tbuckley/cabot-search huggingface dataset:
Abstract P243: Endothelial Function, Arterial Stiffness and Central Blood Pressure are Not Affected by a Single Dose of Dietary Nitrate in Healthy Normotensive Females
Authors: Katharine E Storo, Caleb D Harrison, Evan J Bockover, Brycen J Ratcliffe, Sierra Crowe, Francisco J Morales, Haley M Fair, Alvaro N Gurovich, Colin R Carriker
Journal: Circulation (2018)

Intro: Hypertension is a prominent risk factor for cardiovascular disease and arterial stiffness is a related predictor of both mortality and longitudinal onset of hypertension in normotensive individuals. Both vascular compliance and blood pressure have been shown to improve following dietary nitrate supplementation in some healthy and diseased individuals. Dietary nitrate supplementation increases plasma nitrite and may, therefore, enhance bioavailability of endothelium derived nitric oxide. Chronic increased flow mediated dilation (FMD) and reduction of pulse wave velocity (PWV) reduce a person’s long-term risk for developing endothelial dysfunction, atherosclerosis and hypertension. Hypothesis: We hypothesized that an acute dose of dietary nitrate would improve FMD, decrease PWV and reduce central blood pressure (cBP) in healthy, young females. Methods: Seven healthy, young (21 ± 2 years) females participated in a randomized, double blind, placebo controlled, crossover protocol. Participants had endothelial function measured via FMD, arterial stiffness via PWV and applanation tonometry, and cBP was determined non-invasively using pulse wave analysis following a 12-hour fasting period and 48-hour NIH approved low nitrate diet. Baseline values were measured the day before each treatment visit (placebo or nitrate-rich, separated by a 1-week washout period). Participants consumed either a placebo or nitrate-rich supplement (negligible and 6.2 mmol nitrate, respectively) 2 hours prior to their laboratory visit. Upon arrival, blood was drawn and participants assumed a supine position for 15 minutes. Then brachial artery FMD was assessed via high definition ultrasound imaging following 5 minutes of proximal forearm occlusion, followed by PWV and central blood pressure measurements. Results: Plasma nitrite was elevated following consumption of the nitrate rich supplement compared to placebo (26.33 ± 15.76 and 1.18 ± 0.96 arbitrary units, respectively; p&lt;0.05). However, there was no difference between nitrate rich and placebo treatments for endothelial function as measured by FMD (10.33 ± 1.82 and 9.11 ± 5.43%, respectively; p=0.70). No difference was present between nitrate and placebo groups for PWV (5.99 ± 0.85 and 6.16 ± 0.80 m/s, respectively; p=0.90), systolic cBP (101.57 ± 9.29 and 96.90 ± 20.95 mmHg, respectively; p=0.40) and diastolic cBP (72.57 ± 7.67 and 73.20 ± 5.01 mmHg, respectively; p=0.97). Conclusion: While a single dose of dietary nitrate does increase plasma nitrite, supplementation has minimal effects on FMD, PWV and cBP in young healthy females. Future research should examine longer duration supplementation protocols as well as the changes in vascular health of patients with known disease such as hypertension or peripheral artery disease.
Abstract 14930: Baseline Adverse Electrical Remodeling and the Risk for Ventricular Arrhythmia in Cardiac Resynchronization Therapy Recipients (MADIT CRT)
Authors: Yitschak Biton, Yuriy Shapovalov, Xiaojuan Xia, Jean-Philippe Couderc, Arthur J. Moss, Valentina Kutyifa, Scott Mcnitt, Bronislava Polonsky, Wojciech Zareba
Journal: Circulation (2016)

Introduction: Adverse electrical remodeling (AER), measured as the integral of the QRST segment (QRSTi) has been previously shown to be directly associated with the risk for ventricular arrhythmia ...
Health department must do more to get doctors to work in A&E, says NAO
Authors: Abi Rimmer
Journal: BMJ (2013)

England’s Department of Health must do more to encourage doctors to work in hospital accident and emergency departments, a National Audit Office report on emergency admissions has said.1

The report found that emergency admissions to hospitals in England have continually risen over the past 15 years. In 2012-13 there were 5.3 million emergency admissions, costing the NHS around £12.5bn, the report said.

