tbuckley/cabot-search huggingface dataset:
Tagging Single-Nucleotide Polymorphisms in Antioxidant Defense Enzymes and Susceptibility to Breast Cancer
Authors: Arancha Cebrian, Paul D. Pharoah, Shahana Ahmed, Paula L. Smith, Craig Luccarini, Robert Luben, Karen Redman, Hannah Munday, Douglas F. Easton, Alison M. Dunning, Bruce A.J. Ponder
Journal: Cancer Research (2006)

Abstract It is generally believed that the initiation of breast cancer is a consequence of cumulative genetic damage leading to genetic alterations and provoking uncontrolled cellular proliferation and/or aberrant programmed cell death, or apoptosis. Reactive oxygen species have been related to the etiology of cancer as they are known to be mitogenic and therefore capable of tumor promotion. The aim of this study was to assess the role of common variation in 10 polymorphic genes coding for antioxidant defense enzymes in modulating individual susceptibility to breast cancer using a case-control study (N cases = 4,474 and N controls = 4,580). Both cases and controls were from the East Anglian region of the United Kingdom. We have identified a set of 54 single nucleotide polymorphisms (SNPs) that efficiently tag all the known SNPs in the 10 genes and are also expected to tag any unknown SNPs in each gene. We found no evidence for association of common variants in SOD1, SOD2, GPX1, GPX4, GSR, TXNRD1, and TXN2. There was borderline evidence for association of variants in CAT g27168a {P [2 degrees of freedom (df)] = 0.05}, TXN t2715c [P (2 df) = 0.007], and TXNRD2 A66S and TXNRD2 g23524a (Ptrend = 0.074 and 0.046, respectively). For TXNRD2 A66S [AS versus AA: odds ratio (OR), 1.05; 95% confidence intervals (95% CI), 0.96-1.15; SS versus AA: OR, 1.12; 95% CI, 0.98-1.29], there are bioinformatics data to suggest that it is functional but confirmation in independent data sets is required before they can be regarded as definitive breast cancer susceptibility alleles. Even if confirmed, these four alleles would account for just 0.32% of the excess familial risk of breast cancer. (Cancer Res 2006; 66(2): 1225-33)
In Vivo Identification of the Mitogen-Activated Protein Kinase Cascade as a Central Pathogenic Pathway in Experimental Mesangioproliferative Glomerulonephritis
Authors: Dirk Bokemeyer, Darius Panek, Herbert J. Kramer, Marion Lindemann, Masashi Kitahara, Peter Boor, Dontscho Kerjaschki, James M. Trzaskos, Jürgen Floege, Tammo Ostendorf
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Evidence was recently provided for the activation of extracellular signal-regulated kinase (ERK), the best characterized mitogen-activated protein kinase, as an intracellular convergence point for mitogenic stimuli in animal models of glomerulonephritis (GN). In this study, <i>in vivo</i> ERK activity was blocked, with a pharmacologic inhibitor (U0126) of the ERK-activating kinase, in rats with mesangioproliferative GN. After injection of the monoclonal anti-Thy1.1 antibody (OX-7), the rats were treated (days 3 to 6) with low (10 mg/kg body wt) or high (100 mg/kg body wt) doses of U0126 administered intraperitoneally twice daily. On day 6 after induction of the disease, whole cortical tissue and isolated glomeruli were examined by using kinase activity assays, Western blot analyses, and immunohistochemical assays. Treatment with U0126 significantly reduced glomerular stimulation of ERK in anti-Thy1 GN. In the high dose-treated group, this downregulation was accompanied by a reduction in the number of glomerular mitotic figures, back to healthy control levels, and significant decreases in the numbers of total (<i>P</i> &lt; 0.05) and 5-bromo-2′-deoxyuridine-positive (<i>P</i> &lt; 0.05) glomerular cells. Immunohistochemical double-staining of renal sections demonstrated that mesangial cells were the major glomerular targets of U0126 in anti-Thy1 GN. These observations point to ERK as a putative intracellular mediator of the proliferative response in GN and suggest that pharmacologic treatments that interfere with the activation of ERK may be of potential therapeutic interest.
Action of Tropoelastin and Synthetic Elastin Sequences on Vascular Tone and on Free Ca <sup>2+</sup> Level in Human Vascular Endothelial Cells
Authors: Gilles Faury, Stéphanie Garnier, Anthony S. Weiss, Jean Wallach, Tamàs Fülöp, Marie-Paule Jacob, Robert P. Mecham, Ladislas Robert, Jean Verdetti
Journal: Circulation Research (1998)

