tbuckley/cabot-search huggingface dataset:
Next-generation sequencing to identify predictors of survival after trimodality therapy for esophageal cancer.
Authors: Patrick Oh, Minsi Zhang, Paul Brady, Smita Sihag, Daniela Molena, David H. Ilson, Yelena Yuriy Janjigian, Geoffrey Yuyat Ku, Abraham Jing-Ching Wu
Journal: Journal of Clinical Oncology (2018)

153 Background: Tumor mutation profiling has changed the prognostication and treatment of a wide variety of malignances. However, little is known about whether mutation profiles affect outcome in localized esophageal cancer treated with multimodality therapy. SMAD4 is a gene involved in the regulation of the TGF-β signal transduction pathway by negatively controlling the growth of epithelial cells and has been implicated as a prognostic factor in pancreatic cancer. We undertook an exploratory analysis of tumor mutation profiles, including SMAD4 status, in localized esophageal cancer patients treated with trimodality therapy at our institution. Methods: We identified 66 Stage II-III esophageal cancer patients treated with chemoradiation followed by surgery who had some form of tumor mutation profiling available. Only patients with mutation profiling from pre-treatment biopsy or post-chemoradiation surgical specimen (i.e. not from a subsequent metastatic lesion) were included. Twenty-two patients underwent next-generation sequencing assessing 341 candidate genes via targeted sequencing. Log-rank test was used to assess correlation of mutations to overall survival, and to pathologic response. Results: The median follow-up was 17.1 months. SMAD4 loss was identified in 3 of 22 patients (13.6%) who underwent next-generation sequencing, and was significantly associated with inferior overall survival (p=0.023). No other candidate genes were significantly associated with survival, and no genes were significantly associated with pathologic response. Conclusions: To our knowledge, this is the first analysis of next-generation mutation profiling and outcome in non-metastatic esophageal cancer patients treated with trimodality therapy. Due to the limited numbers, this was an exploratory analysis only. We identified SMAD4 loss as a potential adverse prognostic factor for survival. More next-generation sequencing data from non-metastatic esophageal cancer patients treated with multimodality therapy is needed to further elucidate the potential relationship of SMAD4 loss or other mutations with outcome.
“Four day week” is offered to encourage UK GPs to move to New Zealand
Authors: Abi Rimmer
Journal: BMJ (2015)

A medical recruitment company has offered GPs a four day working week in New Zealand as an alternative to a seven day NHS.

Head Medical, which is based in Edinburgh, emailed 214 GPs who had registered with its service, offering them a better work-life balance in New Zealand. The email was sent after the health secretary, Jeremy Hunt, said that he would introduce seven day services in the NHS.1

Head Medical’s email to GPs said, “Do you ever find yourself daydreaming of working a four day working week with a longer consultation time to spend with your patients and …
Identification and Therapeutic Intervention of Coactivated Anaplastic Lymphoma Kinase, Fibroblast Growth Factor Receptor 2, and Ephrin Type‐A Receptor 5 Kinases in Hepatocellular Carcinoma
Authors: Xin Wang, Minmin Zhang, Fangfang Ping, Hongchun Liu, Jingya Sun, Yueqin Wang, Aijun Shen, Jian Ding, Meiyu Geng
Journal: Hepatology (2018)

Though kinase inhibitors have been heavily investigated in the clinic to combat advanced hepatocellular carcinoma (HCC), clinical outcomes have been disappointing overall, which may be due to the absence of kinase‐addicted subsets in HCC patients. Recently, strategies that simultaneously inhibit multiple kinases are increasingly appreciated in HCC treatment, yet they are challenged by the dynamic nature of the kinase networks. This study aims to identify clustered kinases that may cooperate to drive the malignant growth of HCC. We show that anaplastic lymphoma kinase, fibroblast growth factor receptor 2, and ephrin type‐A receptor 5 are the essential kinases that assemble into a functional cluster to sustain the viability of HCC cells through downstream protein kinase B–dependent, extracellular signal–regulated kinase–dependent, and p38‐dependent signaling pathways. Their coactivation is associated with poor prognosis for overall survival in about 13% of HCC patients. Moreover, their activities are tightly regulated by heat shock protein 90 (Hsp90). Thereby Combined kinase inhibition or targeting of heat shock protein 90 led to significant therapeutic responses both in vitro and in vivo . Conclusion: Our findings established a paradigm that highlights the cooperation of anaplastic lymphoma kinase, fibroblast growth factor receptor 2, and ephrin type‐A receptor 5 kinases in governing the growth advantage of HCC cells, which might offer a conceptual “combined therapeutic target” for diagnosis and subsequent intervention in a subgroup of HCC patients.
ASSOCIATION BETWEEN LEFT ATRIAL SCAR BURDEN AND PERSISTENT VERSUS PAROXYSMAL ATRIAL FIBRILLATION: A RETROSPECTIVE COHORT STUDY
Authors: Oluwaseun Adeola, Dinesh Voruganti, Ghanshyam Palamaner Subash Shantha, Hakeem Ayinde, Chad Ward, Amgad Mentias, Steven Bailin, Michael Giudici
Journal: Journal of the American College of Cardiology (2018)
Pluripotent Stem Cell-Derived Cardiomyocytes as a Platform for Cell Therapy Applications: Progress and Hurdles for Clinical Translation
Authors: Angelos Oikonomopoulos, Tomoya Kitani, Joseph C. Wu
Journal: Molecular Therapy (2018)

