tbuckley/cabot-search huggingface dataset:
p21 promotes oncolytic adenoviral activity in ovarian cancer and is a potential biomarker
Authors: Magdalena B Flak, Claire M Connell, Claude Chelala, Kyra Archibald, Michael A Salako, Katrina J Pirlo, Michelle Lockley, Sally P Wheatley, Frances R Balkwill, Iain A McNeish
Journal: Molecular Cancer (2010)

Abstract The oncolytic adenovirus dl 922-947 replicates selectively within and lyses cells with a dysregulated Rb pathway, a finding seen in &gt; 90% human cancers. dl 922-947 is more potent than wild type adenovirus and the E1B-deletion mutant dl 1520 (Onyx-015). We wished to determine which host cell factors influence cytotoxicity. SV40 large T-transformed MRC5-VA cells are 3-logs more sensitive to dl 922-947 than isogenic parental MRC5 cells, confirming that an abnormal G1/S checkpoint increases viral efficacy. The sensitivity of ovarian cancer cells to dl 922-947 varied widely: IC 50 values ranged from 51 (SKOV3ip1) to 0.03 pfu/cell (TOV21G). Cells sensitive to dl 922-947 had higher S phase populations and supported earlier E1A expression. Cytotoxicity correlated poorly with both infectivity and replication, but well with expression of p21 by microarray and western blot analyses. Matched p21+/+ and -/- Hct116 cells confirmed that p21 influences dl 922-947 activity in vitro and in vivo . siRNA-mediated p21 knockdown in sensitive TOV21G cells decreases E1A expression and viral cytotoxicity, whilst expression of p21 in resistant A2780CP cells increases virus activity in vitro and in intraperitoneal xenografts. These results highlight that host cell factors beyond simple infectivity can influence the efficacy of oncolytic adenoviruses. p21 expression may be an important biomarker of response in clinical trials.
BCR/ABL Promotes Dendritic Cell–Mediated Natural Killer Cell Activation
Authors: Magali Terme, Christophe Borg, François Guilhot, Carole Masurier, Caroline Flament, Erwin F. Wagner, Sophie Caillat-Zucman, Alain Bernheim, Ali G. Turhan, Anne Caignard, Laurence Zitvogel
Journal: Cancer Research (2005)

Abstract BCR/ABL fusion gene, encoding a paradigmatic tyrosine kinase involved in chronic myelogenous leukemia (CML), can modulate the expression of genes involved in natural killer (NK) cell target recognition. Recent reports outline the role of allogeneic antileukemic NK effectors in the graft-versus-leukemia effect but the regulation of NK cell activation in the setting of graft-versus-leukemia effect remains unknown. Here we show that dendritic cells derived from monocytes of CML patients are selectively endowed with NK cell stimulatory capacity in vitro. We further show, using a gene transfer approach in mouse bone marrow progenitors, that ABL/ABL is necessary to promote dendritic cell–mediated NK cell activation. The dendritic cell/NK cell cross-talk in ABL/ABL-induced CML seems unique because JunB or IFN consensus sequence binding protein loss of functions, associated with other myeloproliferative disorders, do not promote dendritic cell–mediated NK cell activation. NK cell activation by leukemic dendritic cells involves NKG2D activating receptors and is blocked by imatinib mesylate. Indeed, ABL/ABL translocation enhances the expression levels of the NKG2D ligands on dendritic cells, which is counteracted by imatinib mesylate. Altogether, the clonal ABL/ABL dendritic cells display the unique and selective ability to activate NK cells and may participate in the NK cell control of CML. This study also highlights the deleterious role of imatinib mesylate at the dendritic cell level for NK cell activation.
MODULATION OF THE IONIC MILIEU OF THE AIRWAY IN HEALTH AND DISEASE
Authors: P.G. Noone, M.D, K.N. Olivier, M.D, M.R. Knowles, M.D
Journal: Annual Review of Medicine (1994)