Although access to consultant advice and diagnostics in emergency departments can cut numbers of admissions, nearly all emergency departments …
Effects of a combined dietary, exercise and behavioral intervention and sympathetic system on body weight maintenance after intended weight loss: Results of a randomized controlled trial
Authors: Knut Mai, Maria Brachs, Verena Leupelt, Reiner Jumpertz-von Schwartzenberg, Lukas Maurer, Annette Grüters-Kieslich, Andrea Ernert, Thomas Bobbert, Heiko Krude, Joachim Spranger
Journal: Metabolism (2018)
Abstract 19457: Pathogenic Role of p53 in the Development and Progression of Pulmonary Hypertension
Authors: Ziyi Wang, Haiyang Tang, Kang Wu, Angela Balistrieri, Jason X Yuan, Jian Wang
Journal: Circulation (2017)

Rationale:  Idiopathic pulmonary arterial hypertension (IPAH) is a fatal and progressive disease characterized by pulmonary vascular wall hypertrophy and obliterative vascular lesions. The tumor suppressor, p53, is a transcription factor that regulates the expression of stress response genes, has been extensively investigated under malignant conditions, and its non-canonical functions have recently been implicated in pulmonary vascular disease. The purpose of this study was to examine whether p53 contributes to the development of pulmonary vasoconstriction and vascular remodeling.   Methods:  Western blot determined expression levels of p53 in the endothelium-denuded pulmonary artery (PA) or whole lungs isolated from normoxic and hypoxic mice. Ubiquitous MDM2 transgenic mice (MDM2 TG ), MDM2 mutant transgenic mice (MDM2 mut-TG ), and wildtype (WT) littermates (6-8 weeks) were exposed to chronic hypoxia (CH, 10% O 2 ) to induce PH. The isolated perfused/ventilated mouse lung was used to determine hypoxic pulmonary vasoconstriction.   Results:  Compared to controls, p53 was downregulated in PA (primarily PA smooth muscle cells (PASMC)) after CH exposure (0.43±0.11 vs. 0.17±0.02, n=4), but upregulated in whole lung tissue (primarily PA endothelial cells (PAEC)) (0.41±0.10 and 0.62±0.07, n=4). In MDM2 mut-TG  mice, the CH-mediated increase in right ventricular systolic pressure (RVSP) (36±3.0 and 27±2.0 mmHg, n=3,  p  p  TG  mice, however, spontaneously developed mild PH under normoxic conditions. CH significantly increased RVSP (36±3.0, 29±2.1 and 27±2.0 mmHg, n=3,  p  p  TG  mice compared to both WT and MDM2 mut-TG  mice.   Conclusions:  These results indicate that downregulated p53 in PASMC and upregulated p53 in PAEC both contribute to the development and progression of pulmonary hypertension. MDM2-p53 signaling may be involved in the transcriptional downregulation and upregulation of p53 in PASMC and PAEC, respectively. Targeting the MDM2/p53 signaling pathway may be an important strategy to develop novel therapies for pulmonary hypertension.
Genome-wide Discovery and Identification of a Novel miRNA Signature for Recurrence Prediction in Stage II and III Colorectal Cancer
Authors: Raju Kandimalla, Feng Gao, Takatoshi Matsuyama, Toshiaki Ishikawa, Hiroyuki Uetake, Naoki Takahashi, Yasuhide Yamada, Carlos Becerra, Scott Kopetz, Xin Wang, Ajay Goel
Journal: Clinical Cancer Research (2018)

