tbuckley/cabot-search huggingface dataset:
Selective Modulation of Nuclear Factor of Activated T-Cell Function in Restenosis by a Potent Bipartite Peptide Inhibitor
Authors: Haixiang Yu, Ilze Bot, Karen Sliedregt, Xingfu Xu, Martine Bot, Sandra H. van Heiningen, Gijs A. van der Marel, Martin R. Bennett, Herman Overkleeft, Theo J.C. van Berkel, Erik A.L. Biessen
Journal: Circulation Research (2011)

Nuclear factor of activated T-cells (NFAT) is importantly implicated in pathological cardiac remodeling and vascular lesion formation. NFAT functionality is mainly regulated by calcineurin, a Ca(2+)-dependent multi-effector phosphatase. Calcineurin inhibitors such as cyclosporine A (CsA) were shown to be effective in the treatment of restenosis and vascular inflammation but with adverse side effects.This prompted the design of more selective inhibitors such as VIVIT and inhibitors of NFAT-calcineurin association, which unfortunately have a poor potency precluding clinical use.Here, we describe the rational design of a potent bipartite inhibitor of NFAT-calcineurin interaction, MCV1, which targets two separate calcineurin docking motifs. Modeling, site-directed mutagenesis, and functional studies demonstrated that MCV1 acts by allosteric modulation of calcineurin. Comparable to CsA, MCV1 prevents NFAT activation at nanomolar potency without impairing calcineurin phosphatase activity, nuclear factor-κB nuclear import, and general cell signaling. In contrast, CsA but not MCV1-activated basal level extracellular signal-regulated kinases activity and prevented nuclear import of calcineurin, independent of NFAT activation. In vivo MCV1 abrogated NFAT-mediated T-cell activation in a model of PMA-elicited peritonitis, whereas topical application of MCV1 markedly reduced neointima formation in a mouse model of restenosis.We designed a bipartite NFAT inhibitor that is more potent than VIVIT and more selective than CsA. MCV1 constitutes not only a powerful tool to unravel NFAT function but also a potential drug candidate for the treatment of diseases implicating NFAT activation.
Hearing Others’ Perspectives When We Hear, “Do Everything!”
Authors: Kirstin Hirni, Brian Carter
Journal: JAMA Pediatrics (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Essential Role of Smad3 in Infarct Healing and in the Pathogenesis of Cardiac Remodeling
Authors: Marcin Bujak, Guofeng Ren, Hyuk Jung Kweon, Marcin Dobaczewski, Anilkumar Reddy, George Taffet, Xiao-Fan Wang, Nikolaos G. Frangogiannis
Journal: Circulation (2007)

Postinfarction cardiac repair is regulated through timely activation and repression of inflammatory pathways, followed by transition to fibrous tissue deposition and formation of a scar. The transforming growth factor-beta/Smad3 pathway is activated in healing infarcts and may regulate cellular events critical for the inflammatory and the fibrotic responses.We examined the effects of Smad3 gene disruption on infarct healing and the pathogenesis of cardiac remodeling. In the absence of injury, Smad3-null hearts had comparable function to and similar morphology as wild-type hearts. Smad3-null animals had suppressed peak chemokine expression and decreased neutrophil recruitment in the infarcted myocardium but showed timely repression of inflammatory gene synthesis and resolution of the inflammatory infiltrate. Although myofibroblast density was higher in Smad3-null infarcts, interstitial deposition of collagen and tenascin-C in the remodeling myocardium was markedly reduced. Compared with wild-type animals, Smad3-/- mice exhibited decreased dilative remodeling and attenuated diastolic dysfunction; however, infarct size was comparable between groups. Transforming growth factor-beta-mediated induction of procollagen type III and tenascin-C in isolated cardiac fibroblasts was dependent on Smad3, which suggests that decreased fibrotic remodeling in infarcted Smad3-null hearts may be due to abrogation of the profibrotic transforming growth factor-beta responses.Smad3 loss does not alter the time course of resolution of inflammation in healing infarcts, but it prevents interstitial fibrosis in the noninfarcted myocardium and attenuates cardiac remodeling. Thus, the Smad3 cascade may be a promising therapeutic target for the treatment of myocardial infarction.
Tumour necrosis factor alpha-driven IL-32 expression in rheumatoid arthritis synovial tissue amplifies an inflammatory cascade
Authors: Bas Heinhuis, Marije I Koenders, Piet L van Riel, Fons A van de Loo, Charles A Dinarello, Mihai G Netea, Wim B van den Berg, Leo A B Joosten
Journal: Annals of the Rheumatic Diseases (2010)

