tbuckley/cabot-search huggingface dataset:
Developmental dynamics of gene expression and alternative polyadenylation in the Caenorhabditis elegans germline
Authors: Sean M. West, Desirea Mecenas, Michelle Gutwein, David Aristizábal-Corrales, Fabio Piano, Kristin C. Gunsalus
Journal: Genome biology (2018)

The 3′ untranslated regions (UTRs) of mRNAs play a major role in post-transcriptional regulation of gene expression. Selection of transcript cleavage and polyadenylation sites is a dynamic process that produces multiple transcript isoforms for the same gene within and across different cell types. Using LITE-Seq, a new quantitative method to capture transcript 3′ ends expressed in vivo, we have characterized sex- and cell type-specific transcriptome-wide changes in gene expression and 3′UTR diversity in Caenorhabditis elegans germline cells undergoing proliferation and differentiation. We show that nearly half of germline transcripts are alternatively polyadenylated, that differential regulation of endogenous 3′UTR variants is common, and that alternative isoforms direct distinct spatiotemporal protein expression patterns in vivo. Dynamic expression profiling also reveals temporal regulation of X-linked gene expression, selective stabilization of transcripts, and strong evidence for a novel developmental program that promotes nucleolar dissolution in oocytes. We show that the RNA-binding protein NCL-1/Brat is a posttranscriptional regulator of numerous ribosome-related transcripts that acts through specific U-rich binding motifs to down-regulate mRNAs encoding ribosomal protein subunits, rRNA processing factors, and tRNA synthetases. These results highlight the pervasive nature and functional potential of patterned gene and isoform expression during early animal development.
Use of 18F-FDG-PET-CT in glioma surveillance: A single centre experience
Authors: Beverly Cheserem, Bernadett Kovacs, Sorin Bucur, Sabina Dizdarevic, Giles Critchley
Journal: Neuro-Oncology (2018)

Radiological surveillance in glioma surgery is primarily with MRI. Differentiating between disease progression and radionecrosis can be challenging. In our unit, in selected cases when there is suspicion of radiological recurrence, progression or to aid in differentiating progression from radionecrosis, we have augmented our surveillance with 18F-FDG-PET-CT which can highlight areas of metabolic activity which correlate with increased tumour activity. We identified 19 cases of PET imaging for glioma surveillance of whom we could assess 17 notes and images. Mean age was 45.06 (30–67) with male: female ratio 9:8. 15 /17(88.2%) patients had surgery and 2 declined surgery(7 biopsy only, 8 debulk and 2 declined surgery). Initial histology was pilocytic astrocytoma (1), grade II (4, 26.7%), grade III (6, 40%), GBM (3) and non-specific tissue (1). 5 patients had evidence of increased uptake on PET and all showed clinical progression, with only 3 clinically fit for surgery (histology showed 2 recurrence, 1 transformation). 10 patients had no increased uptake on FDG with 4 on on-going surveillance for an average of 8.5 years (7–12), 2 clinically progressed at 2 and 8 years after initial presentation at the point of PET imaging and received palliative chemotherapy, 1 had concurrent inoperable lung cancer and was palliated, 1 patient had transformation from glioma grade II - III, 1 had grade 2 histology, and 1 had only gliotic tissue on re-operation A positive FDG PET has a positive correlation with disease progression and may be considered as an adjunct test in glioma surveillance.
microRNA-1246 Is an Exosomal Biomarker for Aggressive Prostate Cancer
Authors: Divya Bhagirath, Thao Ly Yang, Nathan Bucay, Kirandeep Sekhon, Shahana Majid, Varahram Shahryari, Rajvir Dahiya, Yuichiro Tanaka, Sharanjot Saini
Journal: Cancer Research (2018)