▪ Abstract Airway surface liquid (ASL) is an integral part of lung defense mechanisms. Ion transport by airway epithelia regulates the volume and composition of this fluid. A better understanding of the mechanisms of ion transport will enable the development of new therapies for airway diseases associated with defects in these mechanisms. A useful model of a disease with abnormal airway epithelial ion transport is cystic fibrosis (CF), a distinct genetic syndrome of altered lung defense mechanisms characterized by chronic bacterial infection and a steady decline in lung function. Traditional therapies for CF include antibacterial drugs and augmentation of clearance of secretions, but investigators are now studying pharmacological approaches to target the more basic defect of the disease, i.e. abnormal sodium and chloride ion transport. Early treatment in childhood, prior to lung damage, might prevent or at least retard the decline in pulmonary function that remains the hallmark of CF. Ion transport dysfunction may also contribute to other airway diseases such as asthma and chronic bronchitis. Pharmacological intervention at this level may prove beneficial in these common lung diseases as well.
Electrophysiology of the human colon: evidence of segmental heterogeneity.
Authors: G I Sandle, N K Wills, W Alles, H J Binder
Journal: Gut (1986)

The electrical properties of epithelial cell membranes in human descending and ascending colon were studied using microelectrodes and the Na channel blocker amiloride. Under control (pre-amiloride) conditions, the transepithelial electrical measurements in the two colonic segments were similar. The mucosal addition of 0.1 mM amiloride to descending colon totally abolished the transepithelial voltage (Vt) and short-circuit current (Isc), and significantly increased the total tissue resistance (Rt) by 19% (p less than 0.005). Intracellular recordings in descending colon obtained with microelectrodes revealed that the transepithelial effects of amiloride reflected hyperpolarization of the apical membrane and a significant increase in apical membrane resistance, changes which were consistent with amiloride-blockade of apical Na channels and complete inhibition of electrogenic Na transport. An appreciable amiloride-insensitive conductance was also present in the apical membrane of the descending colon. In contrast, the mucosal addition of 0.1 mM amiloride to ascending colon decreased Vt by only 30% (p less than 0.02) and Isc by 43% (p less than 0.05), but had no significant effect on Rt. These results indicate that electrogenic Na transport accounts totally for Isc in human descending colon in vitro, but only partly for Isc in human ascending colon, suggesting that Na transport in ascending colon is mediated primarily by electroneutral processes, and the apical membrane of human descending colon contains an amiloride-sensitive conductance for Na in parallel with an amiloride-insensitive conductance, which may transport K.
Edoxaban versus Warfarin in Patients with Atrial Fibrillation
Authors: Robert P. Giugliano, Christian T. Ruff, Eugene Braunwald, Sabina A. Murphy, Stephen D. Wiviott, Jonathan L. Halperin, Albert L. Waldo, Michael D. Ezekowitz, Jeffrey I. Weitz, Jindřich Špinar, Witold Ruzyllo, Mikhail Ruda, Yukihiro Koretsune, Joshua Betcher, Minggao Shi, Laura T. Grip, Shirali P. Patel, Indravadan Patel, James J. Hanyok, Michele Mercuri, Elliott M. Antman
Journal: New England Journal of Medicine (2013)

Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known.We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding.The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32).Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.).
Inflammatory cell response in bronchoalveolar lavage fluid after nitrogen dioxide exposure of healthy subjects: a dose-response study
Authors: T Sandstrom, N Stjernberg, A Eklund, MC Ledin, L Bjermer, B Kolmodin-Hedman, K Lindstrom, L Rosenhall, T Angstrom
Journal: European Respiratory Journal (1991)