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Regenerative therapy has been applied to restore lost cardiac muscle and cardiac performance. Induced pluripotent stem cells (iPSCs) can provide an unlimited source of cardiomyocytes and therefore play a key role in cardiac regeneration. Despite initial encouraging results from pre-clinical studies, progress toward clinical applications has been hampered by issues such as tumorigenesis, arrhythmogenesis, immune rejection, scalability, low graft-cell survival, and poor engraftment. Here, we review recent developments in iPSC research on regenerating injured heart tissue, including novel advances in cell therapy and potential strategies to overcome current obstacles in the field.
Sixth of GP trainees want to take on partnership after qualifying
Authors: Abi Rimmer
Journal: BMJ (2014)

Just one in six GP trainees wants to take on a partnership after qualifying, a survey by Wessex Local Medical Committees has found. The survey received more than 2071 responses from GP trainees in England, Wales, and Scotland, of whom 700 had qualified this summer.

Only 15% of respondents said that finding a partnership was their preferred career step immediately after qualifying as a GP. …
Per-rectal endoscopic myotomy (PREM) for pediatric Hirschsprung’s disease
Authors: Amol Bapaye, Tarun Bharadwaj, Mahesh Mahadik, Sandeep Ware, Pankaj Nemade, Rajendra Pujari, Jay Bapaye
Journal: Endoscopy (2018)

Corrected by: Correction: Per-rectal endoscopic myotomy (PREM) for pediatric Hirschsprung's diseaseEndoscopy 2018; 50(06): C9-C9DOI: 10.1055/a-0666-6232
Diploma in Tropical Medicine &amp; Hygiene (DTM&amp;H)
Authors: Ruth Suckling
Journal: BMJ (2005)

Anyone with a recognised medical degree, from any country, but the majority are doctors from developed countries planning to work in the tropics. The course is also useful for doctors from tropical countries who want to update their knowledge, and relevant to doctors who diagnose and manage imported infections—for example, specialist registrars in infectious diseases. Agencies such as Medecins Sans Frontieres recruit from the course.

Autumn 2000 at the Liverpool School of Tropical Medicine (LSTM), following completion of my preregistration house officer year. The Liverpool …
Dominant Role for Regulatory T Cells in Protecting Females Against Pulmonary Hypertension
Authors: Rasa Tamosiuniene, Olga Manouvakhova, Paul Mesange, Toshie Saito, Jin Qian, Mrinmoy Sanyal, Yu-Chun Lin, Linh P. Nguyen, Amir Luria, Allen B. Tu, Joshua M. Sante, Marlene Rabinovitch, Desmond J. Fitzgerald, Brian B. Graham, Aida Habtezion, Norbert F. Voelkel, Laure Aurelian, Mark R. Nicolls
Journal: Circulation Research (2018)

