tbuckley/cabot-search huggingface dataset:
Stand Up to Cancer Phase Ib Study of Pan-Phosphoinositide-3-Kinase Inhibitor Buparlisib With Letrozole in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer
Authors: Ingrid A. Mayer, Vandana G. Abramson, Steven J. Isakoff, Andres Forero, Justin M. Balko, María Gabriela Kuba, Melinda E. Sanders, Jeffrey T. Yap, Annick D. Van den Abbeele, Yisheng Li, Lewis C. Cantley, Eric Winer, Carlos L. Arteaga
Journal: Journal of Clinical Oncology (2014)

Purpose Buparlisib, an oral reversible inhibitor of all class I phosphoinositide-3-kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone and with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER-positive breast cancer refractory to endocrine therapy. Patients and Methods Patients received letrozole and buparlisib in two different administration schedules. Outcomes were assessed by standard solid-tumor phase I methods. [ 18 F]fluorodeoxyglucose–positron emission tomography/computed tomography ([ 18 F]FDG-PET/CT) scans were done at baseline and 2 weeks after treatment initiation. Tumor blocks were collected for phosphoinositide-3-kinase pathway mutation analysis. Results Fifty-one patients were allocated sequentially to continuous or intermittent (five on/two off days) buparlisib administration on an every-4-week schedule. Buparlisib's maximum-tolerated dose (MTD) was 100 mg/d. Common drug-related adverse events included ≤ grade 2 hyperglycemia, nausea, fatigue, transaminitis, and mood disorders. The clinical benefit rate (lack of progression ≥ 6 months) among all patients treated at the MTD was 31%, including two objective responses in the continuous dose arm. Of seven patients remaining on treatment ≥ 12 months, three had tumors with PIK3CA hot-spot mutation. Patients exhibiting metabolic disease progression by [ 18 F]FDG-PET/CT scan at 2 weeks progressed rapidly on therapy. Conclusion The letrozole and buparlisib combination was safe, with reversible toxicities regardless of schedule administration. Clinical activity was observed independent of PIK3CA mutation status. No metabolic response by [ 18 F]FDG-PET/CT scan at 2 weeks was associated with rapid disease progression. Phase III trials of buparlisib and endocrine therapy in patients with ER-positive breast cancer are ongoing.
Endothelial S100A1 Modulates Vascular Function via Nitric Oxide
Authors: Sven T. Pleger, David M. Harris, Changguang Shan, Leif E. Vinge, J. Kurt Chuprun, Brett Berzins, Wiebke Pleger, Charles Druckman, Mirko Völkers, Jörg Heierhorst, Erik Øie, Andrew Remppis, Hugo A. Katus, Rosario Scalia, Andrea D. Eckhart, Walter J. Koch, Patrick Most
Journal: Circulation Research (2008)

S100A1, a Ca(2+)-binding protein of the EF-hand type, is known to modulate sarcoplasmic reticulum Ca(2+) handling in skeletal muscle and cardiomyocytes. Recently, S100A1 has been shown to be expressed in endothelial cells (ECs). Because intracellular Ca(2+) ([Ca(2+)](i)) transients can be involved in important EC functions and endothelial NO synthase activity, we sought to investigate the impact of endothelial S100A1 on the regulation of endothelial and vascular function. Thoracic aortas from S100A1 knockout mice (SKO) showed significantly reduced relaxation in response to acetylcholine compared with wild-type vessels, whereas direct vessel relaxation using sodium nitroprusside was unaltered. Endothelial dysfunction attributable to the lack of S100A1 expression could also be demonstrated in vivo and translated into hypertension of SKO. Mechanistically, both basal and acetylcholine-induced endothelial NO release of SKO aortas was significantly reduced compared with wild type. Impaired endothelial NO production in SKO could be attributed, at least in part, to diminished agonist-induced [Ca(2+)](i) transients in ECs. Consistently, silencing endothelial S100A1 expression in wild type also reduced [Ca(2+)](i) and NO generation. Moreover, S100A1 overexpression in ECs further increased NO generation that was blocked by the inositol-1,4,5-triphosphate receptor blocker 2-aminoethoxydiphenylborate. Finally, cardiac endothelial S100A1 expression was shown to be downregulated in heart failure in vivo. Collectively, endothelial S100A1 critically modulates vascular function because lack of S100A1 expression leads to decreased [Ca(2+)](i) and endothelial NO release, which contributes, at least partially, to impaired endothelium-dependent vascular relaxation and hypertension in SKO mice. Targeting endothelial S100A1 expression may, therefore, be a novel therapeutic means to improve endothelial function in vascular disease or heart failure.
Hypoxia, nitrogen balance and body weight
Authors: A.M.W.J. Schols, K.R. Westerterp
Journal: European Respiratory Journal (2002)

