tbuckley/cabot-search huggingface dataset:
Identification of novel recurrent ETV6-IgH fusions in primary central nervous system lymphoma
Authors: Aurélie Bruno, Karim Labreche, Maïlys Daniau, Blandine Boisselier, Guillaume Gauchotte, Louis Royer-Perron, Amithys Rahimian, Frédéric Lemoine, Pierre de la Grange, Justine Guégan, Franck Bielle, Marc Polivka, Clovis Adam, David Meyronet, Dominique Figarella-Branger, Chiara Villa, Fabrice Chrétien, Sandrine Eimer, Frédéric Davi, Audrey Rousseau, Caroline Houillier, Carole Soussain, Karima Mokhtari, Khê Hoang-Xuan, Agusti Alentorn
Journal: Neuro-Oncology (2018)

Primary central nervous system lymphoma (PCNSL) represents a particular entity within non-Hodgkin lymphomas and is associated with poor outcome. The present study addresses the potential clinical relevance of chimeric transcripts in PCNSL discovered by using RNA sequencing (RNA-seq).Seventy-two immunocompetent and newly diagnosed PCNSL cases were included in the present study. Among them, 6 were analyzed by RNA-seq to detect new potential fusion transcripts. We confirmed the results in the remaining 66 PCNSL. The gene fusion was validated by fluorescence in situ hybridization (FISH) using formalin-fixed paraffin-embedded (FFPE) samples. We assessed the biological and clinical impact of one new gene fusion.We identified a novel recurrent gene fusion, E26 transformation-specific translocation variant 6-immunoglobulin heavy chain (ETV6-IgH). Overall, ETV6-IgH was found in 13 out of 72 PCNSL (18%). No fusion conserved an intact functional domain of ETV6, and ETV6 was significantly underexpressed at gene level, suggesting an ETV6 haploinsufficiency mechanism. The presence of the gene fusion was also validated by FISH in FFPE samples. Finally, PCNSL samples harboring ETV6-IgH showed a better prognosis in multivariate analysis, P = 0.03, hazard ratio = 0.33, 95% CI = 0.12-0.88. The overall survival at 5 years was 69% for PCNSL harboring ETV6-IgH versus 29% for samples without this gene fusion.ETV6-IgH is a new potential surrogate marker of PCNSL with favorable prognosis with ETV6 haploinsufficiency as a possible mechanism. The potential clinical impact of ETV6-IgH should be validated in larger prospective studies.
Diploma in forensic medical sciences
Authors: Elizabeth Nimmo
Journal: BMJ (2010)

The diploma course in forensic medical sciences (DipFMS) aims to deliver core knowledge in the forensic medical sciences and is targeted at people from medical and non-medical backgrounds such as pathologists, forensic physicians, emergency service personnel, forensic scientists, precognition agents, solicitors, and police officers. Doctors from all career levels (foundation year to consultant) and various specialties (pathology, emergency medicine, and general practice) were present.

I took this course during core trainee year 2 of my emergency medicine training.

I wanted to gain further knowledge of certain clinical situations that I had been involved in or might become involved in as an emergency medicine trainee—for example, involving people who have been physically and sexually assaulted; cases of child abuse; child deaths; and examination of those being detained. I also wanted to achieve a better understanding of the legal system so that I could competently undertake tasks such …
Abstract P189: Factors Associated With Stenosis on Invasive Coronary Angiography for Persons Living With Human Immunodeficiency Virus (PLWH): The HIV Electronic Comprehensive Cohort of CVD Complications (HIVE-4CVD)
Authors: Andrew Furman, Robert Riestenberg, Anna Pawlowski, Daniel Schneider, Donald M Lloyd-Jones, Matthew J Feinstein
Journal: Circulation (2018)

