tbuckley/cabot-search huggingface dataset:
Quantitative proteomics identifies the membrane-associated peroxidase GPx8 as a cellular substrate of the hepatitis C virus NS3-4A protease
Authors: Kenichi Morikawa, Jérôme Gouttenoire, Céline Hernandez, Viet Loan Dao Thi, Huong T.L. Tran, Christian M. Lange, Michael T. Dill, Markus H. Heim, Olivier Donzé, François Penin, Manfredo Quadroni, Darius Moradpour
Journal: Hepatology (2013)

The hepatitis C virus (HCV) NS3-4A protease is not only an essential component of the viral replication complex and a prime target for antiviral intervention but also a key player in the persistence and pathogenesis of HCV. It cleaves and thereby inactivates two crucial adaptor proteins in viral RNA sensing and innate immunity, mitochondrial antiviral signaling protein (MAVS) and TRIF, a phosphatase involved in growth factor signaling, T-cell protein tyrosine phosphatase (TC-PTP), and the E3 ubiquitin ligase component UV-damaged DNA-binding protein 1 (DDB1). Here we explored quantitative proteomics to identify novel cellular substrates of the NS3-4A protease. Cell lines inducibly expressing the NS3-4A protease were analyzed by stable isotopic labeling using amino acids in cell culture (SILAC) coupled with protein separation and mass spectrometry. This approach identified the membrane-associated peroxidase GPx8 as a bona fide cellular substrate of the HCV NS3-4A protease. Cleavage by NS3-4A occurs at Cys 11, removing the cytosolic tip of GPx8, and was observed in different experimental systems as well as in liver biopsies from patients with chronic HCV. Overexpression and RNA silencing studies revealed that GPx8 is involved in viral particle production but not in HCV entry or RNA replication. We provide proof-of-concept for the use of quantitative proteomics to identify cellular substrates of a viral protease and describe GPx8 as a novel proviral host factor targeted by the HCV NS3-4A protease.
Biphasic Regulation of Renal Proximal Bicarbonate Absorption by Luminal AT1A Receptor
Authors: Yanan Zheng, Shoko Horita, Chiaki Hara, Motoei Kunimi, Hideomi Yamada, Takeshi Sugaya, Atsuo Goto, Toshiro Fujita, George Seki
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Angiotensin II (AngII) regulates renal proximal transport in a biphasic way. It has been recently shown that the basolateral type 1A receptor (AT<sub>1A</sub>) mediates the biphasic regulation of Na<sup>+</sup>-HCO<sub>3</sub><sup>−</sup> cotransporter (NBC) by AngII. However, the receptor subtype(s) responsible for the luminal AngII actions remained to be established. To clarify this issue, the luminal AngII effects in isolated proximal tubules from wild-type (WT) and AT<sub>1A</sub>-deficient mice (AT<sub>1A</sub> KO) were compared. In WT, the rate of bicarbonate absorption (Jhco<sub>3</sub><sup>−</sup>), analyzed with a stop-flow microspectrofluorometric method, was stimulated by 10<sup>−10</sup> mol/L luminal AngII but was inhibited by 10<sup>−6</sup> mol/L luminal AngII. Both stimulatory and inhibitory effects of AngII were completely blocked by valsartan (AT<sub>1</sub> antagonist) but unaffected by PD 123,319 (AT<sub>2</sub> antagonist). In AT<sub>1A</sub> KO, in contrast, luminal AngII (10<sup>−10</sup> − 10<sup>−6</sup> mol/L) did not change Jhco<sub>3</sub><sup>−</sup>. In WT, 10<sup>−6</sup> mol/L luminal AngII increased cell Ca<sup>2+</sup> concentrations ([Ca<sup>2+</sup>]<sub>i</sub>), which was again blocked by valsartan but not by PD 123,319. However, luminal AngII did not increase [Ca<sup>2+</sup>]<sub>i</sub> in AT<sub>1A</sub> KO. On the other hand, the addition of arachidonic acid similarly inhibited Jhco<sub>3</sub><sup>−</sup> in WT and AT<sub>1A</sub> KO. Furthermore, the acute activation of protein kinase C by phorbol 12-myristate 13-acetate similarly stimulated Jhco<sub>3</sub><sup>−</sup> in WT and AT1A KO, indicating that the inhibitory and stimulatory pathways necessary for the AngII actions were preserved in AT<sub>1A</sub> KO. These results indicate that the luminal AT<sub>1A</sub> mediates the biphasic regulation of bicarbonate absorption by luminal AngII, while no evidence was obtained for a role of AT<sub>2</sub>. E-mail:georgeseki-tky@uminac.jp
The Association of Adiponectin with Computed Tomography Phenotypes in Chronic Obstructive Pulmonary Disease
Authors: Brendan J. Carolan, Yu-il Kim, André A. Williams, Katerina Kechris, Sharon Lutz, Nichole Reisdorph, Russell P. Bowler
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder associated with systemic manifestations that contribute to its morbidity and mortality. Recent work suggests that biomarker signatures in the blood may be useful in evaluating COPD phenotypes and may provide insight into the pathophysiology of systemic manifestations. Adiponectin, primarily produced by fat cells, has been implicated in the pathophysiology of emphysema.
Combination of interferon induction therapy and ribavirin in chronic hepatitis C
Authors: Peter Ferenci, Harald Brunner, Karin Nachbaur, Christian Datz, Michael Gschwantler, Harald Hofer, Rudolf Stauber, Franz Hackl, Wolfgang Jessner, Martha Rosenbeiger, Petra Munda-Steindl, Karin Hegenbarth, Alfred Gangl, Wolfgang Vogel
Journal: Hepatology (2001)

