tbuckley/cabot-search huggingface dataset:
Decreased PM <sub>10</sub> Exposure Attenuates Age-Related Lung Function Decline: Genetic Variants in <i>p53</i> , <i>p21</i> , and <i>CCND1</i> Modify This Effect
Authors: Medea Imboden, Joel Schwartz, Christian Schindler, Ivan Curjuric, Wolfgang Berger, Sally L.J. Liu, Erich W. Russi, Ursula Ackermann-Liebrich, Thierry Rochat, Nicole M. Probst-Hensch
Journal: Environmental Health Perspectives (2009)

Decreasing exposure to airborne particulates was previously associated with reduced age-related decline in lung function. However, whether the benefit from improved air quality depends on genetic background is not known. Recent evidence points to the involvement of the genes p53 and p21 and of the cell cycle control gene cyclin D1 (CCND1) in the response of bronchial cells to air pollution.We determined in 4,326 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) whether four single-nucleotide polymorphisms in three genes [CCND1 (rs9344 [P242P], rs667515), p53 (rs1042522 [R72P]), and p21 (rs1801270 [S31R])] modified the previously observed attenuation of the decline in the forced expiratory flow between 25% and 75% of the forced vital capacity (FEF(25-75)) associated with improved air quality.Subjects of the prospective population-based SAPALDIA cohort were assessed in 1991 and 2002 by spirometry, questionnaires, and biological sample collection for genotyping. We assigned spatially resolved concentrations of particulate matter with aerodynamic diameter < or = 10 microm (PM(10)) to each participant's residential history 12 months before the baseline and follow-up assessments.The effect of diminishing PM(10) exposure on FEF(25-75) decline appeared to be modified by p53 R72P, CCND1 P242P, and CCND1 rs667515. For example, a 10-microg/m(3) decline in average PM(10) exposure over an 11-year period attenuated the average annual decline in FEF(25-75) by 21.33 mL/year (95% confidence interval, 10.57-32.08) among participants homozygous for the CCND1 (P242P) GG genotype, by 13.72 mL/year (5.38-22.06) among GA genotypes, and by 6.00 mL/year (-4.54 to 16.54) among AA genotypes.Our results suggest that cell cycle control genes may modify the degree to which improved air quality may benefit respiratory function in adults.
Topotecan Versus Observation After Cisplatin Plus Etoposide in Extensive-Stage Small-Cell Lung Cancer: E7593—A Phase III Trial of the Eastern Cooperative Oncology Group
Authors: Joan H. Schiller, Sudeshna Adak, David Cella, Russell F. DeVore, David H. Johnson
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To determine the efficacy of topotecan in combination with standard chemotherapy in previously untreated patients with extensive-stage small-cell lung cancer (SCLC), the Eastern Cooperative Oncology Group (ECOG) conducted a phase III trial. PATIENTS AND METHODS: Eligible patients had measurable or assessable disease and an ECOG performance status of 0 to 2; stable brain metastases were allowed. All patients received four cycles of cisplatin and etoposide every 3 weeks (step 1; PE). Patients with stable or responding disease were then randomized to observation or four cycles of topotecan (1.5 mg/m 2 /d for 5 days, every 3 weeks; step 2). A total of 402 eligible patients were registered to step 1, and 223 eligible patients were registered to step 2 (observation, n = 111; topotecan, n = 112). RESULTS: Complete and partial response rates to induction PE were 3% and 32%, respectively. A 7% response rate was observed with topotecan (complete response, 2%; partial response, 5%). The median survival time for all 402 eligible patients was 9.6 months. Progression-free survival (PFS) from date of randomization on step 2 was significantly better with topotecan compared with observation (3.6 months v 2.3 months; P &lt; .001). However, overall survival from date of randomization on step 2 was not significantly different between the observation and topotecan arms (8.9 months v 9.3 months; P = .43). Grade 4 neutropenia and thrombocytopenia occurred in 50% and 3%, respectively, of PE patients in step 1 and 60% and 13% of topotecan patients in step 2. Grade 4/5 infection was observed in 4.6% of PE patients and 1.8% of topotecan patients. Grade 3/4 anemia developed in 22% of patients who received topotecan. No difference in quality of life between topotecan and observation was observed at any assessment time or for any of the subscale scores. CONCLUSION: Four cycles of PE induction therapy followed by four cycles of topotecan improved PFS but failed to improve overall survival or quality of life in extensive-stage SCLC. Four cycles of standard PE remains an appropriate first-line treatment for extensive-stage SCLC patients with good performance status.
Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing
Authors: D Thomas
Journal: Cardiovascular Research (2003)