Rationale: Pulmonary arterial hypertension (PH) is a life-threatening condition associated with immune dysregulation and abnormal regulatory T cell (Treg) activity, but it is currently unknown whether and how abnormal Treg function differentially affects males and females. Objective: To evaluate whether and how Treg deficiency differentially affects male and female rats in experimental PH. Methods and Results: Male and female athymic rnu/rnu rats, lacking Tregs, were treated with the VEGFR2 (vascular endothelial growth factor receptor 2) inhibitor SU5416 or chronic hypoxia and evaluated for PH; some animals underwent Treg immune reconstitution before SU5416 administration. Plasma PGI 2 (prostacyclin) levels were measured. Lung and right ventricles were assessed for the expression of the vasoprotective proteins COX-2 (cyclooxygenase 2), PTGIS (prostacyclin synthase), PDL-1 (programmed death ligand 1), and HO-1 (heme oxygenase 1). Inhibitors of these pathways were administered to athymic rats undergoing Treg immune reconstitution. Finally, human cardiac microvascular endothelial cells cocultured with Tregs were evaluated for COX-2, PDL-1, HO-1, and ER (estrogen receptor) expression, and culture supernatants were assayed for PGI 2 and IL (interleukin)-10. SU5416-treatment and chronic hypoxia produced more severe PH in female than male athymic rats. Females were distinguished by greater pulmonary inflammation, augmented right ventricular fibrosis, lower plasma PGI 2 levels, decreased lung COX-2, PTGIS, HO-1, and PDL-1 expression and reduced right ventricular PDL-1 levels. In both sexes, Treg immune reconstitution protected against PH development and raised levels of plasma PGI 2 and cardiopulmonary COX-2, PTGIS, PDL-1, and HO-1. Inhibiting COX-2, HO-1, and PD-1 (programmed death 1)/PDL-1 pathways abrogated Treg protection. In vitro, human Tregs directly upregulated endothelial COX-2, PDL-1, HO-1, ERs and increased supernatant levels of PGI 2 and IL-10. Conclusions: In 2 animal models of PH based on Treg deficiency, females developed more severe PH than males. The data suggest that females are especially reliant on the normal Treg function to counteract the effects of pulmonary vascular injury leading to PH.
Distinct roles for phosphoinositide 3-kinases γ and δ in malignant B cell migration
Authors: Ahmed Y. Ali, Xun Wu, Nour Eissa, Sen Hou, Jean-Eric Ghia, Thomas T. Murooka, Versha Banerji, James B. Johnston, Francis Lin, Spencer B. Gibson, Aaron J. Marshall
Journal: Leukemia (2018)

The PI 3-kinases (PI3K) are essential mediators of chemokine receptor signaling necessary for migration of chronic lymphocytic leukemia (CLL) cells and their interaction with tissue-resident stromal cells. While the PI3Kδ-specific inhibitor idelalisib shows efficacy in treatment of CLL and other B cell malignancies, the function of PI3Kγ has not been extensively studied in B cells. Here, we assess whether PI3Kγ has non-redundant functions in CLL migration and adhesion to stromal cells. We observed that pharmaceutical PI3Kγ inhibition with CZC24832 significantly impaired CLL cell migration, while dual PI3Kδ/γ inhibitor duvelisib had a greater impact than single isoform-selective inhibitors. Knockdown of PI3Kγ reduced migration of CLL cells and cell lines. Expression of the PI3Kγ subunits increased in CLL cells in response to CD40L/IL-4, whereas BCR cross-linking had no effect. Overexpression of PI3Kγ subunits enhanced cell migration in response to SDF1α/CXCL12, with the strongest effect observed within ZAP70 + CLL samples. Microscopic tracking of cell migration within chemokine gradients revealed that PI3Kγ functions in gradient sensing and impacts cell morphology and F-actin polarization. PI3Kγ inhibition also reduced CLL adhesion to stromal cells to a similar extent as idelalisib. These findings provide the first evidence that PI3Kγ has unique functions in malignant B cells.
A multicenter, randomized, controlled trial comparing the occurrence of major adverse cardiovascular events (MACEs) in patients (pts) with prostate cancer (pc) and cardiovascular disease (CVD) receiving degarelix (GnRH receptor antagonist) or leuprolide (GnRH receptor agonist).
Authors: Susan F. Slovin, Chiara Melloni, Samreen Mansor-Lefebvre, Anders Neijber, Matthew Roe
Journal: Journal of Clinical Oncology (2018)

