tbuckley/cabot-search huggingface dataset:
Abstract P1-03-06: <i>GNBP2</i> suppresses tumor growth and cancer stem cell load of triple negative breast cancer by controlling STAT3 pathway
Authors: J Zhang
Journal: Cancer Research (2018)

Abstract Background: Gametogenetin binding protein 2 (GGNBP2) is encoded in human chromosome 17q12-q23, a region known as a breast and ovarian cancer susceptibility locus. GGNBP2 has a single C2H2 zinc finger and a consensus LxxLL nuclear receptor (NR) binding motif. We have reported that GGNBP2 suppresses ERα-positive breast tumorigenesis by acting as a nuclear receptor co-repressor to restrain ERα activity. However, the detailed molecular mechanisms of GGNBP2 and its role in triple negative breast cancer (TNBC) remain largely unclear. Methods: A human breast cancer tissue array containing 138 human breast tumor tissues were utilized to examine GGNBP2 expression in breast cancer samples by IHC. To address the potential anti-breast tumor activity of GGNBP2 in vitro, we expressed exogenous GGNBP2 in TNBC cells, including MDA-MB-231 and Cal51 cell lines. Cell proliferation and cell cycle were assessed by cell growth curve/EdU assays and flow cytometry after propidium Iodide staining. Apoptosis was determined by flow cytometry after annexin V staining, by caspase 3/7 and caspase 9 activity assays. Cancer stem cell properties were determined by expression of CD44/CD24/ALDH1 markers. The levels of phosphorylated STAT3 and total STAT3 were determined by western blot. Quantitative PCR and Western blot were carried out to evaluate the effects of GGNBP2 overexpression on STAT3 target genes, CCND1, Mcl-1, survivin, bax and bim expression. Results: GGNBP2 expression is down-regulated in TNBC cells and patient tumors and it is associated with poor patient survival. Overexpression of GGNBP2 significanly induces cell cycle G0/G1 phase arrest and apoptosis in TNBC cell lines. Expression of cancer stem cell markers also decreased in GGNBP2-overexpressed TNBC cells. GGNBP2 reduces the expression levels of CCND1, Mcl-1 and survivin, promotes the expression levels of bax and bim proteins. Importantly, overexpression of GGNBP2 inhibits STAT3 phosphorylation and STAT3 downstream garget gene expression, including CCND1, Mcl-1 and survivin. Conclusion: GGNBP2 serves as a critical nuclear negative regulator of STAT3-mediated gene expression and tumorigenesis. Citation Format: Zhang J. GNBP2 suppresses tumor growth and cancer stem cell load of triple negative breast cancer by controlling STAT3 pathway [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 P1-03-06.
Application of Strict Criteria for Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features and Encapsulated Follicular Variant Papillary Thyroid Carcinoma: a Retrospective Study of 50 Tumors Previously Diagnosed as Follicular Variant PTC
Authors: Kimberly Point du Jour, Alessandra C. Schmitt, Amy Y. Chen, Christopher C. Griffith
Journal: Endocrine Pathology (2018)
Hepatitis E virus (HEV) in Scotland: evidence of recent increase in viral circulation in humans
Authors: Katrina Thom, Pamela Gilhooly, Karen McGowan, Kristen Malloy, Lisa M Jarvis, Claire Crossan, Linda Scobie, Oliver Blatchford, Alison Smith-Palmer, Mhairi C Donnelly, Janice S Davidson, Ingolfur Johannessen, Kenneth J Simpson, Harry R Dalton, Juraj Petrik
Journal: Eurosurveillance (2018)

