tbuckley/cabot-search huggingface dataset:
Microelectrode Studies on Concealment of Multiple Premature Atrial Responses
Authors: E. Neil Moore
Journal: Circulation Research (1966)

Experiments employing microelectrodes to record from single cells within the AV node and ventricular specialized conduction system during conduction of serially evoked premature atrial responses have demonstrated AV conduction delays and block within both the AV node and ventricular specialized conduction system. The rapid decrease in functional refractory period of fibers within the ventricular specialized conduction system, following a decrease in preceding cycle length, resulted in block within the AV node of most serially concealed premature atrial responses. A one-millisecond change in the time of excitation of a premature atrial response could determine whether block or conduction occurred in the AV node.
Protein quality control in lung disease: it’s all about cloud networking
Authors: Silke Meiners, Catherine M. Greene
Journal: European Respiratory Journal (2014)

Effective protein quality control is central to lung health http://ow.ly/z3zrqProtein quality control involves the comprehensive management of protein function in the cell and is called ''proteostasis'' [1].It ranges from translation and chaperone-assisted three-dimensional folding, interaction with protein partners, signal-induced post-translational modifications to disposal by the proteasome or autophagy pathways.Dysfunctional protein quality control is emerging as a key pathogenic mechanism for chronic lung diseases.Two major hereditary conformational disorders of the lung, cystic fibrosis and a 1 -antitrypsin (a 1 -AT) deficiency, and some familial forms of idiopathic pulmonary fibrosis (IPF) are caused by the expression of mutant and misfolded proteins that disrupt protein homeostasis and drive the onset of pulmonary diseases [2,3].Disturbed proteostasis also causes sporadic respiratory diseases [1,4].Cigarette smoke-induced protein misfolding, aberrant proteasomal protein degradation and induction of autophagy have been observed in chronic obstructive pulmonary disease (COPD) patients and smoke-exposed mice [4,5].Dysregulation of autophagy and endoplasmic reticulum (ER) stress have also been implicated in cystic fibrosis, pulmonary arterial hypertension, IPF and other lung diseases [6,7].Impairment of protein quality control pathways exacerbates the detrimental effects of environmentally induced protein damage in lung pathogenesis [1].The European Respiratory Society (ERS) research seminar Protein Quality Control in Lung Disease, held on March 1-2, 2014, at Lake Starnberg in Germany, brought together international experts to develop a comprehensive view of protein quality control in general and in the lung in particular.Understanding the complex interplay of protein misfolding, ER homeostasis and protein degradation as interrelated components of adaptive proteostasis will identify novel therapeutic targets for treatment of pulmonary diseases, as outlined here. Protein misfoldingProteins are synthesised as an amino acid chain that folds into a well-defined three-dimensional structure.A network of molecular chaperones assists protein folding and maintains functional states [8].Destabilising missense mutations or stress-induced misfolding challenge the proteostasis network and target protein destruction via proteasomal degradation or autophagy.When chaperone-assisted refolding or degradation fails, protein aggregation may occur.Aggregates exert proteotoxicity by interfering with normal proteins and cellular function [8].
Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women.
Authors: D M Gilligan, A A Quyyumi, R O Cannon
Journal: Circulation (1994)