<h3>Background</h3> This paper presents the results of the first UK-wide survey of National Health Service (NHS) general practitioners (GPs) and practice managers (PMs) designed to explore the service improvement activities being undertaken in practices, and the factors that facilitated or obstructed that work. The research was prompted by growing policy and professional interest in the quality of general practice and its improvement. The analysis compares GP and PM involvement in, and experience of, quality improvement activities. <h3>Methods</h3> This was a mixed-method study comprising 26 semistructured interviews, a focus group and two surveys. The qualitative data supported the design of the surveys, which were sent to all 46 238 GPs on the Royal College of General Practitioners (RCGP) database and the PM at every practice across the UK (n=9153) in July 2017. <h3>Results</h3> Responses from 2377 GPs and 1424 PMs were received and were broadly representative of each group. Ninety-nine per cent reported having planned or undertaken improvement activities in the previous 12 months. The most frequent related to prescribing and access. Key facilitators of improvement included ‘good clinical leadership’. The two main barriers were ‘too many demands from external stakeholders’ and a lack of protected time. Audit and significant event audit were the most common improvement tools used, but respondents were interested in training on other quality improvement tools. <h3>Conclusion</h3> GPs and PMs are interested in improving service quality. As such, the new quality improvement domain in the Quality and Outcomes Framework used in the payment of practices is likely to be relatively easily accepted by GPs in England. However, if improving quality is to become routine work for practices, it will be important for the NHS in the four UK countries to work with practices to mitigate some of the barriers that they face, in particular the lack of protected time.
Detection of miR-92a and miR-21 in stool samples as potential screening biomarkers for colorectal cancer and polyps
Authors: Chung Wah Wu, Simon S M Ng, Yu Juan Dong, Siew Chien Ng, Wing Wa Leung, Chung Wa Lee, Yee Ni Wong, Francis K L Chan, Jun Yu, Joseph J Y Sung
Journal: Gut (2011)

<h3>Objective</h3> The detection of molecular markers in stool samples is a potential strategy for colorectal cancer (CRC) screening. This study evaluated the feasibility of detecting miR-21 and miR-92a in stool samples of patients with CRC or polyps. <h3>Methods</h3> The reproducibility of detection and stability of stool-based microRNA were evaluated. Stool samples were collected from 88 patients with CRC, 57 patients with colorectal polyps and 101 healthy controls. MiRNA levels in CRC tissues and stool samples were detected by real-time quantitative reverse transcription PCR. Stool miR-21 and miR-92a levels were compared before and after the removal of tumour or advanced adenoma. <h3>Results</h3> The study demonstrated that stool-based miRNA were stable with highly reproducible detection. The expression of miR-21 and miR-92a was significantly higher in CRC tissues compared with their adjacent normal tissues (p&lt;0.0001). Patients with CRC had a significantly higher stool miR-21 level (p&lt;0.01) and miR-92a level (p&lt;0.0001) compared with normal controls. Stool miR-92a, but not miR-21, was significantly higher in patients with polyps than in controls (p&lt;0.0001). At a cut-off value of 435 copies/ng of stool RNA, miR-92a had a sensitivity of 71.6% and 56.1% for CRC and polyp, respectively, and a specificity of 73.3%. In addition, the stool miR-92a level demonstrated a higher sensitivity for distal CRC than proximal CRC (p&lt;0.05), and a higher sensitivity for advanced adenoma than minor polyps (p&lt;0.05). Removal of tumour resulted in reduced stool miR-21 and miR-92a levels (p&lt;0.01), and the removal of advanced adenoma resulted in a reduction of the stool miR-92a level (p&lt;0.05). <h3>Conclusion</h3> Stool miRNA are useful for screening CRC and polyps.
Comparative clonal analysis of human immunodeficiency virus type 1 (HIV-1)-specific CD4+ and CD8+ cytolytic T lymphocytes isolated from seronegative humans immunized with candidate HIV-1 vaccines.
Authors: S A Hammond, R C Bollinger, P E Stanhope, T C Quinn, D Schwartz, M L Clements, R F Siliciano
Journal: The Journal of Experimental Medicine (1992)