Human hereditary long QT syndrome is a cardiac disease characterized by prolongation of the QT interval and increased susceptibility to ventricular arrhythmias and sudden cardiac death. Mutations in the human-ether-a-go-go-related gene (hERG), encoding the protein underlying the repolarizing cardiac I(Kr) potassium current, cause chromosome 7-linked long QT syndrome 2. Loss of function of mutant hERG channels may be caused by several mechanisms, including altered current kinetics, altered ion selectivity, or defective intracellular protein trafficking. Especially the latter category has become a focus of particular interest recently, because some of the mutant subunits display wild type current properties when normal trafficking is restored and channels are inserted in the cell membrane in vitro. This review summarizes the current knowledge on hERG channel trafficking under physiological and pathological conditions. In addition, therapeutic approaches to restore normal hERG trafficking in vitro and in vivo are discussed.
Intramyocardial Adiposity After Myocardial Infarction
Authors: Jim Pouliopoulos, William W.B. Chik, Ajita Kanthan, Gopal Sivagangabalan, Michael A. Barry, Peter N.A. Fahmy, Christine Midekin, Juntang Lu, Eddy Kizana, Stuart P. Thomas, Aravinda Thiagalingam, Pramesh Kovoor
Journal: Circulation (2013)

Background— Collagen has been attributed as the principal structural substrate of ventricular tachycardia (VT) after myocardial infarction (MI), even though adiposity of myocardium after MI is well recognized histologically. We investigated the effects of intramyocardial adiposity compared with collagen on electrophysiological properties, connexin43 expression, and VT induction after MI. Methods and Results— Simultaneous left ventricular plunge-needle, noncontact mapping was performed in sheep without MI (MI−; n=5), with MI and inducible VT (MI+VT+; n=7), and with MI and no inducible VT (MI+VT−; n=8). Histological intramyocardial quantity of adipose and collagen and degree of discontinuity were coregistered with electrophysiological parameters (MI+; 290 specimens). Additional assessment of connexin43 expression was performed. Left ventricular scar contained a body mass–independent abundance of adipocytes (adipose:collagen=0.8). Increased adipose density and discontinuity contributed to a greater inverse correlation ( r ) with conduction velocity ( r for adipose=0.39, r for discontinuity=0.45, r for collagen=0.26) and electrogram amplitude ( r for adipose=0.73, r for contiguity=0.77, r for collagen=0.68) compared with collagen. Collagen density was similar between the MI+ groups ( P &gt;0.29). However, the MI+VT+ group demonstrated a significant (all P ≤0.01) increase in adipose (8%) and discontinuity (qualitative) and decrease in conduction velocity (13%) and electrogram amplitude (21%) at MI borders compared with the MI+VT− group. In scar, myocytes adjacent to fibrofatty interfaces demonstrated increased connexin43 lateralization. A gradient increase in adipose was observed at sites that supported preferential presystolic VT activation and exhibited attenuation of excitation wavelength ( P &lt;0.001). Conclusions— Intramyocardial adiposity, in association with myocardial discontinuity within left ventricular scar borders, is a significant factor associated with altered electrophysiological properties, aberrant connexin43 expression, and increased propensity for VT after MI.
Decreased fructose-1,6-bisphosphatase-2 expression promotes glycolysis and growth in gastric cancer cells
Authors: He Li, Juan Wang, Huiyu Xu, Rui Xing, Yuanming Pan, Wenmei Li, Jiantao Cui, Hongbing Zhang, Youyong Lu
Journal: Molecular Cancer (2013)

Abstract Background Increasing evidence suggests that cancer is a metabolic disease. Here, we investigated the potential role of fructose-1,6-bisphosphatase-2 (FBP2), the enzyme that catalyses the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate in glucose metabolism, in gastric cancer (GC) development. Results Our data indicated that FBP2 was downregulated in GC tissues (86.2%, 100/116), and absent or low FBP2 expression in GC tissues was correlated with poor survival of GC patients ( P = 0.019). Conversely, ectopic expression of FBP2 in GC cells activated AMP-activated protein kinase (AMPK) signalling, inhibited the Akt-mTOR pathway, suppressed glucose metabolism, enhanced apoptosis, and reduced cell proliferation. Bisulphite genomic sequencing (BGS) in gastric cancer cell lines revealed that the FBP2 promoter region was densely methylated, and treatment of GC cells with the demethylation reagent, 5-aza-2-deoxycytidine (5-Aza), led to an increase in FBP2 expression. Importantly, forced expression of FBP2 abrogated tumour formation of these GC cells in nude mice. Conclusion Our results indicate that FBP2 does negatively regulate cell growth, and reduced expression of FBP2 may contribute to carcinogenesis for GC. These findings suggest that restoration of FBP2 expression can be a promising strategy for the target therapy of GC.
Age and <i>Helicobacter pylori</i> decrease gastric mucosal surface hydrophobicity independently
Authors: A Hackelsberger, U Platzer, M Nilius, V Schultze, T Günther, J E Dominguez-Muñoz, P Malfertheiner
Journal: Gut (1998)

