tbuckley/cabot-search huggingface dataset:
Competition ratios for different specialties and the effect of gender and immigration status
Authors: Scarlett A McNally
Journal: Journal of the Royal Society of Medicine (2008)

Some specialties have always been very competitive. Careers advice for medical students and junior doctors is often patchy.1–3 The Medical Schools Council reported ‘an urgent need’ for medical schools to provide more comprehensive information regarding careers.4 Competition ratios have been published, but these were only to be found in obscure human resources publications5 until Shelley Heard's recent paper in the BMJ Career Focus.6 None of these previous studies mentioned the immigration status of applicants, or the extreme gender differences in applications for different specialties.

There has always been a career-defining moment when a junior doctor obtains a training post in his/her chosen specialty with a National Training Number (NTN). Until 2007, an NTN was only awarded with a Specialist Registrar (SpR) post in the chosen specialty, often following several years in the Senior House Officer (SHO) grade. Modernising Medical Careers (MMC) was an initiative to streamline training and move the career-defining moment to an earlier point in a doctor's career.3,7 There has been little mention of how to select candidates for those popular specialties where 90% of applicants currently do not get a post. With selection occurring earlier, there is even less to choose between candidates. The Tooke report into MMC has recommended moving the career-defining moment two years later, but this is still much earlier than occurred in many specialties prior to 2007.8
Common Variation at<i>BARD1</i>Results in the Expression of an Oncogenic Isoform That Influences Neuroblastoma Susceptibility and Oncogenicity
Authors: Kristopher R. Bosse, Sharon J. Diskin, Kristina A. Cole, Andrew C. Wood, Robert W. Schnepp, Geoffrey Norris, Le B. Nguyen, Jayanti Jagannathan, Michael Laquaglia, Cynthia Winter, Maura Diamond, Cuiping Hou, Edward F. Attiyeh, Yael P. Mosse, Vanessa Pineros, Eva Dizin, Yongqiang Zhang, Shahab Asgharzadeh, Robert C. Seeger, Mario Capasso, Bruce R. Pawel, Marcella Devoto, Hakon Hakonarson, Eric F. Rappaport, Irmgard Irminger-Finger, John M. Maris
Journal: Cancer Research (2012)

Abstract The mechanisms underlying genetic susceptibility at loci discovered by genome-wide association study (GWAS) approaches in human cancer remain largely undefined. In this study, we characterized the high-risk neuroblastoma association at the BRCA1-related locus, BARD1, showing that disease-associated variations correlate with increased expression of the oncogenically activated isoform, BARD1β. In neuroblastoma cells, silencing of BARD1β showed genotype-specific cytotoxic effects, including decreased substrate-adherence, anchorage-independence, and foci growth. In established murine fibroblasts, overexpression of BARD1β was sufficient for neoplastic transformation. BARD1β stabilized the Aurora family of kinases in neuroblastoma cells, suggesting both a mechanism for the observed effect and a potential therapeutic strategy. Together, our findings identify BARD1β as an oncogenic driver of high-risk neuroblastoma tumorigenesis, and more generally, they illustrate how robust GWAS signals offer genomic landmarks to identify molecular mechanisms involved in both tumor initiation and malignant progression. The interaction of BARD1β with the Aurora family of kinases lends strong support to the ongoing work to develop Aurora kinase inhibitors for clinically aggressive neuroblastoma. Cancer Res; 72(8); 2068–78. ©2012 AACR.
Identification of Toll-Like Receptor 3 as a Potential Therapeutic Target in Clear Cell Renal Cell Carcinoma
Authors: Teppei Morikawa, Akira Sugiyama, Haruki Kume, Satoshi Ota, Takeshi Kashima, Kyoichi Tomita, Tadaichi Kitamura, Tatsuhiko Kodama, Masashi Fukayama, Hiroyuki Aburatani
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Renal cell carcinoma (RCC) is one of the most drug-refractory cancers. The aim of this study is to discover a novel therapeutic target molecule for clear cell RCC (CCRCC), which accounts for the majority of RCC. Experimental Design: Gene expression profiles of 27 CCRCCs and 9 normal kidney tissues as well as 15 various adult normal tissues were examined by Affymetrix U133 Plus 2.0 arrays. Among the 34 genes specifically up-regulated in CCRCC, overexpression of Toll-like receptor 3 (TLR3) mRNA and its protein was validated by quantitative reverse transcription-PCR, immunoblot, and immunohistochemistry. The effects of TLR3 signaling on in vitro cell growth were examined. Results: TLR3 gene was highly expressed in CCRCC, with only limited expression in a panel of normal tissues. On immunohistochemical analysis using a monoclonal antibody against TLR3, overexpression of TLR3 was observed in 139 of 189 (73.5%) cases of CCRCC as well as in lung metastatic CCRCC (6 of 8), whereas TLR3 expression was entirely absent in chromophobe RCC (0 of 8). Polyinosinic-polycytidilic acid, a TLR3 ligand, exerted a growth-inhibitory effect against RCC cells in a TLR3-dependent manner. Moreover, a combination of polyinosinic-polycytidilic acid and IFNα exerted a synergistic growth-inhibitory effect against Caki-1 RCC cells. Conclusions: This is the first report that TLR3 is overexpressed in CCRCC. These observations suggest that TLR3 pathway may represent a novel therapeutic target in CCRCC.
The ASRG database: identification and survey of Arabidopsis thalianagenes involved in pre-mRNA splicing
Authors: Bing-Bing Wang, Volker Brendel
Journal: Genome biology (2004)