Purpose: The current tumor-node-metastasis (TNM) staging system is inadequate at identifying patients with high-risk colorectal cancer. Using a systematic and comprehensive biomarker discovery and validation approach, we aimed to identify an miRNA recurrence classifier (MRC) that can improve upon the current TNM staging as well as is superior to currently offered molecular assays.Experimental Design: Three independent genome-wide miRNA expression profiling datasets were used for biomarker discovery (N = 158) and in silico validation (N = 109 and N = 40) to identify an miRNA signature for predicting tumor recurrence in patients with colorectal cancer. Subsequently, this signature was analytically trained and validated in retrospectively collected independent patient cohorts of fresh-frozen (N = 127, cohort 1) and formalin-fixed paraffin-embedded (FFPE; N = 165, cohort 2 and N = 139, cohort 3) specimens.Results: We identified an 8-miRNA signature that significantly predicted recurrence-free interval (RFI) in the discovery (P = 0.002) and two independent publicly available datasets (P = 0.00006 and P = 0.002). The RT-PCR-based validation in independent clinical cohorts revealed that MRC-derived high-risk patients succumb to significantly poor RFI in patients with stage II and III colorectal cancer [cohort 1: hazard ratio (HR), 3.44 (1.56-7.45), P = 0.001; cohort 2: HR, 6.15 (3.33-11.35), P = 0.001; and cohort 3: HR, 4.23 (2.26-7.92), P = 0.0003]. In multivariate analyses, MRC emerged as an independent predictor of tumor recurrence and achieved superior predictive accuracy over the currently available molecular assays. The RT-PCR-based MRC risk score = (-0.1218 × miR-744) + (-3.7142 × miR-429) + (-2.2051 × miR-362) + (3.0564 × miR-200b) + (2.4997 × miR-191) + (-0.0065 × miR-30c2) + (2.2224 × miR-30b) + (-1.1162 × miR-33a).Conclusions: This novel MRC is superior to currently used clinicopathologic features, as well as National Comprehensive Cancer Network (NCCN) criteria, and works regardless of adjuvant chemotherapy status in identifying patients with high-risk stage II and III colorectal cancer. This can be readily deployed in clinical practice with FFPE specimens for decision-making pending further model testing and validation. Clin Cancer Res; 24(16); 3867-77. ©2018 AACRSee related commentary by Rodriguez et al., p. 3787.
Abstract 14346: Short Term Hyperglycaemia Impair Endothelial Progenitor Cells With Improvement After Thymosin Beta-4 Treatment
Authors: Poay Sian Sabrina Lee, Lei Ye, Tiong Cheng Yeo, Arthur Mark Richards, Kian Keong Poh
Journal: Circulation (2013)

Background:  Hyperglycaemia, associated with endothelial dysfunction, is the leading cause of vascular complications in diabetes. Transient hyperglycaemia may occur in stress-related conditions, such as myocardial infarction or gestation. We hypothesize that endothelial progenitor cells (EPCs) may be affected by transient hyperglycaemia and that thymosin beta-4 (TB4), a G-actin-sequestering peptide, may enhance EPC number and function.   Methods:  Peripheral blood mononuclear cells were isolated from healthy (n=20) subjects using Ficoll density gradient centrifugation and grown on fibronectin-coated plates. Enumeration of EPC was performed using flow cytometry of CD34 +  and KDR +  markers. Migration and tubule formation assays were conducted to determine EPC function. EPCs were incubated with medium with no glucose, medium with 5.5mM glucose (normal glycaemic) or 15mM glucose (hyperglycaemic) for 5 days followed by TB4 treatment (1000ng/mL) for 3 days.   Results:  At baseline, there is significantly lower percentage of CD34 +  and KDR +  in EPC treated with 15mM glucose (0.25±0.03%) compared to controls (0.45 ± 0.05%; P   Conclusion:  The number and functionality of EPCs are significantly impaired with presence of 5 days of high glucose. With TB4 treatment, the parameters improved, suggesting potential beneficial effects of TB4 in diabetes.
President of the Royal College of Anaesthetists
Authors: Leyla Sanai
Journal: BMJ (2006)

Dr Peter Simpson, president of the Royal College of Anaesthetists, trained at St Bartholomew9s Hospital, graduating in 1970. He was appointed consultant anaesthetist at Frenchay Hospital, Bristol, in 1982. He has held posts concerned with anaesthesia education, training, and examining in the United Kingdom and Europe, and he is past chairman of the National Confidential Enquiry into Patient Outcome and Death (NCEPOD), deputy chairman of the Postgraduate Medical Education and Training Board (PMETB) and President of the European Society of Anaesthesiology.
Private medical school denies its new MBChB course will increase competition for foundation programme places
Authors: Abi Rimmer
Journal: BMJ (2014)

The dean of medicine at the first private UK medical school1 has denied claims by the BMA that the school’s launch of an MBChB course could exacerbate oversubscription to the foundation programme.

The University of Buckingham’s medical school held an open day for prospective students on 15 January.

