tbuckley/cabot-search huggingface dataset:
TLR-mediated metabolic reprogramming in the tumor microenvironment: potential novel strategies for cancer immunotherapy
Authors: Lan Huang, Huaxi Xu, Guangyong Peng
Journal: Cellular and Molecular Immunology (2018)

Cellular energy metabolism not only promotes tumor cell growth and metastasis but also directs immune cell survival, proliferation and the ability to perform specific and functional immune responses within the tumor microenvironment. A better understanding of the molecular regulation of metabolism in different cell components in the tumor-suppressive microenvironment is critical for the development of effective strategies for human cancer treatments. Toll-like receptors (TLRs) have recently been recognized as critical factors involved in tumor pathogenesis, regulating both tumor cells and tumor-infiltrating innate and adaptive immune cells. However, little is known about the molecular crosstalk between TLR signaling and tumor or/and immune cell metabolism, although there is abundant expression of TLRs in these cells. In this review, we explore the functional role of TLR signaling in reprogramming cell metabolism in the tumor microenvironment. In particular, we discuss how malignant tumors regulate metabolism to support their growth and survival, summarize more recently identified metabolic profiles of different immune cell subsets and TLR-mediated regulation of cellular metabolism in both tumor and immune cells, and further explore potential strategies targeting cell metabolism for TLR-based cancer therapy. An improved understanding of these issues should open new avenues for the development of novel strategies via TLR-mediated metabolic reprogramming of the tumor microenvironment for cancer immunotherapy.
Majority of juniors take a break from training, survey finds
Authors: Abi Rimmer
Journal: BMJ (2018)

Over half of junior doctors take a break during their training, a BMA survey has found.

Jeeves Wijesuriya, BMA junior doctors committee chair, said that the findings meant it was vital for employers to help trainees return to work.

The BMA sent the survey to junior doctors in the UK in autumn 2017 and received 2164 responses.1 It does not have a response rate because the survey was open to all junior doctors, including non-BMA …
Is internship in India similar to a house officer post in the United Kingdom?
Authors: Sunder Raj Gopaul
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>
Doctors must seek feedback from more than 50 people for revalidation
Authors: Helen Jaques
Journal: BMJ (2012)

Doctors will have to seek feedback from up to 45 consecutive patients (minimum 34) and 20 colleagues (minimum 15) on their clinical and professional skills at least once every five years to complete revalidation.

The General Medical Council has developed recommended questionnaires for patients and colleagues that are designed to support doctors in seeking multisource feedback to provide supporting information for revalidation.

The paper based patient questionnaire, which should be administered by reception staff or other clinical staff rather than the doctor in question, asks patients …
局部JTE-052(一种Janus激酶抑制剂) 对患有中度至重度异位性皮炎的日本成人患者的功效和安全性:一项2期、多中心随机、赋形剂对照临床研究
Authors: H. Nakagawa, O. Nemoto, A. Igarashi, T. Nagata
Journal: British Journal of Dermatology (2018)

异位性皮炎(湿疹)是一种慢性且有时为耗弱性的炎症性皮肤病,会引起瘙痒和皮肤屏障功能损坏。目前的疗法包括局部(在皮肤上涂敷)皮质类固醇和钙调神经磷酸酶抑制剂(例如他克莫司);但长期使用局部皮质类固醇可能会导致皮肤变薄,而他克莫司则是刺激性药物。激酶是一种对体内细胞的许多功能都非常重要的一种酶,而Janus激酶(JAK)途径则对炎症有作用。近年来,科学家们开发出了多种可抑制此途径的药物,对炎性皮肤(例如湿疹或银屑病)有潜在效果。来自日本东京和北海道的作者研究了不同浓度(0.5%~3%)的局部JAK抑制剂JTE‐052对患有中度至重度异位性皮炎的成人患者的效果,并将其与自身的赋形剂(添加药物的软膏)和0.1%他克莫司软膏相比较。他们使用了治疗前后4周的改良湿疹面积与严重度分数,以了解各疗法是如何起效的。在使用3%浓度的患者中,有73%的患者的分数有所提高,而该数字在使用安慰剂(赋形剂)软膏的患者中仅为12%。并且在使用他克莫司的患者中,有62%的患者提高了分数。即便是3%浓度的JTE‐052依然耐受性良好,不存在他克莫司所引起的刺激和灼热感,并且使用JTE‐052的患者在开始治疗的一天内即能感觉到瘙痒程度减轻。作者总结道,局部使用此JAK抑制剂对治疗异位性皮炎有效。
Oligometastatic prostate cancer patients stratification: A molecular signature identified by liquid biopsy.
Authors: Luca Triggiani, Lilia Bardoscia, Antonella Colosini, Simona Bernardi, Roberto Bresciani, Chiara Foroni, Nadia Pasinetti, Paolo Borghetti, Bruno Caraffini, Flavia Orizio, Michela Buglione, Stefano M. Magrini
Journal: Journal of Clinical Oncology (2018)

