tbuckley/cabot-search huggingface dataset:
Independent validation of missense polymorphism in HSD3B1 in Japanese men treated with primary androgen-deprivation therapy for metastatic prostate cancer.
Authors: Masaki Shiota, Naohiro Fujimoto, Kenjiro Imada, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Shunichi Kajioka, Takeshi Uchiumi, Masatoshi Eto
Journal: Journal of Clinical Oncology (2018)

179 Background: Recently, genetic polymorphism in HSD3B1 has been shown to be associated with oncological outcome when treated with androgen-deprivation therapy (ADT) for prostate cancer. However, its impact on prognosis among different ethnicities remains unclear. Then, we aimed to investigate the significance of missense polymorphism in HSD3B1 gene encoding 3β-hydroxysteroid dehydrogenase among men treated with primary ADT for metastatic prostate cancer. Methods: This study included 104 Japanese patients with metastatic prostate cancer treated with primary ADT. The association of HSD3B1 (rs1047303, 1245C) with clinicopathological parameters and prognosis, including progression-free survival and overall survival, was examined. Results: Clinicopathological parameters were comparable between men with homozygous wild-type and men with heterozygous and homozygous variant types in HSD3B1 gene. Men carrying heterozygous and homozygous variant types in HSD3B1 gene showed higher progression risk [hazard ratio (95% confidence interval), 2.34 (1.08–4.49), P = 0.033], but not any-caused death risk [hazard ratio (95% confidence interval), 1.36 (0.52–2.92), P = 0.50], compared with men carrying homozygous wild-type. Conclusions: This study confirmed the finding that HSD3B1 genetic variation is associated with high risk of progression in Japanese men treated with primary ADT for metastatic prostate cancer, suggesting universal significance among different ethnicities.
The impact of prostate cancer diagnosis on the quality of life at 3 years: A case control study.
Authors: Florence Menegaux, Xavier Rebillard, Sophie Bouvet, Christel Castelli, Nadine Houede
Journal: Journal of Clinical Oncology (2018)

67 Background: Prostate cancer (PCa) is the most common cancer in men. Former studies showed a time-dependent worsening of sexual or urinary long term side effects following surgery or radiotherapy that affected patients’ quality of life (QoL). These studies could not discriminate between age-related and treatment-related symptoms, as patients were their own controls. We conducted a case-control study evaluating at 3 years QoL and physical/psychological dysfunctions, whereas patients were on watchful waiting or received a treatment. Methods: We used data from the EPICAP population-based case-control carried out by INSERM and including 1700 participants. Eligible cases were men &lt; 75 years old newly diagnosed with PCa in 2012-2014 living in the Hérault geographic area. Controls were men of the same age recruited in the general population of the same area. Participants answered a QoL questionnaire 3 years after intervention. Primary objective was to compare the impact of diagnosis or/and treatments on QoL as measured by the EORTC QLQ-C30 score. Secondary objective was to compare the impact of diagnosis or/and treatments on urinary dysfunctions (IPSS, ICS), sexual dysfunctions (IEEF-5), anxiety (HADS), and occupational integration. We also assessed these QoL parameters depending on the treatment that was received. Results: Median age was 67.9 years old in the cases and 68.4 years old in the control. At 3 years, 376 cases and 352 controls had sent back their questionnaires. Treatments were: RP (258), RT (90), focal therapy (52), hormone therapy (26) and watchful waiting (61) at the time of the study. The results show no difference between cases and controls for the global QoL score. Other parameters are being assessed and will be presented at the meeting. Conclusions: Though prostate cancer cases and population-based controls showed similar global QoL at 3 years after diagnosis, the large EPICAP study will provide a comprehensive framework to go further in the understanding of PCa sequelae and give some hints on the balance between benefit and risk of PSA testing. This study will be the first to evaluate the different types of sequelae as a function of treatments and the occupational integration for patients &lt; 65 years old.
Abstract 19838: The Atypical Cadherin Fat1 Suppresses Vascular Smooth Muscle Mesenchymal Markers and Limits Atherosclerosis
Authors: Charlene M Dunaway, Prameladevi Chinnasamy, Lily Cao, Dario F Riascos-Bernal, Nicholas E Sibinga
Journal: Circulation (2015)

