tbuckley/cabot-search huggingface dataset:
Metformin, Independent of AMPK, Induces mTOR Inhibition and Cell-Cycle Arrest through REDD1
Authors: Isaam Ben Sahra, Claire Regazzetti, Guillaume Robert, Kathiane Laurent, Yannick Le Marchand-Brustel, Patrick Auberger, Jean-François Tanti, Sophie Giorgetti-Peraldi, Frédéric Bost
Journal: Cancer Research (2011)

Abstract Metformin is a widely prescribed antidiabetic drug associated with a reduced risk of cancer. Many studies show that metformin inhibits cancer cell viability through the inhibition of mTOR. We recently showed that antiproliferative action of metformin in prostate cancer cell lines is not mediated by AMP-activated protein kinase (AMPK). We identified REDD1 (also known as DDIT4 and RTP801), a negative regulator of mTOR, as a new molecular target of metformin. We show that metformin increases REDD1 expression in a p53-dependent manner. REDD1 invalidation, using siRNA or REDD1−/− cells, abrogates metformin inhibition of mTOR. Importantly, inhibition of REDD1 reverses metformin-induced cell-cycle arrest and significantly protects from the deleterious effects of metformin on cell transformation. Finally, we show the contribution of p53 in mediating metformin action in prostate cancer cells. These results highlight the p53/REDD1 axis as a new molecular target in anticancer therapy in response to metformin treatment. Cancer Res; 71(13);4366–72. ©2011 AACR.
Corset: enabling differential gene expression analysis for de novoassembled transcriptomes
Authors: Nadia M Davidson, Alicia Oshlack
Journal: Genome biology (2014)

Abstract Next generation sequencing has made it possible to perform differential gene expression studies in non-model organisms. For these studies, the need for a reference genome is circumvented by performing de novo assembly on the RNA-seq data. However, transcriptome assembly produces a multitude of contigs, which must be clustered into genes prior to differential gene expression detection. Here we present Corset, a method that hierarchically clusters contigs using shared reads and expression, then summarizes read counts to clusters, ready for statistical testing. Using a range of metrics, we demonstrate that Corset out-performs alternative methods. Corset is available from https://code.google.com/p/corset-project/ .
Aspirin Use Is Low Among United States Outpatients With Coronary Artery Disease
Authors: Randall S. Stafford
Journal: Circulation (2000)

Background —The goal of the present study was to assess national trends and patterns of aspirin use among outpatients with coronary artery disease. Although there is strong evidence that the use of aspirin reduces the risk of death and recurrent events in patients with coronary artery disease, current national patterns of aspirin use are unknown. Methods and Results —We used data from the 1980 to 1996 National Ambulatory Medical Care Surveys. These surveys provide a nationally representative sample of physician activities during patient visits to physician offices. We evaluated the report of aspirin as a new or continuing medication in 10 942 visits to cardiologists and primary care physicians by patients with coronary artery disease. We evaluated trends in the use of aspirin for 1980 to 1996 and used logistic regression to identify independent predictors of aspirin use for 1993 to 1996. Aspirin use in outpatient visits by persons with coronary artery disease without reported contraindications increased from 5.0% in 1980 to 26.2% in 1996. Large increases occurred in the early 1990s. Independent predictors of aspirin use in 1993 to 1996 were male patient gender (29% versus 21% for females), patient age of &lt;80 years (28% versus 17% for age of ≥80 years), and presence of hyperlipidemia (45% versus 24% for patients without hyperlipidemia; all comparisons P &lt;0.001). Cardiologists (37%) were more likely to report aspirin use than were internists (20%), family physicians (18%), or general practitioners (11%; P &lt;0.001). These effects persisted after we controlled for potential confounders with the use of logistic regression. Conclusions —Although aspirin use in patients with coronary artery disease has increased dramatically, it remains suboptimum. Low rates of aspirin use and variations in use suggest a need to better translate clinical recommendations into practice.
Imaging Correlates of Molecular Signatures in Oligodendrogliomas
Authors: Joseph F. Megyesi, Edward Kachur, Donald H. Lee, Magdalena C. Zlatescu, Rebecca A. Betensky, Peter A. Forsyth, Yoshifumi Okada, Hikaru Sasaki, Masahiro Mizoguchi, David N. Louis, J. Gregory Cairncross
Journal: Clinical Cancer Research (2004)