Background: Persons living with HIV (PLWH) have greater risks for atherosclerotic cardiovascular disease (ASCVD) than uninfected persons. However, data are sparse regarding HIV-specific factors associated with coronary atherosclerosis. Methods: HIVE-4CVD is an electronic data repository of demographic and clinical data collected during the routine clinical care of 5041 PLWH and 10082 uninfected controls frequency matched on age, sex, race, zip code, and clinic location receiving care at Northwestern Medicine from 1/1/2000 to 5/17/2017. Using validated natural language extraction algorithms, we analyzed data on coronary stenosis severity for the 286 PLWH and 266 uninfected controls in HIVE-4CVD who underwent coronary angiography. Stenosis severity was recorded as the highest percentage of stenosis noted for each patient in each artery (LAD, LCx, RCA). Multivariable logistic regression models adjusted for demographics and CVD risk factors were used to evaluate odds of significant (≥50%) coronary stenosis (1) for PLWH versus uninfected controls and (2) across different levels of HIV viremia and immune suppression among PLWH. Results: Of the 286 PLWH and 266 uninfected controls undergoing coronary angiography, 205 (55.4%) PLWH vs. 165 (44.6%) uninfected controls had diagnoses of myocardial infarction (p=0.02). The location and severity of coronary stenoses did not differ significantly for PLWH vs. uninfected controls; mean maximal overall stenosis and mean maximal LAD, RCA, and LCx stenoses were 52.3% vs. 50.2% (p=0.52), 44.5% vs. 42.3% (p=0.48), 37.0% vs. 36.1% (p=0.78) and 31.4% vs. 31.6% (p=0.95) respectively. There was no significant difference in odds of having significant coronary stenosis for PLWH vs. uninfected controls (multivariable-adjusted OR 1.15, 95% CI 0.79-1.70). Among PLWH, peak HIV viral load was associated with borderline significantly greater odds of ≥50% coronary stenosis after adjustment for demographics, CVD risk factors, and HIV therapies (OR 1.07 per 10-fold greater peak HIV viral load, 95% CI 1.00-1.14, p=0.04), but lower Nadir CD4+ T cell count (&lt;200 vs. ≥200 cells/mm 3 ) was not (OR 1.05, 95% CI 0.74-1.48, p=0.79). Conclusions: There was no consistent or significant difference in severity of coronary artery stenosis among PLWH and uninfected controls undergoing invasive coronary angiography in the course of routine clinical care. Higher peak HIV viral load is associated with borderline significantly greater odds of having significant coronary stenosis among PLWH undergoing invasive coronary angiography.
What senior house officer posts are most suited to a career in cardiology?
Authors: Mark Scoote
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>
Clinical outcome of patients with germline DNA repair mutations: Results from a retrospective international study.
Authors: Joaquin Mateo, Heather H. Cheng, Himisha Beltran, David Dolling, Wen Xu, Colin Pritchard, Helen Mossop, Pasquale Rescigno, Raquel Perez-Lopez, Verena Sailer, Michael Paul Kolinsky, Ada Balasopoulou, Claudia Bertan, Suzanne Carreira, Heather Thorne, Robert B. Montgomery, Shahneen Kaur Sandhu, Mark A. Rubin, Peter Nelson, Johann S. De Bono
Journal: Journal of Clinical Oncology (2018)