Introduction: Fat1 controls vascular smooth muscle cell (SMC) growth and migration. In recent studies, we found increased Fat1 expression in atherosclerotic lesions from apoE -/- (KO) mice, and identified vimentin, an intermediate filament protein and mesenchymal marker, as a novel Fat1 interactor also expressed in SMCs. Hypothesis: Fat1 regulation of SMCs limits atherosclerosis, at least in part via Fat1 effects on vimentin. Methods: We generated fat1 SMC-KO ; apoE double knockout (DKO) mice, fed them a high fat diet for 24 weeks, and assessed atherosclerosis analyzing aortic roots and brachiocephalic arteries (BCA) for lesion area, immunohistochemical features, and gene expression. Results: DKO mice (N=10) exhibited larger lesions at the aortic root (80837.0±7942.4) and BCA (36017.2±10496.4) compared to KO controls (64190.2±6539.1 and 19462.9±5246.3, respectively, p&lt;0.05). DKO lesions had larger fibrous caps (40.6±5.5%, N=7) and necrotic cores (30.3±3.2%, N=8) compared to KO samples (26.3±2.9 and 21.6±2.2%, respectively, p&lt;0.05), plus a trend towards increased cellularity (+24%, N=7, p=0.0573). Macrophage number was not different, but SMC area (staining for SM22α) was larger in DKO lesions (1.15±0.25, vs. KO, 0.37±0.08, N=9, p&lt;0.01). Proliferation (phospho-histone H3 staining) was also higher (DKO, 52.6±13.3 vs. KO, 31.4±10.1, N=7 p&lt;0.05). Fat1 and vimentin expression colocalized within fibrous caps, and Fat1-deficient SMCs and lesions expressed more vimentin (&gt;3-fold, p&lt;0.05 by immunoblotting). By co-immunoprecipitation, Fat1 interacted with vimentin and limited its abundance in SMCs; knockdown studies suggested that increased proliferation of Fat1-deficient SMCs depends on vimentin. In addition, Fat1-deficient SMCs showed evidence of E- to N-cadherin switching and upregulation of the Snail1 transcription factor. Conclusions: Our in vivo data support a role for Fat1 in control of SMC proliferation during atherogenesis, and suggest that Fat1-vimentin interaction is important for this regulation. These findings are reminiscent of the epithelial-mesenchymal transition (EMT) program described in proper epithelial cells, suggest that components of this regulatory network are operative in SMCs, and are controlled by Fat1.
INOTERSEN IMPROVES QUALITY OF LIFE IN PATIENTS WITH HEREDITARY TRANSTHYRETIN AMYLOIDOSIS WITH POLYNEUROPATHY AND CARDIOMYOPATHY: RESULTS OF THE PHASE 3 STUDY NEURO-TTR
Authors: Mathew S. Maurer, Stephen Heitner, Brian Drachman, Carol Whelan, Spencer Guthrie, Li Tai, Steve G. Hughes, Brett P. Monia, Elizabeth J. Ackermann, Merrill D. Benson
Journal: Journal of the American College of Cardiology (2018)
Folate Receptor Alpha Peptide Vaccine Generates Immunity in Breast and Ovarian Cancer Patients
Authors: Kimberly R. Kalli, Matthew S. Block, Pashtoon M. Kasi, Courtney L. Erskine, Timothy J. Hobday, Allan Dietz, Douglas Padley, Michael P. Gustafson, Barath Shreeder, Danell Puglisi-Knutson, Dan W. Visscher, Toni K. Mangskau, Glynn Wilson, Keith L. Knutson
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Folate receptor alpha (FR) is overexpressed in several cancers. Endogenous immunity to the FR has been demonstrated in patients and suggests the feasibility of targeting FR with vaccine or other immune therapies. CD4 helper T cells are central to the development of coordinated immunity, and prior work shows their importance in protecting against relapse. Our previous identification of degenerate HLA-class II epitopes from human FR led to the development of a broad coverage epitope pool potentially useful in augmenting antigen-specific immune responses in most patients. Patients and Methods: We conducted a phase I clinical trial testing safety and immunogenicity of this vaccine, enrolling patients with ovarian cancer or breast cancer who completed conventional treatment and who showed no evidence of disease. Patients were initially treated with low-dose cyclophosphamide and then vaccinated 6 times, monthly. Immunity and safety were examined during the vaccine period and up to 1 year later. Results: Vaccination was well tolerated in all patients. Vaccine elicited or augmented immunity in more than 90% of patients examined. Unlike recall immunity to tetanus toxoid (TT), FR T-cell responses developed slowly over the course of vaccination with a median time to maximal immunity in 5 months. Despite slow development of immunity, responsiveness appeared to persist for at least 12 months. Conclusions: The results demonstrate that it is safe to augment immunity to the FR tumor antigen, and the developed vaccine is testable for therapeutic activity in most patients whose tumors express FR, regardless of HLA genotype. Clin Cancer Res; 24(13); 3014–25. ©2018 AACR.
Optimization of mechanical properties, biocorrosion properties and antibacterial properties of wrought Ti-3Cu alloy by heat treatment
Authors: Mianmian Bao, Ying Liu, Xiaoyan Wang, Lei Yang, Shengyi Li, Jing Ren, Gaowu Qin, Erlin Zhang
Journal: Bioactive Materials (2018)

