tbuckley/cabot-search huggingface dataset:
Keratin 19 Expression in Hepatocellular Carcinoma Is Regulated by Fibroblast-Derived HGF via a MET-ERK1/2-AP1 and SP1 Axis
Authors: Hyungjin Rhee, Hye-Young Kim, Ji-Hye Choi, Hyun Goo Woo, Jeong Eun Yoo, Ji Hae Nahm, Jin-Sub Choi, Young Nyun Park
Journal: Cancer Research (2018)

Keratin (KRT) 19 is a poor prognostic marker for hepatocellular carcinoma (HCC); however, regulatory mechanisms underlying its expression remain unclear. We have previously reported the presence of fibrous tumor stroma in KRT19-positive HCC, suggesting that cross-talk between cancer-associated fibroblasts (CAF) and tumor epithelial cells could regulate KRT19 expression. This was investigated in this study using an in vitro model of paracrine interaction between HCC cell lines (HepG2, SNU423) and hepatic stellate cells (HSC), a major source of hepatic myofibroblasts. HSCs upregulated transcription and translation of KRT19 in HCC cells via paracrine interactions. Mechanistically, hepatocyte growth factor (HGF) from HSCs activated c-MET and the MEK-ERK1/2 pathway, which upregulated KRT19 expression in HCC cells. Furthermore, AP1 (JUN/FOSL1) and SP1, downstream transcriptional activators of ERK1/2, activated KRT19 expression in HCC cells. In clinical specimens of human HCC (n = 339), HGF and KRT19 protein expression correlated with CAF levels. In addition, HGF or MET protein expression was associated with FOSL1 and KRT19 expression and was found to be a poor prognostic factor. Analysis of data from The Cancer Genome Atlas also revealed KRT19 expression was closely associated with CAF and MET-mediated signaling activities. These results provide insights into the molecular background of KRT19-positive HCC that display an aggressive phenotype.Significance: These findings reveal KRT19 expression in hepatocellular carcinoma is regulated by cross-talk between cancer-associated fibroblasts and HCC cells, illuminating new therapeutic targets for this aggressive disease. Cancer Res; 78(7); 1619-31. ©2018 AACR.
Almost all doctors now have revalidation support, but hospitals lag behind on appraisal
Authors: Caroline White
Journal: BMJ (2013)

Almost all doctors in England are now linked to organisations able to support their revalidation, but appraisal rates in hospitals “remain significantly behind” those in other sectors, the NHS’s Revalidation Support Team has found.

The team has prepared a report for the England Revalidation Implementation Board on the implementation of revalidation in England.1 The report draws on returns to the team’s Organisational Readiness Self-Assessment exercise and includes information on 161 453 doctors from 621 NHS and non-NHS bodies.

The report shows that, by 31 March 2013, 95% of practitioners were linked to organisations that were ready for revalidation. It also found that although the proportion of doctors who had …
Abstract P1-07-36: Outcomes and failure of primary endocrine therapy for operable breast cancer in the elderly: A regional North-east of England study
Authors: R Thomas, R Rowell, S Crichton, H Cain
Journal: Cancer Research (2018)