The combination of environmental chamber exposure and bronchoalveolar lavage (BAL) was used to study the effects of the common air pollutant nitrogen dioxide (NO2). Eighteen healthy nonsmokers were exposed to NO2 during 20 min in an exposure chamber during light bicycle ergometer work. All subjects were examined with BAL at least 3 wks before exposure, as a reference. The subjects were re-examined with BAL, in groups of eight, 24 h after exposure to 4, 7 and 10 mg NO2.m.3 (2.25, 4.0 and 5.5 ppm), respectively. An inflammatory cell response was found after exposure to all concentrations. An increase in the number of lymphocytes in BAL fluid was observed after 7 and 10 mg.m.3 (p less than 0.05 and 0.02, respectively). An increase in the number of mast cells, that appears to be dose-dependent, was found after exposure to all concentrations. The proportion of lysozyme positive alveolar macrophages was elevated after exposure to 7 mg.m.3. The inflammatory mediators fibronectin, hyaluronan, angiotensin converting enzyme (ACE) and beta 2-microglobulin were unchanged by exposure. Due to the findings of inflammatory cell changes far below the peak exposure limits for work places in industrialized countries, 9-18 mg.m.3, the safety of these limits is questioned. Studies are in progress in our laboratory using BAL to evaluate the effects of repeated NO2 exposure.
Divergence Pattern of Duplicate Genes in Protein-Protein Interactions Follows the Power Law
Authors: Ze Zhang, Z. W. Luo, Hirohisa Kishino, Mike J. Kearsey
Journal: Molecular Biology and Evolution (2004)

The impact of the biological network structures on the divergence between the two copies of one duplicate gene pair involved in the networks has not been documented on a genome scale. Having analyzed the most recently updated Database of Interacting Proteins (DIP) by incorporating the information for duplicate genes of the same age in yeast, we find that there was a highly significantly positive correlation between the level of connectivity of ancient genes and the number of shared partners of their duplicates in the protein-protein interaction networks. This suggests that duplicate genes with a low ancestral connectivity tend to provide raw materials for functional novelty, whereas those duplicate genes with a high ancestral connectivity tend to create functional redundancy for a genome during the same evolutionary period. Moreover, the difference in the number of partners between two copies of a duplicate pair was found to follow a power-law distribution. This suggests that loss and gain of interacting partners for most duplicate genes with a lower level of ancestral connectivity is largely symmetrical, whereas the "hub duplicate genes" with a higher level of ancient connectivity display an asymmetrical divergence pattern in protein-protein interactions. Thus, it is clear that the protein-protein interaction network structures affect the divergence pattern of duplicate genes. Our findings also provide insights into the origin and development of biological networks.
Epistemology, emulators, and extended minds
Authors: Terry Dartnall
Journal: Behavioral and Brain Sciences (2004)

Grush's framework has epistemological implications and explains how it is possible to acquire offline empirical knowledge. It also complements the extended-mind thesis, which says that mind leaks into the world. Grush's framework suggests that the world leaks into the mind through the offline deployment of emulators that we usually deploy in our experience of the world.
Reproducibility of lung volume measurements
Authors: JL Hankinson, J Stocks, R Peslin
Journal: European Respiratory Journal (1998)

