tbuckley/cabot-search huggingface dataset:
Left Bundle-Branch Block Induced by Transcatheter Aortic Valve Implantation Increases Risk of Death
Authors: Patrick Houthuizen, Leen A.F.M. Van Garsse, Thomas T. Poels, Peter de Jaegere, Robert M.A. van der Boon, Ben M. Swinkels, Jurriën M. ten Berg, Frank van der Kley, Martin J. Schalij, Jan Baan, Ricardo Cocchieri, Guus R.G. Brueren, Albert H.M. van Straten, Peter den Heijer, Mohamed Bentala, Vincent van Ommen, Jolanda Kluin, Pieter R. Stella, Martin H. Prins, Jos G. Maessen, Frits W. Prinzen
Journal: Circulation (2012)

Transcatheter aortic valve implantation (TAVI) is a novel therapy for treatment of severe aortic stenosis. Although 30% to 50% of patients develop new left bundle-branch block (LBBB), its effect on clinical outcome is unclear.Data were collected in a multicenter registry encompassing TAVI patients from 2005 until 2010. The all-cause mortality rate at follow-up was compared between patients who did and did not develop new LBBB. Of 679 patients analyzed, 387 (57.0%) underwent TAVI with the Medtronic CoreValve System and 292 (43.0%) with the Edwards SAPIEN valve. A total of 233 patients (34.3%) developed new LBBB. Median follow-up was 449.5 (interquartile range, 174-834) days in patients with and 450 (interquartile range, 253-725) days in patients without LBBB (P=0.90). All-cause mortality was 37.8% (n=88) in patients with LBBB and 24.0% (n=107) in patients without LBBB (P=0.002). By multivariate regression analysis, independent predictors of all-cause mortality were TAVI-induced LBBB (hazard ratio [HR], 1.54; confidence interval [CI], 1.12-2.10), chronic obstructive lung disease (HR, 1.56; CI, 1.15-2.10), female sex (HR, 1.39; CI, 1.04-1.85), left ventricular ejection fraction ≤50% (HR, 1.38; CI, 1.02-1.86), and baseline creatinine (HR, 1.32; CI, 1.19-1.43). LBBB was more frequent after implantation of the Medtronic CoreValve System than after Edwards SAPIEN implantation (51.1% and 12.0%, respectively; P<0.001), but device type did not influence the mortality risk of TAVI-induced LBBB.All-cause mortality after TAVI is higher in patients who develop LBBB than in patients who do not. TAVI-induced LBBB is an independent predictor of mortality.
Toxicity of Adjuvant Endocrine Therapy in Postmenopausal Breast Cancer Patients: A Systematic Review and Meta-analysis
Authors: Eitan Amir, Bostjan Seruga, Saroj Niraula, Lindsay Carlsson, Alberto Ocaña
Journal: JNCI Journal of the National Cancer Institute (2011)

Aromatase inhibitors are associated with consistent improvements in disease-free survival but not in overall survival. We conducted a literature-based meta-analysis of randomized trials to examine whether the relative toxicity of aromatase inhibitors compared with tamoxifen may explain this finding.We conducted a systematic review to identify randomized controlled trials that compared aromatase inhibitors and tamoxifen as primary adjuvant endocrine therapy in postmenopausal women by searching MEDLINE, EMBASE, and databases of the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm associated with one adverse event were computed for prespecified serious adverse events including cardiovascular disease, cerebrovascular disease, bone fractures, thromboembolic events, endometrial carcinoma and other second cancers not including new breast cancer. All statistical tests were two-sided.Seven trials enrolling 30,023 patients met the inclusion criteria. Longer duration of aromatase inhibitor use was associated with increased odds of developing cardiovascular disease (OR = 1.26, 95% CI = 1.10 to 1.43, P < .001; number needed to harm = 132) and bone fractures (OR = 1.47, 95% CI = 1.34 to 1.61, P < .001; number needed to harm = 46), but a decreased odds of venous thrombosis (OR = 0.55, 95% CI = 0.46 to 0.64, P < .001; number needed to harm = 79) and endometrial carcinoma (OR = 0.34, 95% CI = 0.22 to 0.53, P < .001; number needed to harm = 258). Five years of aromatase inhibitors was associated with a non-statistically significant increased odds of death without recurrence compared with 5 years of tamoxifen alone or tamoxifen for 2-3 years followed by an aromatase inhibitor for 2-3 years (OR = 1.11, 95% CI = 0.98 to 1.26, P = .09).The cumulative toxicity of aromatase inhibitors when used as up-front treatment may explain the lack of overall survival benefit despite improvements in disease-free survival. Switching from tamoxifen to aromatase inhibitors reduces this toxicity and is likely the best balance between efficacy and toxicity.
High prevalence of cytotoxin positive <i>Helicobacter pylori</i> in patients unrelated to the presence of peptic ulcers in Japan
Authors: K Ogura, F Kanai, S Maeda, H Yoshida, M Ogura, K-H Lan, K Hirota, T Kawabe, Y Shiratori, M Omata
Journal: Gut (1997)