Estrogen replacement therapy has been associated with a reduction in cardiovascular events in postmenopausal women. One of the mechanisms responsible may be a beneficial effect of estrogen on coronary vascular function. We therefore studied the short-term effects of estrogen on coronary artery dimensions and microvascular resistance in postmenopausal women.Twenty postmenopausal women 61 +/- 7 years old participated in this study. Seven had angiographic evidence of atherosclerosis of the left coronary artery. Coronary artery diameters were measured by quantitative coronary angiography. Blood flow velocity was measured with a Doppler wire placed in a proximal left coronary artery segment. Left coronary artery infusions of acetylcholine (range, 10(-8) to 10(-5) mol/L estimated delivered concentrations) and of adenosine (n = 18) and sodium nitroprusside (n = 10) were performed before and during concomitant continuous intracoronary infusion of 17 beta-estradiol to test endothelium-dependent and independent vasodilation, respectively. Intracoronary infusion of estradiol increased coronary sinus estradiol levels from postmenopausal (16 +/- 11 pg/mL) to premenopausal (282 +/- 121 pg/mL) levels. Estradiol did not affect basal coronary artery diameter, blood flow, or resistance. Epicardial coronary artery constriction induced by acetylcholine infusion in the control study (maximum, 10 +/- 15% from baseline) was prevented during repeat acetylcholine infusion with concomitant estradiol administration (P < .001). Estradiol potentiated the vasodilator coronary microvascular response to acetylcholine as manifest by significantly greater coronary flow (P < .001) and lower coronary resistance (P < .02). The reduction in coronary resistance from baseline in response to acetylcholine was significantly potentiated by estradiol (P = .01), with a mean decrease in coronary vascular resistance during acetylcholine infusion of 20 +/- 38% before and 35 +/- 33% during concomitant estradiol administration. The effect of estradiol on coronary dynamics was similar in women with and women without angiographically apparent left coronary artery atherosclerosis and was most prominent in women with the most impaired responses to acetylcholine at both the epicardial (r = -.72, P < .001) and microvascular (r = -.59, P = .006) coronary artery levels. In contrast, estradiol did not affect the coronary epicardial or microvascular vasodilator responses to adenosine or sodium nitroprusside.Physiological levels of 17 beta-estradiol acutely and selectively potentiate endothelium-dependent vasodilation in both large coronary conductance arteries and coronary microvasuclar resistance arteries of postmenopausal women. This effect may contribute to the reduction in cardiovascular events observed with estrogen replacement therapy.
A Phase I Study of Cixutumumab (IMC-A12) in Combination with Temsirolimus (CCI-779) in Children with Recurrent Solid Tumors: A Children's Oncology Group Phase I Consortium Report
Authors: Maryam Fouladi, John P. Perentesis, Lars M. Wagner, Alexander A. Vinks, Joel M. Reid, Charlotte Ahern, George Thomas, Carol A. Mercer, Darcy A. Krueger, Peter J. Houghton, L. Austin Doyle, Helen Chen, Brenda Weigel, Susan M. Blaney
Journal: Clinical Cancer Research (2014)

Abstract Purpose: To determine the MTD, dose-limiting toxicities (DLT), pharmacokinetics, and biologic effects of cixutumumab administered in combination with temsirolimus to children with refractory solid tumors. Experimental Design: Cixutumumab and temsirolimus were administered intravenously once every 7 days in 28-day cycles. Pharmacokinetic and biology studies, including assessment of mTOR downstream targets in peripheral blood mononuclear cells, were performed during the first cycle. Results: Thirty-nine patients, median age 11.8 years (range, 1–21.5), with recurrent solid or central nervous system tumors were enrolled, of whom 33 were fully assessable for toxicity. There were four dose levels, which included two dose reductions and a subsequent intermediated dose escalation: (i) IMC-A12 6 mg/kg, temsirolimus 15 mg/m2; (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m2; (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m2; and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m2. Mucositis was the predominant DLT. Other DLTs included hypercholesterolemia, fatigue, thrombocytopenia, and increased alanine aminotransferase. Target inhibition (decreased S6K1 and PAkt) in peripheral blood mononuclear cells was noted at all dose levels. Marked interpatient variability in temsirolimus pharmacokinetic parameters was noted. At 8 mg/m2, the median temsirolimus AUC was 2,946 ng • h/mL (range, 937–5,536) with a median sirolimus AUC of 767 ng • h/mL (range, 245–3,675). Conclusions: The recommended pediatric phase II doses for the combination of cixutumumab and temsirolimus are 6 mg/kg and 8 mg/m2, respectively. Clin Cancer Res; 21(7); 1558–65. ©2014 AACR.
Correlations between plasma noradrenaline concentrations, antioxidants, and neutrophil counts after submaximal resistance exercise in men
Authors: A Ramel, K-H Wagner, I Elmadfa
Journal: British Journal of Sports Medicine (2004)

Generation of reactive oxygen species (ROS) during exercise has been linked to increased oxygen consumption. ROS could also be produced by other mechanisms-for example, a respiratory burst of neutrophils or catecholamine auto-oxidation-when oxygen consumption is only moderately increased.To investigate noradrenaline concentrations, neutrophil counts, plasma antioxidants, and lipid oxidation products before and after acute resistance exercise.17 male participants undertook a submaximal resistance exercise circuit (10 exercises; 75% of the one repetition maximum; mean (SD) exercise time, 18.6 (1.1) minutes). Blood samples were taken before and immediately after exercise and analysed for plasma antioxidants, noradrenaline, neutrophils, and lipid oxidation products. Wilcoxon's signed-rank test and Pearson's correlation coefficient were used for calculations.Neutrophils, noradrenaline, fat soluble antioxidants, and lipid oxidation products increased after exercise. Noradrenaline concentrations were associated with higher antioxidant concentrations. Neutrophils were related to higher concentrations of conjugated dienes.Submaximal resistance exercise increases plasma antioxidants. This might reflect enhanced antioxidant defence in response to the oxidative stress of exercise, though this is not efficient for inhibiting lipid oxidation. The correlation between noradrenaline concentrations and plasma antioxidants suggests a modulating role of the stress hormone. Neutrophils are a possible source of oxidative stress after resistance exercise.
Physical Inactivity and Obesity Underlie the Insulin Resistance of Aging
Authors: Francesca Amati, John J. Dubé, Paul M. Coen, Maja Stefanovic-Racic, Frederico G.S. Toledo, Bret H. Goodpaster
Journal: Diabetes Care (2009)