Previous study has shown that Ti-3Cu alloy shows good antibacterial properties (>90% antibacterial rate), but the mechanical properties still need to be improved. In this paper, a series of heat-treatment processes were selected to adjust the microstructure in order to optimize the properties of Ti-3Cu alloy. Microstructure, mechanical properties, biocorrosion properties and antibacterial properties of wrought Ti-3Cu alloy at different conditions was systematically investigated by X-ray diffraction, optical microscope, scanning electron microscope, transmission electron microscopy, electrochemical measurements, tensile test, fatigue test and antibacterial test. Heat treatment could significantly improve the mechanical properties, corrosion resistance and antibacterial rate due to the redistribution of copper elements and precipitation of Ti2Cu phase. Solid solution treatment increased the yield strength from 400 to 740 MPa and improved the antibacterial rate from 33% to 65.2% while aging treatment enhanced the yield strength to 800-850 MPa and antibacterial rate (>91.32%). It was demonstrated that homogeneous distribution and fine Ti2Cu phase plays a very important role in mechanical properties, corrosion resistance and antibacterial properties.
Overall survival and immune responses with sipuleucel-T and enzalutamide: STRIDE study.
Authors: Daniel Peter Petrylak, Charles G. Drake, Christopher Michael Pieczonka, John M. Corman, Jorge A. Garcia, Curtis Dunshee, Tim Van Mouwerik, Robert C. Tyler, Nancy N. Chang, David Quinn
Journal: Journal of Clinical Oncology (2018)

246 Background: STRIDE (NCT01981122) is the first study comparing concurrent (con) vs sequential (seq) enzalutamide (enz) with sipuleucel-T (sip-T) in patients (pts) with metastatic castration-resistant prostate cancer. Pts were followed until death or for 3 years. Methods: Fifty-two pts were randomized 1:1 to 3 sip-T infusions and enz started 2 wks before (n = 25, con) or 10 wks after (n = 27, seq) sip-T. Enz was continued for 52 wks or until disease progression (DP)/toxicity. Time to clinical outcomes was estimated by Kaplan-Meier analysis. Results: Median age (years): con 66; seq 72 (p = 0.01). Baseline characteristics and laboratory values were similar between arms. K-M estimated median follow up: 40.2 months. Clinical trial information: NCT01981122. Conclusions: Long-term follow-up suggests sip-T+enz is well-tolerated with no new safety concerns. Though not powered for such, con vs seq rx did not result in differences in OS or DP; differences in PSA responses cannot be excluded. Larger studies could better evaluate the clinical impact of combining immunotherapy with hormonal agents.[Table: see text]
Editor’s Choice: It’s the patients, stupid
Authors: Tom Moberly
Journal: BMJ (2016)