Abstract A total of 74 small nuclear RNA (snRNA) genes and 395 genes encoding splicing-related proteins were identified in the Arabidopsis genome by sequence comparison and motif searches, including the previously elusive U4atac snRNA gene. Most of the genes have not been studied experimentally. Classification of these genes and detailed information on gene structure, alternative splicing, gene duplications and phylogenetic relationships are made accessible as a comprehensive database of Arabidopsis Splicing Related Genes (ASRG) on our website.
Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism
Authors: Augusto Zani, Mara Cananzi, Francesco Fascetti-Leon, Giuseppe Lauriti, Virpi V Smith, Sveva Bollini, Marco Ghionzoli, Antonello D'Arrigo, Michela Pozzobon, Martina Piccoli, Amy Hicks, Jack Wells, Bernard Siow, Neil J Sebire, Colin Bishop, Alberta Leon, Anthony Atala, Mark F Lythgoe, Agostino Pierro, Simon Eaton, Paolo De Coppi
Journal: Gut (2013)

<h3>Objective</h3> Necrotising enterocolitis (NEC) remains one of the primary causes of morbidity and mortality in neonates and alternative strategies are needed. Stem cells have become a therapeutic option for other intestinal diseases, which share some features with NEC. We tested the hypothesis that amniotic fluid stem (AFS) cells exerted a beneficial effect in a neonatal rat model of NEC. <h3>Design</h3> Rats intraperitoneally injected with AFS cells and their controls (bone marrow mesenchymal stem cells, myoblast) were analysed for survival, behaviour, bowel imaging (MRI scan), histology, bowel absorption and motility, immunofluorescence for AFS cell detection, degree of gut inflammation (myeloperoxidase and malondialdehyde), and enterocyte apoptosis and proliferation. <h3>Results</h3> AFS cells integrated in the bowel wall and improved rat survival and clinical conditions, decreased NEC incidence and macroscopic gut damage, improved intestinal function, decreased bowel inflammation, increased enterocyte proliferation and reduced apoptosis. The beneficial effect was achieved via modulation of stromal cells expressing cyclooxygenase 2 in the lamina propria, as shown by survival studies using selective and non-selective cyclooxygenase 2 inhibitors. Interestingly, AFS cells differentially expressed genes of the Wnt/β-catenin pathway, which regulate intestinal epithelial stem cell function and cell migration and growth factors known to maintain gut epithelial integrity and reduce mucosal injury. <h3>Conclusions</h3> We demonstrated here for the first time that AFS cells injected in an established model of NEC improve survival, clinical status, gut structure and function. Understanding the mechanism of this effect may help us to develop new cellular or pharmacological therapies for infants with NEC.
Association of serum total bilirubin with renal outcome in Japanese patients with stages 3–5 chronic kidney disease
Authors: Teppei Sakoh, Masaru Nakayama, Shigeru Tanaka, Ryota Yoshitomi, Yoriko Ura, Hitomi Nishimoto, Akiko Fukui, Yui Shikuwa, Kazuhiko Tsuruya, Takanari Kitazono
Journal: Metabolism (2015)
Fish oil therapy for IgA nephropathy
Authors: J J Dillon
Journal: Journal of the American Society of Nephrology (1997)

