tbuckley/cabot-search huggingface dataset:
Helicobacter pylori induces β3GnT5 in human gastric cell lines, modulating expression of the SabA ligand sialyl–Lewis x
Authors: Nuno T. Marcos, Ana Magalhães, Bibiana Ferreira, Maria J. Oliveira, Ana S. Carvalho, Nuno Mendes, Tim Gilmartin, Steven R. Head, Céu Figueiredo, Leonor David, Filipe Santos-Silva, Celso A. Reis
Journal: Journal of Clinical Investigation (2008)

Chronic Helicobacter pylori infection is recognized as a cause of gastric cancer. H. pylori adhesion to gastric cells is mediated by bacterial adhesins such as sialic acid–binding adhesin (SabA), which binds the carbohydrate structure sialyl–Lewis x. Sialyl–Lewis x expression in the gastric epithelium is induced during persistent H. pylori infection, suggesting that H. pylori modulates host cell glycosylation patterns for enhanced adhesion. Here, we evaluate changes in the glycosylation-related gene expression profile of a human gastric carcinoma cell line following H. pylori infection. We observed that H. pylori significantly altered expression of 168 of the 1,031 human genes tested by microarray, and the extent of these alterations was associated with the pathogenicity of the H. pylori strain. A highly pathogenic strain altered expression of several genes involved in glycan biosynthesis, in particular that encoding β3 GlcNAc T5 (β3GnT5), a GlcNAc transferase essential for the biosynthesis of Lewis antigens. β3GnT5 induction was specific to infection with highly pathogenic strains of H. pylori carrying a cluster of genes known as the cag pathogenicity island, and was dependent on CagA and CagE. Further, β3GnT5 overexpression in human gastric carcinoma cell lines led to increased sialyl–Lewis x expression and H. pylori adhesion. This study identifies what we believe to be a novel mechanism by which H. pylori modulates the biosynthesis of the SabA ligand in gastric cells, thereby strengthening the epithelial attachment necessary to achieve successful colonization.
Antigen expression determines adenoviral vaccine potency independent of IFN and STING signaling
Authors: Kylie M. Quinn, Daniel E. Zak, Andreia Costa, Ayako Yamamoto, Kathrin Kastenmuller, Brenna J. Hill, Geoffrey M. Lynn, Patricia A. Darrah, Ross W.B. Lindsay, Lingshu Wang, Cheng Cheng, Alfredo Nicosia, Antonella Folgori, Stefano Colloca, Riccardo Cortese, Emma Gostick, David A. Price, Jason G.D. Gall, Mario Roederer, Alan Aderem, Robert A. Seder
Journal: Journal of Clinical Investigation (2015)

Recombinant adenoviral vectors (rAds) are lead vaccine candidates for protection against a variety of pathogens, including Ebola, HIV, tuberculosis, and malaria, due to their ability to potently induce T cell immunity in humans. However, the ability to induce protective cellular immunity varies among rAds. Here, we assessed the mechanisms that control the potency of CD8 T cell responses in murine models following vaccination with human-, chimpanzee-, and simian-derived rAds encoding SIV-Gag antigen (Ag). After rAd vaccination, we quantified Ag expression and performed expression profiling of innate immune response genes in the draining lymph node. Human-derived rAd5 and chimpanzee-derived chAd3 were the most potent rAds and induced high and persistent Ag expression with low innate gene activation, while less potent rAds induced less Ag expression and robustly induced innate immunity genes that were primarily associated with IFN signaling. Abrogation of type I IFN or stimulator of IFN genes (STING) signaling increased Ag expression and accelerated CD8 T cell response kinetics but did not alter memory responses or protection. These findings reveal that the magnitude of rAd-induced memory CD8 T cell immune responses correlates with Ag expression but is independent of IFN and STING and provide criteria for optimizing protective CD8 T cell immunity with rAd vaccines.
LARGE can functionally bypass α-dystroglycan glycosylation defects in distinct congenital muscular dystrophies
Authors: Rita Barresi, Daniel E Michele, Motoi Kanagawa, Hollie A Harper, Sherri A Dovico, Jakob S Satz, Steven A Moore, Wenli Zhang, Harry Schachter, Jan P Dumanski, Ronald D Cohn, Ichizo Nishino, Kevin P Campbell
Journal: Nature Medicine (2004)
Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer
Authors: Raffaele Ciampi, Jeffrey A. Knauf, Roswitha Kerler, Manoj Gandhi, Zhaowen Zhu, Marina N. Nikiforova, Hartmut M. Rabes, James A. Fagin, Yuri E. Nikiforov
Journal: Journal of Clinical Investigation (2005)