Objective To investigate the interplay between IL-32 and tumour necrosis factor alpha (TNFα) during the chronic inflammation of rheumatoid arthritis (RA) and to assess whether anti-TNFα treatment of RA patients modulates synovial IL-32 expression. Methods Induction of IL-32γ by Pam3Cys, lipopolysaccharide, IL-1β or TNFα was investigated in human fibroblast-like synoviocytes (FLS). Stimulation of TNFα production by IL-32γ was studied by adenoviral overexpression of IL-32γ (AdIL-32γ) and lipopolysaccharide stimulation of THP1 cells. Silencing of endogenous IL-32 was employed to study cytokine regulation in FLS. AdIL-32γ followed by TNFα stimulation was performed in FLS to investigate cytokine induction. Immunohistochemistry was applied to study IL-32 expression in synovial biopsies from RA patients. Results TNFα potently induced IL-32γ expression in FLS. Increased TNFα, IL-1β, IL-6 and CXCL8 production was observed after IL-32γ overexpression and lipopolysaccharide stimulation of THP1 cells. TNFα stimulation of FLS after silencing IL-32γ resulted in diminished IL-6 and CXCL8 production, whereas IL-32γ overexpression resulted in enhanced IL-6 and CXCL8 levels. Remarkably, the mechanism through which IL-32γ overexpression induced TNFα, IL-1β and CXCL8 was by counteracting messenger RNA decay. Importantly, treatment of RA patients with anti-TNFα resulted in significant reduction of IL-32 protein in synovial tissue. Conclusions TNFα is a potent inducer of endogenous IL-32 expression and IL-32 itself contributes to prolonged TNFα production, thus inducing an important auto-inflammatory loop. Treatment of RA patients with anti-TNFα antibodies diminished IL-32 expression in synovial tissue. The potent anti-inflammatory effect of TNFα blockade in RA patients may be partly due to the reduction of synovial IL-32 expression.
Prognostic Significance of the Long Pentraxin PTX3 in Acute Myocardial Infarction
Authors: Roberto Latini, Aldo P. Maggioni, Giuseppe Peri, Lucio Gonzini, Donata Lucci, Paolo Mocarelli, Luca Vago, Fabio Pasqualini, Stefano Signorini, Dario Soldateschi, Lorenzo Tarli, Carlo Schweiger, Claudio Fresco, Rossana Cecere, Gianni Tognoni, Alberto Mantovani
Journal: Circulation (2004)

Background— Inflammation has a pathogenetic role in acute myocardial infarction (MI). Pentraxin-3 (PTX3), a long pentraxin produced in response to inflammatory stimuli and highly expressed in the heart, was shown to peak in plasma ≈7 hours after MI. The aim of this study was to assess the prognostic value of PTX3 in MI compared with the best-known and clinically relevant biological markers. Methods and Results— In 724 patients with MI and ST elevation, PTX3, C-reactive protein (CRP), creatine kinase (CK), troponin T (TnT), and N-terminal pro-brain natriuretic peptide (NT-proBNP) were assayed at entry, a median of 3 hours, and the following morning, a median of 22 hours from symptom onset. With respect to outcome events occurring over 3 months after the index event, median PTX3 values were 7.08 ng/mL in event-free patients, 16.12 ng/mL in patients who died, 9.12 ng/mL in patients with nonfatal heart failure, and 6.88 ng/mL in patients with nonfatal residual ischemia (overall P &lt;0.0001). Multivariate analysis including CRP, CK, TnT, and NT-proBNP showed that only age ≥70 years (OR, 2.11; 95% CI, 1.04 to 4.31), Killip class &gt;1 at entry (OR, 2.20; 95% CI, 1.14 to 4.25), and PTX3 (&gt;10.73 ng/mL) (OR, 3.55; 95% CI, 1.43 to 8.83) independently predicted 3-month mortality. Biomarkers predicting the combined end point of death and heart failure in survivors were the highest tertile of PTX3 and of NT-proBNP and a CK ratio &gt;6. Conclusions— In a representative contemporary sample of patients with MI with ST elevation, the acute-phase protein PTX3 but not the liver-derived short pentraxin CRP or other cardiac biomarkers (NT-proBNP, TnT, CK) predicted 3-month mortality after adjustment for major risk factors and other acute-phase prognostic markers.
Chronic Kidney Disease and Cardiovascular Risk
Authors: M. F. O'Rourke
Journal: JAMA (2005)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Activation of Distinct cAMP-Dependent and cGMP-Dependent Pathways by Nitric Oxide in Cardiac Myocytes
Authors: Martin G. Vila-Petroff, Antoine Younes, Josephine Egan, Edward G. Lakatta, Steven J. Sollott
Journal: Circulation Research (1999)