Published reports examining the efficacy of fish oil for preserving renal function in immunoglobulin A (IgA) nephropathy have yielded conflicting results. This investigation was a meta-analysis conducted to determine whether the medical literature supports this therapy. In addition, the sources of variability among published findings were examined. Studies were combined using a random effects model. Five controlled studies were identified, two with positive results and three with negative results. Forty-four percent of the between-study variance could be attributed to differences in follow-up times and, less significantly, the number of renal function measurements; a weighting procedure was developed, eliminating this variance from the combined result. When all studies were combined, the mean effect, +0.25 +/- 0.23 SD (positive effects indicate that treatment was superior to control), was not statistically significant; however, the probability of at least a minor beneficial effect was 75%. Mixed-effects regression suggested that this therapy may be more effective among individuals with more proteinuria. The medical literature, therefore, does not prove the efficacy of fish oil therapy in IgA nephropathy, but suggests that an additional placebo-controlled trial is warranted. A sample-size calculation indicated that such a trial should be larger than those to date or should attempt to increase the treatment effect, perhaps by treating for more than 2 yr or enrolling more severely proteinuric individuals.
So many polyps, so little time: where will our bowel cancer screening colonoscopists come from?
Authors: A. Watson, L. Coleman, A. Haycock, J. Anderson, J. Jankowski, S. Preston
Journal: Gut (2011)

<h3>Introduction</h3> The UK Bowel Cancer Screening Programme (BCSP) aims to reduce colorectal cancer death by removing colonic polyps from FOB positive patients between the ages of 60 and 69. The BCSP relies on skilled, accredited colonoscopists. Between 2006 and 2010, the number of BCSP colonoscopies has risen from 300 to 32 000; this is likely to rise due to increasing FOB testing, follow-up colonoscopies, age-expansion to 75 years and introduction of flexible sigmoidoscopy. There are currently 236 accredited BCSP colonoscopists in the UK. A shortage of BCSP colonoscopists is likely to arise. <h3>Methods</h3> In 2009 an informal survey of gastroenterology trainees revealed only 4/52 with an interest in becoming a BCSP colonoscopist. The 2010 BSG/TiG National Training Survey more accurately assessed gastroenterology manpower as part of a comprehensive online survey that included several questions regarding the BCSP. <h3>Results</h3> There were 283 respondents (approx 36% of trainees nationally). 61.4% (156/254) said there was a ‘moderate’ or ‘large’ amount of exposure to the BCSP in their region. 10.6% (27/254) had ‘no exposure’ to the BCSP. This indicates trainees have a good awareness of the BCSP. Over half (142/256) were aware of the application criteria to become a BCSP colonoscopist. 164/256 (64%) expressed a moderate or high level of interest in becoming a BCSP colonoscopist. Trainees were asked what deterred them from becoming BCSP colonoscopists. Reasons were ranked on a scale of 1 –7 (1 being most relevant). The most common reason for not becoming a BCSP colonoscopist was ‘other pressures on time’ (53.8% giving 1/7 or 2/7). Also of concern was the ‘lack of training in advanced techniques’ (41.7% giving a score of 1/7 or 2/7). 170/250 (68%) of respondents believed their chances of becoming a BCSP colonoscopist were either strong (30/250, 12%) or reasonable (140/250, 56%). <h3>Conclusion</h3> The 2009 the BSG/TiG Manpower data1 indicates there were 1041 consultant gastroenterologists and 795 trainees nationally, with an annual increase of 5% and 7% respectively. With only small increases in the total numbers of consultant gastroenterologists there are significant implications for service provision. Solutions may include increased use of nurse endoscopists, foreign-trained endoscopists or encouragement and more supportive training for new consultants. Any proposed solution will require adherence to good training, accreditation and standards to ensure the continued success of the BCSP.
Comparison of sleep in osteoarthritic patients and age and sex matched healthy controls.
Authors: T J Leigh, I Hindmarch, H A Bird, V Wright
Journal: Annals of the Rheumatic Diseases (1988)