Abstract Molecular subsets of oligodendroglioma behave in biologically distinct ways. Their locations in the brain, rates of growth, and responses to therapy differ with their genotypes. Retrospectively, we inquired whether allelic loss of chromosomal arms 1p and 19q, an early molecular event and favorable prognostic marker in oligodendrogliomas, were reflected in their appearance on magnetic resonance imaging. Loss of 1p and 19q was associated with an indistinct border on T1 images and mixed intensity signal on T1 and T2. Loss of 1p and 19q was also associated with paramagnetic susceptibility effect and with calcification, a common histopathological finding in oligodendrogliomas. These data encourage prospective evaluation of molecular alterations and magnetic resonance imaging characteristics of glial neoplasms.
Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial
Authors: Jürgen Finke, Wolfgang A Bethge, Claudia Schmoor, Hellmut D Ottinger, Matthias Stelljes, Axel R Zander, Liisa Volin, Tapani Ruutu, Dominik A Heim, Rainer Schwerdtfeger, Karin Kolbe, Jiri Mayer, Johan A Maertens, Werner Linkesch, Ernst Holler, Vladimir Koza, Martin Bornhäuser, Hermann Einsele, Hans-Jochem Kolb, Hartmut Bertz, Matthias Egger, Olga Grishina, Gérard Socié
Journal: The Lancet Oncology (2009)
A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease
Authors: Walter Fiedler, Hubert Serve, Hartmut Döhner, Michael Schwittay, Oliver G. Ottmann, Anne-Marie O'Farrell, Carlo L. Bello, Randy Allred, William C. Manning, Julie M. Cherrington, Sharianne G. Louie, Weiru Hong, Nicoletta M. Brega, Giorgio Massimini, Paul Scigalla, Wolfgang E. Berdel, Dieter K. Hossfeld
Journal: Blood (2005)
Acetaminophen-induced microvascular injury in the rat liver: Protection with misoprostol
Authors: Sook Ping Lim, Fiona Jane Andrews, Paul Edmond O’Brien
Journal: Hepatology (1995)

Studies into the mechanism of acetaminophen (APAP)-induced hepatotoxicity have focused mainly at the hepatocellular level. This study aimed to investigate the effect of acetaminophen on the hepatic microvasculature using a vascular casting technique. Acetaminophen was administered at a dose of 650 mg/kg body weight (intraperitoneally) to fasted male Long Evans rats. Microvascular casting was performed at various points after drug administration. Liver casts from control rats showed good patency with normal hepatic microvasculature. Thirty-six hours after overdose with acetaminophen, liver casts showed rounded centrilobular cavities of various sizes, representing regions in which cast-filled sinusoids were absent with relatively normal microvasculature within periportal regions. Evidence of microvascular injury occurred as early as 5 hours after acetaminophen overdose. This injury consisted of changes to centrilobular sinusoids including areas of incomplete filling and dilated centrilobular sinusoids. Misoprostol (a prostaglandin E1 analog) treatment (6 x 25 micrograms/kg) given before and after acetaminophen administration markedly reduced the extent of microvascular injury with only small focal unfilled areas in the casts and a generally intact microvasculature. In conclusion, this study shows that overdosage with APAP resulted in an extensive, characteristic pattern of hepatic microvascular injury in the centrilobular region. The results also suggest that microvascular injury is an early event in the pathogenesis of acetaminophen hepatotoxicity. Misoprostol was found to protect against injury occurring at the microvascular level.
Supermotifs enable natural invariant chain-derived peptides to interact with many major histocompatibility complex-class II molecules.
Authors: G Malcherek, V Gnau, G Jung, H G Rammensee, A Melms
Journal: The Journal of Experimental Medicine (1995)

Class II-associated invariant chain peptides (CLIPs) compete with natural allele-specific ligands for binding to several purified HLA-DR molecules. Truncation and substitution analysis showed that a minimal sequence of 13 amino acids is sufficient for excellent binding to DR17 and DR1. Hydrophobic residues at relative positions 1 and 9 (P1 and P9) which are shared among these DR-ligands, and are found to be anchored in complementary pockets by x-ray crystallography allow specific binding. Two flanking residues at either end next to the specific contact sites Met107 and Met115 contribute to binding irrespective of their side chains, suggesting H-bonds to the major histocompatibility complex (MHC) molecule. Thus, CLIPs behave like conventional ligands, however, lack their allele-specific contact sites. Introduction of the DR17-specific contact site aspartate at P4 dramatically improves invariant chain-peptide binding to DR17, but reduces DR1 binding. By contrast, binding to DR1, but not DR17 is strongly improved after introduction of the DR1-specific contact site alanine at P6. In addition, analyzing the fine specificity of the hydrophobic contact sites at P1 and P9, CLIP variants reflected the allele-specific preferences of DR17- or DR1-ligands, respectively, for aliphatic or aromatic residues. Alignment studies suggest that CLIPs are designed for promiscuous binding in the groove of many MHC class II molecules by taking advantage of one or more supermotifs. One such supermotif, for example, does not include the DR17-specific contact site aspartate at P4, which in conventional natural ligands like Apolipoprotein (2877-94) is necessary to confer a stable conformation. Introduction of aspartate at P4 generates a CLIP variant that is stable in the presence of sodium dodecyl sulfate, such as allele-specific ligands. Studying the stability of class II-CLIP complexes at pH 5, we found that CLIPs, similar to anchor-amputated ligands, can be released from class II molecules, in contrast to conventional natural ligands, which were irreversibly bound. Taken together, our data provide compelling evidence that CLIP peptides bind into the class II groove.
Transmural electrical potential difference of the human colon
Authors: M. G. Geall, R. J. Spencer, S. F. Phillips
Journal: Gut (1969)