Abstract Introduction Primary Endocrine therapy (PET) to treat oestrogen receptor (ER) positive operable breast cancer in the elderly is used widely in the UK. A previous Cochrane analysis revealed its inferiority in long-term local control in comparison to surgery. As such, current guidance from the Society of International Geriatric Oncologists (SIOG) suggest that PET should be reserved for patients with a reduced life-expectancy (2-3 years) or for those considered unfit for surgery. Inaccurate assessment of life expectancy could lead to treatment failure which is potentially catastrophic for the patient. The aim of this study was to evaluate treatment failures in elderly breast cancer patients treated with PET and to determine predictors of failure. Methods A retrospective observational study was performed on consecutive patients with ER positive early stage breast cancer treated with PET between 2005 and 2015 in the three breast units in the north east of England. The primary outcome measure was treatment failure and the secondary outcome measure was disease progression. Results 488 patients were included with mean follow up 31 months (SD 23). 465 (95.2%) patients were started on Letrozole as their initial therapy. Overall, 206 patients were still alive with their disease controlled at the end of follow up, 219 had died with their disease controlled and 63 (12%) experienced treatment failure. Kaplan-Meier survival analysis predicted at 3 years 40% of patients to have died with controlled disease and 10% to have failed, leaving 50% living beyond this point with controlled disease. Regression analysis identified younger age [SHR 0.96 (95% CI 0.94 to 0.99) p 0.013], larger tumours [SHR 1.03 (1.01 to 1.06) p 0.015], grade 3 cancers [SHR 3.58 (1.93 to 6.63) p&amp;lt;0.001] and axillary lymph node metastases [SHR 1.93 (1.06 to 3.52) p 0.030] were all independent predictors of treatment failure. Disease progression was reported in 86 (17.6%) of patients. Conclusions This is the largest retrospective series conducted evaluating PET treatment failure. Our comparably low rate of failure in comparison to that in the literature (12-85%) reflects good clinical acumen. Clear predictors of failure have been identified, which support previous analyses, further validating our results. Patients are able to live longer term (beyond 3 years) and maintain local disease control, which may represent a viable long-term treatment in the absence of risk factors for failure. Further work on our series is underway examining the effect of decision-making on PET outcomes. Citation Format: Thomas R, Rowell R, Crichton S, Cain H. Outcomes and failure of primary endocrine therapy for operable breast cancer in the elderly: A regional North-east of England study [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 P1-07-36.
Viral Fitness Correlates with the Magnitude and Direction of the Perturbation Induced in the Host’s Transcriptome: The Tobacco Etch Potyvirus—Tobacco Case Study
Authors: Héctor Cervera, Silvia Ambrós, Guillermo P Bernet, Guillermo Rodrigo, Santiago F Elena
Journal: Molecular Biology and Evolution (2018)

Determining the fitness of viral genotypes has become a standard practice in virology as it is essential to evaluate their evolutionary potential. Darwinian fitness, defined as the advantage of a given genotype with respect to a reference one, is a complex property that captures, in a single figure, differences in performance at every stage of viral infection. To what extent does viral fitness result from specific molecular interactions with host factors and regulatory networks during infection? Can we identify host genes in functional classes whose expression depends on viral fitness? Here, we compared the transcriptomes of tobacco plants infected with seven genotypes of tobacco etch potyvirus that differ in fitness. We found that the larger the fitness differences among genotypes, the more dissimilar the transcriptomic profiles are. Consistently, two different mutations, one in the viral RNA polymerase and another in the viral suppressor of RNA silencing, resulted in significantly similar gene expression profiles. Moreover, we identified host genes whose expression showed a significant correlation, positive or negative, with the virus' fitness. Differentially expressed genes which were positively correlated with viral fitness activate hormone- and RNA silencing-mediated pathways of plant defense. In contrast, those that were negatively correlated with fitness affect metabolism, reducing growth, and development. Overall, these results reveal the high information content of viral fitness and suggest its potential use to predict differences in genomic profiles of infected hosts.
Abstract OT2-01-01: Observational study of axilla treatment for breast cancer patients with 1 to 3 positive micrometastases or macrometastases in sentinel lymph nodes
Authors: S Imoto, M Saito Oba, N Masuda, T Nagashima, N Wada, T Takashima, M Kitada, M Kawada, T Hayashida, T Taguchi, T Aihara, D Miura, U Toh, M Yoshida, S Sugae, K Yoneyama, H Matsumoto, H Jinno, J Sakamoto
Journal: Cancer Research (2018)