The initial clearance of hepatitis C virus (HCV) during interferon-alfa therapy is dose-dependent. Therefore, higher initial interferon doses (induction therapy) may improve treatment results. This concept was tested in a prospective, randomized controlled trial. Previously untreated patients with chronic hepatitis C were randomized to receive 3 different interferon doses during the first 14 weeks of therapy (Group A, n = 130: 10 MU IntronA [AESCA-Schering Plough, Traiskirchen, Austria]/day for 2 weeks, followed by 10 MU/2 days for 12 weeks; Group B, n = 124: 5 MU/day for 14 weeks; Group C, n = 119; 5 MU/2 days for 14 weeks) followed in all by 5 MU/2 days for 24 weeks. Throughout the whole study all patients received 1 to 1.2 g ribavirin/day. On treatment, no differences in viral clearance rates were observed. Sustained response rates were also not different among the groups (A: 48.5%, B and C: 41.3%, intent to treat). When data were analyzed according to genotypes, sustained response was almost twice as high in patients with genotype 1 receiving high-dose interferon induction therapy (A: 44.2%, B: 28.6%, C: 27%, P &lt; .05). In contrast, results were not different in genotype 3a patients (A: 61.3%, B: 75.9%, C: 56.3%; P &gt; .1). These data indicate that high-dose interferon induction therapy may improve the outcome of interferon/ribavirin combination therapy in genotype 1 patients.
CCR2 Deficiency Prevents Neuronal Dysfunction and Cognitive Impairments Induced by Cranial Irradiation
Authors: Karim Belarbi, Timothy Jopson, Carla Arellano, John R. Fike, Susanna Rosi
Journal: Cancer Research (2012)