A sleep laboratory comparison of the sleep of 14 osteoarthritic patients with that of 16 age and sex matched healthy controls was undertaken. After three nights of adaptation continuous recordings of electroencephalographic (EEG), electro-oculographic (EOG), and electromyographic (EMG) activity were obtained for the next two nights. A comparison of EEG sleep variables during this baseline period showed that osteoarthritic patients had a significantly greater percentage of stage 1 and significantly smaller percentage of stage 2 sleep than control subjects. These findings indicate sleep disturbance in osteoarthritic patients. The limited degree of disturbance observed in these patients may be due to the fact that they were allowed to continue with their normal anti-inflammatory and analgesic medication for the course of the study.
Sodium-Dependent Regulation of Renal Amiloride-Sensitive Currents by Apical P2 Receptors
Authors: Scott S.P. Wildman, Joanne Marks, Clare M. Turner, Liang Yew-Booth, Claire M. Peppiatt-Wildman, Brian F. King, David G. Shirley, WenHui Wang, Robert J. Unwin
Journal: Journal of the American Society of Nephrology (2008)

The epithelial sodium channel (ENaC) plays a major role in the regulation of sodium balance and BP by controlling Na(+) reabsorption along the renal distal tubule and collecting duct (CD). ENaC activity is affected by extracellular nucleotides acting on P2 receptors (P2R); however, there remain uncertainties over the P2R subtype(s) involved, the molecular mechanism(s) responsible, and their physiologic role. This study investigated the relationship between apical P2R and ENaC activity by assessing the effects of P2R agonists on amiloride-sensitive current in the rat CD. Using whole-cell patch clamp of principal cells of split-open CD from Na(+)-restricted rats, in combination with immunohistochemistry and real-time PCR, we found that activation of metabotropic P2R (most likely the P2Y(2) and/or (4) subtype), via phospholipase C, inhibited ENaC activity. In addition, activation of ionotropic P2R (most likely the P2X(4) and/or (4/6) subtype), via phosphatidylinositol-3 kinase, either inhibited or potentiated ENaC activity, depending on the extracellular Na(+) concentration; therefore, it is proposed that P2X(4) and/or (4/6) receptors might function as apical Na(+) sensors responsible for local regulation of ENaC activity in the CD and could thereby help to regulate Na(+) balance and systemic BP.
The Role of DNA Polymerase η in Translesion Synthesis Past Platinum–DNA Adducts in Human Fibroblasts
Authors: Ekaterina Bassett, Nicole M. King, Miriam F. Bryant, Suzanne Hector, Lakshmi Pendyala, Stephen G. Chaney, Marila Cordeiro-Stone
Journal: Cancer Research (2004)