TPS395 Background: Epidemiological studies showed an association between GnRH agonists and a long-term increased risk of CVD, early after treatment initiation and with a higher risk seen in pts with pre-existing CVD. Retrospective pooled safety analyses of 6 randomized trials showed that significantly fewer pts treated with the GnRH receptor antagonists, degarelix, had a CV event or death compared with pts receiving a GnRH receptor agonist. In those studies showing an increased CV risk, Androgen-Deprivation Therapy (ADT) was primarily with GnRH receptor agonists. The mechanistic differences between GnRH antagonists and agonists, including testosterone surge and time to suppression at initiation, effect on follicle-stimulating hormone and on GnRH receptors e.g. T-lymphocytes in atherosclerotic plaque, raises the possibility of different CV risk profiles. The PRONOUNCE trial is the first to prospectively assess whether a GnRH agonist/antagonist can worsen pre-existing CVD; assess the impact of GnRH agonist/antagonist on CV risk biomarkers; and effects of hormonal therapy on immune system. Methods: PRONOUNCE is a multi-center, randomized, controlled trial of 900 men with pc and concomitant CVD, assessing adjudicated MACEs, i.e. myocardial infarction (fatal, non-fatal), stroke (fatal, non-fatal), or death in pts randomized 1:1 to either degarelix or leuprolide according to label recommendations for up to one year. Eligibility include pre-defined CVD, metastatic or locally advanced pc; high-risk disease with plan for definitive radiation therapy (RT); recurrence after local therapy with PSA doubling time &lt;12 months; or salvage RT with neoadjuvant/adjuvant ADT for at least 12 months. Serum samples are collected for the analysis of various CV, inflammatory, and immune biomarkers. The primary endpoint will be based on Kaplan-Meier estimator of survival function and stratified for age group and region. Interim analysis is scheduled when 50% of MACE events have occurred allowing the DSMB to recommend for sample size correction. Clinical trial information: NCT02663908.
FDG PET/CT Findings of Polymorphic Posttransplant Lymphoproliferative Disorders in a Transplanted Kidney
Authors: Yuanyuan Yang, Wei Wang, Ying Kan, Jie Liu, Jigang Yang
Journal: Clinical Nuclear Medicine (2018)

A 55-year-old woman underwent simultaneous liver-kidney transplantation because of polycystic liver and kidney. Six months later, FDG PET/CT was acquired to evaluate possible lesions in the renal graft, which demonstrated abnormal F-FDG accumulation in the renal pelvic lesions without other abnormality. The subsequent pathology examination after biopsy demonstrated the polymorphic posttransplant lymphoproliferative disorders.
Bacteria-like mesoporous silica-coated gold nanorods for positron emission tomography and photoacoustic imaging-guided chemo-photothermal combined therapy
Authors: Cheng Xu, Feng Chen, Hector F. Valdovinos, Dawei Jiang, Shreya Goel, Bo Yu, Haiyan Sun, Todd E. Barnhart, James J. Moon, Weibo Cai
Journal: Biomaterials (2018)
I am a recent medical graduate and my internship will be completed by September 2006. I am interested in building up my career as a surgeon by obtaining the fellowship of the Royal College of Surgeons (FRCS). How can I proceed?
Authors: Umar Sadat
Journal: BMJ (2006)

Have 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 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. <b>www.bmjcareers.com/advicezone</b>
I'm an overseas doctor and I have passed the PLAB tests. I have worked in both general surgery and paediatrics, and I can't decide between the two in terms of my career path. Can you help me?
Authors: Evelyn Ong
Journal: BMJ (2005)

<b>www.bmjcareers.com/advicezone</b> Have 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 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.
Chimeric Antigen Receptor‐T Cell Therapy
Authors: Jochen Buechner, Marie José Kersten, Miriam Fuchs, Florence Salmon, Ulrich Jäger
Journal: HemaSphere (2018)

Chimeric antigen receptor (CAR)-T cell therapy is a new class of cellular immunotherapies that involves ex vivo genetic modification of T cells to incorporate an engineered CAR. After infusion into the patient, the CAR-expressing T cells recognize specific tumor targets and induce an immune response against them. The technology utilized is fundamentally different from previously available cancer treatments. Currently, most CAR-T cell therapies use autologous T cells. Tisagenlecleucel (formerly CTL019) is an anti-CD19 CAR-T cell therapy that was recently approved in the United States for the treatment of pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Tisagenlecleucel has shown robust in vivo expansion and long-term persistence, clinically meaningful durable response and remission rates, and overall survival benefit in pediatric and young adult patients with relapsed/refractory B-ALL and in relapsed/refractory diffuse large B-cell lymphoma. Common adverse events (AEs) include cytokine release syndrome, which may require hospitalization and admission to an intensive care unit, neurological toxicities, and B-cell aplasia. These AEs are manageable when treated by an appropriately trained team. Additional research is required to further develop AE management protocols. In this review, we describe regulatory requirements, clinical considerations, and site-level requirements for clinical study implementation of CAR-T cell therapy in Europe. We also provide a case study of the European experience from the first global clinical trial for tisagenlecleucel, which may serve as a useful starting point for investigators and clinicians looking to implement CAR-T cell therapy at their institutions.
Living together: Malaria and filaria
Authors: Vikarn Vishwajeet, Man Updesh Singh Sachdeva
Journal: American Journal of Hematology (2018)