Gastric mucosal surface hydrophobicity (GMSH) is an essential component of the mucosal defence system that is decreased by Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs). Gastric ulcers occur predominantly in elderly subjects, and may thus reflect diminished mucosal resistance.To investigate whether aging decreases GMSH.One hundred and twenty patients without peptic ulcer disease were divided into three age groups: I (41 years or below); II (41-64 years); and III (65 years or above).Biopsy specimens were taken from the antrum, corpus, and cardia for histology (Sydney system), urease testing for H pylori, and for contact angle measurement of GMSH with a goniometer. The presence of specific H pylori antibodies was checked by immunoblotting.Fifty two patients (43%) were infected, and 68 were uninfected with H pylori. GMSH at all biopsy sites was lower in H pylori infected subjects (p=0.0001), but also decreased with age independently of infection status (p=0.0001). The most notable decrease in GMSH occurred between age groups I and II in those with, and between age groups II and III in those without, H pylori infection. GMSH was greater in antral than in corpus mucosa in both infected (p=0.0001) and uninfected patients (p=0.0003).A physiological decrease in GMSH with aging may contribute to the risk of ulcer development in the elderly, and may act synergistically with H pylori and/or NSAIDs on gastric mucosal defence.
Airway inflammation in iron ore miners exposed to dust and diesel exhaust
Authors: E. Adelroth
Journal: European Respiratory Journal (2006)

The aim of the present study was to investigate if underground miners exposed to dust and diesel exhaust in an iron ore mine would show signs of airway inflammation as reflected in induced sputum. In total, 22 miners were studied, once after a holiday of at least 2 weeks and the second time after 3 months of regular work. Control subjects were 21 "white-collar" workers. All subjects completed a questionnaire regarding medical and occupational history, and underwent lung function testing and induced sputum collection. Total and differential cell counts and analyses of the fluid phase of the induced sputum were performed. Sampling of personal exposure to elemental carbon, nitrogen dioxide and inhalable dust was recorded. The average concentrations of inhalable dust, nitrogen dioxide and elemental carbon were 3.2 mg·m<sup>−3</sup>, 0.28 mg·m<sup>−3</sup> and 27 µg·m<sup>−3</sup>, respectively. Miners had increased numbers of inflammatory cells, mainly alveolar macrophages and neutrophils, and increased concentrations of fibronectin, metalloproteinase-9 and interleukin-10 in induced sputum compared with controls. In conclusion, miners in an underground iron ore mine demonstrated persistent airway inflammation that was as pronounced after a 4-week holiday as after a 3-month period of work underground in the mine.
Natural History of Huntington Disease
Authors: E Ray Dorsey, Christopher A Beck, Kristin Darwin, Paige Nichols, Alicia F D Brocht, Kevin M Biglan, Ira Shoulson
Journal: JAMA Neurology (2013)

Understanding the natural history of Huntington disease will inform patients and clinicians on the disease course and researchers on the design of clinical trials.To determine the longitudinal change in clinical features among individuals with Huntington disease compared with controls.Prospective, longitudinal cohort study at 44 research sites in Australia (n = 2), Canada (n =4), and the United States (n = 38). Three hundred thirty-four individuals with clinically manifest Huntington disease who had at least 3 years of annually accrued longitudinal data and 142 controls consisting of caregivers and spouses who had no genetic risk of Huntington disease.Change in movement, cognition, behavior, and function as measured by the Unified Huntington's Disease Rating Scale, the Mini-Mental State Examination, and vital signs.Total motor score worsened by 3.0 points (95% CI, 2.5-3.4) per year and chorea worsened by 0.3 point per year (95% CI, 0.1-0.5). Cognition declined by 0.7 point (95% CI, 0.6-0.8) per year on the Mini-Mental State Examination. Behavior, as measured by the product of frequency and severity score on the Unified Huntington's Disease Rating Scale, worsened by 0.6 point per year (95% CI, 0.0-1.2). Total functional capacity declined by 0.6 point per year (95% CI, 0.5-0.7). Compared with controls, baseline body mass index was lower in those with Huntington disease (25.8 vs 28.8; P < .001), and average pulse was higher (74.2 vs 69.6 beats/min; P < .001).Over 3 years, the cardinal features of Huntington disease all declined in a monotonic manner. These data quantify the natural history of the disease and may inform the design of trials aimed at reducing its burden.clinicaltrials.gov Identifier: NCT00313495.
CHANCE: comprehensive software for quality control and validation of ChIP-seq data
Authors: Aaron Diaz, Abhinav Nellore, Jun S Song
Journal: Genome biology (2012)