Abstract Because of high heterogeneity, molecular characterization of prostate cancer based on biopsy sampling is often challenging. Hence, a minimally invasive method to determine the molecular imprints of a patient's tumor for risk stratification would be advantageous. In this study, we employ a novel, digital amplification-free quantification method using the nCounter technology (NanoString Technologies) to profile exosomal serum miRNAs (ex-miRNA) from aggressive prostate cancer cases, benign prostatic hyperplasia, and disease-free controls. We identified several dysregulated miRNAs, one of which was the tumor suppressor miR-1246. miR-1246 was downregulated in prostate cancer clinical tissues and cell lines and was selectively released into exosomes. Overexpression of miR-1246 in a prostate cancer cell line significantly inhibited xenograft tumor growth in vivo and increased apoptosis and decreased proliferation, invasiveness, and migration in vitro. miR-1246 inhibited N-cadherin and vimentin activities, thereby inhibiting epithelial–mesenchymal transition. Ex-miR-1246 expression correlated with increasing pathologic grade, positive metastasis, and poor prognosis. Our analyses suggest ex-miR-1246 as a promising prostate cancer biomarker with diagnostic potential that can predict disease aggressiveness. Significance: Dysregulation of exosomal miRNAs in aggressive prostate cancer leads to alteration of key signaling pathways associated with metastatic prostate cancer. Cancer Res; 78(7); 1833–44. ©2018 AACR.
Safeguarding children: recognition and response in child protection
Authors: Craig Brown
Journal: BMJ (2010)

This course is primarily for doctors in training. The session I attended had a mixture of foundation year 2 doctors, paediatric specialist trainees and consultants, and emergency medicine specialist trainees and consultants.

I did this course while I was on the acute care common stem core training level 1 in emergency medicine.

Recent press coverage of high profile child protection cases has again brought into the limelight the issue of child protection. I wanted to increase my knowledge of recognition and response to children at risk of neglect or abuse, and to know how to deal effectively with the situation.

The …
Patients to be surveyed on their involvement in revalidation
Authors: Abi Rimmer
Journal: BMJ (2013)

Patients and general members of the public will be surveyed on their involvement in doctors’ revalidation. The NHS’s Revalidation Support Team has commissioned researchers from Plymouth University Peninsula Schools for Medicine and Dentistry to investigate the role of patients and members of the public. The research will also attempt to identify where patient and public involvement …
PATIENT SELECTION FOR DE-NOVO LEADLESS SINGLE-CHAMBER VENTRICULAR PACING: RESULTS FROM THE MICRA TRANSCATHETER PACING STUDY
Authors: Jonathan P. Piccini, Kurt Stromberg, Kevin Jackson, Robert Kowal, Gabor Duray, Mikhael El-Chami, George Crossley, John Hummel, Calambur Narasimhan, Omar Razali, Philippe Ritter, Paul Roberts, Kyoko Soejima, Dwight Reynolds, Larry Chinitz
Journal: Journal of the American College of Cardiology (2018)
THE IMPACTS OF CONVENTIONAL ECHOCARDIOGRAPHIC PARAMETERS FOR THE PREDICTION OF THE RECURRENCE OF CHRONIC ATRIAL FIBRILLATION AFTER PULMONARY VEIN ISOLATION
Authors: Akihiko Nogami, Kazutaka Aonuma, Tomoo Harada, Yoshihiro Akashi, Emi Nakano
Journal: Journal of the American College of Cardiology (2018)
Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A1c Levels
Authors: Rajesh Garg
Journal: Annals of Internal Medicine (2018)

Letters6 February 2018Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A1c LevelsRajesh Garg, MDRajesh Garg, MDUniversity of Miami, Miller School of Medicine, Miami, Florida (R.G.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0588 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Bergenstal and colleagues' excellent study (1) confirms existing data and removes any doubts about the increased glycation of hemoglobin in black persons. However, clinicians should be careful about applying these findings to their practice. All current evidence on the clinical benefits of glycemic control is based on hemoglobin A1c (HbA1c) rather than blood glucose levels. Hemoglobin A1c goals should therefore remain the same for black and white persons, although physicians should be aware that the risk for hypoglycemia is higher in black persons at the same HbA1c levels.Reference1. Bergenstal RM, Gal RL, Connor CG, Gubitosi-Klug R, Kruger D, Olson BA, et al; T1D Exchange Racial Differences Study Group. Racial differences in the relationship of glucose concentrations and hemoglobin A1c levels. Ann Intern Med. 2017;167:95-102. [PMID: 28605777]. doi:10.7326/M16-2596 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: University of Miami, Miller School of Medicine, Miami, Florida (R.G.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L17-0588. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoRacial Differences in the Relationship of Glucose Concentrations and Hemoglobin A1c Levels Richard M. Bergenstal , Robin L. Gal , Crystal G. Connor , Rose Gubitosi-Klug , Davida Kruger , Beth A. Olson , Steven M. Willi , Grazia Aleppo , Ruth S. Weinstock , Jamie Wood , Michael Rickels , Linda A. DiMeglio , Kathleen E. Bethin , Santica Marcovina , Andreana Tassopoulos , Sooji Lee , Elaine Massaro , Suzan Bzdick , Brian Ichihara , Eileen Markmann , Paul McGuigan , Stephanie Woerner , Michelle Ecker , Roy W. Beck , and Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A1c Levels Richard M. Bergenstal , Robin L. Gal , and Roy W. Beck Metrics 6 February 2018Volume 168, Issue 3Page: 232KeywordsAttentionBloodConflicts of interestDisclosureGlucoseGlycationHbA1cHemoglobinHypoglycemia ePublished: 6 February 2018 Issue Published: 6 February 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Institute of Directors’ certificate in company direction
Authors: Murray Fletcher
Journal: BMJ (2008)