The lysis of infected host cells by virus-specific cytolytic T lymphocytes (CTL) is an important factor in host resistance to viral infection. An optimal vaccine against human immunodeficiency virus type 1 (HIV-1) would elicit virus-specific CTL as well as neutralizing antibodies. The induction by a vaccine of HIV-1-specific CD8+ CTL in humans has not been previously reported. In this study, CTL responses were evaluated in HIV-1-seronegative human volunteers participating in a phase I acquired immune deficiency syndrome (AIDS) vaccine trial involving a novel vaccine regimen. Volunteers received an initial immunization with a live recombinant vaccinia virus vector carrying the HIV-1 env gene and a subsequent boost with purified env protein. An exceptionally strong env-specific CTL response was detected in one of two vaccine recipients, while modest but significant env-specific CTL activity was present in the second vaccinee. Cloning of the responding CTL gave both CD4+ and CD8+ env-specific CTL clones, permitting a detailed comparison of critical functional properties of these two types of CTL. In particular, the potential antiviral effects of these CTL were evaluated in an in vitro system involving HIV-1 infection of cultures of normal autologous CD4+ lymphoblasts. At extremely low effector-to-target ratios, vaccine-induced CD8+ CTL clones lysed productively infected cells present within these cultures. When tested for lytic activity against target cells expressing the HIV-1 env gene, CD8+ CTL were 3-10-fold more active on a per cell basis than CD4+ CTL. However, when tested against autologous CD4+ lymphoblasts acutely infected with HIV-1, CD4+ clones lysed a much higher fraction of the target cell population than did CD8+ CTL. CD4+ CTL were shown to recognize not only the infected cells within these acutely infected cultures but also noninfected CD4+ T cells that had passively taken up gp120 shed from infected cells and/or free virions. These results were confirmed in studies in which CD4+ lymphoblasts were exposed to recombinant gp120 and used as targets for gp120-specific CD4+ and CD8+ CTL clones. gp120-pulsed, noninfected targets were lysed in an antigen-specific fashion by CD4+ but not CD8+ CTL clones. Taken together, these observations demonstrate that in an in vitro HIV-1 infection, sufficient amounts of gp120 antigen are produced and shed by infected cells to enable uptake by cells that are not yet infected, resulting in the lysis of these noninfected cells by gp120-specific, CD4+ CTL.(ABSTRACT TRUNCATED AT 400 WORDS)
Silencing of either SR-A or CD36 reduces atherosclerosis in hyperlipidaemic mice and reveals reciprocal upregulation of these receptors
Authors: P. I. Makinen, J. P. Lappalainen, S. E. Heinonen, P. Leppanen, M. T. Lahteenvuo, J. V. Aarnio, J. Heikkila, M. P. Turunen, S. Yla-Herttuala
Journal: Cardiovascular Research (2010)

Macrophage scavenger receptor A (SR-A) and class B scavenger receptor CD36 (CD36) contribute to foam cell formation and atherogenesis via uptake of modified lipoproteins. So far, the role of these scavenger receptors has been studied mainly using knockout models totally lacking these receptors. We studied the role of SR-A and CD36 in foam cell formation and atherogenesis by RNA interference (RNAi)-mediated silencing, which is a clinically feasible method to down-regulate the expression of these receptors. We constructed lentivirus vectors encoding short hairpin RNAs (shRNAs) against mouse SR-A and CD36. Decreased SR-A but not CD36 expression led to reduced foam cell formation caused by acetylated low-density lipoprotein (LDL) in mouse macrophages, whereas the uptake of oxidized LDL was not altered. More importantly, silencing of SR-A upregulates CD36 and vice versa. In LDL receptor-deficient apolipoprotein B100 (LDLR−/−ApoB100/100) mice kept on a western diet, silencing of either SR-A or CD36 in bone marrow cells led to a marked decrease (37.4 and 34.2%, respectively) in cross-sectional lesion area, whereas simultaneous silencing of both receptors was not effective. Our results suggest that silencing of either SR-A or CD36 alone reduces atherogenesis in mice. However, due to reciprocal upregulation, silencing of both SR-A and CD36 is not effective.
Prognostic analysis and predictive rule for outcome of hospital-treated community-acquired pneumonia
Authors: S Ewig, T Bauer, E Hasper, L Pizzulli, R Kubini, B Luderitz
Journal: European Respiratory Journal (1995)