ChIP-seq is a powerful method for obtaining genome-wide maps of protein-DNA interactions and epigenetic modifications. CHANCE (CHip-seq ANalytics and Confidence Estimation) is a standalone package for ChIP-seq quality control and protocol optimization. Our user-friendly graphical software quickly estimates the strength and quality of immunoprecipitations, identifies biases, compares the user's data with ENCODE's large collection of published datasets, performs multi-sample normalization, checks against quantitative PCR-validated control regions, and produces informative graphical reports. CHANCE is available at https://github.com/songlab/chance .
Acute Febrile Systemic Reaction to Polyvalent Pneumococcal Vaccine
Authors: E. Peter Gabor
Journal: JAMA (1979)

An acute, severe febrile reaction with leukocytosis followed vaccination with polyvalent pneumococcal polysaccharide vaccine in a splenectomized patient with myeloproliferative disease. Recovery required five days.  (JAMA242:2208-2209, 1979)
Biomechanical forces promote blood development through prostaglandin E2 and the cAMP–PKA signaling axis
Authors: Miguel F. Diaz, Nan Li, Hyun Jung Lee, Luigi Adamo, Siobahn M. Evans, Hannah E. Willey, Natasha Arora, Yu-suke Torisawa, Dwayne A. Vickers, Samantha A. Morris, Olaia Naveiras, Shashi K. Murthy, Donald E. Ingber, George Q. Daley, Guillermo García-Cardeña, Pamela L. Wenzel
Journal: The Journal of Experimental Medicine (2015)

Blood flow promotes emergence of definitive hematopoietic stem cells (HSCs) in the developing embryo, yet the signals generated by hemodynamic forces that influence hematopoietic potential remain poorly defined. Here we show that fluid shear stress endows long-term multilineage engraftment potential upon early hematopoietic tissues at embryonic day 9.5, an embryonic stage not previously described to harbor HSCs. Effects on hematopoiesis are mediated in part by a cascade downstream of wall shear stress that involves calcium efflux and stimulation of the prostaglandin E2 (PGE2)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling axis. Blockade of the PGE2-cAMP-PKA pathway in the aorta-gonad-mesonephros (AGM) abolished enhancement in hematopoietic activity. Furthermore, Ncx1 heartbeat mutants, as well as static cultures of AGM, exhibit lower levels of expression of prostaglandin synthases and reduced phosphorylation of the cAMP response element-binding protein (CREB). Similar to flow-exposed cultures, transient treatment of AGM with the synthetic analogue 16,16-dimethyl-PGE2 stimulates more robust engraftment of adult recipients and greater lymphoid reconstitution. These data provide one mechanism by which biomechanical forces induced by blood flow modulate hematopoietic potential.
Proinflammatory Endothelial Activation Detected by Molecular Imaging in Obese Nonhuman Primates Coincides With Onset of Insulin Resistance and Progressively Increases With Duration of Insulin Resistance
Authors: Scott M. Chadderdon, J. Todd Belcik, Lindsay Bader, Melissa A. Kirigiti, Dawn M. Peters, Paul Kievit, Kevin L. Grove, Jonathan R. Lindner
Journal: Circulation (2013)