The elastic properties of extensible tissues such as arteries and skin are mainly due to the presence of elastic fibers whose major component is the extracellular matrix protein elastin. Pathophysiological degradation of this protein leads to the generation of elastin peptides that have been identified in the circulation in the ng/mL to microg/mL range. Similar concentrations of an elastin peptide preparation (kappa-elastin) were previously demonstrated to induce, among other biological actions, a dose- and endothelium-dependent vasorelaxation mediated by the elastin/laminin receptor and by endothelial NO production. To determine the elastin sequence(s) responsible for vasomotor activity and to learn more about possible signaling pathways, we have compared the action of different concentrations (10(-13) to 10(-7) mol/L) of recombinant human tropoelastin, eight synthetic elastin peptides, and a control peptide (VPVGGA) on both rat aortic ring tension and [Ca2+]i of cultured human umbilical vein endothelial cells. No vasoactivity could be detected for VPVGGA and for the elastin-related sequences VGVGVA, PGVGVA, and GVGVA. Tropoelastin, VGV, PGV, and VGVAPG were found to induce an endothelium- and dose-dependent vasorelaxation and to increase endothelial [Ca2+]i, whereas PVGV and VGVA produced these effects only at low concentration (10(-11) mol/L). A likely candidate for mediating the elastin peptide-related effects is the elastin/laminin receptor, since the presence of lactose strongly inhibited the vasoactivity associated with these compounds. Our results show that although the flanking amino acids modulate its activity, VGV seems to be the core sequence recognized by the elastin receptor.
P138 Evaluation of the need for a comprehensive assessment of lung function pre operatively in the morbidly obese
Authors: A. Renton, D. A. Lonsdale, G. V. Miller, J. S. White
Journal: Thorax (2011)

<h3>Introduction and Objectives</h3> Chronic morbid obesity has been shown to impinge on normal respiratory function and can ultimately result in respiratory failure. Lee <i>et al</i> (2010) concluded that a more physiological assessment of individuals in this group is required when they are investigated clinically. Accordingly, the clinical pathway of patients referred for bariatric surgery at York Hospital was changed to include comprehensive Pulmonary Function Tests (PFT9s), as well as the current standard Overnight Pulse Oximetry. The objective was to evaluate the revised clinical service and distinguish if the additional measurements are appropriate for morbidly obese patients as part of their surgical pre-assessment. <h3>Methods</h3> Data were collected from patients undergoing bariatric pre-surgical assessment, between January 2011 and June 2011. PFT9s undertaken included dynamic lung volumes, static lung volumes and transfer factor for carbon monoxide (TL<sub>CO</sub>), using a Medgraphics Plethysmograph system in accordance with recognised standards. Overnight oximetry was performed using Minolta 300i pulse oximeters. Abnormalities of lung function were determined using the BTS (1997) guidelines. Obstructive sleep apnoea (OSA) was diagnosed using the Scottish Intercollegiate Guidelines Network, (2003) guidelines. <h3>Results</h3> A total of 59 patients were included in the study with demographics and measurements summarised in Abstract P138 table 1. 28.8% had normal lung function and no evidence of OSA, 39% had evidence of OSA but normal lung function. 6.8% had abnormal lung function but no OSA and 25.4% had both abnormal lung function and evidence of OSA. <h3>Conclusions</h3> Va and FRC<sub>Pleth</sub> are reduced in all groups but is more significant in both groups with abnormal lung function. Those with combined abnormalities are on average 14.8 and 6 years older than those with no abnormalities or just OSA respectively suggesting the development of these co-morbidities with age. We feel that the finding that 32.2% of bariatric referrals were found to have abnormal lung function justifies the inclusion of these measurements when assessing this category of patient. Also, further assessment following weight loss in order to establish the underlying nature of deficient lung function would be useful.
Gender difference in smoking effects on lung function and risk of hospitalization for COPD: results from a Danish longitudinal population study
Authors: E Prescott, AM Bjerg, PK Andersen, P Lange, J Vestbo
Journal: European Respiratory Journal (1997)

