tbuckley/cabot-search huggingface dataset:
Resistance analysis of genotype 3 hepatitis C virus indicates subtypes inherently resistant to nonstructural protein 5A inhibitors
Authors: David Smith, Andrea Magri, David Bonsall, Camilla L.C. Ip, Amy Trebes, Anthony Brown, Palo Piazza, Rory Bowden, Dung Nguyen, M. Azim Ansari, Peter Simmonds, Eleanor Barnes
Journal: Hepatology (2018)

Hepatitis C virus (HCV) genotype (gt) 3 is highly prevalent globally, with non‐gt3a subtypes common in Southeast Asia. Resistance‐associated substitutions (RASs) have been shown to play a role in treatment failure. However, the role of RASs in gt3 is not well understood. We report the prevalence of RASs in a cohort of direct‐acting antiviral treatment‐naive, gt3‐infected patients, including those with rarer subtypes, and evaluate the effect of these RASs on direct‐acting antivirals in vitro. Baseline samples from 496 gt3 patients enrolled in the BOSON clinical trial were analyzed by next‐generation sequencing after probe‐based enrichment for HCV. Whole viral genomes were analyzed for the presence of RASs to approved direct‐acting antivirals. The resistance phenotype of RASs in combination with daclatasvir, velpatasvir, pibrentasvir, elbasvir, and sofosbuvir was measured using the S52 ΔN gt3a replicon model. The nonstructural protein 5A A30K and Y93H substitutions were the most common at 8.9% (n = 44) and 12.3% (n = 61), respectively, and showed a 10‐fold and 11‐fold increase in 50% effect concentration for daclatasvir compared to the unmodified replicon. Paired RASs (A30K + L31M and A30K + Y93H) were identified in 18 patients (9 of each pair); these combinations were shown to be highly resistant to daclatasvir, velpatasvir, elbasvir, and pibrentasvir. The A30K + L31M combination was found in all gt3b and gt3g samples. Conclusion: Our study reveals high frequencies of RASs to nonstructural protein 5A inhibitors in gt3 HCV; the paired A30K + L31M substitutions occur in all patients with gt3b and gt3g virus, and in vitro analysis suggests that these subtypes may be inherently resistant to all approved nonstructural protein 5A inhibitors for gt3 HCV. (Hepatology 2018).
BMA seeks to improve interdeanery transfer process
Authors: Helen Jaques
Journal: BMJ (2012)

The BMA’s Junior Doctors Committee is in discussions with the Department of Health and deaneries to make the “burdensome” process of transfers of trainees between deaneries more efficient and transparent.

The committee is seeking to establish a national system for interdeanery transfers that will make it clearer where and in what specialties deaneries are accepting transfers.

The interdeanery transfer system allows trainees who have been …
Pharmacokinetics of ZR2002, a combi-molecule with EGFR and DNA-damaging properties and its efficacy in an orthotopic glioblastoma mouse model
Authors: Z. Sharifi, B. Meehan, P. Daniel, K. Eppert, B. Jean-Claude, J. Rak, B. Abdulkarim, S. Sabri
Journal: Annals of Oncology (2018)
Trainees from private schools are less likely to become GPs, researchers say
Authors: Abi Rimmer
Journal: BMJ (2015)

Junior doctors who attended private school are less likely to enter general practice training than those from state schools, researchers have found.

A study by researchers from the University of York’s Centre for Health Economics found that trainees from better off socioeconomic backgrounds were “less likely to be based in general practice than in any other specialty.”1

Using data from the General Medical Council’s 2013 National Training Survey, the researchers found …
The decade of exosomal long RNA species: an emerging cancer antagonist
Authors: Ruihao Zhou, Kaddie Kwok Chen, Jingtao Zhang, Bufan Xiao, Zhaohao Huang, Cheng Ju, Jun Sun, Feifei Zhang, Xiao-Bin Lv, Guofu Huang
Journal: Molecular Cancer (2018)