Abstract Cisplatin, a widely used chemotherapeutic agent, has been implicated in the induction of secondary tumors in cancer patients. This drug is presumed to be mutagenic because of error-prone translesion synthesis of cisplatin adducts in DNA. Oxaliplatin is effective in cisplatin-resistant tumors, but its mutagenicity in humans has not been reported. The polymerases involved in bypass of cisplatin and oxaliplatin adducts in vivo are not known. DNA polymerase η is the most efficient polymerase for bypassing platinum adducts in vitro. We evaluated the role of polymerase η in translesion synthesis past platinum adducts by determining cytotoxicity and induced mutation frequencies at the hypoxanthine guanine phosphoribosyltransferase (HPRT) locus in diploid human fibroblasts. Normal human fibroblasts (NHF1) were compared with xeroderma pigmentosum variant (XPV) cells (polymerase η-null) after treatment with cisplatin. In addition, XPV cells complemented for polymerase η expression were compared with the isogenic cells carrying the empty expression vector. Cytotoxicity and induced mutagenicity experiments were measured in parallel in UVC-irradiated fibroblasts. We found that equitoxic doses of cisplatin induced mutations in fibroblasts lacking polymerase η at frequencies 2- to 2.5-fold higher than in fibroblasts with either normal or high levels of polymerase η. These results indicate that polymerase η is involved in error-free translesion synthesis past some cisplatin adducts. We also found that per lethal event, cisplatin was less mutagenic than UVC. Treatment with a wide range of cytotoxic doses of oxaliplatin did not induce mutations above background levels in cells either expressing or lacking polymerase η, suggesting that oxaliplatin is nonmutagenic in human fibroblasts.
Smoking Amplifies Cardiovascular Risk in Patients With Hypertension and Diabetes
Authors: Robert H. Fagard
Journal: Diabetes Care (2009)

Smoking is considered an important “risk factor” for arterial hypertension and diabetes management, according to, respectively, the current guidelines of the European Society of Hypertension and the European Society of Cardiology on the management of arterial hypertension (1) and the guidelines on diabetes of the European Society of Cardiology and the European Association for the Study of Diabetes (2). The aim of the current article is to further evaluate the effect of smoking on mortality and cause-specific cardiovascular events in hypertension and in diabetes and to assess whether there is a significant interaction between the effects of smoking and diabetes.

To assess the effect of smoking on mortality and cause-specific cardiovascular events, and the interaction between smoking and diabetes, we analyzed a database of 3,468 hypertensive patients without major cardiovascular disease at baseline and with prospective follow-up for morbidity and mortality (3). The database consists of individual data of hypertensive patients from four prospective studies performed in Europe (4–7). Age of the subjects averaged 61 ± 13 years (mean ± SD), 45% were men, and 61% were under antihypertensive treatment at baseline. Office blood pressure averaged 159.0 ± 19.9/91.0 ± 11.7 mmHg and 24-h ambulatory blood pressure 138.1 ± 16.4/82.3 ± 11.0 mmHg. Current smoking and diabetes were coded as yes or no at the baseline examination; 13.7% of the patients smoked and 8.4% had diabetes. We used Cox proportional hazards regression analysis to assess the prognostic significance of smoking, with stratification for study and adjustment for age, sex, diabetes, total cholesterol, 24-h systolic blood pressure, antihypertensive treatment, and BMI. The average 24-h blood pressure was used because its predictive power has been shown to be superior to that of office blood pressure (3). Median follow-up time was 6.57 years (range 0.08–13.1) and total follow-up time amounted to …
Antibodies to GAD and Glycemic Control in Recent-Onset IDDM
Authors: Robert D Hoeldtke, Kimberly D Bryner, Gabriella G Horvath, Michele R Byerly, Gerald R Hobbs, Santica M Marcovina, Ake Lernmark
Journal: Diabetes Care (1997)