In community-acquired pneumonia (CAP) mortality may be reduced by early identification of patients requiring intensive care treatment. The purpose of this study was to determine prognostic factors of outcome in patients with CAP in order to establish a clinically applicable discriminant rule. Ninety three episodes of CAP in 92 patients were retrospectively reviewed with regard to epidemiological, clinical, laboratory and microbiological data. The prognostic analysis included a univariate as well as a multivariate approach, in order to identify parameters associated with death using the Cox regression hazard function in a backward stepwise selection model. The three parameters found to contribute most to the significance of the model were used in a discriminant rule for classification of outcome. The parameters found to be significantly different between survivors and non-survivors were heart rate, systolic and diastolic as well as mean blood pressures, leucocyte count, percentage of lymphocytes, and lactate dehydrogenase (LDH) values. The multivariate analysis revealed that heart rate, systolic arterial pressure, and LDH serum levels were most closely associated with fatal outcome. A prognostic rule composed of the variables heart rate > or = 90 beats.min-1, systolic arterial blood pressure < or = 80 mmHg, and LDH > or = 260 U.l-1 achieved a sensitivity of 77%, a specificity of 75%, and positive and negative predictive values of 42 and 93%, respectively. It was associated with a six fold increased risk of fatal outcome. In conclusion, heart rate, systolic blood pressure, and LDH values were most closely associated with death in a multivariate analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Eosinophil-fibroblast interactions induce fibroblast IL-6 secretion and extracellular matrix gene expression: Implications in fibrogenesis
Authors: Ignatius Gomes, Sameer K. Mathur, Bruce M. Espenshade, Yasuji Mori, John Varga, Steven J. Ackerman
Journal: Journal of Allergy and Clinical Immunology (2005)
MicroRNA-195 promotes palmitate-induced apoptosis in cardiomyocytes by down-regulating Sirt1
Authors: Huaqing Zhu, Yixin Yang, Yanpeng Wang, Jianmin Li, Peter W. Schiller, Tianqing Peng
Journal: Cardiovascular Research (2011)

Free fatty acids induce apoptosis in cardiomyocytes, which is implicated in lipotoxic cardiomyopathy. However, the underlying mechanisms remain not fully understood. MicroRNAs (miRNAs) are non-coding small RNAs that control gene expression at the post-transcriptional level. Dysregulated miRNAs have been shown to be involved in heart diseases. This study was to examine whether miR-195 regulates palmitate-induced cardiomyocyte apoptosis by targeting Sirt1, a known anti-apoptotic protein. In cultured neonatal mouse cardiomyocytes, palmitate up-regulated miR-195 expression, increased reactive oxygen species (ROS) production, and induced apoptosis as determined by up-regulation of caspase-3 activity and DNA fragmentation. Inhibition of miR-195 decreased ROS production and apoptosis in palmitate-stimulated cardiomyocytes. In contrast, a miR-195 mimic enhanced palmitate-induced ROS production and apoptosis. The induction of miR-195 correlated with a reduction in Sirt1 and Bcl-2. We further showed that miR-195 targeted and inhibited Sirt1 expression through two target sites located in the 3′ un-translational region of Sirt1 mRNA. In concordance, inhibition of miR-195 increased Sirt1 protein in cardiomyocytes whereas the miR-195 mimic reduced it. Activation of Sirt1 or overexpression of Bcl-2 inhibited palmitate-induced apoptosis. On the other hand, inhibition of Sirt1 enhanced apoptosis. The inhibitory effect of Sirt1 on apoptosis was associated with a reduction in ROS. This study demonstrates a pro-apoptotic role of miR-195 in cardiomyocytes and identifies Sirt1 as a direct target of miR-195. The effect of miR-195 on apoptosis is mediated through down-regulation of Sirt1 and Bcl-2 and ROS production. Thus, miR-195 may be a new therapeutic target for lipotoxic cardiomyopathy.
Effects of Visit-to-Visit Variability in Systolic Blood Pressure on Macrovascular and Microvascular Complications in Patients With Type 2 Diabetes Mellitus
Authors: Jun Hata, Hisatomi Arima, Peter M. Rothwell, Mark Woodward, Sophia Zoungas, Craig Anderson, Anushka Patel, Bruce Neal, Paul Glasziou, Pavel Hamet, Giuseppe Mancia, Neil Poulter, Bryan Williams, Stephen MacMahon, John Chalmers
Journal: Circulation (2013)

