tbuckley/cabot-search huggingface dataset:
Fibroblast Inward-Rectifier Potassium Current Upregulation in Profibrillatory Atrial Remodeling
Authors: Xiao-Yan Qi, Hai Huang, Balazs Ordog, Xiaobin Luo, Patrice Naud, Yiguo Sun, Chia-Tung Wu, Kristin Dawson, Artavazd Tadevosyan, Yu Chen, Masahide Harada, Dobromir Dobrev, Stanley Nattel
Journal: Circulation Research (2015)

Fibroblasts are involved in cardiac arrhythmogenesis and contribute to the atrial fibrillation substrate in congestive heart failure (CHF) by generating tissue fibrosis. Fibroblasts display robust ion currents, but their functional importance is poorly understood.To characterize atrial fibroblast inward-rectifier K(+) current (IK1) remodeling in CHF and its effects on fibroblast properties.Freshly isolated left atrial fibroblasts were obtained from controls and dogs with CHF (ventricular tachypacing). Patch clamp was used to record resting membrane potential (RMP) and IK1. RMP was significantly increased by CHF (from -43.2±0.8 mV, control, to -55.5±0.9 mV). CHF upregulated IK1 (eg, at -90 mV from -1.1±0.2 to -2.7±0.5 pA/pF) and increased the expression of KCNJ2 mRNA (by 52%) and protein (by 80%). Ba(2+) (300 μmol/L) decreased the RMP and suppressed the RMP difference between controls and dogs with CHF. Store-operated Ca(2+) entry (Fura-2-acetoxymethyl ester) and fibroblast proliferation (flow cytometry) were enhanced by CHF. Lentivirus-mediated overexpression of KCNJ2 enhanced IK1 and hyperpolarized fibroblasts. Functional KCNJ2 suppression by lentivirus-mediated expression of a dominant negative KCNJ2 construct suppressed IK1 and depolarized RMP. Overexpression of KCNJ2 increased Ca(2+) entry and fibroblast proliferation, whereas the dominant negative KCNJ2 construct had opposite effects. Fibroblast hyperpolarization to mimic CHF effects on RMP enhanced the Ca(2+) entry. MicroRNA-26a, which targets KCNJ2, was downregulated in CHF fibroblasts. Knockdown of endogenous microRNA-26 to mimic CHF effects unregulated IK1.CHF upregulates fibroblast KCNJ2 expression and currents, thereby hyperpolarizing RMP, increasing Ca(2+) entry, and enhancing atrial fibroblast proliferation. These effects are likely mediated by microRNA-26a downregulation. Remodeling-induced fibroblast KCNJ2 expression changes may play a role in atrial fibrillation promoting fibroblast remodeling and structural/arrhythmic consequences.
LDL-cholesterol concentrations: a genome-wide association study
Authors: Manjinder S Sandhu, Dawn M Waterworth, Sally L Debenham, Eleanor Wheeler, Konstantinos Papadakis, Jing Hua Zhao, Kijoung Song, Xin Yuan, Toby Johnson, Sofie Ashford, Michael Inouye, Robert Luben, Matthew Sims, David Hadley, Wendy McArdle, Philip Barter, Y Antero Kesäniemi, Robert W Mahley, Ruth McPherson, Scott M Grundy, Sheila A Bingham, Kay-Tee Khaw, Ruth JF Loos, Gérard Waeber, Inês Barroso, David P Strachan, Panagiotis Deloukas, Peter Vollenweider, Nicholas J Wareham, Vincent Mooser
Journal: The Lancet (2008)
NK receptors: it's all in the name
Authors: Salim I Khakoo, KhaleelM Jamil, Kuldeep S Cheent
Journal: Gut (2011)

We read with interest the paper by Muhanna et al on natural killer cells, their role in ameliorating liver fibrosis and in particular the role of inhibitory receptors for major histocompatibility complex (MHC) class I.1 We would like to clarify the often confusing terminology of inhibitory receptors for natural killer cells.