The electrical potential across the human colon was measured by a technique which accurately reflects the true mucosa-to-serosa potential difference. Large negative mucosal potentials were recorded from all regions. The potential difference of the sigmoid colon was significantly greater than that of the rectum. The technique may have important applications to the further study of normal or abnormal colonic function.
Type I IFN signaling in CD8– DCs impairs Th1-dependent malaria immunity
Authors: Ashraful Haque, Shannon E. Best, Marcela Montes de Oca, Kylie R. James, Anne Ammerdorffer, Chelsea L. Edwards, Fabian de Labastida Rivera, Fiona H. Amante, Patrick T. Bunn, Meru Sheel, Ismail Sebina, Motoko Koyama, Antiopi Varelias, Paul J. Hertzog, Ulrich Kalinke, Sin Yee Gun, Laurent Rénia, Christiane Ruedl, Kelli P.A. MacDonald, Geoffrey R. Hill, Christian R. Engwerda
Journal: Journal of Clinical Investigation (2014)

Many pathogens, including viruses, bacteria, and protozoan parasites, suppress cellular immune responses through activation of type I IFN signaling. Recent evidence suggests that immune suppression and susceptibility to the malaria parasite, Plasmodium, is mediated by type I IFN; however, it is unclear how type I IFN suppresses immunity to blood-stage Plasmodium parasites. During experimental severe malaria, CD4+ Th cell responses are suppressed, and conventional DC (cDC) function is curtailed through unknown mechanisms. Here, we tested the hypothesis that type I IFN signaling directly impairs cDC function during Plasmodium infection in mice. Using cDC-specific IFNAR1-deficient mice, and mixed BM chimeras, we found that type I IFN signaling directly affects cDC function, limiting the ability of cDCs to prime IFN-γ–producing Th1 cells. Although type I IFN signaling modulated all subsets of splenic cDCs, CD8– cDCs were especially susceptible, exhibiting reduced phagocytic and Th1-promoting properties in response to type I IFNs. Additionally, rapid and systemic IFN-α production in response to Plasmodium infection required type I IFN signaling in cDCs themselves, revealing their contribution to a feed-forward cytokine-signaling loop. Together, these data suggest abrogation of type I IFN signaling in CD8– splenic cDCs as an approach for enhancing Th1 responses against Plasmodium and other type I IFN–inducing pathogens.
Peak flow rate records in the diagnosis of occupational asthma due to colophony.
Authors: P S Burge, I M O'Brien, M G Harries
Journal: Thorax (1979)

Peak expiratory flow rate (PEFR) has been measured hourly from waking to sleeping in 29 workers with respiratory symptoms exposed to the fumes of soft soldering fluxes containing colophony (pine resin). Thirty-nine records of mean length 33 days have been analysed, and the results compared with the occupational history and bronchial provocation testing in the same workers. From plots of daily mean, maximum, and minimum PEFR, recurring physiological patterns of asthma emerge. The most common pattern is for asthma to increase with each successive working day. Some workers have an equivalent deterioration each working day. Regular recovery patterns taking one, two, and three days are described. The combination of a three-day recovery pattern and a late asthmatic reaction on Monday results in Monday being the best day of each week. Assessment of these records has shown them to be specific and sensitive, provided the worker was not taking corticosteroids or sodium cromoglycate during the period of the record and that bronchodilator usage was kept constant on days at home and at work. The results of the PEFR records correlate well with bronchial provocation testing, and provide a suitable alternative to this for the diagnosis of mild to moderate occupational asthma. The records are of particular use for screening symptomatic workers whose symptoms appear unlikely to be related to work.
Processing of urushiol (poison ivy) hapten by both endogenous and exogenous pathways for presentation to T cells in vitro.
Authors: R S Kalish, J A Wood, A LaPorte
Journal: Journal of Clinical Investigation (1994)