TPS400 Background: Oligometastatic prostate cancer (OPC) may represent the initial step of an unavoidable, rapid progression to a polymetastatic state, or the expression of a real oligometastatic phenotype related to a condition of stable disease for a long time. In the last scenario, stereotactic body radiation therapy (SBRT) can be considered as a potentially curative treatment option for hormone-naïve OPC. We propose a prospective, explorative trail with the aim of identifying by liquid biopsy a molecular signature (genes or differential expression of miRNA), and related clonal evolution, underlying metastatic prostate cancer progression after a course of SBRT. Methods: Study population will be 30 adult, hormone-naïve OPC undergoing SBRT. Table 1 summarizes gene and miRNA panel for molecular analysis. For each patient, 15 ml of peripheral blood will be collected before and at the end of SBRT, every 3 months for the first year, then every 6 months until disease progression, when another blood sample will be collected in case of instrumental evidence of failure (using PET-Choline or CT-scan plus bone scintigraphy). 7.5 ml of peripheral blood will be centrifuged to separate sera and 7.5 ml of peripheral blood will be centrifuged to separate plasma from the other blood components, respectively. Sera and plasma will be stored at -20°C and centralized to CREA Laboratory at our Institution, then immediately processed for cell free DNA (cfDNA) and miRNA extraction for NGS of target genes (by Illumina platforms MiSeq and MiniSeq) and dPCR analysis. Study duration will be 36 months. This protocol has been written and will be conducted in agreement with either the Declaration of Helsinki and subsequent amendments and ICH Harmonized Tripartite Guideline for Good Clinical Practice, and has received approval of local Ethics Committee. Panel for analysis. [Table: see text]
PREDICTORS, COST AND 30-DAY INPATIENT MORTALITY IN PATIENTS UNDERGOING EARLY INVASIVE VERSUS CONSERVATIVE MANAGEMENT FOR UNSTABLE ANGINA/NON ST ELEVATION MYOCARDIAL INFARCTION: INSIGHTS FROM NATIONAL READMISSION DATABASE
Authors: Shanti Patel, Aparna Saha, Priti Poojary, Sumeet Pawar, Jignesh Patel, Kanika Mahajan, Pratik Mondal, Kinsuk Chauhan, Shivkumar Agarwal, Stephan Kamholz, Gerald Hollander, Jacob Shani, Girish Nadkarni
Journal: Journal of the American College of Cardiology (2018)
Serum neuroendocrine (NE) markers and clinical characteristics of treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) in men with metastatic castration resistant prostate cancer (mCRPC): Data from the West Coast Prostate Cancer Dream Team.
Authors: Rahul Raj Aggarwal, Li Zhang, Tomasz M. Beer, Jack Youngren, Alise Stromlund, Alexander Bell, Adam Foye, Denise Playdle, Joshi J. Alumkal, Robert Evan Reiter, Martin Gleave, Christopher P. Evans, George V. Thomas, Jiaoti Huang, Lawrence D. True, Matthew Rettig, Primo Lara, Kim N. Chi, Eric Jay Small
Journal: Journal of Clinical Oncology (2018)

278 Background: Detection of t-SCNC in mCRPC patients relies primarily on histopathologic evaluation (Histo) of a metastatic tumor biopsy (bx), likely leading to underdiagnosis. The clinical features of t-SCNC and the diagnostic utility of serum NE markers (neuron-specific enolase (NSE) and chromogranin (CGA)) were evaluated. Methods: Eligible patients (pts) underwent a metastatic bx at one of 5 centers. Histo was performed by 3 independent pathologists (JH, GT, LT). NE markers were evaluated in a central lab (lower limit = 1 ng/mL). Kruskal-Wallis and chi-square test were used to compare continuous and categorical variables, respectively. Receiver-operative-curve (ROC) analysis of serum NE markers was undertaken. Results: 160 consecutive pts with available Histo and NE markers were included. t-SCNC was found in 27 pts (17%). Detection of t-SCNC was observed in all bx sites, including liver (14%), lymph node (19%) and bone (14%). Clinical features are shown in the Table. By ROC analysis, if both serum NSE was &gt; 6.05 ng/mL and chromogranin was &gt; 3.1 ng/mL, the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for the detection of t-SCNC were 95%, 50%, 98%, and 22%, respectively. Conclusions: Many of the classic features of de novo SCNC, including low PSA levels, do not reliably distinguish t-SCNC. In contrast, serum NE markers have diagnostic utility with high sensitivity and NPV, but low specificity and PPV. Heterogeneous NE differentiation may partially account for these findings. Clinical trial information: NCT02432001. [Table: see text]
Will prolonged study leave still be possible under the new general practitioner contract?
Authors: Bill Irish
Journal: BMJ (2004)