In the article by Muhanna et al , they refer to KIR as ‘killer immunoglobulin-related receptors’. This is not correct. The terminology ‘KIR’ correctly applies to the ‘killer …
Timing of ventricular function recovery after primary stent treatment for acute evolving myocardial infarction
Authors: A. Medina, J.S. de Lezo, E. Hernández, M. Pan, M. Romero, J. Segura, F. Melián, J.R. de Castroviejo, A. Delgado
Journal: Journal of the American College of Cardiology (1998)
The diagnostic performance of scoring systems to identify symptomatic colorectal cancer compared to current referral guidance
Authors: T. Marshall, R. Lancashire, D. Sharp, T. J. Peters, K. K. Cheng, W. Hamilton
Journal: Gut (2011)

<h3>Objectives</h3> To determine the discrimination characteristics of a new algorithm and two existing symptom scoring systems for identification of patients with suspected colorectal cancer. <h3>Design</h3> Derivation of algorithm by a case–control study and assessment of discrimination characteristics using receiver operating characteristics (ROC) curves. Three colorectal cancer scoring systems were investigated. The Bristol–Birmingham (BB) equation, which we derived from a large primary care dataset; the CAPER score, previously derived from a primary care case–control study and a symptom score derived from National Institute of Clinical Excellence (NICE) guidance for urgent referral of symptomatic patients. Their discrimination characteristics were investigated in two datasets: the BB derivation dataset and the CAPER score derivation dataset. The main analyses were ROC curves and the areas under them for all three algorithms in both datasets. <h3>Setting</h3> Electronic primary care databases. <h3>Main outcome measures</h3> Diagnosis of colorectal cancer. <h3>Results</h3> In the BB dataset, areas under the curve were: BB equation 0.83 (95% CI 0.82 to 0.84); CAPER 0.79 (95% CI 0.79 to 0.80); the NICE guidelines 0.65 (95% CI 0.64 to 0.66). In the CAPER dataset, areas under the curve were: BB 0.92 (95% CI 0.91 to 0.94); CAPER 0.91 (95% CI 0.89 to 0.93); NICE guidelines 0.75 (95% CI 0.72 to 0.79). In subjects under 50 the discrimination characteristics of NICE referral guidelines were no better than chance. <h3>Conclusions</h3> Both multivariable symptom scoring systems performed significantly better than NICE referral guidelines.
Elevated Plasma Growth Differentiation Factor-15 Correlates with Lymph Node Metastases and Poor Survival in Endometrial Cancer
Authors: Anne Cathrine Staff, Jone Trovik, Eriksson Ane Gerda Zahl, Elisabeth Wik, Kai C. Wollert, Tibor Kempf, Helga B. Salvesen
Journal: Clinical Cancer Research (2011)

The study objective was to investigate and validate plasma growth differentiation factor-15 (GDF-15) as a predictor of lymph node metastasis and a poor prognosis in primary endometrial cancer.Plasma samples from 510 women treated for endometrial cancer in a primary investigation cohort (n = 44) and a secondary validation cohort (n = 466) were analyzed for GDF-15. Plasma from healthy premenopausal (n = 20) and postmenopausal (n = 20) women, women with borderline (n = 43), benign (n = 144), and malignant ovarian tumors (n = 125) were used for comparison.Median plasma GDF-15 concentration for the endometrial cancer group was elevated (1,077 ng/L) as compared with pre- and postmenopausal controls (590 and 684 ng/L) and women with benign (591 ng/L) or borderline ovarian tumors (718 ng/L; all P < 0.001), but similar to the ovarian cancer group. In the large validation cohort of endometrial carcinomas, high plasma GDF-15 was significantly associated with International Federation of Gynecology and Obstetrics (FIGO) stage III/IV disease, nonendometrioid histology, high grade, older age, postmenopausal status, and lymph node metastases (all P ≤ 0.001). High GDF-15 was also an independent predictor of poor disease-specific and recurrence-free survival.Based on findings indicated in a primary investigation set and confirmed in the large secondary validation set, we report for the first time plasma GDF-15 as a biomarker for endometrial cancer phenotype, including presence of lymph node metastasis and reduced survival. Its applicability as a predictor of metastatic nodes and in monitoring treatment of endometrial cancer needs to be further studied.
Sports and exercise medicine--specialists or snake oil salesmen?
Authors: A Franklyn-Miller, J Etherington, P McCrory
Journal: British Journal of Sports Medicine (2009)

There is a belief that Sports and Exercise Medicine (SEM) is a unique aspect of medical practice because sports physicians care for elite athletes, and athletes are different. This situation can result in the use of unproven therapies which are then justified on the basis that elite athletes need to be at the “cutting edge” of medical treatment in order to return to play as rapidly as possible. In more established fields of medicine, the use of such unproven therapy would lead to considerable professional criticism.1

The concept that “cutting edge” treatment means the integration of anecdotal treatments into conventional sports medicine needs to be addressed urgently. We argue that not only is this approach flawed but that it will limit the development of an evidence base in SEM, is ethically questionable and will ultimately undermine the credibility of the specialty.2 3

Evidence-based medicine, with all its limitations, is a vital component of good clinical practice and enhances patient confidence in medicine. Good clinical practice demands that we search for, and develop, evidence for benefit and safety and then select treatment options according to the best evidence available. For the speciality of SEM, to ignore established evidence-based approaches to medical practice is simply unacceptable in the modern era.