Cranial irradiation can lead to long-lasting cognitive impairments in patients receiving radiotherapy for the treatment of malignant brain tumors. Recent studies have suggested inflammation as a major contributor to these deficits; we determined if the chemokine (C-C motif) receptor 2 (CCR2) was a mediator of cognitive impairments induced by irradiation. Two-month-old male Ccr2 knockout (-/-) and wild-type mice received 10 Gy cranial irradiation or sham-treatment. One month after irradiation, bromodeoxyuridine was injected intraperitoneally for seven consecutive days to label newly generated cells. At two months postirradiation, cognitive function was assessed by novel object recognition and Morris water maze. Our results show that CCR2 deficiency prevented hippocampus-dependent spatial learning and memory impairments induced by cranial irradiation. Hippocampal gene expression analysis showed that irradiation induced CCR2 ligands such as CCL8 and CCR2 deficiency reduced this induction. Irradiation reduced the number of adult-born neurons in both wild-type and Ccr2(-/-) mice, but the distribution pattern of the adult-born neurons through the granule cell layer was only altered in wild-type mice. Importantly, CCR2 deficiency normalized the fraction of pyramidal neurons expressing the plasticity-related immediate early gene Arc. These data offer new insight into the mechanism(s) of radiation-injury and suggest that CCR2 is a critical mediator of hippocampal neuronal dysfunction and hippocampal cognitive impairments after irradiation. Targeting CCR2 signaling could conceivably provide an effective approach to reduce or prevent the incidence and severity of this serious side effect of ionizing irradiation.
Molecular Pathways: Next-Generation Immunotherapy—Inhibiting Programmed Death-Ligand 1 and Programmed Death-1
Authors: Daniel S. Chen, Bryan A. Irving, F. Stephen Hodi
Journal: Clinical Cancer Research (2012)

The aim of T-cell-based immune therapy for cancer has been to generate durable clinical benefit for patients. Following a generation of therapies that largely showed minimal activity, substantial toxicity, and no biomarkers to identify which patients benefit from treatment, early studies are showing signs that programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) inhibitors are highly active. Preclinical and early data from clinical studies suggest that targeting this pathway can induce durable clinical responses in patients in a variety of tumor types, including lung and colon cancer. Furthermore, correlations with tumor PD-L1 expression may enable selection of patients most likely to benefit from treatment. The emerging data not only offer the hope of better cancer therapy but also provide evidence that changes our understanding of how the host immune system interacts with human cancer.
Superoxide dismutases, lung function and bronchial responsiveness in a general population
Authors: M. Siedlinski, C. C. van Diemen, D. S. Postma, J. M. Vonk, H. M. Boezen
Journal: European Respiratory Journal (2009)

Oxidative stress is an important causative factor in the onset and progression of smoking-related lung diseases, such as chronic obstructive pulmonary disease (COPD). Superoxide dismutases (SODs) can prevent an increase in oxidative burden. A total of 1,390 subjects from the prospective Vlagtwedde-Vlaardingen cohort were genotyped for two single nucleotide polymorphisms (SNPs) in SOD2 and four SNPs in SOD3, which were further analysed for associations with the presence of bronchial hyperresponsiveness (BHR; provocative concentration causing a 10% fall in the forced expiratory volume in one second (FEV(1); PC(10) <or=8 mg mL(-1) of histamine), COPD (defined as Global Initiative for Chronic Obstructive Lung Disease stage II or higher), lung function level and the longitudinal course of FEV(1). The intronic C5774T SNP of SOD2 was significantly associated with the presence of COPD and BHR in the total population. The T/T genotype for this polymorphism and the Val/Val genotype for the SOD2 Ala16Val substitution were risk factors for BHR in individuals without COPD. The SOD3 Arg213Gly substitution was associated with slower FEV(1) decline in never-smokers exclusively, and the SOD3 G(-4466)T SNP was associated with a lower vital capacity level. Both SOD2 polymorphisms are associated with bronchial hyperresponsiveness, a risk factor for chronic obstructive pulmonary disease, while SOD2 C5774T additionally confers a risk for chronic obstructive pulmonary disease in the total population. The current authors furthermore confirm previously reported associations of SOD3 single nucleotide polymorphisms with lung function in the general population.
Survivin knockdown and concurrent 4-HPR treatment controlled human glioblastoma in vitro and in vivo
Authors: J. George, N. L. Banik, S. K. Ray
Journal: Neuro-Oncology (2010)