Got a career or related problem that needs answering? Can't 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.
P53 as a predictor of clinical outcome in localized prostate cancer.
Authors: Kate Lynette Mahon, Phillip Stricker, James Kench, Judith Grogan, Warick Delprado, Jenny Turner, Lisa Horvath, David I. Quinn
Journal: Journal of Clinical Oncology (2018)

57 Background: p53 is one of the most common genetic aberrations in human cancer and is associated with poor outcomes with hormone therapy in advanced prostate cancer (PCa). p53 is a well-established predictor of biochemical relapse in PCa, however, increasing evidence from ICECaP has demonstrated that metastatic relapse (MR) not biochemical relapse (BCR) is a surrogate for prostate-cancer specific mortality (PCSM). Furthermore, there are now a range of novel therapeutic strategies targeting p53 mutations and their downstream effector pathways. This study aimed to assess the association between p53 expression and MR/PCSM in men with localized PCa. Methods: The study consisted of 271 men with localized PCa treated with radical prostatectomy. Surgical cancer specimens were stained for p53 by immunohistochemistry (IHC) and scored as a) percentage of p53-positive tumor nuclei in all major foci of cancer within the prostate; and (b) clustering, where the presence of 12 or more p53-positive cells within a x200 power field was deemed “cluster positive”. Results: At a median follow-up of 15.8 years (range 4 months - 24.3 years), 57.5% (156/271) had a biochemical relapse, 18% (49/271) had suffered a metastatic relapse, and 9.5% (25/271) had died of prostate cancer. Increasing percentage of p53 positive nuclei was significantly associated with shorter time to BCR (p &lt; 0.001), MR (p &lt; 0.001) and PCSM (p &lt; 0.001). Half of patients were p53 cluster positive. P53 cluster positivity was significantly associated with all clinical endpoints (BCR: HR 2.0, 95% CI 1.51-2.65, p &lt; 0.001; MR: HR 4.1, 95%CI 2.02-8.14, p &lt; 0.001; PCSM: HR 12.2, 95%CI 1.6-93; p = 0.016). These associations were independent of other established prognostic variables including lymph node status, baseline PSA, Gleason and ISUP grade on multivariable analysis. Conclusions: This study has confirmed the association of p53 in radical prostatectomy tissue with clinically relevant endpoints of metastatic relapse and prostate cancer specific mortality. p53 is a potential stratification factor and may be useful for identifying those who will most benefit from adjuvant therapy. Incorporation of p53 status into ongoing clinical trials is now warranted.
Genetics on the web
Authors: Philip Zack
Journal: BMJ (2005)

www.dh.gov.uk/PolicyAndGuidance/HealthAndSocialCareTopics/Genetics/GeneticsGeneralInformation/GeneticsGeneralArticle/fs/en?CONTENT_ID=4016430&chk=RnGBgL

www.library.nhs.uk/genepool

www.bshg.org.uk

www.clingensoc.org/Trainees/index.htm

http://ghr.nlm.nih.gov

www.geneclinics.org

www.mcri.edu.au/GF/pages/GeneticsFile.asp

www.cafamily.org.uk

www.orpha.net

http://rarediseases.info.nih.gov/html/resources/info_cntr.html

www.geneticseducation.nhs.uk

www.bshg.org.uk/links/links.htm#Genetic\_Knowledge\_Parks

www.bbc.co.uk/science/genes

www.ygyh.org

http://gslc.genetics.utah.edu

www.genome.gov/10001618

www.hgc.gov.uk

www.progress.org.uk

www.genewatch.org

www.ethox.org.uk/Genethics/index.htm

Genetics, a science barely a century old, is being increasingly recognised as fundamental in medicine. Genetic conditions, like cystic fibrosis or haemophilia, are more readily diagnosed and more successfully treated. Genetic influences on medical conditions previously thought of as sporadic (for example, some cancers), are increasingly recognised, and brought into medical practice. This creates a growing demand for doctors who are either knowledgeable in genetics, or who know where to find information when they need it. The UK government recognised this in 2003 with the publication of the white paper “Our Inheritance, Our Future” and the initiatives which followed from it, which included strengthening and expanding specialist services and spreading knowledge about genetics across the NHS.