A recent editorial in the Journal by a group of experienced clinicians argued that an unproven injection therapy for acute muscle strains should be considered “an important …
A miR-208–Mef2 Axis Drives the Decompensation of Right Ventricular Function in Pulmonary Hypertension
Authors: Roxane Paulin, Gopinath Sutendra, Vikram Gurtu, Peter Dromparis, Alois Haromy, Steeve Provencher, Sebastien Bonnet, Evangelos D. Michelakis
Journal: Circulation Research (2014)

Right ventricular (RV) failure is a major cause of morbidity and mortality in pulmonary hypertension, but its mechanism remains unknown. Myocyte enhancer factor 2 (Mef2) has been implicated in RV development, regulating metabolic, contractile, and angiogenic genes. Moreover, Mef2 regulates microRNAs that have emerged as important determinants of cardiac development and disease, but for which the role in RV is still unclear.We hypothesized a critical role of a Mef2-microRNAs axis in RV failure.In a rat pulmonary hypertension model (monocrotaline), we studied RV free wall tissues from rats with normal, compensated, and decompensated RV hypertrophy, carefully defined based on clinically relevant parameters, including RV systolic and end-diastolic pressures, cardiac output, RV size, and morbidity. Mef2c expression was sharply increased in compensating phase of RVH tissues but was lost in decompensation phase of RVH. An unbiased screening of microRNAs in our model resulted to a short microRNA signature of decompensated RV failure, which included the myocardium-specific miR-208, which was progressively downregulated as RV failure progressed, in contrast to what is described in left ventricular failure. With mechanistic in vitro experiments using neonatal and adult RV cardiomyocytes, we showed that miR-208 inhibition, as well as tumor necrosis factor-α, activates the complex mediator of transcription 13/nuclear receptor corepressor 1 axis, which in turn promotes Mef2 inhibition, closing a self-limiting feedback loop, driving the transition from compensating phase of RVH toward decompensation phase of RVH. In our model, serum tumor necrosis factor-α levels progressively increased with time while serum miR-208 levels decreased, mirroring its levels in RV myocardium.We describe an RV-specific mechanism for heart failure, which could potentially lead to new biomarkers and therapeutic targets.
Selective Excision of Metastatic Brain Tumors Originating in the Motor Cortex With Preservation of Function
Authors: Robert J. Weil, Russell R. Lonser
Journal: Journal of Clinical Oncology (2005)

Brain metastases are common in patients with cancer and can cause considerable morbidity or death. Metastasis in eloquent areas of the brain, particularly the primary motor cortex, may present significant treatment challenges.Seventeen consecutive patients with metastasis within the primary motor cortex underwent selective microsurgical tumor resection. Operative, hospital, neuroimaging, and follow-up information was reviewed.There were 10 women and seven men (mean age, 54.3 years) who underwent 17 operations for symptomatic brain metastases. Motor cortex was identified and tumor (mean volume, 10.2 cm(3)) was completely resected in all patients. Three patients had transient or reversible complications. Karnofsky performance scores improved in 16 of 17 patients at 4 weeks postoperatively, with a mean improvement of 1.8 grades compared with preoperative scores (P < .05). Overall survival of 16 patients with distant follow-up (> 6 months or until death) averaged 10.6 +/- 4.4 months, with nine of 16 (56%) assessable patients surviving 1 year or longer. Survival of these 16 patients, by recursive partitioning analysis (RPA), was 11.2, 13.3, and 6.7 months for RPA classes I, II, and III, respectively. The cause of death in 14 of 15 patients who have died was progressive systemic disease; in one patient it was a combination of systemic and distant CNS disease progression. There were no local CNS recurrences.Complete microsurgical resection of metastatic tumors in the primary motor cortex is feasible and efficacious, results in a sustained improvement in performance outcomes, and permits satisfactory long-term survival.
Twist Is Required for Thrombin-Induced Tumor Angiogenesis and Growth
Authors: Liang Hu, Jennifer M. Roth, Peter Brooks, Sherif Ibrahim, Simon Karpatkin
Journal: Cancer Research (2008)