Background Previous studies showed low levels of circulating hepatitis E virus (HEV) in Scotland. We aimed to reassess current Scottish HEV epidemiology. Methods: Blood donor samples from five Scottish blood centres, the minipools for routine HEV screening and liver transplant recipients were tested for HEV antibodies and RNA to determine seroprevalence and viraemia. Blood donor data were compared with results from previous studies covering 2004–08. Notified laboratory-confirmed hepatitis E cases (2009-16) were extracted from national surveillance data. Viraemic samples from blood donors (2016) and chronic hepatitis E transplant patients (2014–16) were sequenced. Results: Anti-HEV IgG seroprevalence varied geographically and was highest in Edinburgh where it increased from 4.5% in 2004–08) to 9.3% in 2014–15 (p = 0.001). It was most marked in donors &lt; 35 years. HEV RNA was found in 1:2,481 donors, compared with 1:14,520 in 2011. Notified laboratory-confirmed cases increased by a factor of 15 between 2011 and 2016, from 13 to 206. In 2011–13, 1 of 329 transplant recipients tested positive for acute HEV, compared with six cases of chronic infection during 2014–16. Of 10 sequenced viraemic donors eight and all six patients were infected with genotype 3 clade 1 virus, common in European pigs. Conclusions: The seroprevalence, number of viraemic donors and numbers of notified laboratory-confirmed cases of HEV in Scotland have all recently increased. The causes of this change are unknown, but need further investigation. Clinicians in Scotland, particularly those caring for immunocompromised patients, should have a low threshold for testing for HEV.
CORONARY CALCIFICATION ON PRE-ABLATION COMPUTED TOMOGRAPHY IS NOT ASSOCIATED WITH ATRIAL FIBRILLATION RECURRENCE FOLLOWING ABLATION
Authors: Efstratios Koutroumpakis, Wafic Itani, Meena Zakher, Benjamin Schwartz, John Espey, Camille Dumas, John Fantauzzi, Elizabeth Rau, David Steckman, Mikhail Torosoff
Journal: Journal of the American College of Cardiology (2018)
Financial Incentives and Vulnerable Populations — Will Alternative Payment Models Help or Hurt?
Authors: Karen E. Joynt Maddox
Journal: New England Journal of Medicine (2018)

Interview with Dr. Karen Joynt Maddox on alternative payment models and disincentives for treating high-risk patients. (09:43)Download Understanding clinicians' likely responses to the incentives provided by alternative payment models, and therefore the potential consequences for vulnerable populations, is critical if we wish to maximize benefits and reduce harms.
Filaggrin gene mutations may influence the persistence of food allergies in Japanese primary school children
Authors: M. Kono, M. Akiyama, Y. Inoue, T. Nomura, A. Hata, Y. Okamoto, T. Takeichi, Y. Muro, W.H.I. McLean, H. Shimizu, K. Sugiura, Y. Suzuki, N. Shimojo
Journal: British Journal of Dermatology (2018)
The incidence of tuberculosis among adolescents and young adults: a global estimate
Authors: Kathryn J. Snow, Charalambos Sismanidis, Justin Denholm, Susan M. Sawyer, Stephen M. Graham
Journal: European Respiratory Journal (2018)

Historical data show that the risk of tuberculosis increases dramatically during adolescence, and young people face unique challenges in terms of case detection and effective treatment. However, little is known about the burden of tuberculosis among young people in the modern era. This study aimed to provide the first estimates of the global and regional incidence of tuberculosis among young people aged 10-24 years.Using the World Health Organization (WHO) database of tuberculosis notifications for 2012, we estimated the burden of tuberculosis among young people by WHO region. Adjustments were made for incomplete age disaggregation and underreporting, using supplementary data from several countries representing diverse tuberculosis epidemics.We estimate that 1.78 million (uncertainty interval (UI) 1.23-3.00 million) young people developed tuberculosis in 2012, accounting for 17% of all new tuberculosis cases globally. Young people in the WHO South East Asian Region (721 000, UI 473 000-1.35 million) and the WHO African Region (534 000, UI 359 000-912 000) experienced the greatest number of tuberculosis episodes.Young people suffer a considerable burden of tuberculosis. Age-specific burden of disease estimation for this age group is complicated by incomplete age disaggregation of tuberculosis data, highlighting the importance of continued surveillance system strengthening.
Spikes in air pollution raise heart risk as much as sustained exposure, study suggests
Authors: Susan Mayor
Journal: BMJ (2018)

Rapid increases in air pollution are associated with more than double the odds of myocardial infarction (MI), which is similar to the impact of sustained exposure to poor air quality, a study has found.1

“Our study suggests that the risk of heart attack associated with nitrogen oxides depends on the dynamics and extent of increases, and not only on exposure to high concentrations,” said the senior author, Florian Rakers, from Jena University Hospital in central Germany.