The chief executive of the NHS, David Nicholson, is on record as saying that in the next couple of years he wants a doctor to be applying for every chief executive position advertised. Even if this is not achieved within this ambitious timeframe, it is widely acknowledged that clinicians must be more engaged in the direction and management of the NHS. If this is to be achieved, it is essential that more doctors undertake further development of their management knowledge and skills.

Current directors (both established, and new to the role), and senior executives preparing to become directors, in public, private, and not for profit organisations. The participants on my course represented a range of business backgrounds, namely manufacturing, retail, and service industries; I was the only health professional.

I had been a consultant in palliative medicine for more than 12 years, and director of medical services in a …
Can health-related quality of life (HRQoL) predict conditional survival (CS) in metastatic renal cell carcinoma? Results from a large phase 3 trial.
Authors: Justin Doan, Bill Malcolm, Eduardas Valaitis, Kristopher Hoover, Saby George
Journal: Journal of Clinical Oncology (2018)

691 Background: In the absence of mature overall survival (OS) endpoints, interim clinical trial data can be used to predict long-term survival in patients (pts) with advanced malignancies and inform trial continuation, treatment preference, and reimbursement decisions. Research shows that HRQoL assessments can be associated with OS, offering potential utility for validated HRQoL scales. We describe a predictive model used to determine the extent to which HRQoL data could predict CS (survival conditional on progression at either 6 or 12 months). Methods: Using pt-level data from a large phase III trial of nivolumab vs everolimus, a simulation approach with a survival random forest algorithm identified factors statistically important in predicting CS from a large number of covariates measured at baseline. Stepwise Cox proportional hazard survival models were fitted using covariates identified as important. Baseline scores and change over time were tested to determine the influence on the predictive power of the HRQoL data. Results: For both nivolumab and everolimus, baseline FKSI values were significant predictors of CS; median survival times roughly doubled for pts with baseline FKSI scores ≥30 vs pts with scores &lt; 30 (nivolumab, 31.3-16.6; everolimus, 26.6-11). Baseline FKSI scores were the most important predictor vs the other baseline covariates from the survival random forest simulation, and a statistically significant covariate when fitting a stepwise Cox proportional hazard survival model. Change in scores over time influenced CS for pts with high baseline scores, and pts who demonstrated improvement in scores vs baseline had significantly higher CS vs pts with low baseline and no improvement in scores vs baseline. However, when examining change in HRQoL score over time, the statistical importance of the covariate begins to diminish due to high correlations with factors such as adverse events and weight change. Conclusions: We found that HRQoL data, specifically the FKSI, could be useful in predicting CS, especially at the onset of a trial. The importance of the FKSI score in predicting CS could be a powerful complement to existing clinical prognostic factors.
Careers in the pharmaceutical industry
Authors: Stephen Jones
Journal: BMJ (2008)

Pharmaceutical medicine became a recognised specialty in 2002 and offers a challenging and rewarding medical career. It provides the opportunity to advance the therapeutic armamentarium available to clinicians, and the satisfaction that you are helping patients worldwide. After working in the NHS for five years I switched to the pharmaceutical industry and found my knowledge and skills transferable.

Activities in the industry differ depending on the stage in a drug’s development. Before a drug can be marketed the industry has to demonstrate appropriate manufacturing standards and establish the drug’s risk-benefit profile (using information from toxicology and clinical trials). The prospectively collected safety and efficacy data are put before the regulatory authorities, who evaluate whether the efficacy demonstrated outweighs the risk (or potential risk). Where the balance is favourable the drug may be approved for marketing. If it is approved, post-marketing activities include marketing for any indications agreed with the local regulatory authority and continuous safety monitoring. Additional clinical trials (phase IV) may be undertaken. Most drugs don’t make it to the market, so their research and development costs are recouped by the few that do.