Exosomes have emerged as a novel approach for the treatment and diagnosis of cancer after RNA content was discovered in exosomes in 2007. As important meditators of intercellular communication, exosomes have become a strong focus of investigation for researchers in the past decade, as witnessed through the exponential increase of research on exosomes. The capability of exosomes to transfer functionally active cargo highlights their importance as promising biomarkers and diagnostic molecules, as well as prospective drug delivery systems. The accessibility of exosomes in nearly all biofluids additionally alludes to its unprecedented ability in various types of cancers due to its extensive impact on tumor formation and progression. This review analyzes the role of exosomal long RNA species, which is comprised of mRNA, lncRNA, and circRNA, in tumor formation and progression, with an emphasis on their potential as future diagnostic biomarkers and treatment vectors in cancer biology. Their alignment with the development of exosomal databases is further examined in this review, in view of the accumulation of studies published on exosomes in the past decade.
Safety and clinical activity of pembrolizumab immunotherapy and multi-organ site ablative stereotactic body radiotherapy (iMOSART) in patients with advanced solid tumors.
Authors: Jeffrey Lemons, Jason J. Luke, Theodore Karrison, Sean Pitroda, James Melotek, Yuanyuan Zha, Hania A Al-Hallaq, Ainhoa Arina, Linda A. Janisch, Paul J Chang, Jyoti D. Patel, Gini F. Fleming, John William Moroney, Manish Sharma, Julia R. White, Mark J. Ratain, Thomas Gajewski, Ralph R. Weichselbaum, Steven J. Chmura
Journal: Journal of Clinical Oncology (2018)

20 Background: Clinical responses to PD1 blockade have been linked to IFN-γ associated gene expression in the tumor microenvironment. Stereotactic body radiotherapy (SBRT) can stimulate innate and adaptive immunity to potentially augment immunotherapy. Anti-PD1 treatment outcomes are improved with lower disease burden and multi-site radiation is an emerging paradigm for eradicating metastatic disease. Methods: We conducted a phase I study for patients with metastatic solid tumors who progressed on standard treatment. The primary aim was to evaluate the safety of pembrolizumab Immunotherapy with Multi-Organ Site Ablative stereotactic body Radiation Therapy (iMOSART). Two to four metastases were chosen for each patient and not all sites of disease were targeted with SBRT. Metastases &gt; 65cc were partially irradiated. Pembrolizumab was initiated within 7 days after the final SBRT treatment. Results: 79 patients were enrolled, three patients did not receive any treatment and three patients only received SBRT. The 73 patients included in the analysis were treated with SBRT and at least 1 cycle of pembrolizumab. 94.5% of patients had two lesions treated with SBRT. Median follow-up for toxicity was 5.5 months (IQR 3.3-8.1). Six patients experienced dose-limiting toxicity (DLT) with no radiation dose reductions. RECIST overall objective response rate was 13.5% in the 68 patients with imaging follow-up. Superior control of irradiated lesions was observed compared to non-irradiated target lesions for the 52 patients with paired data (p = 0·0005) with a mean percent tumor burden change -21·7% (SD 24·3%) for irradiated lesions vs. 1·7% (SD 46·3%) for non-irradiated lesions (p = 0·0008). While abscopal response defined by 30% reduction in any single non-irradiated measurable lesion was present in 26·9% of patients, abscopal response was 13·2% when defined by 30% reduction in aggregate diameter of non-irradiated measurable lesions. Conclusions: iMOSART was well tolerated with acceptable toxicity. Further randomized studies are warranted to investigate the potential clinical benefit of this combination approach. Clinical trial information: NCT02608385.
Photoacoustic‐Enabled Self‐Guidance in Magnetic‐Hyperthermia Fe@Fe<sub>3</sub>O<sub>4</sub> Nanoparticles for Theranostics In Vivo
Authors: Ping Zhou, Heng Zhao, Quan Wang, Zhiguo Zhou, Jing Wang, Guang Deng, Xiyou Wang, Qian Liu, Hong Yang, Shiping Yang
Journal: Advanced Healthcare Materials (2018)