Survivin is highly expressed in most cancers, including glioblastoma, and it plays a significant role in inhibiting apoptosis and promoting tumor growth. Treatment of cancer cells with N-(4-hydroxyphenyl) retinamide (4-HPR) induces apoptosis through destabilization of mitochondrial membrane and activation of caspase-mediated apoptotic pathways. We studied the efficacy of a combination of survivin knockdown and 4-HPR treatment to induce apoptosis and inhibit invasion, angiogenesis, and growth of human glioblastomas in vitro and in vivo. Using a plasmid encoding survivin shRNA, we downregulated survivin in glioblastoma U251MG and U118MG cells and simultaneously treated with 1 µM 4-HPR for 48 hours. Cells following treatments were subjected to the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and invasion assays. In vivo angiogenesis and tumor regression studies were performed in nude mice. TUNEL assay demonstrated apoptosis in more than 80% of cells after survivin knockdown and 4-HPR treatment. Matrigel invasion assays demonstrated marked decreases in tumor cell invasion. In vivo angiogenesis studies depicted a remarkable inhibition of neovascularization due to the knockdown of survivin and 4-HPR treatment. Imaging of intracerebral tumorigenesis and longitudinal studies on subcutaneous solid tumor formation showed dramatic decreases in tumorigenesis and solid tumor progression, respectively, after treatment with the combination. Studies to elucidate the molecular mechanisms of the inhibition of angiogenesis and tumor regression demonstrated marked decreases in proliferating cell nuclear antigen, metalloproteinase-9, vascular endothelial growth factor, basic fibroblast growth factor, and CD31 in solid tumors. Our data demonstrated that survivin knockdown and concurrent 4-HPR treatment could be a novel therapeutic strategy for controlling growth of human glioblastomas.
Phase II clinical trials of cisplatin-then-paclitaxel and paclitaxel-then-cisplatin in patients with previously untreated advanced epithelial ovarian cancer
Authors: C.J. Poole, T. Perren, A. Burton, S.D. Jordan, A.H. Jenkins, J.J. Mould, D.A. Spooner, D. Luesley, K.K. Chan, S. Sturman, H.M. Earl
Journal: Annals of Oncology (2000)

To examine the activity and safety of two sequentially scheduled chemotherapy regimens comprising four cycles of paclitaxel (pctx) 200 mg/m2/3 hours then four cycles ofcisplatin (cisDDP) 100 mg/m2, and vice versa, in patients with previously untreated advanced ovarian cancer.Between January 1994 and February 1996, we recruited 30 patients to the pctx-then-cisDDP regimen and 29 to cisDDP-then-pctx, in parallel phase II trials.Both regimens were predictably active with responses seen in 22 of 30 patients (OR 74%; CR 27%, PR 47%) treated with pctx-then-cisDDP, as against 13 of 21 patients (OR 62%; CR 38%, PR 24%) treated with cisDDP-then-pctx. The OR rate to four cycles of pctx (induction) was 43%, with 27% disease progression; the OR to four cycles of cisDDP (induction) was 57%, with 5% progression. However, progression rates across both induction and consolidation phases were 16% (pctx-then-cisDDP) and 29% (cisDDP-then-pctx). Both regimens were unacceptably neurotoxic. II patients suffering grade 3 sensory neurotoxicity (5 on pctx-then-cisDDP, 6 on cisDDP-then-pctx) and 20 having grade 3 deafness (9 on pctx- then-cisDDP, 11 on cisDDP-then-pctx).The activity of these sequential regimens justifies their further development using the less neurotoxic platinum analogue carboplatin, perhaps combining paclitaxel with other platinum non-cross resistant drugs.
Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at <i>MSH5, HLA-DPB1</i> and <i>HLA-G</i>
Authors: Michelle M A Fernando, Jan Freudenberg, Annette Lee, David Lester Morris, Lora Boteva, Benjamin Rhodes, María Francisca Gonzalez-Escribano, Miguel Angel Lopez-Nevot, Sandra V Navarra, Peter K Gregersen, Javier Martin, Timothy J Vyse
Journal: Annals of the Rheumatic Diseases (2012)