For the non-specialist, genetics can seem to be an esoteric field, apparently complex, with unfamiliar terminology from alleles (different forms of the same gene, like the A, B, and O forms of the ABO blood group gene) to zygotes (fertilised eggs). However, as James Curran pointed out in his previous article on …
Skills gained in training fellowships could be recognised through “credentialing,” says GMC
Authors: Abi Rimmer
Journal: BMJ (2014)

Skills developed by doctors while training during fellowships could be recognised through “credentialing,” the General Medical Council has said.

The GMC said that credentialing would involve awarding “credentials” to doctors who have shown sufficient competency in a defined area of practice. Once achieved, it is expected that credentials would appear on a doctor’s entry on the GMC’s list of registered medical practitioners.1

The GMC, which is working on a framework for credentialing, has said that credentials will apply to defined areas of practice.2 The Shape of Training review said of credentialing: “In our …
Time to Converge FDA Decisions and Evidence Syntheses for Long-Acting Muscarinic Antagonists and SMART in Guidelines for the Treatment of Asthma
Authors: Jerry A. Krishnan, David H. Au
Journal: JAMA (2018)

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Impact of new systemic therapies on overall survival (OS) of patients (pts) with metastatic castration resistant prostate cancer (mCRPC) in a hospital-based registry.
Authors: Edoardo Francini, Kathryn P. Gray, Grace Shaw, Carolyn Evan, Anis Hamid, Caitlin E Perry, Philip W. Kantoff, Mary-Ellen Taplin, Christopher Sweeney
Journal: Journal of Clinical Oncology (2018)

203 Background: From 2004 to 2009, mCRPC treatment options were limited to docetaxel (D), mitoxantrone, first generation anti-androgens (AA), estrogens, steroids, and ketoconazole, with only D showing OS benefit. Since 2010, five new therapies prolonged OS and were approved for mCRPC: sipuleucel-T, cabazitaxel, abiraterone acetate, enzalutamide, and radium 223. We sought to assess the aggregate impact of new therapies on OS. Methods: We used the DFCI CRIS database to identify cohorts of pts who developed mCRPC between 2004-2007 (cohort A) and 2010-2013 (cohort B). Therapies for mCRPC in each cohort were annotated. Given the median follow-up (FU) was 10.6 years (yrs) in cohort A and 4.6 yrs in cohort B, we evaluated OS, defined as time from mCRPC per PCWG3 criteria to death from all causes or last follow-up visit within 5 yrs (truncated OS). Kaplan-Meier method estimated the time to events distribution with median (95% CI). Cox proportional hazards model evaluated effects of treatment groups on disease outcomes with estimates of hazard ratio (95% CI). Results: Of the 583 pts identified, 317 (54%) were in cohort A and 266 (46%) in cohort B. Pts in cohort B had a significantly longer median OS (p&lt;0.001), a 5-yr OS of 26% vs. 10%, and a 31% reduced risk of death compared to cohort A (HR=0.69; 95% CI, 0.57-0.83) (see Table). On multivariable analysis, adjusting for prior local Rx, ECOG PS, and the number of agents received, longer OS is confirmed associated with cohort B vs. A and also with ECOG PS status 0 vs. 1, number of agents received 5-12 vs. ≤3. Conclusions: Using the DFCI prostate cancer database, therapies approved for mCRPC since 2010 showed a modest impact on OS, with a median improvement of 6 months. There was a more substantial effect on long term survivors with 2.6 fold increase of 5-yr OS. [Table: see text]
NHS clinical negligence claims are up by 30%
Authors: Helen Jaques
Journal: BMJ (2011)

The number of clinical negligence claims received by the NHS Litigation Authority, which deals with liability claims against NHS organisations in England, rose by 30% from 6652 in 2009-10 to 8655 in 2010-11, bringing the total cost of clinical claim payments to £863.4m in the past financial year.

The authority’s total liabilities for existing and anticipated clinical and non-clinical negligence claims were nearly £17bn for 2010-11, up from just under £15bn in 2009-10.