Background —It has been reported that infection with vacuolating cytotoxin positive Helicobacter pylori strains is associated with gastroduodenal disease in Western countries. Aims —To evaluate the prevalence of cytotoxin producing strains among patients with H pylori infection in relation to gastrointestinal diseases in Japan. Patients —Ninety seven patients undergoing endoscopy. Methods —A Western blot assay was conducted to detect serum antibodies against the cytotoxin using recombinant cytotoxin (VacA protein) as an antigen. To obtain a purified recombinant cytotoxin, the vacA gene (2233 nucleotides) was cloned into an expression vector to produce the protein (744 amino acids), which was expressed in Escherichia coli . Results —Serum IgG antibodies to the cytotoxin were present in 85%, 95%, 95%, and 100% of infected patients with gastric ulcer (n=26), duodenal ulcer (n=21), chronic gastritis (n=19), and endoscopically normal mucosa (n=14), respectively. Conclusion —The western blot method using recombinant VacA protein is simple and useful for detecting antibody to vacuolating cytotoxin. This method showed antibodies against cytotoxin were highly prevalent, even in subjects with endoscopically normal mucosa in Japan, indicating that the cytotoxin may not be an independent cause of gastrointestinal diseases induced by H pylori infection.
Mycobacterial Subversion of Chemotherapeutic Reagents and Host Defense Tactics: Challenges in Tuberculosis Drug Development
Authors: Liem Nguyen, Jean Pieters
Journal: The Annual Review of Pharmacology and Toxicology (2009)

Recent worldwide emergence of multidrug-resistant and extensively drug-resistant tuberculosis is threatening to destabilize tuberculosis control programs and urging global attention to the development of alternative tuberculosis therapies. Major roadblocks limiting the development and effectiveness of new drugs to combat tuberculosis are the profound innate resistance of Mycobacterium tuberculosis to host defense mechanisms as well as its intrinsic tolerance to chemotherapeutic reagents. The triangle of interactions among the pathogen, the host responses, and the drugs used to cure the disease are critical for the outcome of tuberculosis. We must better understand this three-way interaction in order to develop drugs that are able to kill the bacillus in the most effective way and minimize the emergence of drug resistance. Here we review our recent understanding of the molecular basis underlying intrinsic antibiotic resistance and survival tactics of M. tuberculosis. This knowledge may help to reveal current targets for the development of novel antituberculosis drugs.
Effect of Methyldopa on Plasma Renin Activity in Man
Authors: SHAKIL MOHAMMED, ALFRED F. FASOLA, PHILIP J. PRIVITERA, RAYMOND J. LIPICKY, B. L. MARTZ, THOMAS E. GAFFNEY
Journal: Circulation Research (1969)

The effect of methyldopa on plasma renin activity was studied in one hypertensive and four normotensive human volunteers. Peripheral venous blood for the estimation of plasma renin activity was obtained with the subjects supine and in a 70° head-up tilted position before, during and, in two subjects, after treatment with oral methyldopa. Despite a reduction in mean arterial pressure, the plasma renin activity was decreased by methyldopa in each subject. The increase in plasma renin activity associated with tilting, however, was not significantly suppressed by methyldopa. These results indicate that treatment with methyldopa can simultaneously decrease mean arterial pressure and plasma renin activity and it is possible that these effects may be causally related.
A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma
Authors: Tim Hon Man Chan, Chi Ho Lin, Lihua Qi, Jing Fei, Yan Li, Kol Jia Yong, Ming Liu, Yangyang Song, Raymond Kwok Kei Chow, Vanessa Hui En Ng, Yun-Fei Yuan, Daniel G Tenen, Xin-Yuan Guan, Leilei Chen
Journal: Gut (2013)