A 36-year-old male, working for few days as a laborer in Jorden, returned to India when he had single episode of high grade fever which was followed by yellow discoloration of sclera and urine, clay colored stools, and intense pruritis. At the time of presentation, he was afebrile, icteric, and pale. His liver was enlarged and was 5 cm below right costal margin. Investigations revealed altered liver function with elevated transaminases and raised serum bilirubin (26.5 mg/dL) with conjugated fraction of 12.9 mg/dL. Patient was HBsAg positive and was negative for anti Hepatitis A Virus (HAV)/Hepatitis E Virus (HEV)/Hepatitis C Virus (HCV) . The complete blood counts showed hemoglobin of 95 g/L, leukocyte count of 13 × 109/L, and platelet count of 414 × 109/L. The peripheral blood film showed presence of trophozoites in RBCs, morphologically consistent with Plasmodium vivax.1 The amount of parasitemia was approximately 1%. In addition, tail end of smear revealed microfilariae, morphologically consistent with Wuchereria bancrofti (body showing discrete nuclei; tapering tail and nuclei not reaching till the tip of tail) with exception of no clearly demarcated sheath, which is known at times to be under-stained with Giemsa stain2 (Image 1A,B). May–Grunwald–Giemsa stained peripheral blood film showing malarial trophozoite inside enlarged RBC (arrows) and a microfilaria in same low power field (A) as well as in the high power field (B). [Color figure can be viewed at wileyonlinelibrary.com] This case showed both P. vivax and microfilariae in same field of peripheral blood film, from an adult male who was also HBsAg positive. The observation of two different parasites in single blood film is good example for young hematopathologists, highlighting the importance of both low and high power screening of smears. There are no conflicts of interest amongst the authors. All the authors have contributed equally and have read the manuscript.
Increasing Pulmonary Arterial Pressure at Low Level of Exercise in Asymptomatic, Organic Mitral Regurgitation
Authors: Oumhani Toubal, Haifa Mahjoub, Christophe Thébault, Marie-Annick Clavel, Abdellaziz Dahou, Julien Magne, Kim O’Connor, Jonathan Beaudoin, Mathieu Bernier, Florent Le Ven, Philippe Pibarot
Journal: Journal of the American College of Cardiology (2018)
Animal rights and human rights
Authors: Rhona MacDonald
Journal: BMJ (2004)

When I was a teenager I was heavily into animal rights and spent a lot of time campaigning against vivisection. Then I realised that many people in the world are treated worse than animals and poured all my energies into human rights instead. I have been vegetarian for 20 years and do not want any animal to be hurt on my behalf, but I can appreciate how …
BMA agrees to enter into preliminary talks on consultant contract
Authors: Caroline White
Journal: BMJ (2013)

Consultant negotiators from England and Northern Ireland will go ahead with preliminary talks with NHS Employers about possible changes to their terms and conditions, the BMA has said.

The Scottish and Welsh Consultants Committees have decided not to take part in UK level discussions, on the grounds that this would not be in the best interests of senior doctors in their countries.

The Department of Health in …
Correction: Critical role for Sec22b-dependent antigen cross-presentation in antitumor immunity
Authors: Andrés Alloatti, Derek C. Rookhuizen, Leonel Joannas, Jean-Marie Carpier, Salvador Iborra, Joao G. Magalhaes, Nader Yatim, Patrycja Kozik, David Sancho, Matthew L. Albert, Sebastian Amigorena
Journal: The Journal of Experimental Medicine (2018)
IL-7–dependent maintenance of ILC3s is required for normal entry of lymphocytes into lymph nodes
Authors: Jie Yang, Ferry Cornelissen, Natalie Papazian, Rogier M. Reijmers, Miriam Llorian, Tom Cupedo, Mark Coles, Benedict Seddon
Journal: The Journal of Experimental Medicine (2018)

IL-7 is essential for the development and homeostasis of T and B lymphocytes and is critical for neonatal lymph node organogenesis because Il7−/− mice lack normal lymph nodes. Whether IL-7 is a continued requirement for normal lymph node structure and function is unknown. To address this, we ablated IL-7 function in normal adult hosts. Either inducible Il7 gene deletion or IL-7R blockade in adults resulted in a rapid loss of lymph node cellularity and a corresponding defect in lymphocyte entry into lymph nodes. Although stromal and dendritic cell components of lymph nodes were present in normal numbers and representation, innate lymphoid cell (ILC) subpopulations were substantially decreased after IL-7 ablation. Testing lymphocyte homing in bone marrow chimeras reconstituted with Rorc−/− bone marrow confirmed that ILC3s in lymph nodes are required for normal lymphocyte homing. Collectively, our data suggest that maintenance of intact lymph nodes relies on IL-7–dependent maintenance of ILC3 cells.