218 Background: CRPC is enriched for germline mutations in DNA damage repair genes (gDDRm). BRCA2 mutations (g BRCA2m) associate with poor prognosis from localized PC, but prognostic and predictive value for standard therapy in CRPC is unclear. We reviewed clinical outcome of 390 patients previously tested for gDDRm. Methods: Patient records were reviewed for 372 patients from 3 institutions (Royal Marsden UK, Weill-Cornell NY, University of Washington, WA) with gDDRm status previously published (Pritchard et al, NEJM 2016) and 18 g BRCA1/2m carriers from KConFab consortium (Australia). Baseline characteristics and survival were annotated. Response (PSA50%/RECIST) and PFS (RECIST/PSA progression or start of a new therapy due to clinical progression) were collected for Abiraterone, Enzalutamide and Docetaxel. To account for potential differences between cohorts, a mixed effect model (Weibull distribution) with random intercept per cohort was pursued. Results: dDDRm status was available for n = 390 (60 gDDRm+, including 37 g BRCA2m, and 330 gDDRm-). Overall, 74% and 69% received Docetaxel and Abiraterone/Enzalutamide respectively; 47% gDDRm+ and 34% gDDRm- received PARPi and/or platinum. Median overall survival from CRPC was 3.0 vs 3.2 years in gDDRm+ vs gDDRm- (p = 0.73; g BRCA2m = 3.0 years, p = 0.72). Age and Gleason score at diagnosis were associated with survival from castration-resistance in multivariate analysis. Median PFS on Docetaxel for gDDRm+ (6.8 months; 6.3 for g BRCA2m) and gDDRm- (5.1 months) were not significantly different (p = 0.2). Similarly, RR to Docetaxel was similar for the two groups (61% vs 54% in gDDRm+ vs gDDRm-; 63% g BRCA2m). Median PFS and RR on first Abiraterone/Enzalutamide were similar across groups (PFS: 8.3 months gDDRm+, 8.3 months for gDDRm-; p = 0.9; RR 46% vs 56% respectively) The Interaction of PARPi/platinum therapy among gDDRm+ patients resulted in an aHR for OS from CRPC of 0.59 (95%CI 0.28-1.25; p = 0.17). Conclusions: In this retrospective analysis, CRPC patients with gDDRm still benefited from standard therapies similarly to non-mutation carriers; interpretation of survival data should consider the high proportion treated with PARPi/platinum.
Seropositivity and response to RTX: Data from the CERERRA collaboration
Authors: K Chatzidionysiou, E. Lie, E. Nasonov, G. Lukina, Merete Lund Hetland, U. Tarp, I. Ancuta, K. Pavelka, D. Nordström, C. Gabay, H. Canhao, M. Tomsic, P. Van Riel, J. Gomez-Reino, T. Kvien, R. Van Vollenhoven
Journal: Annals of the Rheumatic Diseases (2012)
P107 Targeting activated synovial fibroblasts using photodynamic therapy in experimental arthritis
Authors: DN Dorst, M Rijpkema, M Buitinga, M Brom, DL Bos, A Freimoser, C Klein, B Walgreen, PM van der Kraan, M Gotthardt, MI Koenders
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Activated synovial fibroblasts (SF) are characterised by the expression of Fibroblast Activation Protein (FAP). Here, we investigated the potential of photodynamic therapy (PDT) targeting FAP to selectively induce cell death in these cells. In PDT, a light-sensitive molecule is delivered to a target cell and activated with light of a specific wavelength. This causes cell death through the production of reactive oxygen species. <h3>Methods</h3> The anti-FAP antibody 28 H1 was conjugated with the photosensitizer IRDye700DX (28H1-700DX). <i>In vitro</i> PDT assays were performed with 3 T3 fibroblasts stably transfected with FAP. 3T3-FAP cells were incubated with 28H1-700DX or a control conjugate for 4 hours, and exposed to varying 690 nm light doses. Subsequently, cell viability was measured using the CellTiter-Glo assay. For <i>in vivo</i> biodistribution, 5 days after onset of antigen-induced arthritis (AIA) C57Bl6 mice were injected with 28H1±700 DX labelled with radioactive Indium for quantification purposes (expressed as% injected dose per gram tissue (%ID/g)). For the PDT treatment experiment, arthritic mice were injected at day 5 of AIA with 28H1-700DX or PBS and exposed to 50 or 90 J/cm<sup>2</sup> light 24 hours post injection. Joints were isolated at day 10 for histological analysis. <h3>Results</h3> To assess PDT efficacy, we applied 13.7 J/cm2 light exposure to 3T3-FAP cells incubated with 6.67 pM 28H1-700DX, which significantly reduced cell viability (89.27%±2.48 compared to control (p&lt;0.001)). No cell death was observed with the control 700DX-conjugate. Conjugating the anti-FAP antibody to 700DX changed the <i>in vivo</i> biodistribution of the antibody, with a higher accumulation in the liver (27,06±0,95%ID/g vs. 6,08±0,42%ID/g with control (p&lt;0,001)) and lower blood levels (5,32±0,36%ID/g vs. 12,72±0,80%ID/g with control (p&lt;0,001)). Accumulation in the arthritic joints was not significantly different. Histological analysis of the PDT-treated mouse knee joints is ongoing. <h3>Conclusions</h3> We have demonstrated fibroblast-specific cell death using 700DX-conjugated 28 H1 PDT, indicating FAP-based PDT as a promising new tool in treating RA. Furthermore, we demonstrated that adding 700DX results in faster liver clearance of the antibody, but does not affect uptake in the inflamed knee joint. Future research will further elucidate the applicability of our conjugate for PDT in animal models of RA. <h3>Disclosure of interest</h3> None declared
Subcutaneous methotrexate in patients with moderate-to-severe psoriasis: a critical appraisal
Authors: T. Tsakok, Z.K. Jabbar-Lopez, C.H. Smith
Journal: British Journal of Dermatology (2018)