The industry adopts a multidisciplinary approach and the roles available to the pharmaceutical doctor are varied. Pre-marketing research roles (clinical pharmacology and clinical development) entail working on phase I-III clinical trials; post-marketing roles (medical affairs/marketing) ensure accuracy of promotional material and input into phase IV clinical studies, and may involve training medical representatives. Other roles include drug safety officer (pharmacovigilance) to monitor drug safety and changes to a drug’s risk-benefit profile. Regulatory roles are within the regulatory authorities (for example, the Medicines and Healthcare products Regulatory Agency in the United Kingdom) or within companies, to ensure regulatory requirements are met. Health outcomes/economics is an expanding …
Physical activity levels in adults and older adults 3–4 years after pedometer-based walking interventions: Long-term follow-up of participants from two randomised controlled trials in UK primary care
Authors: Tess Harris, Sally M. Kerry, Elizabeth S. Limb, Cheryl Furness, Charlotte Wahlich, Christina R. Victor, Steve Iliffe, Peter H. Whincup, Michael Ussher, Ulf Ekelund, Julia Fox-Rushby, Judith Ibison, Stephen DeWilde, Cathy McKay, Derek G. Cook
Journal: PLoS Medicine (2018)

Background Physical inactivity is an important cause of noncommunicable diseases. Interventions can increase short-term physical activity (PA), but health benefits require maintenance. Few interventions have evaluated PA objectively beyond 12 months. We followed up two pedometer interventions with positive 12-month effects to examine objective PA levels at 3–4 years. Methods and findings Long-term follow-up of two completed trials: Pedometer And Consultation Evaluation-UP (PACE-UP) 3-arm (postal, nurse support, control) at 3 years and Pedometer Accelerometer Consultation Evaluation-Lift (PACE-Lift) 2-arm (nurse support, control) at 4 years post-baseline. Randomly selected patients from 10 United Kingdom primary care practices were recruited (PACE-UP: 45–75 years, PACE-Lift: 60–75 years). Intervention arms received 12-week walking programmes (pedometer, handbooks, PA diaries) postally (PACE-UP) or with nurse support (PACE-UP, PACE-Lift). Main outcomes were changes in 7-day accelerometer average daily step counts and weekly time in moderate-to-vigorous PA (MVPA) in ≥10-minute bouts in intervention versus control groups, between baseline and 3 years (PACE-UP) and 4 years (PACE-Lift). PACE-UP 3-year follow-up was 67% (681/1,023) (mean age: 59, 64% female), and PACE-Lift 4-year follow-up was 76% (225/298) (mean age: 67, 53% female). PACE-UP 3-year intervention versus control comparisons were as follows: additional steps/day postal +627 (95% CI: 198–1,056), p = 0.004, nurse +670 (95% CI: 237–1,102), p = 0.002; total weekly MVPA in bouts (minutes/week) postal +28 (95% CI: 7–49), p = 0.009, nurse +24 (95% CI: 3–45), p = 0.03. PACE-Lift 4-year intervention versus control comparisons were: +407 (95% CI: −177–992), p = 0.17 steps/day, and +32 (95% CI: 5–60), p = 0.02 minutes/week MVPA in bouts. Neither trial showed sedentary or wear-time differences. Main study limitation was incomplete follow-up; however, results were robust to missing data sensitivity analyses. Conclusions Intervention participants followed up from both trials demonstrated higher levels of objectively measured PA at 3–4 years than controls, similar to previously reported 12-month trial effects. Pedometer interventions, delivered by post or with nurse support, can help address the public health physical inactivity challenge. Trial registrations PACE-UP isrctn.com ISRCTN98538934; PACE-Lift isrctn.com ISRCTN42122561.
P081 Sclerostin affects rankl-mediated osteoclast differentiation
Authors: J Intemann, C Wehmeyer, V Kracke, E Werbenko, P Paruzel, I Kramer, M Kneissel, T Pap, B Dankbar
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Sclerostin is a Wnt inhibitor and has anti-anabolic effects on bone formation by negatively regulating osteoblast differentiation. The lack of sclerostin in humans and mice leads to a higher bone mass and bone strength known as sclerosteosis. Therefore, inhibition of sclerostin is currently investigated as a treatment against osteoporosis. Surprisingly, the genetic deficiency or pharmacological inhibition of sclerostin causes a deterioration of disease severity in a TNFα-dependent arthritis mouse model (hTNFtg). hTNFtg mice lacking sclerostin displayed enhanced joint inflammation, cartilage loss and bone erosion associated with an elevated number of osteoclasts within the joint. <h3>Objectives</h3> We want to investigate the impact of sclerostin on osteoclast differentiation and bone erosion in arthritis. <h3>Methods</h3> Sclerostin knockout (sost<sup>-/-</sup>) mice were crossbred with hTNFtg mice to obtain sost<sup>-/-</sup>/hTNFtg synovial fibroblasts. Co-cultures of synovial fibroblasts and wildtype bone marrow macrophages were analysed by TRAP staining. RANKL expression was measured by ELISA and cytokine expression by array analysis and Western Blot. Moreover, the influence of sclerostin on osteoclastogenesis was additionally analysed in mono-cultures. <h3>Results</h3> In our co-culture system of synovial fibroblasts and bone marrow derived macrophages, fibroblasts from sost<sup>-/-</sup>/hTNFtg mice strongly promote osteoclastogenesis in comparison to hTNFtg synovial fibroblasts. Notably, no increased expression of receptor activator of NF-kB ligand (RANKL) was detectable in sost<sup>-/-</sup>/hTNFtg fibroblasts even after stimulation with inflammatory cytokines. Interestingly, basal secretion of IL-1α, which is known to stimulate osteoclastogenesis, was higher in sost<sup>-/-</sup>/hTNFtg compared to hTNFtg fibroblasts. Accordingly, sclerostin inhibited osteoclastogenesis when administered in the pre-differentiation phase, whereas no effect was observed in the differentiation phase, indicating an inhibitory effect of sclerostin on osteoclast precursors. <h3>Conclusions</h3> Sclerostin deficiency in hTNFtg synovial fibroblasts promotes RANKL-mediated osteoclastogenesis, which is most likely dependent on IL-1α. <h3>Disclosure of interest</h3> None declared
Abstract P181: Contribution of C-Reactive Protein to Racial Disparities in Incident Hypertension: The REasons for Geographic And Racial Differences in Stroke Study (REGARDS)
Authors: Timothy B Plante, D L Long, George Howard, April P Carson, Virginia J Howard, Suzanne E Judd, Nancy S Jenny, Neil A Zakai, Mary Cushman
Journal: Circulation (2018)