Abstract [Background] Axilla surgery in node-positive breast cancer is dramatically changing from axillary lymph node dissection (ALND) to sentinel node biopsy (SNB). From the results of ACOSOG Z0011, IBCSG23-01 and AMAROS trials, adjuvant therapy and regional node irradiation could reduce regional lymph node recurrence for sentinel node-positive breast cancer patients. However, optimal indication of SNB alone remains uncertain. Trial design: To evaluate the outcome of sentinel node-positive breast cancer patients, the Japanese Society for Sentinel Node Navigation Surgery (SNNS) conducted a prospective cohort study in 2013 (UMIN000011782, Jpn J Clin Oncol, p.876-9, 2014). [Eligibility criteria] For eligible patients, SNB was performed or scheduled after 1 January 2012. Then 1 to 3 positive micrometastases or macrometastases in sentinel lymph nodes are confirmed by histological or molecular diagnosis. Primary chemotherapy before or after SNB is also acceptable for registration. [Specific aims] The primary endpoint is the 5-year recurrence rate of regional lymph node in patients treated with SNB alone. The secondary endpoint is the 5-year overall survival rate of this cohort. Patients treated with SNB followed by ALND are also registered simultaneously to compare the prognosis. The propensity score matching (PSM) is used to make the distributions of baseline risk factors comparable. [Statistical method] Based on an estimated recurrence rate of 5% at 5 years among patients treated with SNB alone, 240 patients are needed to give a 80% power to reject the null hypothesis that the recurrence rate is 10% with a one-sided type I error rate of 2.5%. If we consider that some patients will be lost to follow-up or become ineligible, a total of 250 patients will be needed to comprise the sample. [Present accrual] Eight hundred and eighty patients who underwent SNB alone or SNB followed by ALND were registered from 27 participating institutes between 2013 and 2016. Data cleaning is being performed. Patient's background and PSM will be reported. Citation Format: Imoto S, Saito Oba M, Masuda N, Nagashima T, Wada N, Takashima T, Kitada M, Kawada M, Hayashida T, Taguchi T, Aihara T, Miura D, Toh U, Yoshida M, Sugae S, Yoneyama K, Matsumoto H, Jinno H, Sakamoto J. Observational study of axilla treatment for breast cancer patients with 1 to 3 positive micrometastases or macrometastases in sentinel lymph nodes [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 OT2-01-01.
Abstract P1-02-09: Targeting breast cancer stem cell state equilibrium through modulation of redox signaling
Authors: M Luo, L Shang, M Brooks, E Jiagge, Y Zhu, S Conley, MA Fath, R Harouaka, SD Merajver, DR Spitz, MS Wicha
Journal: Cancer Research (2018)

Abstract Breast cancer stem cells (BCSCs) maintain the plasticity to transition between quiescent mesenchymal- (M) and proliferative epithelial-like (E) states, but how this plasticity is regulated under metabolic/oxidative stress is poorly understood. Here, we show that M- and E-BCSCs exhibit markedly different sensitivities to the inhibitors of glycolysis and redox metabolism. Metabolic/Oxidative stress generated by 2DG/H2O2 or hypoxia promotes ROSlo M-BCSCs transition to their ROShi E-state. This transition is reversed by the antioxidant N-acetyl cysteine and facilitated by the activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust expression of NRF2/NFE2L2 and a wide variety of NRF2 downstream antioxidant responsive genes including the family of drug transporters and detoxification enzymes, NADPH production as well as the thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Suppression of NRF2 activity by a small-molecular inhibitor Trigonelline or shNRF2 mediated knockdown significantly decreased ALDH+ E- but not CD24-CD44+ M-BCSCs. This specific vulnerability of E-BCSCs to the inhibition of NRF2-mediated antioxidant defenses was also observed following inhibition of the downstream TXN and GSH antioxidant pathways, which promotes ROS-mediated differentiation and subsequent apoptosis of E-BCSCs. Co-inhibition of glycolysis and TXN/GSH pathways synergistically suppressed tumor growth and tumor initiating potential in two patient-derived xenograft models of triple negative breast cancer by eliminating both M- and E-BCSCs. Together, our studies reveal novel cellular and molecular mechanisms demonstrating how modulation of redox signaling regulates the equilibrium of two distinct BCSC states. These studies define the metabolic vulnerabilities of M- and E-BCSCs, and also provide a novel therapeutic approach to collectively target these distinct CSC states. As the CSC state equilibrium may be similarly regulated across a spectrum of tumors with diverse oncogenic drivers, this approach may have broad therapeutic applicability. Citation Format: Luo M, Shang L, Brooks M, Jiagge E, Zhu Y, Conley S, Fath MA, Harouaka R, Merajver SD, Spitz DR, Wicha MS. Targeting breast cancer stem cell state equilibrium through modulation of redox signaling [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 P1-02-09.
GMC considers removing link between trainees’ revalidation date and CCT
Authors: Abi Rimmer
Journal: BMJ (2014)

The General Medical Council is considering removing the link between the date when trainees obtain their certificate of completion of training (CCT) and their revalidation date.