Genes crucial for cancer development can be mutated via various mechanisms, which may reflect the nature of the mutagen. In thyroid papillary carcinomas, mutations of genes coding for effectors along the MAPK pathway are central for transformation. BRAF point mutation is most common in sporadic tumors. By contrast, radiation-induced tumors are associated with paracentric inversions activating the receptor tyrosine kinases RET and NTRK1. We report here a rearrangement of BRAF via paracentric inversion of chromosome 7q resulting in an in-frame fusion between exons 1–8 of the AKAP9 gene and exons 9–18 of BRAF. The fusion protein contains the protein kinase domain and lacks the autoinhibitory N-terminal portion of BRAF. It has elevated kinase activity and transforms NIH3T3 cells, which provides evidence, for the first time to our knowledge, of in vivo activation of an intracellular effector along the MAPK pathway by recombination. The AKAP9-BRAF fusion was preferentially found in radiation-induced papillary carcinomas developing after a short latency, whereas BRAF point mutations were absent in this group. These data indicate that in thyroid cancer, radiation activates components of the MAPK pathway primarily through chromosomal paracentric inversions, whereas in sporadic forms of the disease, effectors along the same pathway are activated predominantly by point mutations.
Leu-8/CD7 antigen expression by CD3+ T cells: Comparative analysis of skin and blood in mycosis fungoides/Sézary syndrome relative to normal blood values
Authors: Gary S. Wood, Steven R. Hong, Dennis T. Sasaki, Elizabeth A. Abel, Richard T. Hoppe, Roger A. Warnke, Vera B. Morhenn
Journal: Journal of the American Academy of Dermatology (1990)
Treating viral hepatitis C: efficacy, side effects, and complications
Authors: M P Manns
Journal: Gut (2006)

The treatment of hepatitis C has dramatically improved over the past decade. Unlike any other chronic viral infection, a significant proportion of patients with chronic hepatitis C can be cured. However, the current standard therapy--pegylated interferon alpha and ribavirin--has its limitations. Limited efficacy in patients with hepatitis C virus (HCV) genotype 1 and the side effect profile will necessitate the development of new therapeutic approaches. This review describes the efficacy and optimisation of the current standard therapy of hepatitis C and its problems in special patient populations. New treatment directions beyond interferon alpha based therapies are on the horizon.
Effects of endothelial and inducible nitric oxide synthases inhibition on circulatory function in rats after myocardial infarction
Authors: M Gaballa
Journal: Cardiovascular Research (1999)