Warren et al.1 set out to assess the effect of an intensified dosing schedule of subcutaneous methotrexate in patients with moderate‐to‐severe chronic plaque psoriasis. This was a prospective, double‐blind, randomized (3 : 1), placebo‐controlled study, conducted across 16 centres in Germany, France, the Netherlands and the U.K. Methotrexate‐naive adults with a diagnosis of moderate‐to‐severe chronic plaque psoriasis for at least 6 months before baseline were randomly assigned to receive weekly subcutaneous injections of either methotrexate at a starting dose of 17·5 mg, or placebo for 16 weeks (first phase). Dose escalation to 22·5 mg per week was implemented after 8 weeks if patients did not achieve ≥ 50% improvement in Psoriasis Area and Severity Index (PASI 50). Treatment was combined with folic acid 5 mg per week. The first phase of the study was followed by an open‐label period from 16 to 52 weeks (second phase), in which both groups received weekly methotrexate injections. At week 24, dose escalation to 22·5 mg per week was possible in patients not achieving PASI 50. Psoriasis severity was measured using PASI. The authors also used two other psoriasis severity measures and two quality‐of‐life measures, looked at safety indices and performed a substudy analysing paired skin biopsies at baseline and week 16 (histopathology, immunohistochemistry and expression of interleukin‐17A, interferon‐γ and tumour necrosis factor‐α). The primary outcome was the proportion of patients reaching PASI 75 at week 16. In total 120 patients were included in this trial, most of whom were middle‐aged white men with long‐standing psoriasis, and the mean body mass index was 30·1 kg m−2. PASI 75 was achieved in 41% of patients receiving methotrexate vs. 10% of patients receiving placebo (relative risk 3·93, 95% confidence interval 1·31–11·81; P = 0·0026) at week 16. Subcutaneous methotrexate was generally well tolerated, with no serious adverse events related to this treatment over the 52‐week study. Warren et al. conclude that the 52‐week risk–benefit profile of subcutaneous methotrexate is favourable in patients with psoriasis.
ANTICOAGULATION IN CONCURRENT MESENTERIC ISCHEMIA AND INFECTIVE ENDOCARDITIS IN THE PRESENCE OF INFLAMMATORY BOWEL DISEASE
Authors: Mehran Abolbashari, Ahmed Ibrahim, Ruben Montanez, Aymen Albaghdadi, Mohamed Teleb, Debabrata Mukherjee, Subrata Kar
Journal: Journal of the American College of Cardiology (2018)
Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with severe liver fibrosis
Authors: Salvatore Petta, Luigi Elio Adinolfi, Anna Ludovica Fracanzani, Francesca Rini, Rosalia Caldarella, Vincenza Calvaruso, Calogero Cammà, Marcello Ciaccio, Vito Di Marco, Stefania Grimaudo, Anna Licata, Aldo Marrone, Riccardo Nevola, Rosaria Maria Pipitone, Antonio Pinto, Luca Rinaldi, Daniele Torres, Antonino Tuttolomondo, Luca Valenti, Silvia Fargion, Antonio Craxì
Journal: Journal of Hepatology (2018)
Early myeloma-related death in elderly patients: development of a clinical prognostic score and evaluation of response sustainability role
Authors: Paula Rodríguez-Otero, María Victoria Mateos, Joaquín Martínez-López, Nerea Martín-Calvo, Miguel-Teodoro Hernández, Enrique M. Ocio, Laura Rosiñol, Rafael Martínez, Ana-Isabel Teruel, Norma C. Gutiérrez, Joan Bargay, Enrique Bengoechea, Yolanda González, Jaime Pérez de Oteyza, Mercedes Gironella, Cristina Encinas, Jesús Martín, Carmen Cabrera, Luis Palomera, Felipe de Arriba, María Teresa Cedena, Bruno Paiva, Noemí Puig, Albert Oriol, Joan Bladé, Juan José Lahuerta, Jesús F. San Miguel
Journal: Leukemia (2018)
Doctors are still doubtful of benefits of revalidation, study finds
Authors: Abi Rimmer
Journal: BMJ (2014)