Samantha Dolan, the joint deputy chairwoman of the BMA’s medical students committee, warned that …
The role of <i>HNF4A</i> in <i>GATA4</i>-deficiency phenotypes of hepatocellular carcinoma.
Authors: Yu Bin Tan, Timothy Shuen, Han Chong Toh
Journal: Journal of Clinical Oncology (2018)

284 Background: Hepatocellular carcinoma (HCC) is the 2nd leading global cause of cancer death. Recently, we have discovered previously undescribed deletion and germline mutation of GATA4 and showed that GATA4 is a key differentiation driver and metabolic regulator in HCC. However, as GATA4 is mostly deleted in HCC, targeting GATA4-downstream molecules is ideal. In this study, proof-of-concept experiments were conducted to show that introduction of HNF4A, which is a GATA4-regulated downstream target, could partially rescue the impaired phenotypes in GATA4-deficient HCC cell line. Methods: Correlation analysis using gene expression microarray of human HCC samples was conducted to identify the genes that are positively correlated with GATA4. A transgenic mouse model with a liver-specific conditional GATA4 knockout was designed to identify liver morphology and gene expression changes which are correlated with the loss of Gata4 in the mouse liver. CRISPR-mediated knockout of GATA4 and lentiviral HNF4A overexpression was carried out in a GATA4-deficient HCC cell lines, PLC/PRF/5 and Hep3B, followed by proliferation, apoptosis, cell cycle and senescence functional assays. Results: Pearson correlation analysis from human HCC samples showed that expression of HNF4A is positively correlated with that of GATA4. Livers from conditional Gata4 knockout mice had lower Hnf4a gene expression when compared to age-matched control mice. Loss of function analysis by CRISPR-mediated GATA4 knockout further showed downregulation of HNF4A in GATA4-deficient PLC/PRF/5 cell line. Lentiviral HNF4A overexpression in PLC/PRF/5 and Hep3B demonstrated reduced proliferation and increased apoptosis while PLC/PRF/5 also showed cell cycle arrest at G2/M phase when compared to control. However, no senescence induction was detected in HNF4A-overexpressing cells. Conclusions: Transgenic mouse data, CRISPR-mediated knockout and analysis of HCC samples showed that HNF4A is a key GATA4-downstream target. HNF4A overexpression decreases proliferation, increases apoptosis and cell cycle arrest in GATA4-deficient HCC cell lines, thus representing a possible therapeutic target for HCC.
Incidences of visceral metastases from prostate cancer increase after progression of castration-resistant status.
Authors: Hiroaki Iwamoto, Kouji Izumi, Yoshifumi Kadono, Atsushi Mizokami
Journal: Journal of Clinical Oncology (2018)

291 Background: Recent advances in castration-resistant prostate cancer (CRPC) therapy are remarkable, but we often experience a case of visceral metastases caused after CRPC progression and few data regarding the onset of visceral metastases after CRPC are available. In the present study, we retrospectively examined visceral metastases of prostate cancer (PCa) at our hospital. Methods: Between 2000 and 2014, 1038 patients with PCa were treated at our hospital. We collected and retroactively analyzed data from medical charts. Variables of interest included the ratio to cause CRPC and visceral metastases, the relationship between the number of therapeutic agents and visceral metastases, overall survival (OS), etc. Results: Patients were diagnosed with T1-2 (72.1%), T3-4 (24.5%), N1 (10.3%), M1 (11.7%), and M1c (1.8 %). There were 144 (19.8 %) patients with CRPC and 43 (33.1%) patients with visceral metastases after CRPC progression. Patients with CRPC showed significantly longer OS than patients without CRPC (p &lt; 0.01). Of those with CRPC, patients with visceral metastases exhibited significantly shorter OS (p &lt; 0.01). Patients with liver/adrenal gland metastases exhibited the shortest OS of all patients with CRPC (p = 0.02). At diagnosis, the sites of visceral metastases included lung (89.5%), liver (5.3%), and adrenal glands (5.3%). After CRPC progression, new visceral metastases were found in the lung (47.3%), liver (43.6%), and adrenal gland (9.1%). Liver and adrenal gland metastases significantly increased after CRPC progression (p &lt; 0.01). Additionally, the rate of new visceral metastases significantly increased as the number of therapeutic agents increased (p &lt; 0.0001). The median number of therapeutic agents being used was determined at the onset of visceral metastases to the lung (1), liver , and adrenal grand (5) (p &lt; 0.001). Conclusions: Our findings confirmed that visceral metastases, especially liver and adrenal gland metastases, confer the worst survival. These metastases significantly increased as patients underwent powerful androgen deprivation therapy . Future prognostic improvements are expected through continued development of therapies for visceral metastases.
P300 brain-computer interface: comparing faces to size matched non-face stimuli
Authors: M. R. Kellicut-Jones, E. W. Sellers
Journal: Brain-Computer Interfaces (2018)