In October 1992 three phrases were listed on a sign in the headquarters of the team leading Bill Clinton’s US presidential campaign: “Change vs more of the same. The economy, stupid. Don’t forget health care.”

The second of those phrases became the de facto slogan for Clinton’s 1992 campaign. It is now shorthand both …
Clothes maketh the new consultant
Authors: Mruthunjayan Swamy
Journal: BMJ (2007)

<h3>Abstract</h3> Abiotic stress is a major force of selection that organisms are constantly facing. While the evolutionary effects of various stressors have been broadly studied, it is only more recently that the relevance of interactions between evolution and underlying ecological conditions, that is, eco-evolutionary feedbacks, have been highlighted. Here, we experimentally investigated how populations adapt to pH-stress under high population densities. Using the protist species <i>Tetrahymena thermophila</i>, we studied how four different genotypes evolved in response to stressfully low pH conditions and high population densities. We found that genotypes underwent evolutionary changes, some shifting up and others shifting down their intrinsic rates of increase (<i>r</i><sub>0</sub>). Overall, evolution at low pH led to the convergence of <i>r</i><sub>0</sub> and intraspecific competitive ability (<i>α</i>) across the four genotypes. Given the strong correlation between <i>r</i><sub>0</sub> and <i>α</i>, we argue that this convergence was a consequence of selection for increased density-dependent fitness at low pH under the experienced high density conditions. Increased density-dependent fitness was either attained through increase in <i>r</i><sub>0</sub>, or decrease of <i>α</i>, depending on the genetic background. In conclusion, we show that demography can influence the direction of evolution under abiotic stress.
Intensive weight management in primary care improved weight loss and remission of type 2 diabetes
Authors: Anupam Goel
Journal: Annals of Internal Medicine (2018)

Source Citation Lean ME, Leslie WS, Barnes AC, et al. Primary care–led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2017. [Epub ahead of print]. 29221645
Tumor-Resident Dendritic Cells and Macrophages Modulate the Accumulation of TCR-Engineered T Cells in Melanoma
Authors: Alastair Hotblack, Angelika Holler, Alice Piapi, Sophie Ward, Hans J. Stauss, Clare L. Bennett
Journal: Molecular Therapy (2018)