OBJECTIVE Age-associated insulin resistance may underlie the higher prevalence of type 2 diabetes in older adults. We examined a corollary hypothesis that obesity and level of chronic physical inactivity are the true causes for this ostensible effect of aging on insulin resistance. RESEARCH DESIGN AND METHODS We compared insulin sensitivity in 7 younger endurance-trained athletes, 12 older athletes, 11 younger normal-weight subjects, 10 older normal-weight subjects, 15 younger obese subjects, and 15 older obese subjects using a glucose clamp. The nonathletes were sedentary. RESULTS Insulin sensitivity was not different in younger endurance-trained athletes versus older athletes, in younger normal-weight subjects versus older normal-weight subjects, or in younger obese subjects versus older obese subjects. Regardless of age, athletes were more insulin sensitive than normal-weight sedentary subjects, who in turn were more insulin sensitive than obese subjects. CONCLUSIONS Insulin resistance may not be characteristic of aging but rather associated with obesity and physical inactivity.
MST1 Is a Multifunctional Caspase-Independent Inhibitor of Androgenic Signaling
Authors: Bekir Cinar, Filiz Kisaayak Collak, Delia Lopez, Seckin Akgul, Nishit K. Mukhopadhyay, Murat Kilicarslan, Daniel G. Gioeli, Michael R. Freeman
Journal: Cancer Research (2011)

The MST1 serine-threonine kinase, a component of the RASSF1-LATS tumor suppressor network, is involved in cell proliferation and apoptosis and has been implicated in cancer. However, the physiologic role of MST1 in prostate cancer (PCa) is not well understood. Here, we investigated the possibility of a biochemical and functional link between androgen receptor (AR) and MST1 signaling. We showed that MST1 forms a protein complex with AR and antagonizes AR transcriptional activity as shown by coimmunoprecipitation (co-IP), promoter reporter analysis, and molecular genetic methods. In vitro kinase and site-specific mutagenesis approaches indicate that MST1 is a potent AR kinase; however, the kinase activity of MST1 and its proapoptotic functions were shown not to be involved in inhibition of AR. MST1 was also found in AR-chromatin complexes, and enforced expression of MST1 reduced the binding of AR to a well-characterized, androgen-responsive region within the prostate-specific antigen promoter. MST1 suppressed PCa cell growth in vitro and tumor growth in mice. Because MST1 is also involved in regulating the AKT1 pathway, this kinase may be an important new link between androgenic and growth factor signaling and a novel therapeutic target in PCa.
Mind your rhythms: an important role for circadian genes in neuroprotection
Authors: Colleen A. McClung
Journal: Journal of Clinical Investigation (2013)

Circadian rhythms govern nearly every physiological process in our brains and bodies. At the most basic level, the molecular clockwork in each cell interacts with metabolic cycles to influence the redox state, allowing for increased cellular activity at specific times of day. In this issue of the JCI, Musiek et al. show that genetic disruptions in the positive arm of the molecular clock can lead to severe astrogliosis, which likely occurs through disruptions in output genes that keep oxidative stress in check. This study demonstrates the importance of proper circadian protein function in the maintenance of neuronal integrity.
Prognostic gene expression signature associated with two molecularly distinct subtypes of colorectal cancer
Authors: Sang Cheul Oh, Yun-Yong Park, Eun Sung Park, Jae Yun Lim, Soo Mi Kim, Sang-Bae Kim, Jongseung Kim, Sang Cheol Kim, In-Sun Chu, J Joshua Smith, R Daniel Beauchamp, Timothy J Yeatman, Scott Kopetz, Ju-Seog Lee
Journal: Gut (2011)