A total of £729.1m was paid out in damages and legal costs for clinical negligence claims …
What's the FOX Got to Do with the KITten? Regulating the Lineage-Specific Transcriptional Landscape in GIST
Authors: Donna M. Lee, Anette Duensing
Journal: Cancer Discovery (2018)

Abstract Summary: Transcriptional regulation of the KIT receptor tyrosine kinase, a master regulator in gastrointestinal stromal tumors (GIST) and their precursors, the interstitial cells of Cajal (ICC), is part of a positive feedback loop involving the transcription factor ETV1. A new study now shows that the forkhead box (FOX) family transcription factor FOXF1 not only is an upstream regulator of ETV1 and hence ICC/GIST lineage-specific gene transcription, but also functions as lineage-specific pioneer factor with an active role in chromatin rearrangement to facilitate ETV1 binding and transcriptional activity. Cancer Discov; 8(2); 146–9. ©2018 AACR. See related article by Ran et al., p. 234.
David Oliver: Getting serious about prevention
Authors: David Oliver
Journal: BMJ (2018)

It’s hard to attend any conference or read any report on health service reform without prevention of ill health featuring prominently. What might once have seemed a radical proposition is now an orthodoxy—but people commenting on health system redesign still advocate a greater focus on prevention and early intervention as if it’s a revelation, even for those in government.

The arguments advanced for prevention contain two broad elements. Firstly, our health services are still too centred on responding to ill health, especially acute illness in excessively hospital based models. We therefore need a shift of resources and approaches to ensure that more people remain well for longer (primary prevention) or are supported to self manage any long term …
PROGNOSTIC VALUE OF NUTRITION STATUS AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Yohsuke Honda, Motoharu Araki, Shigemitsu Shirai, Kenji Makino, Takahiro Tokuda, Masakazu Tsutumi, Shinsuke Mori, Yasunari Sakamoto, Norihiro Kobayashi, Masahiro Yamawaki, Keisuke Hirano, Yoshiaki Ito
Journal: Journal of the American College of Cardiology (2018)
NON-INVASIVE “GOLD STANDARD” ASSESSMENT OF VENTRICULO-ARTERIAL FUNCTION USING SIMULTANEOUS CARDIOVASCULAR MAGNETIC RESONANCE IMAGING AND ARTERIAL TONOMETRY: EVALUATION OF LEFT VENTRICULAR PRESSURE-VOLUME AND AORTIC PRESSURE-FLOW RELATIONSHIPS
Authors: Mayooran Namasivayam, Audrey Adji, Linda Lin, Christopher Hayward, Michael Feneley, Michael O’Rourke, David Muller, Andrew Jabbour
Journal: Journal of the American College of Cardiology (2018)
CONCURRENT DOUBLE VALVE-IN-VALVE TRANSCATHETER HEART VALVE REPLACEMENT FOR FAILED MITRAL AND AORTIC BIOPROSTHESES
Authors: Yemisi Adejumo, Shing-Chiu Wong, Arash Salemi, Jiwon Kim, Maria Karas, Geoffrey Bergman, Evelyn M. Horn, Robert Minutello
Journal: Journal of the American College of Cardiology (2018)
Tumor–Stroma IL1β-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemoresistance, and Poor Prognosis in Pancreatic Cancer
Authors: Daoxiang Zhang, Lin Li, Hongmei Jiang, Qiong Li, Andrea Wang-Gillam, Jinsheng Yu, Richard Head, Jingxia Liu, Marianna B. Ruzinova, Kian-Huat Lim
Journal: Cancer Research (2018)

Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of IL1 receptor-associated kinase 4 (IRAK4) suppresses NFκB activity and promotes response to chemotherapy in PDAC cells. In this study, we report that CAF in PDAC tumors robustly express activated IRAK4 and NFκB. IRAK4 expression in CAF promoted NFκB activity, drove tumor fibrosis, and supported PDAC cell proliferation, survival, and chemoresistance. Cytokine array analysis of CAF and microarray analysis of PDAC cells identified IL1β as a key cytokine that activated IRAK4 in CAF. Targeting IRAK4 or IL1β rendered PDAC tumors less fibrotic and more sensitive to gemcitabine. In clinical specimens of human PDAC, high stromal IL1β expression associated strongly with poor overall survival. Together, our studies establish a tumor-stroma IL1β-IRAK4 feedforward signal that can be therapeutically disrupted to increase chemotherapeutic efficacy in PDAC.
Doctors in emergency medicine less certain than others about career choice
Authors: Helen Jaques
Journal: BMJ (2013)

Doctors who choose to specialise in emergency medicine are less certain about their career choice than doctors who pick other specialties, a study published in Emergency Medicine Journal has found.1

Medical graduates who chose to work in emergency medicine are less likely to be definite about their career than doctors who pick general practice and those who chose other hospital specialties, the study found. …