Systemic lupus erythematosus (SLE) is a chronic multisystem genetically complex autoimmune disease characterised by the production of autoantibodies to nuclear and cellular antigens, tissue inflammation and organ damage. Genome-wide association studies have shown that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk for SLE in European and Chinese populations. However, the causal variants remain elusive due to tight linkage disequilibrium across disease-associated MHC haplotypes, the highly polymorphic nature of many MHC genes and the heterogeneity of the SLE phenotype.A high-density case-control single nucleotide polymorphism (SNP) study of the MHC region was undertaken in SLE cohorts of Spanish and Filipino ancestry using a custom Illumina chip in order to fine-map association signals in these haplotypically diverse populations. In addition, comparative analyses were performed between these two datasets and a northern European UK SLE cohort. A total of 1433 cases and 1458 matched controls were examined.Using this transancestral SNP mapping approach, novel independent loci were identified within the MHC region in UK, Spanish and Filipino patients with SLE with some evidence of interaction. These loci include HLA-DPB1, HLA-G and MSH5 which are independent of each other and HLA-DRB1 alleles. Furthermore, the established SLE-associated HLA-DRB1*15 signal was refined to an interval encompassing HLA-DRB1 and HLA-DQA1. Increased frequencies of MHC region risk alleles and haplotypes were found in the Filipino population compared with Europeans, suggesting that the greater disease burden in non-European SLE may be due in part to this phenomenon.These data highlight the usefulness of mapping disease susceptibility loci using a transancestral approach, particularly in a region as complex as the MHC, and offer a springboard for further fine-mapping, resequencing and transcriptomic analysis.
Calcific Aortic Valve Stenosis: Methods, Models, and Mechanisms
Authors: Jordan D. Miller, Robert M. Weiss, Donald D. Heistad
Journal: Circulation Research (2011)

Calcific aortic valve stenosis (CAVS) is a major health problem facing aging societies. The identification of osteoblast-like and osteoclast-like cells in human tissue has led to a major paradigm shift in the field. CAVS was thought to be a passive, degenerative process, whereas now the progression of calcification in CAVS is considered to be actively regulated. Mechanistic studies examining the contributions of true ectopic osteogenesis, nonosseous calcification, and ectopic osteoblast-like cells (that appear to function differently from skeletal osteoblasts) to valvular dysfunction have been facilitated by the development of mouse models of CAVS. Recent studies also suggest that valvular fibrosis, as well as calcification, may play an important role in restricting cusp movement, and CAVS may be more appropriately viewed as a fibrocalcific disease. High-resolution echocardiography and magnetic resonance imaging have emerged as useful tools for testing the efficacy of pharmacological and genetic interventions in vivo. Key studies in humans and animals are reviewed that have shaped current paradigms in the field of CAVS, and suggest promising future areas for research.
Differential effects of atorvastatin, pravastatin, rosuvastatin and simvastatin on lungs from mice exposed to cigarette smoke
Authors: Samuel Valenca, Thiago Ferreira, Alan Lopes, Denise Cardoso, Karla Pires, Larissa Silva-Neto, Manuella Lanzetti, Jackson Alves, Eduardo Trajano, Renata Nesi, Marina Barroso, Romulo Pinto, Cláudia Benjamim, Luís Porto
Journal: European Respiratory Journal (2012)

Short-term cigarette smoke (CS) exposure leads to acute lung inflammation through its influence on oxidants/antioxidants imbalance, but lately statins have shows anti-inflammatory and antioxidant effects. Therefore, we aimed analyzing the effects of four different statins on the lungs of mice exposed CS. Male C57Bl/6 mice were divided into six groups (n=8 each): Mice exposed to the smoke from 12 cigarettes/day/5 days (CS group); exposed to smoke from 12 cigarettes per day for 5 days plus atorvastatin (10 mg/kg/day; CS+A group), or pravastatin (5 mg/kg/day; CS+P group), or rousovastatin (5 mg/kg/day; CS+R group) or sinvastatin (20 mg/kg/day; CS+S group); control group was sham-smoked. One day after the last CS exposure, mice were sacrificed, the bronchoalveolar lavage fluid (BAL) was performed and the lungs were removed for histological analysis and homogenized for biochemical analyses. Oxidant levels were reduced in CS+S (p
HELLP babies link a novel lincRNA to the trophoblast cell cycle
Authors: Marie van Dijk, Hari K. Thulluru, Joyce Mulders, Omar J. Michel, Ankie Poutsma, Sandra Windhorst, Gunilla Kleiverda, Daoud Sie, Augusta M.A. Lachmeijer, Cees B.M. Oudejans
Journal: Journal of Clinical Investigation (2012)