The antigen processing requirements for urushiol, the immunogen of poison ivy (Toxicodendron radicans), were tested by presentation of urushiol to cultured human urushiol-responsive T cells. Urushiol was added to antigen-presenting cells (APC) either before or after fixation with paraformaldehyde. Three distinct routes of antigen processing were detected. CD8+ and CD4+ T cells, which were dependent upon processing, proliferated if urushiol was added to APC before fixation, but did not proliferate when urushiol was added to APC after fixation. Processing of urushiol for presentation to CD8+ T cells was inhibited by azide, monensin, and brefeldin A. This suggests that urushiol was processed by the endogenous pathway. In contrast, presentation of urushiol to CD4+ T cells was inhibited by monensin but not by brefeldin A. This was compatible with antigen processing by the endosomal (exogenous) pathway. Finally, certain CD8+ T cells recognized urushiol in the absence of processing. These cells proliferated in response to APC incubated with urushiol after fixation. Classification of contact allergens by antigen processing pathway may predict the relative roles of CD4+ and CD8+ cells in the immunopathogensis of allergic contact dermatitis.
Inhibition of the malate–aspartate shuttle by pre-ischaemic aminooxyacetate loading of the heart induces cardioprotection
Authors: Nicolaj Brejnholt Støttrup, Bo Løfgren, Rune Dupont Birkler, Jan Møller Nielsen, Lixing Wang, Christopher Anthony Caldarone, Steen Buus Kristiansen, Hussain Contractor, Mogens Johannsen, Hans Erik Bøtker, Torsten Toftegaard Nielsen
Journal: Cardiovascular Research (2010)

Preserved mitochondrial function is essential for protection against ischaemia–reperfusion (IR) injury. The malate–aspartate (MA) shuttle constitutes the principal pathway for transport of reducing cytosolic equivalents for mitochondrial oxidation. We hypothesized that a transient shut-down of the MA-shuttle by aminooxyacetate (AOA) during ischaemia and early reperfusion modulates IR injury by mechanisms comparable to ischaemic preconditioning (IPC). Isolated perfused rat hearts exposed to 40 min global no-flow ischaemia were studied in: (i) control, (ii) pre-ischaemic AOA (0.1 mM), (iii) IPC, and (iv) AOA+IPC hearts. IR injury was evaluated by infarct size and haemodynamic recovery. Tracer-estimated glucose oxidation and metabolic changes in glycogen, lactate, pyruvate, tricarboxylic acid (TCA) cycle intermediates, and ATP degradation products were measured. The effects of AOA on complex I respiration and reactive oxygen species (ROS) production were examined in isolated rabbit mitochondria. Treatment with AOA, IPC, or AOA+IPC induced significant infarct reduction; 28 ± 6, 30 ± 3, and 18 ± 1%, respectively, vs. 52 ± 5% of left ventricular (LV) mass for control (P < 0.01 for all). LV-developed pressure improved to 60 ± 3, 63 ± 5 and 53 ± 4 vs. 31 ± 5 mmHg (P < 0.01 for all) after 2 h reperfusion. Pre-ischaemic AOA administration inhibited glycolysis and increased glucose oxidation during post-ischaemic reperfusion similar to IPC, and suppressed complex I respiration and ROS production in the non-ischaemic heart. Changes in lactate, pyruvate, TCA intermediates, and ATP end products suggested an AOA inhibition of the MA-shuttle during late ischaemia and early reperfusion. Inhibition of the MA-shuttle during ischaemia and early reperfusion is proposed as a mechanism to reduce IR injury.
Malignant astrocytomas of elderly patients lack favorable molecular markers: an analysis of the NOA-08 study collective
Authors: B. Wiestler, R. Claus, S. A. Hartlieb, M. G. Schliesser, E. K. Weiss, T. Hielscher, M. Platten, L. M. Dittmann, C. Meisner, J. Felsberg, C. Happold, M. Simon, G. Nikkhah, K. Papsdorf, J. P. Steinbach, M. Sabel, C. Grimm, D. Weichenhan, B. Tews, G. Reifenberger, D. Capper, W. Muller, C. Plass, M. Weller, W. Wick
Journal: Neuro-Oncology (2013)