Ongoing clinical trials explore T cell receptor (TCR) gene therapy as a treatment option for cancer, but responses in solid tumors are hampered by the immunosuppressive microenvironment. The production of TCR gene-engineered T cells requires full T cell activation in vitro, and it is currently unknown whether in vivo interactions with conventional dendritic cells (cDCs) regulate the accumulation and function of engineered T cells in tumors. Using the B16 melanoma model and the inducible depletion of CD11c+ cells in CD11c.diphtheria toxin receptor (DTR) mice, we analyzed the interaction between tumor-resident cDCs and engineered T cells expressing the melanoma-specific TRP-2 TCR. We found that depletion of CD11c+ cells triggered the recruitment of cross-presenting cDC1 into the tumor and enhanced the accumulation of TCR-engineered T cells. We show that the recruited tumor cDCs present melanoma tumor antigen, leading to enhanced activation of TCR-engineered T cells. In addition, detailed analysis of the tumor myeloid compartment revealed that the depletion of a population of DT-sensitive macrophages can contribute to the accumulation of tumor-infiltrating T cells. Together, these data suggest that the relative frequency of tumor-resident cDCs and macrophages may impact the therapeutic efficacy of TCR gene therapy in solid tumors. Ongoing clinical trials explore T cell receptor (TCR) gene therapy as a treatment option for cancer, but responses in solid tumors are hampered by the immunosuppressive microenvironment. The production of TCR gene-engineered T cells requires full T cell activation in vitro, and it is currently unknown whether in vivo interactions with conventional dendritic cells (cDCs) regulate the accumulation and function of engineered T cells in tumors. Using the B16 melanoma model and the inducible depletion of CD11c+ cells in CD11c.diphtheria toxin receptor (DTR) mice, we analyzed the interaction between tumor-resident cDCs and engineered T cells expressing the melanoma-specific TRP-2 TCR. We found that depletion of CD11c+ cells triggered the recruitment of cross-presenting cDC1 into the tumor and enhanced the accumulation of TCR-engineered T cells. We show that the recruited tumor cDCs present melanoma tumor antigen, leading to enhanced activation of TCR-engineered T cells. In addition, detailed analysis of the tumor myeloid compartment revealed that the depletion of a population of DT-sensitive macrophages can contribute to the accumulation of tumor-infiltrating T cells. Together, these data suggest that the relative frequency of tumor-resident cDCs and macrophages may impact the therapeutic efficacy of TCR gene therapy in solid tumors.
RCGP calls for £15m emergency fund to save practices from closure
Authors: Abi Rimmer
Journal: BMJ (2014)

The Royal College of General Practitioners has called for around £15m to help practices cope with changes to their funding and save them from closure.

The college has urged government ministers to set up the emergency stability fund £15m to stave off the closure of up to 100 general practices in England.

In 2013 the government decided to begin phasing out the minimum practice income guarantee (MPIG) over a seven year period starting in April 2014.1 The RCGP believes that the removal of the MIPG could affect …
Differences in TP53 Mutation Carrier Phenotypes Emerge From Panel-Based Testing
Authors: Huma Q Rana, Rebecca Gelman, Holly LaDuca, Rachel McFarland, Emily Dalton, Jennifer Thompson, Virginia Speare, Jill S Dolinsky, Elizabeth C Chao, Judy E Garber
Journal: JNCI Journal of the National Cancer Institute (2018)

Li-Fraumeni syndrome (LFS) has traditionally been identified by single-gene testing (SGT) of TP53 triggered by clinical criteria, but the widespread use of multigene panel tests (MGPTs) has upended this paradigm. We sought to compare the personal and family cancer histories of TP53-positive result (TP53+) carriers who were identified by either MGPT or SGT. Of 44 310 individuals who underwent testing of TP53 in a single clinical diagnostic laboratory between 2010 and 2014, 44 086 (40 885 MGPT and 3201 SGT) met study eligibility criteria. Personal cancer histories were available for 38 938 subjects. The frequency of germline TP53 results and various phenotypic manifestations were compared according to test type. All statistical tests were two-sided. MGPT TP53+ individuals (n = 126) had an older median age at first cancer than SGT TP53+ carriers (n = 96; women: median = 36 vs 28 years, P < .001; and men: median = 40 vs 15 years, P = .004). The median age of breast cancer diagnosis was 40 years in MGPT TP53+ women vs 33 years in SGT TP53+ women (P < .001). In both cohorts, childhood and LFS core cancers, and for women, multiple primary cancers (not multiple breast tumors), were associated with TP53+ results. Established LFS testing criteria were less often met by MGPT TP53+ individuals. MGPT TP53+ individuals differ in phenotype from those ascertained through SGT and are notably older at cancer diagnosis and less likely to meet LFS clinical criteria. These findings suggest that LFS may have a greater phenotypic spectrum than previously appreciated. This has implications for the counseling of MGPT TP53+ individuals. Prospective follow-up of these individuals and families is needed to re-evaluate cancer risks.
Clinical academic posts held by women rose by 41% in a decade
Authors: Abi Rimmer
Journal: BMJ (2015)

The number of clinical academic posts held by women has risen by 41% since 2004, show figures from the Medical Schools Council.