Objectives: To examine the relative roles of eNOS and iNOS (endothelial and inducible nitric oxide synthases) on basal and β-adrenergic receptor (β-AR)-stimulated arterial hemodynamic responses after myocardial infarction (MI). Methods: Left ventricular (LV) pressures and steady-state and pulsatile arterial hemodynamics were measured at baseline, and after acute NOS inhibition with either NG-nitro-l-arginine methyl ester (l-NAME, 100 mg/kg) or iNOS inhibition with aminoguanidine (AG, 75 mg/kg) in sham-operated and MI Sprague–Dawley rats. Results: In sham rats, l-NAME decreased (P<0.05) peak positive LV dP/dt and aortic blood velocity by 19% and 53%, respectively, and increased (P<0.05) mean arterial pressure (MAP), systemic vascular resistance, and LV end-diastolic pressure (EDP) by 20, 189 and 89%, respectively. The frequency-dependent components of hemodynamics including aortic input impedance modulus, characteristic impedance, and phase shift were increased (P<0.05) with l-NAME, while pulsatile power was decreased (P<0.05). AG increased (P<0.05) aortic input impedance modulus and characteristic impedance but had no effect on any other hemodynamic variable. In MI rats, l-NAME decreased (P<0.05) LV dP/dt and aortic blood velocity by 22 and 55%, respectively, and increased (P<0.05) SVR by 108%. There was no effect of l-NAME on MAP or LV EDP in MI rats. After MI, AG increased (P<0.05) heart rate and LV dP/dt but had no effect on other LV or pulsatile hemodynamic variables. Compared to sham rats, heart rate, LV dP/dt, and blood velocity–isoproterenol dose responses were shifted downward (P<0.05), while SVR–isoproterenol dose response was shifted upward (P<0.05) in MI rats. In sham rats, l-NAME potentiated (P<0.05, at >10−2 μg/kg) the isoproterenol-induced increase in LV dP/dt and aortic blood velocity, and potentiated (P<0.05) the isoproterenol-induced decline in SVR. As expected, AG had no effects on isoproterenol-stimulated hemodynamics in sham rats. After MI, there was no effect of l-NAME or AG on isoproterenol-stimulated hemodynamics. Conclusions: (1) Circulatory and cardiac responses to inhibition of NO by l-NAME suggest that eNOS, but not iNOS, is the principal regulator of integrated arterial hemodynamic function in rats. (2) Both basal and β-AR-stimulated NO regulation of hemodynamic are attenuated after MI. (3) The attenuation of arterial hemodynamic effects after isoproterenol is mediated, in part, by alterations in the β-AR-activation of eNOS system after MI.
Interleukin-1 beta-converting enzyme-like protease cleaves DNA-dependent protein kinase in cytotoxic T cell killing.
Authors: Q Song, S R Burrows, G Smith, S P Lees-Miller, S Kumar, D W Chan, J A Trapani, E Alnemri, G Litwack, H Lu, D J Moss, S Jackson, M F Lavin
Journal: The Journal of Experimental Medicine (1996)