Abstract Twist, a master regulator of embryonic morphogenesis, induces functions that are also required for tumor invasion and metastasis. Because thrombin contributes to the malignant phenotype by up-regulating tumor metastasis, we examined its effect on Twist in five different tumor cell lines and two different endothelial cell lines. Thrombin up-regulated Twist mRNA and protein in all seven cell lines. Down-regulation of Twist in B16F10 tumor cell lines led to a ∼3-fold decrease in tumor growth on a chorioallantoic membrane assay and ∼2-fold decrease in syngeneic mice. Angiogenesis was decreased ∼45% and 36%, respectively. The effect of Twist on angiogenesis was further examined and compared with the effect of thrombin. In studies using a Twist-inducible plasmid, several identical vascular growth factors and receptors were up-regulated ∼2- to 3-fold in tumor cells as well as human umbilical vascular endothelial cells by both Twist as well as thrombin (vascular endothelial growth factor, KDR, Ang-2, matrix metalloproteinase 1, GRO-α, and CD31). Thrombin-induced endothelial cell chemotaxis and Matrigel endothelial cell tubule formation were similarly regulated by Twist. Thus, thrombin up-regulates Twist, which is required for thrombin-induced angiogenesis as measured by endothelial cell migration, Matrigel tubule formation, and tumor angiogenesis. [Cancer Res 2008;68(11):4296–302]
Heterogeneity of clones from a human metastatic melanoma detected by autologous cytotoxic T lymphocyte clones.
Authors: A Anichini, G Fossati, G Parmiani
Journal: The Journal of Experimental Medicine (1986)

The possibility that a single human tumor may be composed of an heterogeneous population of cells with respect to susceptibility to lysis by autologous CTL clones was investigated by testing six cytolytic clones derived by micromanipulation against the autologous metastatic melanoma, Me28, and against 31 clones derived from Me28 by cloning in soft agar. Highly significant differences in the lysis of many tumor clones were observed by three of the CTL effectors in comparison with the cytotoxicity achieved on Me28. These results indicate that cloned cellular reagents can detect heterogeneity among cells isolated from the same melanoma, and suggest that the target determinants recognized on the autologous tumor might be differentially expressed on different neoplastic cells.
Training practitioners to deliver opportunistic multiple behaviour change counselling in primary care: a cluster randomised trial
Authors: C. C. Butler, S. A. Simpson, K. Hood, D. Cohen, T. Pickles, C. Spanou, J. McCambridge, L. Moore, E. Randell, M. F. Alam, P. Kinnersley, A. Edwards, C. Smith, S. Rollnick
Journal: BMJ (2013)

<b>Objectives</b> To evaluate the effect of training primary care health professionals in behaviour change counselling on the proportion of patients self reporting change in four risk behaviours (smoking, alcohol use, exercise, and healthy eating). <b>Design</b> Cluster randomised trial with general practices as the unit of randomisation. <b>Setting</b> General practices in Wales. <b>Participants</b> 53 general practitioners and practice nurses from 27 general practices (one each at all but one practice) recruited 1827 patients who screened positive for at least one risky behaviour. <b>Intervention</b> Behaviour change counselling was developed from motivational interviewing to enable clinicians to enhance patients’ motivation to change health related behaviour. Clinicians were trained using a blended learning programme called Talking Lifestyles. <b>Main outcome measures </b>Proportion of patients who reported making beneficial changes in at least one of the four risky behaviours at three months. <b>Results</b> 1308 patients from 13 intervention and 1496 from 14 control practices were approached: 76% and 72% respectively agreed to participate, with 831 (84%) and 996 (92%) respectively screening eligible for an intervention. There was no effect on the primary outcome (beneficial change in behaviour) at three months (362 (44%) <i>v</i> 404 (41%), odds ratio 1.12 (95% CI 0.90 to 1.39)) or on biochemical or biometric measures at 12 months. More patients who had consulted with trained clinicians recalled consultation discussion about a health behaviour (724/795 (91%) <i>v</i> 531/966 (55%), odds ratio 12.44 (5.85 to 26.46)) and intended to change (599/831 (72%) <i>v</i> 491/996 (49%), odds ratio 2.88 (2.05 to 4.05)). More intervention practice patients reported making an attempt to change (328 (39%) <i>v</i> 317 (32%), odds ratio 1.40 (1.15 to 1.70)), a sustained behaviour change at three months (288 (35%) <i>v</i> 280 (28%), odds ratio 1.36 (1.11 to 1.65)), and reported slightly greater improvements in healthy eating at three and 12 months, plus improved activity at 12 months. Training cost £1597 per practice. <b>Discussion</b> Training primary care clinicians in behaviour change counselling using a brief blended learning programme did not increase patients reported beneficial behaviour change at three months or improve biometric and a biochemical measure at 12 months, but it did increase patients’ recollection of discussing behaviour change with their clinicians, intentions to change, attempts to change, and perceptions of having made a lasting change at three months. Enduring behaviour change and improvements in biometric measures are unlikely after a single routine consultation with a clinician trained in behaviour change counselling without additional intervention. <b>Trial registration</b> ISRCTN 22495456
MGMT-Independent Temozolomide Resistance in Pediatric Glioblastoma Cells Associated with a PI3-Kinase–Mediated <i>HOX</i>/Stem Cell Gene Signature
Authors: Nathalie Gaspar, Lynley Marshall, Lara Perryman, Dorine A. Bax, Suzanne E. Little, Marta Viana-Pereira, Swee Y. Sharp, Gilles Vassal, Andrew D.J. Pearson, Rui M. Reis, Darren Hargrave, Paul Workman, Chris Jones
Journal: Cancer Research (2010)