Many doctors still believe that revalidation is not relevant to them, research carried out by the NHS’s Revalidation Support Team has found.

The team carried out research between June and December last year into the benefits and effects of revalidation during the first year of its implementation. Revalidation was launched in December 2012, and so far over 36 000 doctors have gone through the process.1

The researchers received 3500 responses to a survey designed to assess the impact of revalidation. Of these responses, 2499 came from doctors, 719 from appraisers, 192 from responsible officers (who make recommendations on appraisal), and 124 from designated bodies (the organisations that provide doctors with a regular appraisal and help them with revalidation). …
Mycobacterium tuberculosis Mce2E suppresses the macrophage innate immune response and promotes epithelial cell proliferation
Authors: Lihua Qiang, Jing Wang, Yong Zhang, Pupu Ge, Qiyao Chai, Bingxi Li, Yi Shi, Lingqiang Zhang, George Fu Gao, Cui Hua Liu
Journal: Cellular and Molecular Immunology (2018)
RARE GENETIC VARIANTS IN FLNC-ENCODED FILAMIN C MAY SERVE AS A PATHOGENIC SUBSTRATE FOR ARRHYTHMOGENIC BI-LEAFLET MITRAL VALVE PROLAPSE SYNDROME WITH CONCOMITANT LEFT VENTRICULAR ENLARGEMENT
Authors: John Giudicessi, Johan Bos, David Tester, Samuel Asirvatham, Suraj Kapa, Peter Noseworthy, Michael Ackerman
Journal: Journal of the American College of Cardiology (2018)
IMPACT OF SMALL DEVICE USE IN THE PROXIMAL LAD VERSUS OTHER CORONARY SEGMENTS ON LONG-TERM CLINICAL OUTCOMES: AN ADAPT-DES SUB-ANALYSIS
Authors: Evan Shlofmitz, Akiko Maehara, Bernhard Witzenbichler, David Metzger, Michael Rinaldi, Ernest Mazzaferri, Peter Duffy, Giora Weisz, Franz-Josef Neumann, Timothy Henry, David Cox, Thomas Stuckey, Bruce Brodie, Yangbo Liu, Ajay Kirtane, Gary Mintz, Gregg Stone
Journal: Journal of the American College of Cardiology (2018)
Hepatology in a changing health care landscape: A call for health services research
Authors: Lisa B. VanWagner, Fasiha Kanwal
Journal: Hepatology (2018)

With the passage of the Affordable Care Act followed by the physician payment reform, there is an urgent need to better understand the complex relationships between structure (including incentives), processes, and outcomes of health care and, based on this understanding, identify interventions that can ensure delivery of high‐value care to patients with liver disease. As hepatologists, how do we systematically address these issues and ensure that we provide high‐value care to our patients? These factors combine in the burgeoning field of health services research. This article seeks to describe how health services research influences the practice of hepatology, the tools and technologies it utilizes, as well as how interested individuals can seek to acquire knowledge and methodological training in health services research. Finally, we summarize the current state of health services research in hepatology and liver transplantation. (H epatology 2018).
GPs favour “tartanisation” of contract over a separate contract for Scotland
Authors: Helen Jaques
Journal: BMJ (2012)

General practitioners have rejected calls for a Scotland only contract in favour of using flexibilities in the current UK wide contract to make it more appropriate for the Scottish population.