Background— Recent evidence suggests that visit-to-visit variability in systolic blood pressure (SBP) and maximum SBP are predictors of cardiovascular disease. However, it remains uncertain whether these parameters predict the risks of macrovascular and microvascular complications in patients with type 2 diabetes mellitus. Methods and Results— The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) was a factorial randomized controlled trial of blood pressure lowering and blood glucose control in patients with type 2 diabetes mellitus. The present analysis included 8811 patients without major macrovascular and microvascular events or death during the first 24 months after randomization. SBP variability (defined as standard deviation) and maximum SBP were determined during the first 24 months after randomization. During a median 2.4 years of follow-up from the 24-month visit, 407 major macrovascular (myocardial infarction, stroke, or cardiovascular death) and 476 microvascular (new or worsening nephropathy or retinopathy) events were observed. The association of major macrovascular and microvascular events with SBP variability was continuous even after adjustment for mean SBP and other confounding factors (both P &lt;0.05 for trend). Hazard ratios (95% confidence intervals) for the highest tenth of SBP variability were 1.54 (0.99–2.39) for macrovascular events and 1.84 (1.19–2.84) for microvascular events in comparison with the lowest tenth. For maximum SBP, hazard ratios (95% confidence intervals) for the highest tenth were 3.64 (1.73–7.66) and 2.18 (1.04–4.58), respectively. Conclusion— Visit-to-visit variability in SBP and maximum SBP were independent risk factors for macrovascular and microvascular complications in type 2 diabetes mellitus. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique Identifier: NCT00145925.
Anorexia and Bulimia Nervosa
Authors: W. H. Kaye, K. L. Klump, G. K. W. Frank, M. Strober
Journal: Annual Review of Medicine (2000)

▪ Abstract Anorexia nervosa (AN) and bulimia nervosa (BN) are disorders characterized by abnormal patterns of weight regulation and eating behavior and by disturbances in attitudes and perceptions toward weight and body shape. Etiologic research has indicated substantial genetic influence on these disorders, suggesting significant biological contributions to their development. Obsessional, perfectionistic, and anxious personality styles may be premorbid traits that contribute to this pathogenesis. Studies of neuroendocrine, neuropeptide, and neurotransmitter functioning in patients with AN and BN indicate that disturbances of these systems may contribute to the maintenance as well as the etiology of these sometimes fatal disorders. The efficacy of psychological treatments and pharmacotherapy has been more clearly established for BN than for AN.
Impulsive and Compulsive Behaviors in Parkinson's Disease
Authors: B.B. Averbeck, S.S. O'Sullivan, A. Djamshidian
Journal: Annual Review of Clinical Psychology (2013)

Impulsive-compulsive behaviors (ICBs) in Parkinson's disease (PD) are a common and devastating side effect of dopamine replacement therapy. In this review we describe the phenomenology, prevalence, and risk factors of patients with PD. Results of behavioral studies assessing the neuropsychological profile of patients with PD emphasize that the ICBs, which are behavioral addictions, are not hedonically motivated. Rather, other factors such as the inability to cope with uncertainty may be triggering ICBs. New insights from functional imaging studies, strengthening the incentive salience hypothesis, are discussed, and therapeutic guidelines for the management of ICBs in PD are given.
Modeling of Neural Circuits: What Have We Learned?
Authors: A I Selverston
Journal: Annual Review of Neuroscience (1993)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Effect of Risk-Reduction Counseling With Rapid HIV Testing on Risk of Acquiring Sexually Transmitted Infections
Authors: Lisa R. Metsch, Daniel J. Feaster, Lauren Gooden, Bruce R. Schackman, Tim Matheson, Moupali Das, Matthew R. Golden, Shannon Huffaker, Louise F. Haynes, Susan Tross, C. Kevin Malotte, Antoine Douaihy, P. Todd Korthuis, Wayne A. Duffus, Sarah Henn, Robert Bolan, Susan S. Philip, Jose G. Castro, Pedro C. Castellon, Gayle McLaughlin, Raul N. Mandler, Bernard Branson, Grant N. Colfax
Journal: JAMA (2013)

To increase human immunodeficiency virus (HIV) testing rates, many institutions and jurisdictions have revised policies to make the testing process rapid, simple, and routine. A major issue for testing scale-up efforts is the effectiveness of HIV risk-reduction counseling, which has historically been an integral part of the HIV testing process.
Treatment of adenoviral pneumonitis with intravenous ribavirin and immunoglobulin.
Authors: I Sabroe, J McHale, D R Tait, W A Lynn, K N Ward, S Shaunak
Journal: Thorax (1995)

A 67 year old woman developed a severe adenoviral pneumonitis whilst receiving immunosuppressive therapy. She showed clinical and radiological evidence of a response to treatment with nebulised and intravenous ribavirin and intravenous pooled normal human immunoglobulin. To our knowledge this is the first time that such a therapeutic approach has been used in the treatment of a condition which normally carries a very high mortality.