He warned, “The impact of rapid increases in …
Most organisations in England are ready for revalidation
Authors: Caroline White
Journal: BMJ (2012)

Most doctors in England have the organisational backup they need to begin revalidation from the end of this year—the scheduled start date—concludes the latest report from the NHS Revalidation Support Team.

But the appraisal rate across the country is still patchy, particularly for consultants and for staff, specialty, and associate specialist (SAS) doctors, says the report, which will inform the health secretary Andrew Lansley’s decision on whether to give the go ahead for revalidation.

The support team’s second Organisational Readiness Self-Assessment report captures the state of readiness for revalidation of organisations that employ or contract with doctors (designated bodies).1 This year, 654 designated bodies completed the self assessment, equating to a 95% …
I am planning to pursue a career in psychiatry once qualified and am particularly interested in forensic psychiatry. How competitive is it and which qualities are most useful?
Authors: Rahul Rao
Journal: BMJ (2004)

<i>Got a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.</i>
Postgraduate certificate in patient safety and clinical risk management
Authors: Nigel Acheson, Helen Mary Smith
Journal: BMJ (2011)

This course has now been discontinued.

The course, run by the University of Leeds School of Medicine, is open to all healthcare professionals with an undergraduate degree in a healthcare related discipline, and it is designed to introduce participants to the principles of patient safety and clinical risk management. We were consultants when we took the course; other participants included doctors in training and a pharmacist.

One of the authors (HMS) had spent a week on the patient safety officer executive officer development programme at the Institute for Health Improvement in Boston, Massachusetts. Enthused by the content of this programme, she was …
Efficacy and safety of biologics in relapsing polychondritis: a French national multicentre study
Authors: Guillaume Moulis, Grégory Pugnet, Nathalie Costedoat-Chalumeau, Alexis Mathian, Gaëlle Leroux, Jonathan Boutémy, Olivier Espitia, Laurence Bouillet, Sabine Berthier, Jean-Baptiste Gaultier, Pierre-Yves Jeandel, Amadou Konaté, Arsène Mékinian, Elisabeth Solau-Gervais, Benjamin Terrier, Daniel Wendling, Fanny Andry, Camille Garnier, Pascal Cathébras, Laurent Arnaud, Aurore Palmaro, Patrice Cacoub, Zahir Amoura, Jean-Charles Piette, Philippe Arlet, Maryse Lapeyre-Mestre, Laurent Sailler
Journal: Annals of the Rheumatic Diseases (2018)

To assess the efficacy and the safety of biologics in a cohort of patients with relapsing polychondritis (RP).We conducted a French multicentre retrospective cohort study including patients treated with biologics for RP. Efficacy outcomes were clinical response (partial or complete) and complete response during the first 6 months of exposure, plus daily corticosteroid dose at 6 months. Other outcomes were adverse drug reactions (ADRs), persistence of biologics and factors associated with a response.This study included 41 patients exposed to 105 biologics (tumour-necrosis factor (TNF) inhibitors, n=60; tocilizumab, n=17; anakinra, n=15; rituximab, n=7; abatacept, n=6). Overall response rate during the first 6 months of exposure was 62.9%. Complete response rate was 19.0%. Reduced corticosteroid doses were highly variable among patients. ADRs were mostly infections (n=42). Reasons for biologic withdrawal (73.3%) were insufficient efficacy (34.3%; ranging from 23.5% for tocilizumab to 72.7% for etanercept), loss of efficacy (18.1%) and ADRs (20.9%; mostly for anakinra: 46.7%). Persistence was comparable among biologic classes. Among TNF inhibitors, the highest persistence was observed with adalimumab. Differences in clinical response rates were observed depending on biologics and organ involvement. There were trends towards a lower response rate in cases with associated myelodysplastic syndrome and for a higher response rate for nasal/auricular chondritis, sternal chondritis and concomitant exposure to non-biologic disease-modifying antirheumatic drugs.This study describes the efficacy of biologics for refractory RP. However, the number of complete responses was low and there were concerns about the risk of ADRs, particularly infections.
Molecular Imaging of Apoptosis in Cancer Therapy-Related Cardiac Dysfunction Before LVEF Reduction
Authors: Takehiro Nakahara, Artiom Petrov, Takashi Tanimoto, Farhan Chaudhry, Navneet Narula, Surya V. Seshan, Jeffrey A. Mattis, Koon Yan Pak, Gagan Sahni, Aarti Bhardwaj, Partho P. Sengupta, Amy Tiersten, H. William Strauss, Jagat Narula
Journal: JACC. Cardiovascular imaging (2018)
COMPARISON OF ECMO AND PLVAD FOR PATIENTS WITH CARDIOGENIC SHOCK UNDERGOING HIGH-RISK PERCUTANEOUS CORONARY INTERVENTION
Authors: Rajkumar Doshi, Krunalkumar Patel, Jay Shah, Rajiv Jauhar, Zainulabedin Waqar, Perwaiz Meraj
Journal: Journal of the American College of Cardiology (2018)
Alzheimer’s Disease in Physicians — Assessing Professional Competence and Tempering Stigma
Authors: Gayatri Devi
Journal: New England Journal of Medicine (2018)