Cytotoxic T cells (CTL) represent the major defense mechanism against the spread of virus infection. It is believed that the pore-forming protein, perforin, facilitates the entry of a series of serine proteases (particularly granzyme B) into the target cell which ultimately leads to DNA fragmentation and apoptosis. We demonstrate here that during CTL-mediated cytolysis the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), an enzyme implicated in the repair of double strand breaks in DNA, is specifically cleaved by an interleukin (IL)-1 beta-converting enzyme (ICE)-like protease. A serine protease inhibitor, 3,4-dichloroisocoumarin (DCl), which is known to block granzyme B activity, inhibited CTL-induced apoptosis and prevented the degradation of DNA-PKcs in cells but failed to prevent the degradation of purified DNA-PKcs by CTL extracts. However, Tyr-Val-Ala-Asp-CH2Cl (YVAD-CMK) and other cysteine protease inhibitors prevented the degradation of purified DNA-PKcs by CTL extracts. Furthermore, incubation of DNA-PKcs with granzyme B did not produce the same cleavage pattern observed in cells undergoing apoptosis and when this substrate was incubated with either CTL extracts or the ICE-like protease, CPP32. Sequence analysis revealed that the cleavage site in DNA-PKcs during CTL killing was the same as that when this substrate was exposed to CPP32. This study demonstrates for the first time that the cleavage of DNA-PKcs in this intact cell system is exclusively due to an ICE-like protease.
Growth Hormone Receptor Antagonism Prevents Early Renal in Nonobese Diabetic Mice
Authors: YAEL SEGEV, DANIEL LANDAU, RUTH RASCH, ALLAN FLYVBJERG, MOSHE PHILLIP
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The growth hormone (GH)/insulin-like growth factor (IGF) axis is involved in diabetic renal disease. The role of a specific GH receptor (GHR) antagonist in the development of early renal changes in nonobese diabetic (NOD) mice was investigated. Female diabetic (nonketotic) NOD mice treated with a polyethylene glycol-treated GHR antagonist (2 mg/kg, every other day) (DA group) or saline (D group) and their nonhyperglycemic age-matched littermates (control animals) were euthanized 3 wk after the onset of diabetes. Body weights at euthanasia were similar among the groups. Serum GH levels were markedly elevated, and serum IGF-I levels were significantly decreased in D and DA animals, compared with controls. The increases in kidney weights and glomerular volumes observed for the D group were absent in the DA group. Albuminuria was increased in the D group but was normalized in the DA group. Extractable renal IGF-I protein levels were increased in the D group but were partially normalized in the DA group. Renal IGF-binding protein 1 mRNA levels were increased in the D group but returned to almost normal levels in the DA animals. Kidney IGF-I and GHR mRNA levels were decreased in both the D and DA groups. Renal GH-binding protein mRNA levels remained unchanged in both diabetic groups. GHR antagonism had a blunting effect on renal/glomerular hypertrophy and albuminuria in diabetic NOD mice. These salutary effects were associated with concomitant inhibition of increased renal IGF-I protein levels and were obtained without affecting either somatic growth or circulating GH and IGF-I levels. Therefore, modulation of GH effects may have beneficial therapeutic implications in diabetic nephropathy.
Presidential Health and the Public's Need to Know
Authors: Howard Markel, Alexandra M Stern
Journal: JAMA (2008)

S THE WAR-HERO-TURNED-POLITICIAN CONTEMplatedasecondrunforthepresidency,severalurgent concerns were on his mind. Foremost was his recent diagnosis of a medical condition that could cause sudden death or serious disability. The candidate’s most trusted medical and political advisors persuaded him to avoid divulging such potent information to the public lest it ruin him at the polls. This political scenario is not drawn from the 2008 presidential election currently occupying the minds of many Americans. It occurred 53 years ago, shortly after President Dwight D. Eisenhower’s 1955 myocardial infarction and before he announced his ultimately successful candidacy for reelection. At the time, the details of that near fatal event, as well as Eisenhower’s 1956 intestinal obstruction and a mild stroke with transient motor aphasia in 1957, were shrouded in secrecy. Throughout his second term, Eisenhower’s delicate health was a constant preoccupation. 1 The failure of presidents or presidential candidates to disclose their health status and histories is hardly a trait of one political party. Throughout US history, public officials often have been hesitant to inform the public about past and present medical conditions for fear of negatively influencing voters and providing their opponents with an opportunity to attack their fitness to lead. 2,3
C-Reactive Protein Elevation in Patients With Atrial Arrhythmias
Authors: Mina K. Chung, David O. Martin, Dennis Sprecher, Oussama Wazni, Anne Kanderian, Cynthia A. Carnes, John A. Bauer, Patrick J. Tchou, Mark J. Niebauer, Andrea Natale, David R. Van Wagoner
Journal: Circulation (2001)