Recent findings suggest that females may be more susceptible than males to the deleterious influence of tobacco smoking in developing chronic obstructive pulmonary disease (COPD). This paper studies the interaction of gender and smoking on development of COPD as assessed by lung function and hospital admission. A total of 13,897 subjects, born after 1920, from two population studies, 9,083 from the Copenhagen City Heart Study (CCHS) and 4,814 from the Glostrup Population Studies (GPS), were followed for 7-16 yrs. Data were linked with information on hospital admissions caused by COPD. Based on cross-sectional data, in the CCHS the estimated excess loss of forced expiratory volume in one second (FEV1) per pack-year of smoking was 7.4 mL in female smokers who inhaled and 6.3 mL in male smokers who inhaled. In the GPS, the corresponding excess loss of FEV1 was 10.5 and 8.4 mL in females and males, respectively. Two hundred and eighteen subjects in the CCHS and 23 in the GPS were hospitalized during follow-up. Risk associated with pack-years was higher in females than in males (relative risks (RRs) for 1-20, 20-40 and >40 pack-years were 7.0 (3.5-14.1), 9.8 (4.9-19.6) and 23.3 (10.7-50.9) in females, and 3.2 (1.1-9.1), 5.7 (2.2-14.3) and 8.4 (3.3-21.6) in males) but the interaction term gender x pack-years did not reach significance (p=0.08). Results were similar in the GPS. After adjusting for smoking in more detail, females in both cohorts had an increased risk of hospitalization for COPD compared to males with a RR of 1.5 (1.2-2.1) in the CCHS and 3.6 (1.4-9.0) in the GPS. This was not likely to be caused by a generally increased rate of hospital admission for females. Results were similar when including deaths from COPD as endpoint. In two independent population samples, smoking had greater impact on the lung function of females than males, and after adjusting for smoking females subsequently suffered a higher risk of being admitted to hospital for COPD. Results suggest that adverse effects of smoking on lung function may be greater in females than in males.
Nitric oxide synthase-derived plasma nitrite predicts exercise capacity
Authors: Tienush Rassaf, Thomas Lauer, Christian Heiss, Jan Balzer, Sarah Mangold, Thorsten Leyendecker, Jessica Rottler, Christine Drexhage, Christian Meyer, Malte Kelm
Journal: British Journal of Sports Medicine (2007)

Background: Nitrite is the main oxidation product of nitric oxide (NO) in plasma. It sensitively reflects changes in endothelial NO synthase (eNOS) activity under fasting conditions and serves as an endocrine NO donor, contributing to the regulation of blood flow through reaction with haemoglobin. As NO is necessary to maintain an adequate vascular response to the increased demands of blood flow, it is believed to be important for vasodilation induced by exercise. Objective: To investigate whether the capacity of the vasculature to produce nitrite is associated with exercise performance. Design: With the use of chemiluminescence detection, nitrite concentrations in 55 healthy subjects (mean (SEM) age 40 (2) years; 22 men) were studied before and after an exercise test, and endothelial function was determined by measuring flow-mediated dilation of the brachial artery using high-resolution ultrasound. In a subset of subjects, the NOS inhibitor, N G -monomethyl- l -arginine, was applied to elucidate the effect of eNOS on changes in nitrite. Results: Exercise significantly (p&lt;0.001) increased plasma nitrite from 97 (6) to 125 (8) nM. The relative increase in plasma nitrite was related to flow-mediated dilation (6.1 (0.3)%; r = 0.36; p = 0.01). N G -Monomethyl- l -arginine blocked increases in nitrite. Post-exercise nitrite concentration correlated with exercise performance, as determined by maximally reached stress power (r = 0.37; p&lt;0.007), and inversely with age. Multivariate analysis showed that both age and post-exercise nitrite concentration were independent predictors of stress endurance and power. Conclusion: The results suggest a role for plasma nitrite in the adaptation of haemodynamics during exercise. An impaired increase in plasma nitrite may limit exercise capacity.
Hypertension Caused by Angiotensin II Infusion Involves Increased Superoxide Production in the Central Nervous System
Authors: Matthew C. Zimmerman, Eric Lazartigues, Ram V. Sharma, Robin L. Davisson
Journal: Circulation Research (2004)

Hypertension caused by angiotensin II (Ang II) infusion is associated with oxidative stress in the peripheral vasculature and kidney. The role of redox mechanisms in the central nervous system (CNS), a tissue known to be pivotal in Ang II–dependent hypertension, has not been investigated. We recently identified superoxide (O 2 ·− ) in the brain as a key signaling intermediate in the transient pressor response elicited by acute injection of Ang II directly into the CNS. Here we tested the hypothesis that hypertension caused by chronic systemic infusion of Ang II is mediated by a central neurogenic mechanism involving O 2 ·− . Infusion of Ang II (600 ng · kg −1 · min −1 ) over a 2-week period in mice caused a gradually developing hypertension that was correlated with marked elevations in O 2 ·− production specifically in the subfornical organ (SFO), a brain region lying outside the blood–brain barrier and known to be a primary sensor for blood-borne Ang II. Adenoviral-mediated delivery of cytoplasmically targeted superoxide dismutase (SOD) selectively to this site prevented the hypertension and the increased O 2 ·− production, whereas gene transfer of SOD targeted to the extracellular matrix had no effect. These data suggest that increased intracellular O 2 ·− production in the SFO is critical in the development of Ang II–induced hypertension.
Update in Chronic Obstructive Pulmonary Disease 2011
Authors: Alvar Agustí, Peter J. Barnes
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