<h3>Objective</h3> Hepatocellular carcinoma (HCC) is a heterogeneous tumour displaying a complex variety of genetic and epigenetic changes. In human cancers, aberrant post-transcriptional modifications, such as alternative splicing and RNA editing, may lead to tumour specific transcriptome diversity. <h3>Design</h3> By utilising large scale transcriptome sequencing of three paired HCC clinical specimens and their adjacent non-tumour (NT) tissue counterparts at depth, we discovered an average of 20 007 inferred A to I (adenosine to inosine) RNA editing events in transcripts. The roles of the double stranded RNA specific ADAR (Adenosine DeAminase that act on RNA) family members (ADARs) and the altered gene specific editing patterns were investigated in clinical specimens, cell models and mice. <h3>Results</h3> HCC displays a severely disrupted A to I RNA editing balance. <i>ADAR1</i> and <i>ADAR2</i> manipulate the A to I imbalance of HCC via their differential expression in HCC compared with NT liver tissues. Patients with <i>ADAR1</i> overexpression and <i>ADAR2</i> downregulation in tumours demonstrated an increased risk of liver cirrhosis and postoperative recurrence and had poor prognoses. Due to the differentially expressed <i>ADAR1</i> and <i>ADAR2</i> in tumours, the altered gene specific editing activities, which was reflected by the hyper-editing of <i>FLNB</i> (filamin B, β) and the hypo-editing of <i>COPA</i> (coatomer protein complex, subunit α), are closely associated with HCC pathogenesis. In vitro and in vivo functional assays prove that <i>ADAR1</i> functions as an oncogene while <i>ADAR2</i> has tumour suppressive ability in HCC. <h3>Conclusions</h3> These findings highlight the fact that the differentially expressed ADARs in tumours, which are responsible for an A to I editing imbalance, has great prognostic value and diagnostic potential for HCC.
Interaction between complement proteins C5b-7 and erythrocyte membrane sialic acid.
Authors: P Marshall, A Hasegawa, E A Davidson, V Nussenzweig, M Whitlow
Journal: The Journal of Experimental Medicine (1996)

The initial phase of membrane attack by complement is the interaction between C5b6, C7, and the cell membrane that leads to the insertion of C5b-7. Here we investigate the role of sialic acid residues in the assembly of C5b-7 intermediates on erythrocyte cell membranes. We find that C5b6 binds to glycophorin, whereas C5 or C6 does not bind, and desialylation of the glycophorin abolishes C5b6 binding. Complement lysis is inhibited by either masking glycophorin sialic acid with F(ab) fragments of an mAb, or by removal of the sialylated region of glycophorin by mild trypsinization. Gangliosides inhibit C5b-7 deposition when added to the aqueous phase. Asialogangliosides and synthetic gangliosides lacking the carboxylic acid residue have no inhibitory activity. We conclude that C5b6 binds to sialylated molecules on the erythrocyte surface. We propose a new model of membrane attack in which C5b6 initially binds to membranes via ionic forces. C7 then binds to C5b6, disrupting the ionic interaction and leading to the exposure of hydrophobic domains. Sialic acid is known to inhibit complement activation. Thus, these findings reveal a paradoxical role for sialic acid in complement attack; the presence of sialic acid inhibits the generation of C5b6, but once the membrane attack pathway is initiated, sialic acid enhances complement lysis.
Markers of inflammation and bone remodelling associated with improvement in clinical response measures in psoriatic arthritis patients treated with golimumab
Authors: Carrie L Wagner, Sudha Visvanathan, Michael Elashoff, Iain B McInnes, Philip J Mease, Gerald G Krueger, Frederick T Murphy, Kim Papp, Juan J Gomez-Reino, Michael Mack, Anna Beutler, Dafna Gladman, Arthur Kavanaugh
Journal: Annals of the Rheumatic Diseases (2012)