Test reproducibility is an important consideration when interpreting results and should be set as a goal during data collection. Reproducibility criteria may need to be different for different subject groups and are instrument and procedure-dependent. Ideally, the within-subject variability for each lung volume and measurement technique used should be established for each laboratory. These values also need to be established for each different subject group (age and disease). At a minimum, test reproducibility should be monitored and controlled and each laboratory should define their between-day reproducibility of measurements on at least one "reference" subject from ongoing periodic (e.g., weekly or monthly) measurements as part of their laboratory's quality control programme. For plethysmographic measurements functional residual capacity (FRC)pleth multiple determinations and a corresponding test reproducibility criteria is probably justified.
Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice
Authors: S. Lim
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Theophylline is widely used in the treatment of asthma, and there is evidence that theophylline has anti-inflammatory or immunomodulatory effects. A study was undertaken to determine whether theophylline added to low dose inhaled steroids would be as efficacious as high dose inhaled steroids in asthma. <h3>METHODS</h3> In a study in general practice of 155 recruited asthmatic patients with continuing symptomatic asthma while on 400 μg beclomethasone dipropionate (BDP) daily and inhaled β<sub>2</sub> agonist as required, the effect of (1) continuing low dose inhaled steroids alone (LDS, 200 μg BDP twice daily), (2) low dose inhaled steroids plus low dose theophylline (LDT, 400 mg daily), or (3) high dose inhaled steroids (HDS, 500 μg BDP) over a six month period was examined. <h3>RESULTS</h3> One hundred and thirty patients completed the study. Between group comparison using analysis of variance showed no overall differences in peak flow measurements, diurnal variation, and symptom scores. Changes in evening peak flows approached significance at the 5% level (p=0.077). The mean improvement in evening peak flow in the LDT compared with the LDS group was 20.6 l/min (95% confidence interval (CI) –2.5 to 38.8). In the LDT group there was an increase in evening peak flows at the end of the study compared with entry values (22.5 l/min), while in the LDS and HDS groups evening peak flows increased by 1.9 and 8.3 l/min, respectively. There was no significant difference in exacerbations or in side effects. <h3>CONCLUSION</h3> There were no overall significant differences between the low dose steroid, low dose steroid with theophylline, and the high dose steroid groups. The greatest within-group improvement in evening peak flows was found after theophylline. A larger study may be necessary to show significant effects.
Report of the National Heart, Lung, and Blood Institute’s Working Group on Obesity and Other Cardiovascular Risk Factors in Congenital Heart Disease
Authors: Victoria L. Pemberton, Brian W. McCrindle, Shari Barkin, Stephen R. Daniels, Sarah E. Barlow, Helen J. Binns, Meryl S. Cohen, Christina Economos, Myles S. Faith, Samuel S. Gidding, Caren S. Goldberg, Rae-Ellen Kavey, Patricia Longmuir, Albert P. Rocchini, Linda Van Horn, Jonathan R. Kaltman
Journal: Circulation (2010)

O besity among North American youth has risen to epi- demic levels and is expected to result in costly and burdensome health problems, most notably type 2 diabetes mellitus and premature coronary artery disease.In the 2001-2002 National Health and Nutrition Examination Survey survey, 31% of children aged 6 to 19 years were overweight, defined as body mass index (BMI) at the 85th to 95th percentile, or obese (BMI Ն95th percentile). 1 Recent research indicates that a significant portion of children with congenital heart disease (CHD) are also obese or overweight. 2 Although much has been written on obesity prevention and management of children with normal hearts, 3 little is known about how children with CHD will be affected.The National Heart, Lung, and Blood Institute convened a Working Group (WG) on obesity and other cardiovascular risk factors in congenital heart disease in May 2009 to address knowledge gaps, challenges, and opportunities related to research, policies, and the clinical care of children born with CHD who also have or are at risk for obesity and other cardiovascular risk factors. 4The WG was composed of individuals with expertise in pediatric obesity and pediatric cardiology with the goals of summarizing the existing evidence on obesity and cardiovascular risk prevention and treatment in the CHD population, raising awareness of missing data, and presenting data from "healthy" children with potential applicability to children with CHD.In this report, we discuss the prevalence of obesity, potential etiological factors, possible sequelae, and obesity and cardiovascular risk management and treatment in patients with CHD.The recommendations of the WG are presented.
Metabolite Profiling and Cardiovascular Event Risk
Authors: Peter Würtz, Aki S. Havulinna, Pasi Soininen, Tuulia Tynkkynen, David Prieto-Merino, Therese Tillin, Anahita Ghorbani, Anna Artati, Qin Wang, Mika Tiainen, Antti J. Kangas, Johannes Kettunen, Jari Kaikkonen, Vera Mikkilä, Antti Jula, Mika Kähönen, Terho Lehtimäki, Debbie A. Lawlor, Tom R. Gaunt, Alun D. Hughes, Naveed Sattar, Thomas Illig, Jerzy Adamski, Thomas J. Wang, Markus Perola, Samuli Ripatti, Ramachandran S. Vasan, Olli T. Raitakari, Robert E. Gerszten, Juan-Pablo Casas, Nish Chaturvedi, Mika Ala-Korpela, Veikko Salomaa
Journal: Circulation (2015)