The text that follows reviews and discusses the papers published in the Journal on chronic obstructive pulmonary disease (COPD) during 2011. Whenever relevant, works published earlier or elsewhere are included. The reader is referred to the original papers for further details. We have organized the review according to the following subheadings: Risk Factors, Natural History, Physiology, Disease Mechanisms, Phenotypes and Biomarkers, Comorbidities, Management, and Exacerbations.
OT1-02-13: Cardiac Biomarkers on Trastuzumab (Cabot Trial): Determining the Cardiac Biomarker Profile in Breast Cancer Patients Receiving Adjuvant Trastuzumab Therapy.
Authors: VNC Kumar, P Kavsak, S Rask, SD Mukherjee, P Ellis, B Dhesy-Thind
Journal: Cancer Research (2011)

Abstract Background Trastuzumab is a humanized anti-HER2 monoclonal antibody that has demonstrated a 50% reduction in the risk of HER2+ breast cancer recurrence. This benefit is at the risk of possible cardiac dysfunction. Detecting trastuzumab-related cardiotoxicity based on physical examination and assessment of left ventricular ejection fraction (LVEF) by serial echocardiography or multi gated acquisition (MUGA) scan, has low diagnostic sensitivity and low predictive power in detecting subclinical myocardial injury. There is interest in developing simple, non-invasive, and cost-effective tools for early identification of trastuzumab-related cardiotoxicity. Use of easily detectible cardiac biomarkers in blood, such as cardiac troponins (cTnT and cTnI) and natriuretic peptides (NPs), are being evaluated. Kavsak et al. have studied a high-sensitivity cTn (hs-cTn) assay that is 10-fold more sensitive, and may be able to identify evolving injury earlier when compared to the conventional cTn assays. B-type natriuretic peptide (BNP) has been established as an indicator for heart failure. Pro-BNP is secreted from the cardiac ventricles in response to increased pressure and volume and is divided into NT-pro-BNP and BNP. The longer half-life of NT-proBNP may make it a more accurate predictor of ventricular stress. Trial design: This is a pilot single institution, prospective cohort study of 25 patients. Breast cancer patients will be seen at the Juravinski Cancer Centre, Hamilton, Canada. Biomarkers will be collected at baseline, then days 1 and 2 of every 21 day cycle for the first 3 months, then every 42 days for the next 3 months. LVEF will be measured at baseline and then every 3 months while on trastuzumab. Eligibility criteria: Patients with stage I-III, HER2 positive (3+ by immunohistochemistry or FISH+) breast cancer receiving adjuvant trastuzumab therapy. Patients who have received prior trastuzumab therapy or are unable to provide informed consent will be excluded. Specific aims: To determine the biological profile of cardiac biomarkers — cTnT, hs-cTn, and NT-proBNP — in patients on adjuvant trastuzumab; and, to determine if elevations in these biomarkers correlate with LVEF. Statistical methods: A convenient sample size of 25 patients will be entered into this pilot study. The minimum of 20 patients is a requirement by the Clinical Laboratory Standards Institute (CLSI) to formally accept existing reference ranges for the cardiac biomarkers to be used in the HER2 breast cancer population (National Committee for Clinical Laboratory Standards (NCCLS)). Present accrual and target accrual: 8 patients have enrolled to date. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-02-13.
Site of upper airway obstruction in obstructive apnoea and influence of sleep stage
Authors: AN Boudewyns, PH Van de Heyning, WA De Backer
Journal: European Respiratory Journal (1997)