The number of patients age >65 years with malignant gliomas is increasing. Prognosis of these patients is worse compared with younger patients. To determine biological differences among malignant gliomas of different age groups and help to explain the survival heterogeneity seen in the NOA-08 trial, the prevalence and impact of recently established biomarkers for outcome in younger patients were characterized in elderly patients. Prevalences of mutations of isocitrate dehydrogenase 1 (IDH1) and histone H3.3 (H3F3A), the glioma cytosine–phosphate–guanine island methylator phenotype (G-CIMP), and methylation of alkylpurine DNA N-glycosylase (APNG) and peroxiredoxin 1 (PRDX1) promoters were determined in a representative biomarker subset (n = 126 patients with anaplastic astrocytoma or glioblastoma) from the NOA-08 trial. IDH1 mutations (R132H) were detected in only 3/126 patients, precluding determination of an association between IDH mutation and outcome. These 3 patients also displayed the G-CIMP phenotype. None of the IDH1 wild-type tumors were G-CIMP positive. Mutations in H3F3A were absent in all 103 patients sequenced for H3F3A. MassARRAY analysis of the APNG promoter revealed generally low methylation levels and failed to confirm any predictive properties for benefit from alkylating chemotherapy. Neither did PRDX1 promoter methylation show differential methylation or association with outcome in this cohort. In a 170-patient cohort from The Cancer Genome Atlas database matched for relevant prognostic factors, age ≥65 years was strongly associated with shorter survival. Despite an age-independent stable frequency of O6-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, tumors in this age group largely lack prognostically favorable markers established in younger glioblastoma patients, which likely contributes to the overall worse prognosis of elderly patients. However, the survival differences hint at fundamental further differences among malignant gliomas of different age groups.
Decreased Fibronectin Production Significantly Contributes to Dysregulated Repair of Asthmatic Epithelium
Authors: Anthony Kicic, Teal S. Hallstrand, Erika N. Sutanto, Paul T. Stevens, Michael S. Kobor, Christopher Taplin, Peter D. Paré, Richard P. Beyer, Stephen M. Stick, Darryl A. Knight
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Damage to airway epithelium is followed by deposition of extracellular matrix (ECM) and migration of adjacent epithelial cells. We have shown that epithelial cells from children with asthma fail to heal a wound in vitro.Objectives: To determine whether dysregulated ECM production by the epithelium plays a role in aberrant repair in asthma.Methods: Airway epithelial cells (AEC) from children with asthma (n = 36), healthy atopic control subjects (n = 23), and healthy nonatopic control subjects (n = 53) were investigated by microarray, gene expression and silencing, transcript regulation analysis, and ability to close mechanical wounds.Measurements and Main Results: Time to repair a mechanical wound in vitro by AEC from healthy and atopic children was not significantly different and both were faster than AEC from children with asthma. Microarray analysis revealed differential expression of multiple gene sets associated with repair and remodeling in asthmatic AEC. Fibronectin (FN) was the only ECM component whose expression was significantly lower in asthmatic AEC. Expression differences were verified by quantitative polymerase chain reaction and ELISA, and reduced FN expression persisted in asthmatic cells over passage. Silencing of FN expression in nonasthmatic AEC inhibited wound repair, whereas addition of FN to asthmatic AEC restored reparative capacity. Asthmatic AEC failed to synthesize FN in response to wounding or cytokine/growth factor stimulation. Exposure to 5′, 2′deoxyazacytidine had no effect on FN expression and subsequent analysis of the FN promoter did not show evidence of DNA methylation.Conclusions: These data show that the reduced capacity of asthmatic epithelial cells to secrete FN is an important contributor to the dysregulated AEC repair observed in these cells.
Osteogenesis imperfecta: an x ray fibre diffraction study.
Authors: J P Bradshaw, A Miller
Journal: Annals of the Rheumatic Diseases (1986)

The use of x ray fibre diffraction to study the molecular architecture of healthy and diseased human tendon is described. The three dimensional structure of human (finger) tendon is derived to high resolution and is shown to be very similar to that reported for rat tail tendon. In particular the presence of the 38 A row line in the diffraction pattern suggests that a high degree of lateral order within the collagen fibrils is a more widespread feature of tendon tissue than was formerly realised. Axially projected electron density maps of the 670 A unit repeat of the collagen fibrils of this tissue, and of tendon tissue from three cases of osteogenesis imperfecta (OI), are calculated and compared. The results are in agreement with recent biochemical studies in suggesting that type I (Sillence) OI is principally a quantitative, rather than a qualitative, defect of type I collagen biosynthesis. The features by which a molecular lesion may be recognised and characterised from diffraction data are discussed.