Abstract Magnetic nanoparticles have gained much interest for theranostics benefited from their intrinsic integration of imaging and therapeutic abilities. Herein, c(RGDyK) peptide PEGylated Fe@Fe 3 O 4 nanoparticles (RGD‐PEG‐MNPs) are developed for photoacoustic (PA)‐enabled self‐guidance in tumor‐targeting magnetic hyperthermia therapy in vivo. In the α v β 3 ‐positive U87MG glioblastoma xenograft model, the PA signal of RGD‐PEG‐MNPs reaches its maximum in the tumor at 6 h after intravenous administration. This signal is enhanced by 2.2‐folds compared to that of the preinjection and is also 2.2 times higher than that in the blocking group. It demonstrates the excellent targeting property of RGD‐PEG‐MNPs. With the guidance of the PA, an effective magnetic hyperthermia to tumor is achieved using RGD‐PEG‐MNPs.
EFFECT OF EARLY INTRAVENOUS METOPROLOL ADMINISTRATION ON ISCHEMIA SEVERITY DURING ONGOING MYOCARDIAL INFARCTION: INSIGHTS FROM AN ELECTROCARDIOGRAPHY ANALYSIS
Authors: Raquel Diaz-Munoz, Rodrigo Fernandez-Jimenez, Maria Jose Valle-Caballero, Borja Ruiz-Mateos, Gonzalo Pizarro, Leticia Fernandez-Friera, Jose Antonio Iglesias-Vazquez, Patricia Fernan, Valentin Fuster, Juan C. Garcia-Rubira, Borja Ibanez
Journal: Journal of the American College of Cardiology (2018)
CONCOMITANT ASYMPTOMATIC MAY-THURNER AND SYMPTOMATIC NUTCRACKER SYNDROME: IS ILIAC VEIN STENTING ESSENTIAL?
Authors: Andrew Herman, Modushudan Bhattacharjee, Michelle N. Maneevese, Bella P. Desai, Anil K. Pillai, David L. Heredia
Journal: Journal of the American College of Cardiology (2018)
Abstract ES8-3: Circulating complexes of stromal and tumor cells in breast cancer metastasis
Authors: D El-Ashry
Journal: Cancer Research (2018)

Abstract The establishment of breast cancer metastases at sites distant from the primary lesion site is predicated on the ability of breast cancer cells to mobilize from the primary tumor, survive in circulation, and colonize in a suitable and permissive metastatic niche. While quantitation of individual CTCs has prognostic value in breast cancer patients with metastatic disease, and elevated counts of CTCs may associate with poor outcome in early breast cancer, recent evidence from mouse models indicates that CTCs in clusters have a greater capacity to produce metastases than individual CTCs and new studies in breast cancer suggest that the presence of CTC clusters in patients can be prognostic. We have found in breast cancer patients, clusters of circulating cells that include CTCs, immune cells, and stromal cells found in the tumor microenvironment, specifically cancer associated fibroblasts (CAFs). Like CTC and circulating CAF (cCAF) counts, the incidence and number of CTC/cCAF clusters increases with disease stage. While the clinical significance of circulating complexes of CTCs and stromal cells remains to be fully elucidated, the recent identification of cCAFs in the peripheral blood of patients with metastatic breast cancer, traveling individually or in clusters with CTCs emphasizes the potential importance of stromal cells as circulating mediators of cancer metastasis. Preclinical murine models of breast cancer metastasis provide opportunities to observe the composition, dynamics, and behavior of these circulating CTC/stromal cell complexes, and to interrogate mechanisms driving their mobilization and clustering. Identifying the cellular components in these circulating complexes, and understanding the mechanisms by which they facilitate breast cancer metastasis, may provide novel therapeutic avenues for the treatment or prevention of metastatic breast cancer. Citation Format: El-Ashry D. Circulating complexes of stromal and tumor cells in breast cancer metastasis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES8-3.
Seeking a fresh approach
Authors: Tom Moberly
Journal: BMJ (2014)

The prospect that UK doctors may end up out of work as a result of poor workforce planning was raised by the BMA earlier this month. The results of the latest census of consultants from the Royal College of Physicians (http://careers.bmj.com/careers/advice/view-article.html?id=20017182) are unlikely to allay such concerns. The college found that workforce planning had become “almost impossible” because too few trainees are …
London GPs blame poor communication by hospitals for “unsustainable” workload
Authors: Helen Jaques
Journal: BMJ (2013)

Most general practitioners in London believe that their workload is unsustainable, with many citing poor communication from secondary care as a key driver of their workload.

A survey by Londonwide Local Medical Committees of 666 GPs—the organisation’s biggest survey to date—found that 86% of GPs in the capital did not think that their daily workload was manageable. A similar proportion (83%) said that their workload was “unsustainable.”

More work coming out of secondary care, an increase in non-clinical administrative work, high …
Brief Report: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multiple-Dose Study to Evaluate AMG 557 in Patients With Systemic Lupus Erythematosus and Active Lupus Arthritis
Authors: Laurence E. Cheng, Zahir Amoura, Benjamin Cheah, Falk Hiepe, Barbara A. Sullivan, Lei Zhou, Gregory E. Arnold, Wayne H. Tsuji, Joan T. Merrill, James B. Chung
Journal: Arthritis & Rheumatology (2018)