Various sites along the upper airway (UA) are prone to narrow and collapse in patients affected by obstructive sleep apnoea. Sleep stages may eventually alter these sites. The present study was designed to determine the site(s) of UA obstruction and the influence of sleep stage on the pattern of obstruction. Twenty eight obstructive sleep apnoea patients underwent UA pressure measurements during polysomnography. Solid-state pressure sensors were located at the nasopharynx, oropharynx, tongue base, hypopharynx and oesophagus and the lower limit of UA obstruction was determined relying on the observed pressure pattern. The site of UA obstruction varied among consecutive apnoeas in all but two patients. The lower limit of UA obstruction was predominantly located at the nasoand oropharynx. Rapid eye movement (REM) sleep was associated with a tendency for obstruction to extend towards lower levels of the UA and nasopharyngeal occlusion was significantly less observed during REM compared to oropharyngeal obstruction. Upper airway obstruction involves more than one specific site of the upper airway in the majority of sleep apnoea patients. Obstruction at lower levels of the upper airway is more likely to be observed during rapid eye movement sleep.
Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice
Authors: Matthew J. Christopher, Mahil Rao, Fulu Liu, Jill R. Woloszynek, Daniel C. Link
Journal: The Journal of Experimental Medicine (2011)

Granulocyte colony-stimulating factor (G-CSF), the prototypical mobilizing cytokine, induces hematopoietic stem and progenitor cell (HSPC) mobilization from the bone marrow in a cell-nonautonomous fashion. This process is mediated, in part, through suppression of osteoblasts and disruption of CXCR4/CXCL12 signaling. The cellular targets of G-CSF that initiate the mobilization cascade have not been identified. We use mixed G-CSF receptor (G-CSFR)–deficient bone marrow chimeras to show that G-CSF–induced mobilization of HSPCs correlates poorly with the number of wild-type neutrophils. We generated transgenic mice in which expression of the G-CSFR is restricted to cells of the monocytic lineage. G-CSF–induced HSPC mobilization, osteoblast suppression, and inhibition of CXCL12 expression in the bone marrow of these transgenic mice are intact, demonstrating that G-CSFR signals in monocytic cells are sufficient to induce HSPC mobilization. Moreover, G-CSF treatment of wild-type mice is associated with marked loss of monocytic cells in the bone marrow. Finally, we show that bone marrow macrophages produce factors that support the growth and/or survival of osteoblasts in vitro. Together, these data suggest a model in which G-CSFR signals in bone marrow monocytic cells inhibit the production of trophic factors required for osteoblast lineage cell maintenance, ultimately leading to HSPC mobilization.
Biological effects of short-term, high-concentration exposure to methyl isocyanate. III. Influence on gas exchange in the guinea pig lung.
Authors: M R Fedde, D E Dodd, C M Troup, E H Fowler
Journal: Environmental Health Perspectives (1987)

The influence of methyl isocyanate (MIC) inhalation on the gas exchange function of the lungs in guinea pigs was studied by measuring arterial blood gases, pH, and tracheal pressure during constant-volume, artificial ventilation with air or 100% O2 at 40 and 120 min after exposure. A 15 min exposure to MIC at concentrations of 240 to 628 ppm caused a marked reduction in PaO2 and pHa and an elevated tracheal pressure during artificial ventilation. The low PaO2 was only slightly elevated when the animals were ventilated with 100% O2. Although the dry-wet lung weight ratio was reduced at the highest exposure concentration, the effect was not severe and no significant increase in lung water was found at the lower concentrations. MIC inhalation caused severe pulmonary blood shunting and ventilation/perfusion imbalance. This, in turn, led to hypoxemia, metabolic acidosis, and tissue hypoxia, which could produce death. The pulmonary gas exchange deficit likely resulted from bronchial and bronchiolar obstruction caused by sloughed epithelium and other debris from intra- and extrapulmonary airways.
Coevolution of Codon Usage and tRNA Genes Leads to Alternative Stable States of Biased Codon Usage
Authors: P. G. Higgs, W. Ran
Journal: Molecular Biology and Evolution (2008)

The typical number of tRNA genes in bacterial genomes is around 50, but this number varies from under 30 to over 120. We argue that tRNA gene copy numbers evolve in response to translational selection. In rapidly multiplying organisms, the time spent in translation is a limiting factor in cell division; hence, it pays to duplicate tRNA genes, thereby increasing the concentration of tRNA molecules in the cell and speeding up translation. In slowly multiplying organisms, translation time is not a limiting factor, so the overall translational cost is minimized by reducing the tRNAs to only one copy of each required gene. Translational selection also causes a preference for codons that are most rapidly translated by the current tRNAs; hence, codon usage and tRNA gene content will coevolve to a state where each is adapted to the other. We show that there is often more than one stable coevolved state. This explains why different combinations of tRNAs and codon bias can exist for different amino acids in the same organism. We analyze a set of 80 complete bacterial genomes and show that the theory predicts many of the trends that are seen in these data.