Nitric oxide (NO) donors were recently shown to produce biphasic contractile effects in cardiac tissue, with augmentation at low NO levels and depression at high NO levels. We examined the subcellular mechanisms involved in the opposing effects of NO on cardiac contraction and investigated whether NO modulates contraction exclusively via guanylyl cyclase (GC) activation or whether some contribution occurs via cGMP/PKG-independent mechanisms, in indo 1-loaded adult cardiac myocytes. Whereas a high concentration of the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 100 micromol/L) significantly attenuated contraction amplitude by 24.4+/-4.5% (without changing the Ca2+ transient or total cAMP), a low concentration of SNAP (1 micromol/L) significantly increased contraction amplitude (38+/-10%), Ca2+ transient (26+/-10%), and cAMP levels (from 6.2 to 8.5 pmol/mg of protein). The negative contractile response of 100 micromol/L SNAP was completely abolished in the presence of the specific blocker of PKG KT 5823 (1 micromol/L); the positive contractile response of 1 micromol/L SNAP persisted, despite the presence of the selective inhibitor of GC 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 micromol/L) alone, but was completely abolished in the presence of ODQ plus the specific inhibitory cAMP analog Rp-8-CPT-cAMPS (100 micromol/L), as well as by the NO scavenger oxyhemoglobin. Parallel experiments in cell suspensions showed significant increases in adenylyl cyclase (AC) activity at low concentrations (0.1 to 1 micromol/L) of SNAP (AC, 18% to 20% above basal activity). We conclude that NO can regulate both AC and GC in cardiac myocytes. High levels of NO induce large increases in cGMP and a negative inotropic effect mediated by a PKG-dependent reduction in myofilament responsiveness to Ca2+. Low levels of NO increase cAMP, at least in part, by a novel cGMP-independent activation of AC and induce a positive contractile response.
HbA1c in Early Diabetic Pregnancy and Pregnancy Outcomes
Authors: Gunnar L. Nielsen, Margrethe Møller, Henrik T. Sørensen
Journal: Diabetes Care (2006)

To assess the association between first-trimester HbA(1c) (A1C) and the risk of adverse pregnancy outcomes in type 1 diabetic pregnancies.We identified all pregnant diabetic women in a Danish county from 1985 to 2003. A1C values from first trimester were collected, and pregnancy outcome was dichotomized as good (i.e., babies surviving the 1st month of life without major congenital abnormalities) and adverse (i.e., spontaneous and therapeutic abortion, stillbirth, neonatal death, or major congenital abnormalities detected within the 1st month). The prevalence of adverse outcomes was calculated according to quintiles of A1C. We computed receiver operating characteristic and lowess curve estimates and fitted logistic regression models to calculate prevalence odds ratio while adjusting for confounding by White class and smoking status.Of 573 pregnancies, 165 (29%) terminated with adverse outcomes. The prevalence of adverse outcomes varied sixfold from 12% (95% CI 7.2-17) in the lowest to 79% (60-91) in the highest quintile of A1C exposure. From A1C levels >7%, we found an almost linear association between A1C and risk of adverse outcome, whereby a 1% increase in A1C corresponded to 5.5% (3.8-7.3) increased risk of adverse outcome.Starting from a first-trimester A1C level slightly <7%, there is a dose-dependent association between A1C and the risk of adverse pregnancy outcome without indication of a plateau, below which the association no longer exits. A1C, however, seems to be of limited value in predicting outcome in the individual pregnancy.
Purification to homogeneity of B cell stimulating factor. A molecule that stimulates proliferation of multiple lymphokine-dependent cell lines.
Authors: K Grabstein, J Eisenman, D Mochizuki, K Shanebeck, P Conlon, T Hopp, C March, S Gillis
Journal: The Journal of Experimental Medicine (1986)