Board papers presented to a meeting of the GMC’s revalidation implementation advisory board on 13 December 2013 said that the regulator was considering amending its current processes so that doctors in training were revalidated once every five years, in line with all other doctors.1

Currently doctors in training are revalidated every five years …
Ambient ozone and influenza transmissibility in Hong Kong
Authors: Sheikh Taslim Ali, Peng Wu, Simon Cauchemez, Daihai He, Vicky J. Fang, Benjamin J. Cowling, Linwei Tian
Journal: European Respiratory Journal (2018)

Understanding the environmental drivers of influenza transmissibility would contribute to the early intervention and long-term control strategies of seasonal influenza, a serious public health problem that causes considerable morbidity and mortality each year. Within the burgeoning literature on influenza transmission, there are conflicting lines of evidence on the role of the environment [1]. Besides meteorological factors, it is also uncertain how common air pollutants such as ozone (O3), sulfur dioxides (SO2), nitrogen dioxide (NO2), nitric oxide (NO) and particulate matter may affect influenza transmission [2]. The objective of our study was to examine the relationship of influenza transmissibility in Hong Kong with common air pollutants and other environmental factors, including ultraviolet radiation and absolute humidity. Higher levels of ambient ozone are associated with reduced influenza transmissibility <http://ow.ly/zr9030j3Tcn> The authors thank Julie Au (The University of Hong Kong, Hong Kong Special Administrative Region, China) for technical assistance.
Emergency obstetric and newborn care: life saving skills course (LSS EOC &amp; NC)
Authors: Emma Hulme
Journal: BMJ (2009)

Each year, more than 529 000 women die from the complications of pregnancy and childbirth. In 2006 the Royal College of Obstetricians and Gynaecologists in partnership with the Liverpool School of Tropical Medicine introduced a course providing training in essential obstetric and newborn care structured around the leading causes of maternal mortality, with an emphasis on practice in poor settings. In June 2008 (24-26) I attended the course as I was about to embark on a year’s mission work in a rural Ugandan hospital. I had only four months obstetric and gynaecology training as a foundation house officer 2 and thought the course might somewhat prepare me. Now two months into my new role the course …
Kir2.1 Interaction with Stk38 Promotes Invasion and Metastasis of Human Gastric Cancer by Enhancing MEKK2–MEK1/2–ERK1/2 Signaling
Authors: Cheng-Dong Ji, Yan-Xia Wang, Dong-Fang Xiang, Qiang Liu, Zhi-Hua Zhou, Feng Qian, Lang Yang, Yong Ren, Wei Cui, Sen-Lin Xu, Xi-Long Zhao, Xia Zhang, Yan Wang, Peng Zhang, Ji-Ming Wang, You-Hong Cui, Xiu-Wu Bian
Journal: Cancer Research (2018)

Potassium ion channels are emerging as promalignant factors involved in cancer progression. In this study, we found that invading human gastric cancer cells express high levels of inwardly rectifying potassium channel 2.1 (Kir2.1). Silencing Kir2.1 markedly reduced the invasive and metastatic capabilities as well as the epithelial-mesenchymal transition (EMT) of gastric cancer cells. The promalignant nature of Kir2.1 in gastric cancer cells was independent of potassium permeation but relied on its interaction with serine/threonine-protein kinase 38 (Stk38) to inhibit ubiquitination and degradation of mitogen-activated protein kinase kinase kinase 2 (MEKK2). Degradation of MEKK2 was mediated by small mothers against decapentaplegic-specific E3 ubiquitin protein ligase 1 (Smurf1), which resulted in activation of the MEK1/2-ERK1/2-Snail pathway in gastric cancer cells. In human gastric cancer tissues, expression was high and positively correlated with invasion depth and metastatic status of the tumors as well as poor overall patient survival. Cox regression analysis identified Kir2.1 as an independent prognostic indicator for patients with gastric cancer. Our results suggest that Kir2.1 is an important regulator of gastric cancer malignancy and acts as a novel prognostic marker and a therapeutic target for gastric cancer.
Transoral Endoscopic Thyroidectomy—An Emerging Remote Access Technique for Thyroid Excision
Authors: William B. Inabnet, Gustavo Fernandez-Ranvier, Hyunsuk Suh
Journal: JAMA Surgery (2018)