Delegates at the Scottish Local Medical Committees conference in Clydebank defeated a motion calling for a separate GP contract to be negotiated in Scotland and instead passed a motion supporting “tartanisation” of the UK …
Krüppel-like Factor 4 Suppresses Serine/Threonine Kinase 33 Activation and Metastasis of Gastric Cancer through Reversing Epithelial–Mesenchymal Transition
Authors: Fanyang Kong, Tao Sun, Xiangyu Kong, Dacheng Xie, Zhaoshen Li, Keping Xie
Journal: Clinical Cancer Research (2018)

Background: Cancers with aberrant expression of Serine/threonine kinase 33 (STK33) has been reported to be particularly aggressive. However, its expression, clinical significance, and biological functions in gastric cancer remain largely unknown. In the present study, we determined the expression and function of STK33 in gastric cancer and delineated the clinical significance of the Krüppel-like factor 4 (KLF4)/STK33 signaling pathway.Methods: STK33 expression and its association with multiple clinicopathologic characteristics were analyzed immunohistochemically in human gastric cancer specimens. STK33 knockdown and overexpression were used to dissect the underlying mechanism of its functions in gastric cancer cells. Regulation and underlying mechanisms of STK33 expression by KLF4 in gastric cancer cells were studied using cell and molecular biological methods.Results: Drastically higher expression of STK33 was observed in gastric cancer and gastric intraepithelial neoplasia tissues compared with adjacent normal gastric tissues. Increased STK33 expression correlated directly with tumor size, lymph node, and distant metastasis; and patients with low STK33 expression gastric cancer were predicted to have a favorable prognosis. Enforced expression of STK33 promoted gastric cancer cell proliferation, migration, and invasion in vitro and in vivo, whereas reduced STK33 did the opposite. Moreover, STK33 promoted epithelial-mesenchymal transition (EMT) in vitro Mechanistically, KLF4 transcriptionally inhibited STK33 expression in gastric cancer cells. KLF4-mediated inhibition of gastric cancer cell invasion was reversed by upregulation of STK33 expression.Conclusions: STK33 has pro-tumor function and is a critical downstream mediator of KLF4 in gastric cancer. STK33 may serve as a potential prognostic marker and therapeutic target for gastric cancer. Clin Cancer Res; 24(10); 2440-51. ©2018 AACR.
hPCL3s Promotes Hepatocellular Carcinoma Metastasis by Activating β-Catenin Signaling
Authors: Zhen Cai, Zhen-Yu Qian, Hao Jiang, Ning Ma, Zhi Li, Li-Yu Liu, Xin-Xin Ren, Yu-Rong Shang, Jing-Jing Wang, Jing-Jing Li, Dong-Ping Liu, Xiu-Ping Zhang, Dan Feng, Qian-Zhi Ni, Yuan-Yuan Feng, Nan Li, Xiao-Yan Zhou, Xiang Wang, Ying Bao, Xue-Li Zhang, Yue-Zhen Deng, Dong Xie
Journal: Cancer Research (2018)

Two isoforms of human Polycomb-like protein 3 (hPCL3) have been reported as components of the nuclear Polycomb repressive complex 2 (PRC2), with the short isoform (hPCL3s) showing a dominant cytoplasmic localization. The function of cytoplasmic hPCL3s has, however, not been addressed. In this study, we report that hPCL3s is upregulated in clinical hepatocellular carcinoma (HCC) samples and its expression correlated with HCC clinical features. hPCL3s positively regulated the migration, invasion, and metastasis of HCC cells. hPCL3s interacted with components of the cytoplasmic β-catenin destruction complex, inhibited β-catenin degradation, and activated β-catenin/T-cell factor signaling. Downstream of the β-catenin cascade, IL6 mediated the motility-promoting functions of hPCL3s. Forced expression of hPCL3s in the liver of a HCC mouse model promoted tumorigenesis and metastasis. Taken together, these data show that hPCL3s promotes the metastasis of HCC by activating the β-catenin/IL6 pathway.Significance: hPCL3s has an oncogenic role in hepatocellular carcinoma by activating the β-catenin/IL6 signaling axis to promote metastasis. Cancer Res; 78(10); 2536-49. ©2018 AACR.