Murine B cell stimulating factor 1 (BSF-1) was purified to homogeneity from supernatants of a stimulated thymoma cell line. A protein of 18.4 kD with a unique N-terminal amino acid sequence was identified. BSF-1 had a sp act of at least 3.28 X 10(8) U/mg. In addition to its B cell-stimulatory activity, BSF-1 also stimulated the proliferation of several IL-2- and IL-3-dependent cell lines. We conclude that BSF-1 is both a growth factor and a differentiation factor. Finally, these results also suggest additional biologic properties of BSF-1 on lineages besides B lymphocytes.
Direct evidence for calcium conductance of hyperpolarization-activated cyclic nucleotide-gated channels and human native If at physiological calcium concentrations
Authors: G. Michels, M. C. Brandt, N. Zagidullin, I. F. Khan, R. Larbig, S. van Aaken, J. Wippermann, U. C. Hoppe
Journal: Cardiovascular Research (2008)

The hyperpolarization-activated cyclic nucleotide-gated (HCN) current I(f)/I(HCN) is generally thought to be carried by Na(+) and K(+) under physiological conditions. Recently, Ca(2+) influx through HCN channels has indirectly been postulated. However, direct functional evidence of Ca(2+) permeation through I(f)/I(HCN) is still lacking.To possibly provide direct evidence of Ca(2+) influx through I(HCN)/I(f), we performed inside-out and cell-attached single-channel recordings of heterologously expressed HCN channels and native rat and human I(f), since Ca(2+)-mediated I(f)/I(HCN) currents may not readily be recorded using the whole-cell technique. Original current traces demonstrated HCN2 Ca(2+) inward currents upon hyperpolarization with a single-channel amplitude of -0.87+/-0.06 pA, a low open probability of 3.02+/-0.48% (at -110 mV, n=6, Ca(2+) 2 mmol/L), and a Ca(2+) conductance of 8.9+/-1.2 pS. I(HCN2-Ca2+) was significantly activated by the addition of cAMP with an increase in the open probability and suppressed by the specific I(f) inhibitor ivabradine, clearly confirming that Ca(2+) influx indeed was conducted by HCN2 channels. Changing [Na(+)] (10 vs. 100 mmol/L) in the presence or absence of 2 mmol/L Ca(2+) caused a simple shift of the reversal potential along the voltage axis without significantly affecting Na(+)/Ca(2+) conductance, whereas the K(+) conductance of HCN2 increased significantly in the absence of external Ca(2+) with increasing K(+) concentrations. The mixed K(+)-Ca(2+) conductance, however, was unaffected by the external K(+) concentration. Notably, we could also record hyperpolarization-activated Ca(2+) permeation of single native I(f) channels in neonatal rat ventriculocytes and human atrial myocytes in the presence of blockers for all known cardiac calcium conduction pores (Ca(2+) conductance of human I(f), 9.19+/-0.34 pS; amplitude, -0.81+/-0.01 pA; open probability, 1.05+/-0.61% at -90 mV).We directly show Ca(2+) permeability of native rat and, more importantly, human I(f) at physiological extracellular Ca(2+) concentrations at the physiological resting membrane potential. This might have particular implications in diseased states with increased I(f) density and HCN expression.
Endogenous human cytomegalovirus gB is presented efficiently by MHC class II molecules to CD4<b>+</b> CTL
Authors: Nagendra R. Hegde, Claire Dunn, David M. Lewinsohn, Michael A. Jarvis, Jay A. Nelson, David C. Johnson
Journal: The Journal of Experimental Medicine (2005)