OBJECTIVE To analyze the effect of antibodies to glutamic acid decarboxylase (GAD65Ab) and islet cells (ICA512Ab) on glycemic control early in IDDM. RESEARCH DESIGN AND METHODS GAD65Ab and ICA512Ab were measured twice in 35 patients (10 male, 25 female; age 10–40 years) initially within 2 years of diagnosis and again 1 year later. The glycosylated hemoglobin was measured one to four times each year, and the average glycosylated hemoglobin for the preceding year was calculated each time the antibodies were measured. RESULTS The mean HbA1 at the time of the initial evaluation was 8.04 ± 0.30 (reference range 4.7–7.3% for nondiabetic patients), the average GAD65Ab index was 0.735 ± 0.306, and the mean ICA512Ab index was 1.94 ± 0.65. The GAD65Ab index correlated with HbA1 (r = 0.41, P &amp;lt; 0.025), whereas the ICA512Ab index did not (r = 0.13). One year later, the mean GAD65Ab index was 0.94 ± 0.34, the mean ICA512Ab index was 1.04 ± 0.40, and the mean HbA1 was 9.03 ± 0.30. The GAD65Ab index correlated with HbA1 (r = 0.61 P &amp;lt; 0.001), whereas the ICA512Ab index did not (r = −0.06). Stratification of patients into tertiles according to the average GAD65 index revealed, at the follow-up evaluation, that the better glycemic control in the lowest GAD65Ab tertile was accomplished with significantly less insulin (0.43 ± 0.08 U/kg for the lowest tertile vs. 0.71 ± 0.09 and 0.64 ± 0.09 for the middle and highest tertiles, respectively; P &amp;lt; 0.05). CONCLUSIONS In summary, patients with IDDM and low GAD65Ab have better glycemic control even though they require less insulin. The ICA512Ab index, however, fails to correlate with glycemia.
Human T cell activation. II. A new activation pathway used by a major T cell population via a disulfide-bonded dimer of a 44 kilodalton polypeptide (9.3 antigen).
Authors: T Hara, S M Fu, J A Hansen
Journal: The Journal of Experimental Medicine (1985)

In previous studies (17-21), monoclonal antibody (mAb) 9.3 has been shown to react with a major population of human T cells, which include T4+ helper/inducer T cells and T8+ cytotoxic T cells. In this investigation, mAb 9.3 was shown to precipitate a disulfide-bonded dimer of a 44 kD polypeptide. Comodulation experiments showed that this molecule is not linked to T3/Ti or T11 antigens. mAb 9.3 was capable of inducing T cell proliferation in the presence of 12-o-tetradecanoyl phorbol-13-acetate (TPA). This effect was monocyte-independent. T cell activation with mAb 9.3 and TPA was associated with increases in interleukin 2(IL-2) receptor expression and IL-2 secretion. mAb 9.3 did not activate T cells, even with the addition of IL-1 or IL-2. Modulation of the T3 complex did not abolish mAb 9.3-induced T cell proliferation in the presence of TPA. These results suggest that the 9.3 antigen may serve as a receptor for an activation pathway restricted to a T cell subset.
Neuregulins and Cancer
Authors: Juan Carlos Montero, Ruth Rodríguez-Barrueco, Alberto Ocaña, Elena Díaz-Rodríguez, Azucena Esparís-Ogando, Atanasio Pandiella
Journal: Clinical Cancer Research (2008)

Abstract The neuregulins represent the largest subclass of polypeptide factors of the epidermal growth factor family of ligands. These molecules are synthesized as membrane-bound, biologically active growth factors that act by binding to the HER/ErbB receptor tyrosine kinases. Preclinical data have indicated that increased expression and function of neuregulins may provoke cancer. Furthermore, neuregulin expression has been detected in several neoplasias, and their presence may correlate with response to treatments that target the HER receptors such as trastuzumab. In addition, the neuregulins have also been implicated in resistance to anti-HER therapies. Therefore, targeting of the neuregulins may be helpful in neoplastic diseases in which these polypeptide factors contribute to tumor generation and/or maintenance.