Sensitivity to temozolomide is restricted to a subset of glioblastoma patients, with the major determinant of resistance being a lack of promoter methylation of the gene encoding the repair protein DNA methyltransferase MGMT, although other mechanisms are thought to be active. There are, however, limited preclinical data in model systems derived from pediatric glioma patients. We screened a series of cell lines for temozolomide efficacy in vitro, and investigated the differential mechanisms of resistance involved. In the majority of cell lines, a lack of MGMT promoter methylation and subsequent protein overexpression were linked to temozolomide resistance. An exception was the pediatric glioblastoma line KNS42. Expression profiling data revealed a coordinated upregulation of HOX gene expression in resistant lines, especially KNS42, which was reversed by phosphoinositide 3-kinase pathway inhibition. High levels of HOXA9/HOXA10 gene expression were associated with a shorter survival in pediatric high-grade glioma patient samples. Combination treatment in vitro of pathway inhibition and temozolomide resulted in a highly synergistic interaction in KNS42 cells. The resistance gene signature further included contiguous genes within the 12q13-q14 amplicon, including the Akt enhancer PIKE, significantly overexpressed in the KNS42 line. These cells were also highly enriched for CD133 and other stem cell markers. We have thus shown an in vitro link between phosphoinositide 3-kinase-mediated HOXA9/HOXA10 expression, and a drug-resistant, progenitor cell phenotype in MGMT-independent pediatric glioblastoma.
Exacerbations in cystic fibrosis: 3 {middle dot} Management
Authors: A Smyth, J S Elborn
Journal: Thorax (2007)

Exacerbations of pulmonary symptoms in patients with cystic fibrosis must be recognised early and treated vigorously in order to maintain pulmonary function and relieve symptoms. The aetiology of these exacerbations is discussed, together with the options for treatment and the evidence to support treatment choices.
Building Clinical Trials Capacity for Tuberculosis Drugs in High-Burden Countries
Authors: Neil Schluger, Unni Karunakara, Christian Lienhardt, Thomas Nyirenda, Richard Chaisson
Journal: PLoS Medicine (2007)

The experience of the British Medical Research Council's TB research units provides a useful template for planning the renewal of capacity for clinical trials in TB [1].Over 40 years, the Medical Research Council evaluated all the drugs currently in use for the treatment of TB.To do this, they tested roughly 250 different regimens, enrolling over 25,000 patients in trials.Why so many?Patients with TB are treated with regimens, not individual drugs.Even if a single new drug is approved for the treatment of TB, finding its optimal dosage, dosing frequency, and companion drugs will require several trials.Many questions need to be answered through a variety of clinical trials as described in Table 2.For example, moxifloxacin and gatifloxacin are promising compounds that provide Building Clinical Trials Capacity for Tuberculosis Drugs in High-Burden Countries
A Preeclampsia-like Syndrome Characterized by Reversible Hypertension and Proteinuria Induced by the Multitargeted Kinase Inhibitors Sunitinib and Sorafenib
Authors: T. V. Patel, J. A. Morgan, G. D. Demetri, S. George, R. G. Maki, M. Quigley, B. D. Humphreys
Journal: JNCI Journal of the National Cancer Institute (2008)

The oral multitargeted kinase inhibitors (MTKI) sunitinib (SU11248, Sutent; Pfizer, New York) and sorafenib (BAY 43-9006, Nexavar; Bayer Pharmaceuticals, West Haven, CT, and Onyx Pharmaceuticals, Emeryville, CA) are increasingly used to treat malignant solid tumors. These small-molecule agents inhibit signaling through receptor tyrosine kinases such as vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, and c-KIT, among others (1). In the kidney, glomerular podocytes express VEGF and glomerular endothelial cells express VEGF receptors. Podocyte-specific deletion of a single VEGF allele causes proteinuria and capillary endotheliosis in rodents, and disrupted glomerular VEGF signaling is strongly implicated in the pathogenesis of human preeclampsia (2–4).