Background— High-throughput profiling of circulating metabolites may improve cardiovascular risk prediction over established risk factors. Methods and Results— We applied quantitative nuclear magnetic resonance metabolomics to identify the biomarkers for incident cardiovascular disease during long-term follow-up. Biomarker discovery was conducted in the National Finnish FINRISK study (n=7256; 800 events). Replication and incremental risk prediction was assessed in the Southall and Brent Revisited (SABRE) study (n=2622; 573 events) and British Women’s Health and Heart Study (n=3563; 368 events). In targeted analyses of 68 lipids and metabolites, 33 measures were associated with incident cardiovascular events at P &lt;0.0007 after adjusting for age, sex, blood pressure, smoking, diabetes mellitus, and medication. When further adjusting for routine lipids, 4 metabolites were associated with future cardiovascular events in meta-analyses: higher serum phenylalanine (hazard ratio per standard deviation, 1.18; 95% confidence interval, 1.12–1.24; P =4×10 –10 ) and monounsaturated fatty acid levels (1.17; 1.11–1.24; P =1×10 –8 ) were associated with increased cardiovascular risk, while higher omega-6 fatty acids (0.89; 0.84–0.94; P =6×10 –5 ) and docosahexaenoic acid levels (0.90; 0.86–0.95; P =5×10 –5 ) were associated with lower risk. A risk score incorporating these 4 biomarkers was derived in FINRISK. Risk prediction estimates were more accurate in the 2 validation cohorts (relative integrated discrimination improvement, 8.8% and 4.3%), albeit discrimination was not enhanced. Risk classification was particularly improved for persons in the 5% to 10% risk range (net reclassification, 27.1% and 15.5%). Biomarker associations were further corroborated with mass spectrometry in FINRISK (n=671) and the Framingham Offspring Study (n=2289). Conclusions— Metabolite profiling in large prospective cohorts identified phenylalanine, monounsaturated fatty acids, and polyunsaturated fatty acids as biomarkers for cardiovascular risk. This study substantiates the value of high-throughput metabolomics for biomarker discovery and improved risk assessment.
Proximal gastric vagotomy, fundoplication, and lesser-curve necrosis.
Authors: T Kennedy, P Magill, G W Johnston, T G Parks
Journal: BMJ (1979)

Out of 400 patients who underwent proximal gastric vagotomy (PGV), three developed lesser-curve necrosis (LCN) leading to perforation within the first seven days. In each case diagnosis was delayed but the patient survived after a second operation. In each an associated Nissen fundoplication had been carried out; we used the combined operation in only 33 patients. Delayed LCN occurred in a patient who had undergone splenectomy at the time of the PGV and in a fifth patient treated elsewhere who had also undergone fundoplication. These findings indicate that early postoperative gastric distension with gas, not readily voided after fundoplication, may aggravate local vascular factors and predispose to LCN. We suggest that PGV combined with fundoplication may be dangerous.
Topotecan in combination with carboplatin: phase I trial evaluation of two treatment schedules
Authors: A.B. Simpson, P.M. Calvert, J.A. Sludden, A.V. Boddy, M.J. Griffin, A. Schätzlein, P. Wilson, K. Fishwick, A. Wheatley, G.A. Ross, A.H. Calvert, C.J. Twelves
Journal: Annals of Oncology (2002)
Using protein complexes to predict phenotypic effects of gene mutation
Authors: Hunter B Fraser, Joshua B Plotkin
Journal: Genome biology (2007)

Abstract Background Predicting the phenotypic effects of mutations is a central goal of genetics research; it has important applications in elucidating how genotype determines phenotype and in identifying human disease genes. Results Using a wide range of functional genomic data from the yeast Saccharomyces cerevisiae , we show that the best predictor of a protein's knockout phenotype is the knockout phenotype of other proteins that are present in a protein complex with it. Even the addition of multiple datasets does not improve upon the predictions made from protein complex membership. Similarly, we find that a proxy for protein complexes is a powerful predictor of disease phenotypes in humans. Conclusion We propose that identifying human protein complexes containing known disease genes will be an efficient method for large-scale disease gene discovery, and that yeast may prove to be an informative model system for investigating, and even predicting, the genetic basis of both Mendelian and complex disease phenotypes.