Introduction: In the US, blacks are at higher risk of hypertension than whites. The single largest contributor to this disparity is the Southern Diet pattern. Inflammation biomarkers are associated with risk of hypertension, and C-reactive protein (CRP) is higher in blacks than whites. We studied whether elevated CRP in blacks relative to whites contributes to the racial disparity in hypertension in blacks. Methods: We included 6,548 black and white men and women age ≥45 years from the REGARDS cohort without hypertension at baseline ('03-'07) and who completed visit 2 in '13-'16. Incident hypertension was defined as BP ≥140/90 mm Hg or hypertension medication use at visit 2. Using logistic regression, the black:white odds ratio (OR) for incident hypertension was calculated adjusting for age, sex, race, and baseline SBP. We assessed the percent change in the black:white OR for incident hypertension after adding CRP. The 95% CI was calculated using 1,000 bootstrapped samples. We determined the impact of known hypertension risk factors and anti-inflammatory medications on the percent mediation by CRP. Results: Hypertension developed in 46% of blacks and 33% of whites. Adjusting for demographics, the black:white OR (95% CI) was 1.51, which was reduced to 1.46, a 9.3% reduction (95% CI 5.4%, 13.2%) by CRP (Table). In models including exercise, waist circumference, BMI, and depressive symptoms, the percent mediation by CRP was 3.7% (1.0%, 6.4%). Similar patterns were seen for models incorporating socioeconomic factors and medication use. After adding Southern diet pattern and dietary Na/K ratio, CRP no longer attenuated the association (1.3% mediation; -1.5, 4.1). Conclusions: CRP significantly attenuated the black-white difference in incident hypertension; however, once dietary factors were accounted for, CRP had no impact on the black:white difference in incident hypertension. Thus, inflammation as measured by CRP, may be part of the reason that dietary factors influence the black:white disparity in incident hypertension.