Human cytomegalovirus (HCMV) infects endothelial, epithelial, and glial cells in vivo. These cells can express MHC class II proteins, but are unlikely to play important roles in priming host immunity. Instead, it seems that class II presentation of endogenous HCMV antigens in these cells allows recognition of virus infection. We characterized class II presentation of HCMV glycoprotein B (gB), a membrane protein that accumulates extensively in endosomes during virus assembly. Human CD4+ T cells specific for gB were both highly abundant in blood and cytolytic in vivo. gB-specific CD4+ T cell clones recognized gB that was expressed in glial, endothelial, and epithelial cells, but not exogenous gB that was fed to these cells. Glial cells efficiently presented extremely low levels of endogenous gB--expressed by adenovirus vectors or after HCMV infection--and stimulated CD4+ T cells better than DCs that were incubated with exogenous gB. Presentation of endogenous gB required sorting of gB to endosomal compartments and processing by acidic proteases. Although presentation of cellular proteins that traffic into endosomes is well known, our observations demonstrate for the first time that a viral protein sorted to endosomes is presented exceptionally well, and can promote CD4+ T cell recognition and killing of biologically important host cells.
Grading of distal colorectal adenomas as predictors for proximal colonic neoplasia and choice of endoscope in population screening: experience from the Norwegian Colorectal Cancer Prevention study (NORCCAP)
Authors: G Gondal
Journal: Gut (2003)

<b>Background and aims:</b> The purpose of this study was to evaluate the utility of easily measured clinical variables at flexible sigmoidoscopy (FS) screening that might predict a proximal advanced neoplasm (PAN). <b>Methods:</b> We studied 1833 subjects with biopsy verified adenomas at FS who subsequently underwent full colonoscopy. <b>Results:</b> A total of 387 (21%) subjects had proximal colonic neoplasms (PCN) and 85 (5%) had PAN. In univariate comparison, the risk of PAN increased more than threefold in the presence of a distal adenoma measuring either ≥10 mm in diameter or containing villous components. Multiplicity of distal adenomas, severe dysplasia, or age ≥60 years increased the risk of PAN more than twofold. In the multivariate model, the presence of a distal adenoma ≥10 mm, villousness, and multiplicity maintained their significance as predictive variables for increased risk of proximal neoplasms, whereas sex and severe dysplasia lost their significance. By recommending colonoscopy only to individuals with multiple (&gt;1) adenomas or any high risk adenoma at FS, we would have reduced the number of colonoscopies by 1209 (66%) but would have missed 32 (38%) participants with PAN and 217 (56%) with PCN. By using a 60 cm endoscope instead of an ordinary colonoscope at FS, nine (2%) participants with advanced neoplasms, including three patients with cancer, would have been missed. <b>Conclusion:</b> The present study supports the concept of defining "any adenoma" as a positive FS, qualifying for colonoscopy. We recommend the use of an ordinary colonoscope instead of a 60 cm sigmoidoscope for FS screening examinations.
Increased Mortality Associated With the Metabolic Syndrome in Older Women With Diabetes
Authors: Teresa A. Hillier, Joanne H. Rizzo, Kathryn L. Pedula, Jane A. Cauley, Ann V. Schwartz, Kristine E. Ensrud, Warren S. Browner
Journal: Diabetes Care (2005)

About 25% of U.S. adults have the metabolic syndrome (1), a cluster of central obesity; abnormal glucose, insulin, and lipids; and hypertension. Clinicians and the media have increasingly emphasized its diagnosis and treatment (2,3). Several recent prospective studies associate increased cardiovascular disease (CVD) or total mortality risk with the metabolic syndrome in men and younger adults (4–10). Over 90% of CVD mortality in women occurs after 65 years of age (11), and women with diabetes lose sex-protective effects; their CVD relative risk is even greater than men with diabetes (12). Whether the metabolic syndrome increases mortality risk in addition to diabetes is unclear. We prospectively evaluated the syndrome’s association with CVD mortality in older women and whether its risk is greater than diabetes alone.

From 1986 to 1988, the Study of Osteoporotic Fractures (SOF) recruited 9,704 community-dwelling women, ≥65 years of age (>99% Non-Hispanic White) in four U.S. regions: Baltimore County, Maryland; Minneapolis, Minnesota; Portland, Oregon; and the Monongahela Valley near Pittsburgh, Pennsylvania (13). Women unable to walk without assistance and those with bilateral hip replacements were excluded. All participants provided written consent, and SOF was approved by each site’s institutional review board.

Waist and hip circumference were measured by standardized protocol (14) to the nearest 0.10 cm with steel tape. Weight was measured by balance beam, height by stadiometer. Blood pressure was measured supine and after standing 1 min; the average …