To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis (PsA).GO-REVEAL was a randomised, placebo-controlled study of golimumab in patients with active PsA. Samples were collected from 100 patients at baseline, week 4 and week 14, and analysed for serum-based biomarkers and protein profiling (total 92 markers); data were correlated with clinical measures at week 14.Serum levels of a subset of proteins (apolipoprotein C III, ENRAGE, IL-16, myeloperoxidase, vascular endothelial growth factor, pyridinoline, matrix metalloproteinase 3, C-reactive protein (CRP), carcinoembryonic antigen, intercellular adhesion molecule 1 and macrophage inflammatory protein 1α) at baseline or week 4 were strongly associated with American College of Rheumatology 20% improvement (ACR20) response and/or disease activity score in 28 joints (DAS28) at week 14. A smaller subset of proteins was significantly associated with a 75% improvement in the psoriasis area and severity index score (PASI75) at week 14, (adiponectin, apolipoprotein CIII, serum glutamic oxaloacetic transaminase, and tumour necrosis factor α). Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures, and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone.This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20, DAS28, or PASI75 responses following golimumab treatment.
ACE Inhibition Is Renoprotective among Obese Patients with Proteinuria
Authors: Francesca Mallamaci, Piero Ruggenenti, Annalisa Perna, Daniela Leonardis, Rocco Tripepi, Giovanni Tripepi, Giuseppe Remuzzi, Carmine Zoccali
Journal: Journal of the American Society of Nephrology (2011)

Obesity may increase the risk for progression of CKD, but the effect of established renoprotective treatments in overweight and obese patients with CKD is unknown. In this post hoc analysis of the Ramipril Efficacy In Nephropathy (REIN) trial, we evaluated whether being overweight or obese influences the incidence rate of renal events and affects the response to ramipril. Of the 337 trial participants with known body mass index (BMI), 105 (31.1%) were overweight and 49 (14.5%) were obese. Among placebo-treated patients, the incidence rate of ESRD was substantially higher in obese patients than overweight patients (24 versus 11 events/100 person-years) or than those with normal BMI (10 events/100 person-years); we observed a similar pattern for the combined endpoint of ESRD or doubling of serum creatinine. Ramipril reduced the rate of renal events in all BMI strata, but the effect was higher among the obese (incidence rate reduction of 86% for ESRD and 79% for the combined endpoint) than the overweight (incidence rate reduction of 45 and 48%, respectively) or those with normal BMI (incidence rate reduction of 42 and 45%, respectively). We confirmed this interaction between BMI and the efficacy of ramipril in analyses that adjusted for potential confounders, and we observed a similar effect modification for 24-hour protein excretion. In summary, obesity predicts a higher incidence of renal events, but treatment with ramipril can essentially abolish this risk excess. Furthermore, the reduction in risk conferred by ramipril is larger among obese than nonobese patients.
A Regulatory Role for TRAF1 in Antigen-induced Apoptosis of T Cells
Authors: Daniel E. Speiser, Soo Young Lee, Brian Wong, Joseph Arron, Angela Santana, Young-Yun Kong, Pamela S. Ohashi, Yongwon Choi
Journal: The Journal of Experimental Medicine (1997)

Tumor necrosis factor receptor (TNFR)–associated factor 2 (TRAF2) and TRAF1 were found as components of the TNFR2 signaling complex, which exerts multiple biological effects on cells such as cell proliferation, cytokine production, and cell death. In the TNFR2-mediated signaling pathways, TRAF2 works as a mediator for activation signals such as NF-κB, but the role of TRAF1 has not been previously determined. Here we show in transgenic mice that TRAF1 overexpression inhibits antigen-induced apoptosis of CD8+ T lymphocytes. Our results demonstrate a biological role for TRAF1 as a regulator of apoptotic signals and also support the hypothesis that the combination of TRAF proteins in a given cell type determines distinct biological effects triggered by members of the TNF receptor superfamily.
Characterization and enrichment of fetal rat hepatoblasts by immunoadsorption (“panning”) and fluorescence-activated cell sorting
Authors: Samuel H. Sigal, Shlomo Brill, Lola M. Reid, Isabel Zvibel, Sanjeev Gupta, Douglas Hixson, Ronald Faris, Patricia A. Holst
Journal: Hepatology (1994)