Atrial fibrillation (AF) may persist due to structural changes in the atria that are promoted by inflammation. C-reactive protein (CRP), a marker of systemic inflammation, predicts cardiovascular events and stroke, a common sequela of AF. We hypothesized that CRP is elevated in patients with atrial arrhythmias.Using a case-control study design, CRP in 131 patients with atrial arrhythmias was compared with CRP in 71 control patients. Among arrhythmia patients, 6 had frequent atrial ectopy or tachycardia, 86 had paroxysmal AF, 39 had persistent AF lasting >30 days, and 70 had lone arrhythmias. CRP was higher in arrhythmia than in control patients (median, 0.21 versus 0.096 mg/dL; P<0.001). Arrhythmia patients in AF within 24 hours before sampling had higher CRP than those in sinus rhythm (0.30 versus 0.15 mg/dL; P<0.001). CRP in controls was not different than in patients with atrial ectopy or tachycardia. Lone arrhythmia patients had a CRP of 0.21 mg/dL, which was not significantly lower than arrhythmia patients with structural heart disease (CRP, 0.23 mg/dL) but higher than controls (P=0.002). Persistent AF patients had a higher CRP (0.34 mg/dL) than paroxysmal AF patients (0.18 mg/dL; P=0.008); both groups had higher CRP levels than controls (P</=0.005).CRP is elevated in AF patients. This study is the first to document elevated CRP in non-postoperative arrhythmia patients. These findings are reinforced by stepwise CRP elevation with higher AF burden. Although the cause of elevated CRP levels in AF patients remains unknown, elevated CRP may reflect an inflammatory state that promotes the persistence of AF.
Mitochondrial Uncoupling Proteins in Energy Expenditure
Authors: Leslie P. Kozak, Mary-Ellen Harper
Journal: Annual Review of Nutrition (2000)

Four recently discovered homologues of the brown adipose tissue–specific mitochondrial uncoupling protein (UCP1) vary from 29% to 58% in their similarity to UCP1. Although these homologues share important structural features with UCP1 and like UCP1 can reduce the mitochondrial membrane potential when expressed in yeast, there is no clear evidence that they can function thermogenically in vivo. On the other hand, evidence continues to accumulate indicating that the up-regulation of Ucp1 reduces excessive adiposity.
Restenosis after carotid artery stenting and endarterectomy: a secondary analysis of CREST, a randomised controlled trial
Authors: Brajesh K Lal, Kirk W Beach, Gary S Roubin, Helmi L Lutsep, Wesley S Moore, Mahmoud B Malas, David Chiu, Nicole R Gonzales, J Lee Burke, Michael Rinaldi, James R Elmore, Fred A Weaver, Craig R Narins, Malcolm Foster, Kim J Hodgson, Alexander D Shepard, James F Meschia, Robert O Bergelin, Jenifer H Voeks, George Howard, Thomas G Brott
Journal: The Lancet Neurology (2012)

BackgroundIn the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), the composite primary endpoint of stroke, myocardial infarction, or death during the periprocedural period or ipsilateral stroke thereafter did not differ between carotid artery stenting and carotid endarterectomy for symptomatic or asymptomatic carotid stenosis. A secondary aim of this randomised trial was to compare the composite endpoint of restenosis or occlusion.MethodsPatients with stenosis of the carotid artery who were asymptomatic or had had a transient ischaemic attack, amaurosis fugax, or a minor stroke were eligible for CREST and were enrolled at 117 clinical centres in the USA and Canada between Dec 21, 2000, and July 18, 2008. In this secondary analysis, the main endpoint was a composite of restenosis or occlusion at 2 years. Restenosis and occlusion were assessed by duplex ultrasonography at 1, 6, 12, 24, and 48 months and were defined as a reduction in diameter of the target artery of at least 70%, diagnosed by a peak systolic velocity of at least 3·0 m/s. Studies were done in CREST-certified laboratories and interpreted at the Ultrasound Core Laboratory (University of Washington). The frequency of restenosis was calculated by Kaplan-Meier survival estimates and was compared during a 2-year follow-up period. We used proportional hazards models to assess the association between baseline characteristics and risk of restenosis. Analyses were per protocol. CREST is registered with ClinicalTrials.gov, number NCT00004732.Findings2191 patients received their assigned treatment within 30 days of randomisation and had eligible ultrasonography (1086 who had carotid artery stenting, 1105 who had carotid endarterectomy). In 2 years, 58 patients who underwent carotid artery stenting (Kaplan-Meier rate 6·0%) and 62 who had carotid endarterectomy (6·3%) had restenosis or occlusion (hazard ratio [HR] 0·90, 95% CI 0·63–1·29; p=0·58). Female sex (1·79, 1·25–2·56), diabetes (2·31, 1·61–3·31), and dyslipidaemia (2·07, 1·01–4·26) were independent predictors of restenosis or occlusion after the two procedures. Smoking predicted an increased rate of restenosis after carotid endarterectomy (2·26, 1·34–3·77) but not after carotid artery stenting (0·77, 0·41–1·42).InterpretationRestenosis and occlusion were infrequent and rates were similar up to 2 years after carotid endarterectomy and carotid artery stenting. Subsets of patients could benefit from early and frequent monitoring after revascularisation.FundingNational Institute of Neurological Disorders and Stroke and Abbott Vascular Solutions.
Vitiligo assessment methods - Vitiligo Area Scoring Index and Vitiligo European Task Force assessment
Authors: I. Kohli, J. Veenstra, I. Hamzavi
Journal: British Journal of Dermatology (2015)