The HELLP syndrome is a pregnancy-associated disease inducing hemolysis, elevated liver enzymes, and low platelets in the mother. Although the HELLP symptoms occur in the third trimester in the mother, the origin of the disease can be found in the first trimester fetal placenta. A locus for the HELLP syndrome is present on chromosome 12q23 near PAH. Here, by multipoint nonparametric linkage, pedigree structure allele sharing, and haplotype association analysis of affected sisters and cousins, we demonstrate that the HELLP locus is in an intergenic region on 12q23.2 between PMCH and IGF1. We identified a novel long intergenic noncoding RNA (lincRNA) transcript of 205,012 bases with (peri)nuclear expression in the extravillous trophoblast using strand-specific RT-PCR complemented with RACE and FISH. siRNA-mediated knockdown followed by RNA-sequencing, revealed that the HELLP lincRNA activated a large set of genes that are involved in the cell cycle. Furthermore, blocking potential mutation sites identified in HELLP families decreased the invasion capacity of extravillous trophoblasts. This is the first large noncoding gene to be linked to a Mendelian disorder with autosomal-recessive inheritance.
PHD Inhibition Mitigates and Protects Against Radiation-Induced Gastrointestinal Toxicity via HIF2
Authors: Cullen M. Taniguchi, Yu Rebecca Miao, Anh N. Diep, Colleen Wu, Erinn B. Rankin, Todd F. Atwood, Lei Xing, Amato J. Giaccia
Journal: Science Translational Medicine (2014)

Pharmacologic inhibition or knockout of HIF-prolyl hydroxylases in mice reduces morbidity and mortality from radiation-induced gastrointestinal syndrome.
Effect of inhaled bronchodilators on inspiratory capacity and dyspnoea at rest in COPD
Authors: F. Di Marco, J. Milic-Emili, B. Boveri, P. Carlucci, P. Santus, F. Casanova, M. Cazzola, S. Centanni
Journal: European Respiratory Journal (2002)

It has been shown that patients with chronic obstructive pulmonary disease (COPD) develop dynamic hyperinflation (DH), which contributes to dyspnoea and exercise intolerance. Formoterol, salmeterol and oxitropium have been recommended for maintenance therapy in COPD patients, but their effect on DH has only been assessed for salmeterol. The aim of the present study was to compare the acute effect of four inhaled bronchodilators (salbutamol, formoterol, salmeterol and oxitropium) and placebo on forced expiratory volume in one second, inspiratory capacity, forced vital capacity and dyspnoea in COPD patients. A cross-over, randomised, double-blind, placebo-controlled study was carried out on 20 COPD patients. Patients underwent pulmonary function testing and dyspnoea evaluation, in basal condition and 5, 15, 30, 60 and 120 min after bronchodilator or placebo administration. The results indicate that in chronic obstructive pulmonary disease patients with decreased baseline inspiratory capacity, there was a much greater increase of inspiratory capacity after bronchodilator administration, which correlated closely with the improvement of dyspnoea sensation at rest. For all bronchodilators used, inspiratory capacity reversibility should be tested at 30 min following the bronchodilator. On average, formoterol elicited the greatest increase in inspiratory capacity than the other bronchodilators used, though the difference was significant only with salmeterol and oxitropium. The potential advantage of formoterol needs to be tested in a larger patient population.