Interview with Dr. Gayatri Devi on assessment and support for physicians with Alzheimer’s disease. (10:54)Download Policies are needed to aid the increasing numbers of working health care professionals who have Alzheimer’s disease, while safeguarding their communities. The emphasis should be on supporting, not penalizing, impaired physicians.
The National Diabetes Education Program at 20 Years: Lessons Learned and Plans for the Future
Authors: Linda M. Siminerio, Ann Albright, Judith Fradkin, Joanne Gallivan, Jude McDivitt, Betsy Rodríguez, Diane Tuncer, Faye Wong
Journal: Diabetes Care (2018)

The National Diabetes Education Program (NDEP) was established to translate findings from diabetes research studies into clinical and public health practice. Over 20 years, NDEP has built a program with partnership engagement that includes science-based resources for multiple population and stakeholder audiences. Throughout its history, NDEP has developed strategies and messages based on communication research and relied on established behavior change models from health education, communication, and social marketing. The program’s success in continuing to engage diverse partners after 20 years has led to time-proven and high-quality resources that have been sustained. Today, NDEP maintains a national repository of diabetes education tools and resources that are high quality, science- and audience-based, culturally and linguistically appropriate, and available free of charge to a wide variety of audiences. This review looks back and describes NDEP’s evolution in transforming and communicating diabetes management and type 2 diabetes prevention strategies through partnerships, campaigns, educational resources, and tools and identifies future opportunities and plans.
Avelumab as neoadjuvant therapy in subjects with muscle-invasive urothelial carcinoma (AURA trial).
Authors: Nieves Martinez Chanza, Thierry Andre Roumeguere, Spyridon Sideris, Thierry Gil, Alexandre Peltier, Ahmad Awada
Journal: Journal of Clinical Oncology (2018)

TPS535 Background: Avelumab, a fully human anti-PD-L1 IgG1 monoclonal antibody, is approved in monotherapy for the advanced disease. For patients with non metastatic muscle-invasive bladder cancer (MIBC) the preferred treatment nowadays consists of a multimodal approach comprising neoadjuvant cisplatin-based chemotherapy followed by surgery. However, the benefit of the neoadjuvant chemotherapy (NAC) is modest and an important proportion of patients do not benefit providing unnecessary toxicity. In addition, forty per cent of this population is ineligible for platinum-based therapies and currently no medical alternative option exist. This trial will attempt to answer several open questions: what is the role of the immunotherapy in the neoadjuvant setting? Is efficacy of immunotherapy influenced by the association with cytotoxic agents? Which agents (anthracyclins, platin or taxanes)? Do cisplatin-ineligible patients benefit from this approach? Is there any predictive biomarker for chemotherapy and/or immunotherapy? Methods: This is a randomized phase 2 study in subject candidates for a NAC followed by surgery (EudraCT Number: 2017-002758-35). The study will recruit cisplatin eligible and ineligible patients. For the group of cisplatin-eligible, chemotherapy with high dose of Metotrexate-Vinblastin-Adriamycin-Cisplatin or Cisplatin-Gemcitabine will be associated with Avelumab. For the group of cisplatin-ineligible, Avelumab as monotherapy or associated with Paclitaxel-Gemcitabine will be used. Four cycles of treatment are provided. A radiological evaluation will be performed after 2 cycles and if evidence of progressive disease exists the neoadjuvant treatment will be stopped and the surgery will be performed (Table 1 represents the study design). The primary objective is to determine the pathologic complete response as well as to assess the toxicity profile. Blood, urine and stool samples will be collected at different points to perform translational researches. Clinical trial information: 2017-002758-35.
A Preexisting Rare <i>PIK3CA</i>E545K Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in <i>NRAS</i> Melanoma and Is Dependent on S6K1 Signaling
Authors: Gabriele Romano, Pei-Ling Chen, Ping Song, Jennifer L. McQuade, Roger J. Liang, Mingguang Liu, Whijae Roh, Dzifa Y. Duose, Fernando C.L. Carapeto, Jun Li, Jessica L.F. Teh, Andrew E. Aplin, Merry Chen, Jianhua Zhang, Alexander J. Lazar, Michael A. Davies, P. Andrew Futreal, Rodabe N. Amaria, David Y. Zhang, Jennifer A. Wargo, Lawrence N. Kwong
Journal: Cancer Discovery (2018)