The council’s 13th survey of clinical academic staffing levels found that the number of women working in clinical academic posts had increased from 680 in 2004 to 958 in 2014.

A total of 3131 full time equivalent (FTE) medical academics were employed at lecturer grade and above by medical schools in …
PROGNOSTIC VALUE OF THE COMBINATION OF SIMPLE RISK INDEX AND MODERATE TO SEVERE ACUTE KIDNEY INJURY IN PATIENTS ADMITTED FOR ACUTE DECOMPENSATED HEART FAILURE
Authors: Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Shunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Tsutomu Kawai, Masahiro Seo, Iyo Ikeda, Eiji Fukuhara, Jun Nakamura, Makoto Abe, Kazuya Tanabe, Kiyomi Kayama, Masatsugu Kawahira, Masatake Fukunami
Journal: Journal of the American College of Cardiology (2018)
Metaplastic Squamous Cell Carcinoma of Breast Demonstrated on 18F-FDG PET/CT
Authors: Hongyan Yin, Yan Xiu, Rongkui Luo, Hongwei Zhang, Hongcheng Shi
Journal: Clinical Nuclear Medicine (2018)

A 32-year-old woman presented with 3 months' history of rapid enlargement of the left breast and superficial ulceration. Staging F-FDG PET/CT performed after admission demonstrated a hypermetabolic mass in the left breast, with smaller hypermetabolic areas in the left axillary and internal mammary lymph nodes, as well as in the sternum. Postoperatively, the mass was diagnosed as metaplastic squamous cell carcinoma of the breast.
UK immigration policies are incompatible with NHS needs, says GP trainer
Authors: Abi Rimmer
Journal: BMJ (2015)

The UK’s immigration policies are not compatible with the NHS’s workforce need to hire more doctors from overseas, a GP trainer has said.

Kamal Sidhu, a GP trainer in County Durham, told BMJ Careers, “Immigration policies of Australia, Canada, and New Zealand, the favoured destinations, are much more attractive and fairer for international graduates and their families,” he said. “The existing immigration policies in the UK are completely out of sync with the demands of the NHS, especially when general practice does not even figure in the Home Office’s list of categories that are facing a workforce shortage.”

Earlier …
GMC to notify doctors of revalidation dates from December 2012
Authors: Matthew Billingsley
Journal: BMJ (2012)

The General Medical Council has confirmed that from December doctors will begin to receive letters notifying them of their date for revalidation. It is expected that all 230 000 licensed doctors in the United Kingdom will have their dates confirmed by the end of March 2013.

Doctors will be given a minimum of six months warning of their first revalidation date, with the first dates scheduled for April 2013.

Trainee doctors will be given a slightly longer window, with revalidation dates running until December 2017. …
DDRB recommends pay rise of 1% for doctors
Authors: Abi Rimmer
Journal: BMJ (2017)

UK doctors should receive a 1% pay rise in 2017-18, the Review Body on Doctors’ and Dentists’ Remuneration (DDRB) has said.

The BMA said that the recommended increase was below the current cost of living and would come as a “bitter blow” to doctors.

In a report outlining its recommendations for 2017-18, the DDRB said that there should be a base increase of 1% to the national salary scales for salaried doctors in England, Wales, and Northern Ireland. It also said that the maximum and minimum of the …
FREQUENT SUPRAVENTRICULAR PREMATURE COMPLEXES AS A PREDICTION OF ATRIAL FIBRILLATION: SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Narut Prasitlumkum, Pattara Rattanawong, Nath Limpruttidham, Chanavuth Kanitsoraphan, Pichatorn Suppakitjanusant
Journal: Journal of the American College of Cardiology (2018)