<h3>Aims</h3> Despite continual efforts to develop prognostic and predictive models of colorectal cancer by using clinicopathological and genetic parameters, a clinical test that can discriminate between patients with good or poor outcome after treatment has not been established. Thus, the authors aim to uncover subtypes of colorectal cancer that have distinct biological characteristics associated with prognosis and identify potential biomarkers that best reflect the biological and clinical characteristics of subtypes. <h3>Methods</h3> Unsupervised hierarchical clustering analysis was applied to gene expression data from 177 patients with colorectal cancer to determine a prognostic gene expression signature. Validation of the signature was sought in two independent patient groups. The association between the signature and prognosis of patients was assessed by Kaplan–Meier plots, log-rank tests and the Cox model. <h3>Results</h3> The authors identified a gene signature that was associated with overall survival and disease-free survival in 177 patients and validated in two independent cohorts of 213 patients. In multivariate analysis, the signature was an independent risk factor (HR 3.08; 95% CI 1.33 to 7.14; p=0.008 for overall survival). Subset analysis of patients with AJCC (American Joint Committee on Cancer) stage III cancer revealed that the signature can also identify the patients who have better outcome with adjuvant chemotherapy (CTX). Adjuvant chemotherapy significantly affected disease-free survival in patients in subtype B (3-year rate, 71.2% (CTX) vs 41.9% (no CTX); p=0.004). However, such benefit of adjuvant chemotherapy was not significant for patients in subtype A. <h3>Conclusion</h3> The gene signature is an independent predictor of response to chemotherapy and clinical outcome in patients with colorectal cancer.
TNFα inhibitors restrict T cell activation and cycling via Notch-1 signalling in inflammatory bowel disease
Authors: Lael Werner, Uta Berndt, Daniela Paclik, Silvio Danese, Anja Schirbel, Andreas Sturm
Journal: Gut (2011)

<h3>Background</h3> Tumour necrosis factor α (TNFα) inhibitors such as adalimumab and infliximab are frequently prescribed for inflammatory bowel disease (IBD). Despite the clinical success of TNFα inhibitors, their physiological mode of action is not fully understood. The aim of this study was to investigate the mode of action of anti-TNFα agents in IBD. <h3>Methods</h3> It was hypothesised that Notch mediates anti-TNFα action in T cells. A study was carried out to identify Notch-1 as a link by which anti-TNFα antibodies mediate their inhibitory functions. <h3>Results</h3> TNFα inhibitors induced T cell apoptosis, inhibited activation, reduced cytokine secretion and restricted cell cycling. TNFα blockade at several levels showed that TNFα is responsible for inducing apoptosis by anti-TNFα but not for cell cycle restriction. By linking Notch and TNFα it was shown that (1) Notch-1 mucosal expression differs in inflamed and non-inflamed mucosa and increases in response to anti-TNFα treatment; (2) Notch-1 function is regulated by TNFα inhibitors; (3) Notch-1 binds to TNFα; and (4) Notch-1 inhibition prevents anti-TNFα-induced T cell cycle arrest but not apoptosis. <h3>Conclusions</h3> TNFα inhibitors potently inhibit T cell function. By demonstrating for the first time that Notch-1 mediates the inhibitory effects of adalimumab and infliximab on T cell cycling, this study reveals a new mode of action and also an underlying signalling pathway by which biological agents act in IBD.
Epidemiology of biopsy proven giant cell arteritis in northwestern Spain: trend over an 18 year period
Authors: M A Gonzalez-Gay
Journal: Annals of the Rheumatic Diseases (2001)