Abstract Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS-mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CAE545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CAE545K-induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways. Significance: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CAE545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CAE545K-expressing NRAS-mutant melanoma cells to MEKi + CDK4i. Cancer Discov; 8(5); 556–67. ©2018 AACR. See related commentary by Sullivan, p. 532. See related article by Teh et al., p. 568. This article is highlighted in the In This Issue feature, p. 517
Does depression treatment improve the survival of depressed patients with cancer? A long-term follow-up of participants in the SMaRT Oncology-2 and 3 trials
Authors: Amy Mulick, Jane Walker, Stephen Puntis, Katy Burke, Stefan Symeonides, Charlie Gourley, Marta Wanat, Chris Frost, Michael Sharpe
Journal: The Lancet Psychiatry (2018)
Performance verification of a plasma-based PD-L1 test that reliably measures mRNA expression from patients with NCSLC.
Authors: Hestia S. Mellert, Leisa Jackson, Gary Anthony Pestano
Journal: Journal of Clinical Oncology (2018)

156 Background: The detection of circulating nucleic acids using non-invasive blood-draws has become highly relevant to clinical testing. In this study we report on the development of a blood-based PD-L1 test for immunotherapy selection. Methods: We have previously reported on the analytic performance of a droplet digital™ PCR (ddPCR) assay for circulating cytokeratin 19 and PD-L1. Using a variable threshold based on a logistic regression score for the blood assay and a 1% IHC (immunohistochemistry) tissue cut-off, concordance was 80% (n = 16). Positive calls for the blood-based PD-L1 assay ranged from 2 to 124 copies. In this study we focused on variables that could impact concordance of the blood assay and tissue results. Criteria included droplet counts for tissue and blood mRNA transcripts and tumor proportion score (TPS) for the tissue IHC assay (22C3 pharmDx). Results: We examined the correlation between PD-L1 in formalin-fixed paraffin-embedded (FFPE) tissue by IHC, mRNA expression in serial cut FFPE sections, and in matched plasma samples collected at the time of tissue resection. Five cases were assayed to confirm PD-L1 positivity by tissue. We successfully recovered RNA from serial tissue sections for each case and detected PD-L1 levels ranging from 6 to 1272 copies. Plasma samples were available for four of the cases for circulating RNA evaluation, and we were successful in detecting PD-L1 in all cases (copy range 32-138). While all four cases contained detectible PD-L1 mRNA in tissue and circulation, we observed little concordance between these levels in tissue and blood. Conclusions: We have developed methods to measure the dynamic range of PD-L1 from plasma. We have shown feasibility of these methods by evaluating key immune and cancer-specific RNAs. The current study demonstrates that although the development of quantitative assays for mRNA in blood is possible, concordance with traditional clinical tissue assays such as IHC may not be a useful validation measure. We have initiated prospective validation studies that will continue to evaluate PD-L1 expression by IHC and in the blood-based assay, and will also monitor patient performance measures in response to immunotherapy.