To evaluate the safety and potential efficacy of AMG 557, a fully human antibody directed against the inducible T cell costimulator ligand (ICOSL) in patients with systemic lupus erythematosus (SLE) with arthritis.In this phase Ib, randomized, double-blind, placebo-controlled study, patients received AMG 557 210 mg (n = 10) or placebo (n = 10) weekly for 3 weeks, then every other week for 10 additional doses. The corticosteroid dosage was tapered to ≤7.5 mg/day by day 85, and immunosuppressants were discontinued by day 29. Primary end points on day 169 were safety, immunogenicity, the Lupus Arthritis Response Index (LARI; defined by a reduction in the tender and swollen joint counts), ≥1-letter improvement in the musculoskeletal domain of the British Isles Lupus Assessment Group (BILAG) index, and medication discontinuation. The secondary/exploratory end points were changes in the tender and swollen joint counts, BILAG index scores (musculoskeletal, global), and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).The incidence of adverse events, most of which were mild, was similar between groups. LARI responses occurred in 3 of 10 patients receiving AMG 557 and 1 of 10 patients receiving placebo (P = 0.58). More patients in the AMG 557 group achieved a ≥4-point improvement in the SLEDAI score on day 169 (7 of 10 patients) compared with the placebo group (2 of 10 patients) (P = 0.07). Patients treated with AMG 557 (versus placebo) had greater improvements from baseline in the global BILAG index scores (-36.3% versus -24.7%) and the SLEDAI score (-47.8% versus -10.7%) and in tender (-22.8% versus -13.5%) and swollen (-62.1% versus -7.8%) joint counts on day 169.AMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE.
NHS locum agency is to be part privatised
Authors: Abi Rimmer
Journal: BMJ (2016)

The government is to sell a majority shareholding in NHS Professionals, an NHS owned locum agency.

A spokeswoman for the Department of Health for England said that the when the new company took over NHS Professionals it would be able to use “NHS Professionals” as a trading name but would not be able to use the NHS brand logo.

NHS Professionals has a bank of over 90 000 workers, including locum doctors, nurses, and allied health professionals, and holds contracts with 55 NHS trusts.

In a written statement to the House of Commons the health minister …
P041 Tissue gene profiling uncovers cadherin 11 related signatures in rheumatoid arthritis patients
Authors: K Hatje, T Kam-Thong, D Hartl, G Duchateau-Nguyen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Cadherin 11 is selectively expressed by synovial fibroblasts and plays a role in the pathogenesis of rheumatoid arthritis (RA).<sup>1</sup> Consequently, blocking cadherin 11 function in inflamed tissues may represent a potentially effective and novel therapy for RA. <h3>Objectives</h3> Here we interrogated publicly available transcriptomics datasets from RA patients synovial tissue and healthy controls using pre-defined primary cell gene signatures to better understand the heterogeneity of the underlying pathology. In addition, we analysed the association of these gene signatures with the expression of cadherin 11 gene to narrow down the underlying mechanistic network on which targeted treatments and biomarkers can be developed. <h3>Methods</h3> We used two publicly available transcriptomics studies from NCBI Gene Expression Omnibus<sup>2</sup> performed on synovial tissue of RA patients and healthy controls: GSE7307 (RA=5, healthy=7) and GSE77298 (RA=16, healthy=7). The pre-defined gene signatures were derived from ENCODE primary cell expression data<sup>3</sup> and signature enrichment was applied using the BioQC package.<sup>4</sup>Principal component analysis (PCA) was applied on the BioQC enrichment scores to (i) identify potential clusters of samples and to (ii) identify the gene signatures responsible for the clustering. In addition, associations between cadherin 11 gene expression and gene signatures were tested. <h3>Results</h3> In both studies, cadherin 11 was higher expressed in RA patients compared to healthy controls. PCA performed on gene enrichment scores showed RA patients clustered apart from the healthy controls. Moreover, fibroblast, macrophage, lymphocyte and osteoclast gene signatures were significantly enriched in the RA patients compared to healthy controls in both studies. Unexpectedly, an adipokine-related signature was significantly enriched in RA patients from one transcriptomics dataset (GSE77298), while only showing a trend in the second set (GSE7037). In addition, in both studies Cadherin 11 was associated positively with fibroblast and lymphocyte signatures and negatively with adipokines-related signature. <h3>Conclusions</h3> The identified cadherin 11 related gene signatures expand our knowledge on cadherin 11 biology in human RA and may serve as potential biomarkers for RA studies in the future. <h3>References</h3> . Lee, et al. <i>Science</i>2007;315:1006–10. . https://www.ncbi.nlm.nih.gov/geo/ . ENCODE Project Consortium. Nature2012;489(7414):57–74. . Zhang, et al. BMC Genomics2017;18(1):277. <h3>Disclosure of interest</h3> K. Hatje Employee of: Roche, T. Kam-Thong Employee of: Roche, D. Hartl Employee of: Roche, G. Duchateau-Nguyen Employee of: Roche
I am a graduate from India and I finished my internship in 2002. After that I did a house job in medicine for six months. I recently took my Professional and Linguistic Assessments Board (PLAB) test part 2. Am I eligible for a foundation programme year 2 post?
Authors: Rahul Rao
Journal: BMJ (2005)

