, Henk-Jan Guchelaar
Journal: Clinical Cancer Research (2018)

Purpose: The survival of patients with clear cell metastatic renal cell carcinoma (cc-mRCC) has improved substantially since the introduction of tyrosine kinase inhibitors (TKI). With the fact that TKIs interact with immune responses, we investigated whether polymorphisms of genes involved in immune checkpoints are related to the clinical outcome of cc-mRCC patients treated with sunitinib as first TKI.Experimental Design: Twenty-seven single-nucleotide polymorphisms (SNP) in CD274 (PD-L1), PDCD1 (PD-1), and CTLA-4 were tested for a possible association with progression-free survival (PFS) and overall survival (OS) in a discovery cohort of 550 sunitinib-treated cc-mRCC patients. SNPs with a significant association (P < 0.05) were tested in an independent validation cohort of 138 sunitinib-treated cc-mRCC patients. Finally, data of the discovery and validation cohort were pooled for meta-analysis.Results:CTLA-4 rs231775 and CD274 rs7866740 showed significant associations with OS in the discovery cohort after correction for age, gender, and Heng prognostic risk group [HR, 0.84; 95% confidence interval (CI), 0.72-0.98; P = 0.028, and HR, 0.73; 95% CI, 0.54-0.99; P = 0.047, respectively]. In the validation cohort, the associations of both SNPs with OS did not meet the significance threshold of P < 0.05. After meta-analysis, CTLA-4 rs231775 showed a significant association with OS (HR, 0.83; 95% CI, 0.72-0.95; P = 0.008). Patients with the GG genotype had longer OS (35.1 months) compared with patients with an AG (30.3 months) or AA genotype (24.3 months). No significant associations with PFS were found.Conclusions: The G-allele of rs231775 in the CTLA-4 gene is associated with an improved OS in sunitinib-treated cc-mRCC patients and could potentially be used as a prognostic biomarker. Clin Cancer Res; 24(10); 2350-6. ©2018 AACR.
Seven day working will require “massive expansion” in consultant numbers, House of Lords hears
Authors: Abi Rimmer
Journal: BMJ (2014)

Seven day working among consultants will require a “massive expansion” in numbers if it is to succeed, a House of Lords debate on seven day working has heard.

Speaking during the debate last week, Conservative peer Bernard Ribeiro, a former president of the Royal College of Surgeons, said it was important that the public understood what they would receive from a seven day NHS service. 

“When we promise them the same service at weekends as in the week, they will assume that that implies seven day working,” Ribeiro said. “That means that there will need to be a massive expansion of consultant numbers.”

Philip …
ANALYSIS OF OUTCOMES IN ACUTE MYOCARDIAL INFARCTION IN SETTING OF COCAINE ABUSE
Authors: Abhishek Mishra, Sopan Lahewala, Prashant Patel, Nirali Patel, Shilpkumar Arora, Byomesh Tripathi, Abhishek Deshmukh, Apurva Apurva Badheka, Edo Kaluski
Journal: Journal of the American College of Cardiology (2018)
OUTCOMES OF POLYTETRAFLUOROETHYLENE COVERED STENTS IN PATIENTS WITH CORONARY ARTERY PERFORATION AND CORONARY ARTERY ANEURYSM
Authors: Parth Parikh, Kinjal Banerjee, Kesavan Sankaramangalam, Ravi Nair, Russell Raymond, Stephen Ellis, E. Murat Tuzcu, Samir Kapadia
Journal: Journal of the American College of Cardiology (2018)
Safety and Antitumor Activity of Pembrolizumab in Patients with Estrogen Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer
Authors: Hope S. Rugo, Jean-Pierre Delord, Seock-Ah Im, Patrick A. Ott, Sarina A. Piha-Paul, Philippe L. Bedard, Jasgit Sachdev, Christophe Le Tourneau, Emilie M.J. van Brummelen, Andrea Varga, Roberto Salgado, Sherene Loi, Sanatan Saraf, Dina Pietrangelo, Vassiliki Karantza, Antoinette R. Tan
Journal: Clinical Cancer Research (2018)

Purpose: We investigated the safety and antitumor activity of the anti-programmed death 1 monoclonal antibody pembrolizumab in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer with programmed death ligand 1-positive (PD-L1-positive) tumors in the phase Ib open-label, multicohort KEYNOTE-028 (NCT02054806) study.Patients and Methods: Patients with ER+/HER2- advanced breast cancer with PD-L1-positive tumors (combined positive score ≥1) received pembrolizumab (10 mg/kg every 2 weeks) up to 2 years or until confirmed progression/intolerable toxicity. Primary endpoints were safety and overall response rate (ORR), based on Response Evaluation Criteria in Solid Tumors, version 1 (RECIST v1.1) as assessed by investigator review.Results: Between April 2014 and January 2015, 25 patients were enrolled. Median number of prior therapies for breast cancer, including endocrine agents, was 9 (range, 3-15). Median follow-up was 9.7 months (range, 0.7-31.8 months). Three patients experienced partial response (PR) and none experienced complete response (CR), resulting in an ORR of 12.0% (95% CI, 2.5%-31.2%); 16% of patients had stable disease (SD) and clinical benefit rate (CR + PR + [SD for ≥24 weeks]) was 20% (95% CI, 7-41). Median duration of response was 12.0 months (range, 7.4-15.9 months). The incidence of treatment-related adverse events was 64%; nausea (20%) and fatigue (12%) were most common and were predominantly grade 1/2. No treatment-related discontinuations or deaths occurred.Conclusions: Pembrolizumab was well tolerated with modest but durable overall response in certain patients with previously treated, advanced, PD-L1-positive, ER+/HER2- breast cancer. Clin Cancer Res; 24(12); 2804-11. ©2018 AACR.
LATE PCI IN STEMI: A COMPLEX INTERACTION BETWEEN DELAY AND AGE
Authors: Raffaele Bugiardini, Edina Cenko, Jinsung Yoon, Beatrice Ricci, Davor Milicic, Sasko Kedev, Zorana Vasiljevic, Olivia Manfrini, Mihaela van der Schaar, Lina Badimon
Journal: Journal of the American College of Cardiology (2018)
One in 30 foundation posts were unfilled in 2012-13
Authors: Abi Rimmer
Journal: BMJ (2013)

About one in 30 places in the first year of foundation training in 2012-13 were not filled, figures from the UK Foundation Programme Office show.

In August last year 238 (3.1%) of the 7627 posts in foundation year 1 (F1) were not filled, along with 1.7% of F2 posts, says the Foundation Programme Office’s annual report.1

Around half (110) of the unfilled F1 posts …