Journal Article Vitiligo assessment methods – Vitiligo Area Scoring Index and Vitiligo European Task Force assessment Get access I. Kohli, I. Kohli Multicultural Dermatology Center Department of Dermatology Henry Ford Hospital New Center One 3031 West Grand Blvd Suite 800 Detroit MI 48202 U.S.A Search for other works by this author on: Oxford Academic Google Scholar J. Veenstra, J. Veenstra School of Medicine Wayne State University Detroit MI U.S.A Search for other works by this author on: Oxford Academic Google Scholar I. Hamzavi I. Hamzavi Multicultural Dermatology Center Department of Dermatology Henry Ford Hospital New Center One 3031 West Grand Blvd Suite 800 Detroit MI 48202 U.S.A Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 172, Issue 2, 1 February 2015, Pages 318–319, https://doi.org/10.1111/bjd.13531 Published: 01 February 2015
Hepatitis C virusâinduced up-regulation of protein phosphatase 2A inhibits histone modification and DNA damage repair
Authors: Francois H. T. Duong, Verena Christen, Shanshan Lin, Markus H. Heim
Journal: Hepatology (2009)

The molecular mechanisms underlying hepatocarcinogenesis in chronic viral hepatitis are poorly understood. A potential tumorigenic pathway could involve protein phosphatase 2A (PP2A) and protein arginine methyltransferase 1 (PRMT1), because both enzymes are dysregulated in chronic hepatitis C, and both enzymes have been involved in chromatin remodeling and DNA damage repair. We used cell lines that allow the inducible expression of hepatitis C virus proteins (UHCV57.3) and of the catalytic subunit of PP2A (UPP2A-C8) as well as Huh7.5 cells infected with recombinant cell culture–derived hepatitis C virus (HCVcc) to study epigenetic histone modifications and DNA damage repair. The induction of viral proteins, the overexpression of PP2Ac, or the infection of Huh7.5 cells with HCVcc resulted in an inhibition of histone H4 methylation/acetylation and histone H2AX phosphorylation, in a significantly changed expression of genes important for hepatocarcinogenesis, and inhibited DNA damage repair. Overexpression of PP2Ac in NIH-3T3 cells increased anchorage-independent growth. These changes were partially reversed by the treatment of cells with the methyl-group donor S-adenosyl-L-methionine (SAMe). Conclusion: Hepatitis C virus–induced overexpression of PP2Ac contributes to hepatocarcinogenesis through dysregulation of epigenetic histone modifications. The correction of defective histone modifications by S-adenosyl-L-methionine makes this drug a candidate for chemopreventive therapies in patients with chronic hepatitis C who are at risk for developing hepatocellular carcinoma. (HEPATOLOGY 2010.)