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>
Arno Motulsky: Father of pharmacogenetics
Authors: Bob Roehr
Journal: BMJ (2018)

Credit: UW Medicine Medical Genetics

“Mensch”: this is probably the best single word to describe the late Arno Motulsky. The Yiddish word means someone of honour and integrity, a core goodness, and accomplishment, who lacks pretence and is worthy of emulation.

Sure, there were the discoveries, the publications, and the honours that marked a long and storied career, which earned him the sobriquet “father of pharmacogenetics.” But Motulsky took equal joy in rounds with patients, which continued into his 70s, and in the successes of generations of researchers he mentored. What comes through most in reading the autobiographical essay he wrote in 2016 is the optimism, generosity, and joy that permeated his life.



Credit: Clare McLean, UW Medicine

“It was [Motulsky’s] vision to study how heredity could be involved in practically everything,” Francis Collins, director of the National Institutes of Health and leader of the Human Genome Project, told the New York Times . He added: “The relationship between heredity and the response to drug therapy—nobody was thinking about that until he stated it 60 years ago. He anticipated it decades before science made it possible to get the answers that he dreamt of.”

Yet all of that was nearly cut short …
DAYS ALIVE AND OUTSIDE OF HOSPITAL IS GREATER AMONG PATIENTS WITH TRANSTHYRETIN CARDIAC AMYLOIDOSIS COMPARED TO LIGHT CHAIN CARDIAC AMYLOIDOSIS AFTER INITIAL HOSPITALIZATION
Authors: Jonah Rubin, Sergio Teruya, Stephen Helmke, Julissa Alvarez, Mathew Maurer
Journal: Journal of the American College of Cardiology (2018)
Evaluation of a predefined AS threshold in a large cohort of men with localized prostate cancer.
Authors: Daniel Canter, Julia E. Reid, Maria Latsis, Margaret Variano, Shams Halat, Kristen E. Gurtner, Michael K. Brawer, Steven Stone, Stephen Bardot
Journal: Journal of Clinical Oncology (2018)

36 Background: Men with newly diagnosed, localized prostate cancer (PC) have historically been selected for active surveillance (AS) using clinicopathologic features. However, a clinical cell−cycle risk (CCR) score has been developed to include both molecular [cell cycle progression (CCP) RNA signature] and clinical [Cancer of the Prostate Risk Assessment (CAPRA)] features. Previous validations have demonstrated that this combined CCR score provides improved prognostic information relative to molecular or clinical features alone. As such, a CCR threshold score has been recently developed and validated to identify men with low−risk disease who may be candidates for AS. Here, we have evaluated the performance of the AS threshold in a contemporary cohort of men with newly diagnosed localized PC. Methods: Men with localized adenocarcinoma of the prostate who were treated at the Ochsner Clinic between 2006 and 2011 (4 patients were diagnosed in 2012−2014) were evaluated. Formalin−fixed paraffin embedded biopsy tissue and was analyzed for the RNA expression of 46 genes to obtain a CCP score. The CCR score was calculated as (0.57xCCP) + (0.39xCAPRA). A CCR score threshold of 0.8 has been previously validated in a cohort of conservatively managed men. Men with a CCR score equal to the threshold had an estimated 10−year disease−specific mortality risk of 3.3%, while men with scores below the threshold had a 2.7% risk. Results: Complete molecular and clinical information were available for 767 men with a median clinical follow−up time of 5.6 years measured from date of diagnosis. Overall, 217 men had CCR scores ≤ 0.8. Of these, 125 were treated by radical prostatectomy, 61 with radiation, 2 with radiation with hormones, 2 with hormones only, and 19 with watchful waiting. Treatment for eight men was unknown. One patient (0.5%) with a CCR score below the AS threshold progressed to metastatic disease, and was initially treated with radiation. Conclusions: We evaluated the performance of a previously validated AS threshold on a contemporary US cohort. Although the majority of the patients in this study were treated, the observed metastatic event rate of 0.5% supports that the CCR threshold can be safely used to identify candidates for AS.