Non-invasive brain–computer interface (BCI) technology can restore communication for those unable to communicate due to loss of muscle control. Nonetheless, compared to augmentative and alternative communication (AAC) devices requiring muscular control, BCIs provide relatively slow communication. Therefore, implementing techniques improving BCI speed and accuracy is important. Previous studies indicate that facial stimuli elicit N170 and N400 components, in addition to the P300 component associated with P300 BCI. These additional components can increase speed and accuracy. Our study investigated the influence of image size and content using four conditions: large face, small face, large non-face, and small non-face. We predicted faces would provide higher accuracy than non-face stimuli and larger stimuli would provide higher accuracy than small stimuli. We found no significant difference in performance between conditions; however, significant waveform differences were found in each condition.
Improvement of immune response after radiofrequency ablation in colorectal cancer.
Authors: Katia Lemdani, Nathalie Mignet, Johanne Seguin, Frederique Peschaud, Jean-François Emile, Vincent Boudy, Claude Capron, Robert Malafosse
Journal: Journal of Clinical Oncology (2018)

102 Background: Radiofrequency ablation (RFA) efficiency of liver tumors is compromised by high rates of relapse. Death of cancer cells by hyperthermia induced tumor antigen releasing, expression of danger signals that activate a specific T-cell response. This effect is ineffective to avoid recurrence. We propose to combine RFA with priming of a strong immune antitumor response as curative treatment of an aggressive colorectal cancer (CRC) in immunocompetent mouse. Methods: RFA was used to treat a CT26- luc tumor as primary lesion. In two distinct clinical situations, macroscopic or microscopic distant tumors were established as secondary lesions. The immune response was modulated by the injection, in the treated area, of a thermo-reversible hydrogel loaded by GM-CSF and BCG, targeting recruitment and maturation of dendritic cells. In mice with far large lesions, this strategy was combined with PD1checkpoint inhibition. The efficiency was assessed on survival, evolution of distant lesions, characterization of tumoral lymphocyte infiltration TNF-α and IFN-y expression in peripheral T lymphocytes. Results: The in situ immunogel injection after RFA resulted in prolonged survival of mice. Regression of distant lesions was related to the induction of a strong systemic antitumor immune response and a great improvement of tumor infiltration by CD3 + T lymphocytes. In adjuvant situation, the use of immunogel induced a complete cure of microscopic secondary lesions without another treatment. Immune escape of large secondary lesions was reversed by association of the RFA-immunogel vaccination with a systemic immune checkpoint inhibition, separately ineffective. Conclusions: Validation of this strategy, combining RFA of macroscopic lesions and activation of a strong immune response controlling the residual disease, could result in the design of a clinical assay including this approach within a standard treatment of colorectal liver metastases. The synergy between in situ immunomodulation as priming process and checkpoint blockade, ineffective alone in metastatic microsatellite stable CRC or after single RFA, allows reconsidering the use of checkpoint inhibitors in CRC.
ADVICE ZONE SPECIAL: GETTING A JOB IN THE CITY
Authors: Christopher J Kelly
Journal: BMJ (2007)

Have a career related problem that needs answering? Can9t find the 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> <b>Christopher Kelly</b> answers the most common questions from his recent article “Banking on it”<sup>1</sup>
Transport of the critically ill patient
Authors: Garry Summers
Journal: BMJ (2012)

As a junior critical care doctor working in a district general hospital, I’ve occasionally been asked to transport a sick patient. Whether it’s from the intensive care unit to radiology, the emergency department to theatre, or the unsettling inter-hospital transfer, it can be a hair raising prospect. Up to this point I’d accomplished a few transfer missions with little more training than a few words of advice (“Keep them paralysed and they won’t pull out the tube”). Now I thought that it was time to learn how to do it properly.

It’s for anyone potentially involved in transfers, so the critical care realm was well represented. My group consisted mainly of emergency department doctors, who often take unwell patients to …