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Abstract 17064: Number of Circulating Progenitor Cells in Hypertensive Symptomatic Women With Non-obstructive CAD: a Substudy of NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation-Cardiovascular Disease Cohort (WISE-CVD)
Authors: Mahan Shahrivari, Mark S Segal, C. Noel Bairey Merz, Arshed A Quyyumi, Edmund K Waller, Carl J Pepine
Journal: Circulation (2016)

Introduction:  Hypertension (HTN) is associated with inflammation and loss of structural integrity and functional impairment of the vasculature and among women carries the highest attributable risk of mortality. Circulating progenitor cells (PCs) play a key role in endothelial homoeostasis and promote vascular repair. Reductions of circulating PCs and their functional activity are associated with cardiovascular risk factors, but the relation between HTN and PCs remains unclear.   Objective:  To test the hypothesis that numbers of circulating PCs are related to systolic blood pressure (SBP) in women with symptoms/signs of ischemic heart disease (IHD) without obstructive CAD.   Methods:  Circulating PC counts were measured using flow cytometry for expression of CD34, CD133, CXCR4 and VEGFR2 epitopes on CD45med mononuclear cells from peripheral blood of 285 women enrolled in the WISE-CVD cohort. Correlation analyses were conducted between SBP and circulating PC numbers.   Results:  The age of these women was 60±11 years (mean±SD), 34% had a history of HTN, 10% diabetes, 10% hyperlipidemia, and 7% smoking. Higher SBP correlated with lower circulating levels of CD34+ (r=-0.19, p=0.001), CD34+/CD133+ (r=-0.20, p=0.001), CD34+/CXCR4+ (r=-0.14, p=0.01), and CD34+/CXCR4+/CD133+ (r=-0.15, p=0.01). In multivariate analysis after adjusting for CAD, diabetes, hyperlipidemia, and usage of antihypertensive medications, SBP remained significantly associated with lower CD34+ (beta coefficient= -2.95, p=0.004), CD34+/CD133+ (beta coefficient= -3.48, p   Conclusions:  Among women with symptoms/signs of IHD without obstructive CAD, there is a significant association between SBP and reduced fraction of circulating PCs. Less circulating PCs may contribute to impaired vascular repair among women with HTN. These findings merit further investigation in other cohorts.
Transcriptomic landscape of acute promyelocytic leukemia reveals aberrant surface expression of the platelet aggregation agonist Podoplanin
Authors: Vincent-Philippe Lavallée, Jalila Chagraoui, Tara MacRae, Miriam Marquis, Arnaud Bonnefoy, Jana Krosl, Sébastien Lemieux, Anne Marinier, Caroline Pabst, Georges-Étienne Rivard, Josée Hébert, Guy Sauvageau
Journal: Leukemia (2018)
Sustained long-lasting responses after lenalidomide discontinuation in patients with chronic lymphocytic leukemia
Authors: Paolo Strati, Alessandra Ferrajoli, William G. Wierda, Nitin Jain, Philip A. Thompson, Susan M. O’Brien, Katy Rezvani, Hagop M. Kantarjian, Jan A. Burger, Christina O. Hinojosa, Michael J. Keating, Zeev Estrov
Journal: Leukemia (2018)
After two years of anaesthetics, I am considering a change of career to general practice. Will these two years count? If I take and pass the first part of the FRCA, could I do occasional lists at a local hospital once I am a GP?
Authors: Roger Charlton
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>
THE VOLUME OF DENERVATED MYOCARDIUM PREDICTS SUDDEN CARDIAC DEATH (SCD) AND ICD THERAPIES FOR VF BUT NOT ICD THERAPIES FOR SLOWER VENTRICULAR TACHYARRHYTHMIA (VT): AN ANALYSIS OF THE PREDICTION OF ARRHYTHMIC EVENTS WITH POSITRON EMISSION TOMOGRAPHY (PAREPET) STUDY
Authors: Vasvi Singh, Saurabh Malhotra, John Canty, James Fallavollita
Journal: Journal of the American College of Cardiology (2018)
Editor’s Choice: Team talk
Authors: Tom Moberly
Journal: BMJ (2015)

Discussion of doctors’ communication most often focuses on the messages that doctors provide, intentionally or unintentionally, to patients. But the roots of many complaints about care of patients, malpractice claims, and disciplinary procedures lie in the mix-ups, omissions, and misunderstandings that occur in the communication between one doctor and another.

A 2009 review of the care of patients who died in hospital …