Inflammation and insulin resistance (IR) are associated processes that potentiate risk for cardiovascular disease in obesity. The temporal relation between IR and inflammation is not completely characterized. We hypothesized that endothelial cell adhesion molecule expression in large arteries is an early event that coincides with diet-induced obesity and IR in primates.Ten adult male rhesus macaques were studied at baseline and every 4 to 6 months on a high-fat diet for 2 years. Truncal fat, carotid intima-media thickness, plasma inflammatory biomarkers, and carotid P-selectin and vascular cell adhesion molecule-1 expression by contrast-enhanced ultrasound molecular imaging were assessed. Intravenous glucose tolerance test was performed at baseline and at 4 and 18 months. A high-fat diet produced a rapid increase (P<0.01) in weight, truncal fat, and degree of IR indicated by the insulin area under the curve and glucose disappearance rate on intravenous glucose tolerance test, all of which worsened minimally thereafter. Molecular imaging detected a progressive increase in endothelial cell adhesion molecule expression over time (5- to 7-fold greater than control agent signal at 2 years; P<0.01). Changes in intima-media thickness were not detected until 2 years and, although there was a trend toward an increase in plasma markers of inflammation (monocyte chemotactic protein-1, C-reactive protein), the pattern of increase varied considerably over time.In primates with diet-induced obesity, endothelial inflammatory activation is an early event that occurs coincident with the development of IR and long before any measurable change in carotid intima-media thickness. Endothelial activation is related more to the duration rather than to the severity of IR and is not mirrored by changes in plasma biomarkers.
Triamterene inhibits the delayed rectifier potassium current (IK) in guinea pig ventricular myocytes.
Authors: P Daleau, J Turgeon
Journal: Circulation Research (1994)

In humans, proarrhythmia during therapy with action potential-prolonging drugs can be associated with hypokalemia often provoked by concomitant administration of diuretic agents. Consequently, therapy with class III antiarrhythmics and K(+)-sparing diuretics, such as triamterene, may be indicated. Triamterene, along with its K(+)-sparing properties, exhibits other pharmacological effects. In the heart, it can increase action potential duration (guinea pig atria and papillary muscles), protect against reperfusion-induced arrhythmias (rat), and increase the QT interval (humans). Therefore, studies were undertaken to assess effects of triamterene on cardiac K+ repolarizing currents. Guinea pig ventricular myocytes were superfused at 30 degrees C with Cd(2+)-containing solution to block Isi and held at -40 mV to inactivate INa. Currents were measured in the whole-cell configuration of the patch-clamp technique. The delayed rectifier outward current (IK) was elicited by short (250-millisecond) and long (5000-millisecond) depolarizing pulses, and time-independent currents were assessed by a rapid ramp test protocol. After high-voltage long pulses (+50 mV; 5000 milliseconds), tail current amplitude of the slow component of IK (IKs) was decreased 36 +/- 6% (n = 6) and 51 +/- 8% (n = 6) by triamterene 10(-5) and 10(-4) mol/L, respectively. After low-voltage short pulses (-20 mV; 250 milliseconds), tail current amplitude corresponding essentially to the rapid component of IK (IKr) was decreased only 14 +/- 11% (n = 9) and 19 +/- 10% (n = 10) by triamterene 10(-5) and 10(-4) mol/L, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
The ERCP quality network benchmarking practice and performance; a comparison of UK and USA
Authors: K. Oppong, D. Garrow, C. Zsilavecz, P. Cotton
Journal: Gut (2011)

<h3>Introduction</h3> There is increasing interest in documenting the performance of individual Endoscopists, for their own education and to ensure quality standards. What has been lacking hitherto is an infrastructure to facilitate collection and analyses of data to allow practitioners to easily compile a ‘report card’ of their own practice or benchmark themselves against their peers. The ERCP Quality Network is a web based tool started in the USA.1 <h3>Methods</h3> Anonymised key data points (indications, sedation/anaesthesia, therapies, successes and adverse events), on each case are uploaded through a web based interface onto a central server hosted by Olympus America. This analysis is limited to the 51 endoscopists based in USA and the 12 in the UK who have each entered more than 30 cases. The results were evaluated in aggregate. <h3>Results</h3> The table 1 shows some of the areas where practice differed between countries. Those Endoscopists reporting their data in Britain are clearly doing less complex procedures as judged by the accepted complexity grade2 with lower (but acceptable) technical success rates. The differences were maintained when the comparison was restricted to cases performed with conscious sedation. The proportion of complex ‘grade 3’ cases was significantly higher in USA. The other striking difference is in the use of anaesthesia, that is, 3% versus 62%. <h3>Conclusion</h3> These data do not purport to reflect average UK and US practice, since the participants are self-selected, and not necessarily representative. The UK data compares favourably with the BSG ERCP audit in which only 77% of trained endoscopists achieved a cannulation rate of greater than 80%.3 The collection of this level of data about ones own practice is likely to become mandatory in the near future. In the UK the driver for collection of quality data is likely to be revalidation. The ERCP Quality Network is available to use and is a practical tool for self monitoring of quality outcomes and benchmarking against peers.