In Europe giant cell arteritis (GCA) is more common in Scandinavian countries than in southern regions. Epidemiological studies on GCA in other more distant countries have indicated a progressive increase in incidence. A regular cyclical pattern in incidence of GCA over 20 years has been reported in Olmsted County (Minnesota, USA). In contrast, no cyclical fluctuation has been recently reported in Sweden. To investigate further the epidemiology of GCA in southern Europe the trend in incidence and fluctuations of this vasculitis over 18 years in the Lugo region of northwestern Spain were examined.A retrospective study of biopsy proven GCA diagnosed between 1 January 1981 and 31 December 1998 at a single hospital for a well defined population of almost 250 000 people. Annual incidence was calculated for the whole group of patients and for men and women separately. Monthly variations, annual peaks of incidence, and trend in the incidence of biopsy proven GCA with and without polymyalgia rheumatica (PMR) were also examined.One hundred and sixty one Lugo residents were diagnosed with biopsy proven GCA between 1981 and 1998. The average annual incidence for the population aged 50 and older was 10.24/100 000 (men 11.00/100 000, women 9.57/100 000). A progressive increase in the incidence in both men and women was seen. In men there was an annual increase of 8% (95% CI 4% to 13%; p<0.0001). In women the annual increase was 11% (95% CI 5% to 17%; p<0.0001). The overall annual increase for men and women was 10% (95% CI 6% to 14%; p<0.0001). No seasonal pattern or peaks in the incidence were seen. During the period 1981-94 GCA was more common in men than in women. In contrast, during the last years of study the increase in incidence was higher in women. In women the annual ratio of incidence of GCA with PMR/incidence of GCA without PMR was generally higher than 1. However, in men the annual ratio was initially 1 but decreased gradually, indicating a progressive decrease in the proportion of men with biopsy proven GCA associated with PMR.In northwestern Spain there has been a progressive increase in GCA incidence. As seen in other countries where GCA is more common, during the past few years the increase in incidence has been mainly due to a higher number of new cases in women.
Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation
Authors: Stuart J Connolly, Janice Pogue, Robert G Hart, Stefan H Hohnloser, Marc Pfeffer, Susan Chrolavicius, Salim Yusuf
Journal: New England Journal of Medicine (2009)

Vitamin K antagonists reduce the risk of stroke in patients with atrial fibrillation but are considered unsuitable in many patients, who usually receive aspirin instead. We investigated the hypothesis that the addition of clopidogrel to aspirin would reduce the risk of vascular events in patients with atrial fibrillation.
Prevalence and Treatment of Low HDL Cholesterol Among Primary Care Patients With Type 2 Diabetes
Authors: Richard W. Grant, James B. Meigs
Journal: Diabetes Care (2007)

Patients with diabetes remain at high risk for cardiovascular events despite aggressive blood pressure, LDL cholesterol, and blood glucose control. We identified prevalence and predictors of low HDL cholesterol, characterized current lipid therapy, and estimated the theoretical benefit of more effective HDL cholesterol-raising methods among patients with type 2 diabetes.We analyzed a primary care-based population of patients with type 2 diabetes (n = 7,692) in 12 eastern Massachusetts outpatient practices. We grouped fibrates, niacins, and n-3 fatty acid preparations as nonstatin HDL cholesterol-raising medicines, and we used published studies to estimate the potential benefit of raising HDL cholesterol levels in this population.Nearly half (49.5%) of patients had low HDL cholesterol (<40 mg/dl for men, <50 mg/dl for women). Low HDL cholesterol was independently associated with prevalent cardiovascular disease (CVD), younger age, and higher A1C levels. Nearly two-thirds of patients (63.0%) were prescribed a statin (67.6% of patients below the HDL cholesterol goal, 80.5% of patients with CVD). In contrast, only 7.9% of patients were prescribed a nonstatin HDL cholesterol-raising medication, including 16.4% of patients below the HDL cholesterol goal with CVD. Based on published studies, normalizing low HDL cholesterol in this primary care cohort would correspond to an estimated CVD mortality reduction of 42% in women and 23% in men.Nearly half of the patients in this large primary care cohort had low HDL cholesterol levels. In contrast to frequent statin use, few patients were prescribed currently available medicines to raise HDL cholesterol. Low HDL cholesterol represents a highly prevalent and potentially modifiable risk factor for CVD prevention in type 2 diabetes.
Young black women have more aggressive breast cancers than white women
Authors: Janice Hopkins Tanne
Journal: BMJ (2004)

New rules in the United States that came into effect this week require doctors and hospitals to take certain specified steps to prevent operating on the wrong body part or wrong patient.Among the requirements, surgeons and nurses must take what is being referred to as "time out" before operating on patients, to confirm that the right patient is on the table and that doctors are operating on the right body part and the right side of the body.Hospital regulators hope the rules, which came into effect on 1 July, will put an end to growing reports of operations on the wrong site or the wrong patient or that involved the wrong procedure."These should never happen," said Dr Dennis O'Leary, who heads the Joint Commission on Accreditation of Healthcare Organizations, the agency that accredits medical facilities in the United States, allowing them to continue to operate.The agency can revoke the accreditation of hospitals or other surgery sites that don't comply with the new safety steps.No precise figures on exactly how many such mistakes occur are available, because the commission receives only voluntary reports.It is assumed that the reports are only a small percentage of the 70 million operations done in the United States each year.