We developed methods for enriching fetal hepatoblasts by combining panning and multiparametric fluorescence-activated cell sorting. In unpurified, dissociated fetal liver cell suspensions of embryonic age day 15, 3.2% +/- 1.3% and 2.5% +/- 0.7% cells expressed albumin and alpha-fetoprotein, respectively. The remainder exhibited a hemopoietic, endothelial or stromal cell phenotype. Cells were panned first with an antibody to red blood cells to remove erythroid cells and then with monoclonal antibodies OX-43/OX-44 to remove hemopoietic and endothelial cells. This procedure eliminated 84% of fetal hepatic cells, with enrichment of the remainder for albumin or alpha-fetoprotein expression (up to sixfold increase). Flow cytometric analysis of unlabeled cells revealed two populations, which differed in granularity and autofluorescence. After panning, fluorescence-activated cell sorting for agranular cells yielded OX-43/44-positive cells that were essentially all hemopoietic precursor cells or OX-43/44-negative cells that were mostly hemopoietic precursor cells, along with 3.0% +/- 0.7% alpha-fetoprotein-positive cells. In contrast, sorting for granular, OX-43/44-negative cells enriched for predominantly alpha-fetoprotein-positive, parenchymal precursor cells (75.1% +/- 4.7%). Multiparametric flow cytometric analysis of the expression of an oval cell antigen, OC.3, which is a bile duct and putative liver stem cell marker, showed that most OC.3-positive cells coexpressed OX-43/OX-44 and morphologically were hemopoietic precursor cells. However, approximately 30% of the OX-43/44-negative, granular cells expressed OC.3. Although the physiological significance of OC.3-positive hepatoblasts remains to be determined, the ability to isolate distinct liver cell populations by means of fluorescence-activated cell sorting should facilitate further studies.(ABSTRACT TRUNCATED AT 250 WORDS)
OP15 Discovery of new liver fibrosis markers in hepatitis C patients using proteomics
Authors: B. Gangadharan, M. Bapat, J. Rossa, R. Antrobus, D. Chittenden, B. Kampa, E. Barnes, R. A. Dwek, N. Zitzmann
Journal: Gut (2011)

<h3>Introduction</h3> Liver biopsy is the reference standard for assessing liver fibrosis, and no reliable non-invasive diagnostic approach is available to discriminate between the intermediate stages of fibrosis. Therefore suitable serological biomarkers of liver fibrosis are urgently needed. <h3>Aim</h3> The objective of this study was to use proteomics to identify novel fibrosis biomarkers in hepatitis C patients with different degrees of liver fibrosis. <h3>Method</h3> Proteins in plasma samples from healthy control individuals and patients with hepatitis C virus (HCV) induced cirrhosis were analysed using a proteomics technique—two dimensional gel electrophoresis (2-DE). This technique separated the proteins in plasma samples of control and cirrhotic patients and by visualising the separated proteins we were able to identify proteins which were increasing or decreasing in hepatic cirrhosis. Identified markers were validated across all Ishak stages and compared to the markers used in FibroTest, Enhanced Liver Fibrosis (ELF) test, Hepascore and FIBROSpect by western blotting. <h3>Results</h3> 44 candidate biomarkers for hepatic fibrosis were identified of which 20 were novel. western blot validation of all candidate markers using plasma samples from patients across all Ishak fibrosis scores showed that the markers which changed with increasing fibrosis most consistently included lipid transfer inhibitor protein, complement C3d, corticosteroid-binding globulin, apolipoprotein J and apolipoprotein L1. These five novel markers which are secreted in blood showed a promising consistent change with increasing fibrosis stage when compared to the markers used for the FibroTest, ELF test, Hepascore and FIBROSpect. <h3>Conclusion</h3> This study identifies 20 novel fibrosis biomarker candidates. The proteins identified by these improved approaches may help to assess hepatic fibrosis and eliminate the need for invasive liver biopsies.
Clarifying the Cardiac Proteasome Paradox
Authors: Christopher C. Glembotski
Journal: Circulation Research (2012)

C orrect folding of proteins is crucial for proper protein, cell, and organ function. 1Mutations and cellular stresses, some of which occur during pathology, can lead to incorrect folding and subsequent loss of protein function.If it goes uncorrected, then this loss of protein function, along with the toxicity associated with the accumulation of misfolded proteins in cells, results in eventual organ failure. 2 Many diseases, including neurodegenerative, hepatic, endocrine, and cardiovascular disorders, are thought to be associated with, if not caused by, the organ failure resulting from the accumulation of misfolded proteins. 3For example, in the heart, accumulation of misfolded proteins has been associated with hypertrophic and dilated cardiomyopathies as well as ischemic heart disease.