tbuckley/cabot-search huggingface dataset:
Thrombomodulin Prolongs Thrombin-Induced Extracellular Signal–Regulated Kinase Phosphorylation and Nuclear Retention in Endothelial Cells
Authors: Jean-Marc Olivot, Eva Estebanell, Monique Lafay, Brigitte Brohard, Martine Aiach, Francine Rendu
Journal: Circulation Research (2001)

Abstract —On endothelial cells, thrombin binds to thrombomodulin (TM), an integral membrane-bound glycoprotein, and to protease-activated receptors (PARs). Thrombin binding to TM modulates endothelial cell and smooth muscle cell proliferation mediated through PAR1. We studied the phosphorylation and nuclear translocation of extracellular signal–regulated kinases (ERKs) 1 and 2 in human umbilical vein endothelial cells activated by thrombin. Thrombin and thrombin receptor–activating peptide (TRAP)-induced DNA synthesis were significantly inhibited by PD98059, an inhibitor of ERK phosphorylation. Immunoblots of phosphorylated ERKs (pERKs) and immunocytochemical studies of pERK localization revealed differences in the signal generated by thrombin and TRAP. After a short activation (15 minutes), the phosphorylation and the intracellular localization of pERKs were the same with the 2 agonists. After 4 hours, however, pERKs were visualized in the nuclei of thrombin-activated cells but barely detectable in TRAP-activated cells. Moreover, after 4 hours, the pERKs were visualized in the nuclei of cells stimulated by TRAP in the presence of a thrombin mutant that bound to TM, whereas they were around the nuclei in cells stimulated by thrombin in the presence of a monoclonal antibody preventing thrombin binding to TM. The results demonstrate that ERKs are involved in human umbilical vein endothelial cell DNA synthesis mediated by PAR agonists, that the duration of pERK nuclear retention is in inverse ratio to the mitogenic response, and that in addition to its role in the regulation of blood coagulation, TM acts as a thrombin receptor that modulates the duration of pERK nuclear retention and cell proliferation in response to thrombin.
Risk of Perforation After Colonoscopy and Sigmoidoscopy: A Population-Based Study
Authors: Nicolle M Gatto, Harold Frucht, Vijaya Sundararajan, Judith S Jacobson, Victor R Grann, Alfred I Neugut
Journal: JNCI Journal of the National Cancer Institute (2003)

Although the risk of bowel perforation is often cited as a major factor in the choice between colonoscopy and sigmoidoscopy for colorectal screening, good estimates of the absolute and relative risks of perforation are lacking.We used a large population-based cohort that consisted of a random sample of 5% of Medicare beneficiaries living in regions of the United States covered by the Surveillance, Epidemiology, and End Results (SEER) Program registries to determine rates of perforation in people aged 65 years and older. We identified individuals who were cancer-free and had undergone colonoscopy or sigmoidoscopy between 1991 and 1998, calculated both the incidence and risk of perforation within 7 days of the procedure, and explored the impact on incidence and risk of perforation of age, race/ethnicity, sex, comorbidities, and indication for the procedure. We also estimated the risk of death after perforation. Risks were calculated with odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided.There were 77 perforations after 39 286 colonoscopies (incidence = 1.96/1000 procedures) and 31 perforations after 35 298 sigmoidoscopies (incidence = 0.88/1000 procedures). After adjustment, the OR for perforation from colonoscopy relative to perforation from sigmoidoscopy was 1.8 (95% CI = 1.2 to 2.8). Risk of perforation from either procedure increased in association with increasing age (P(trend)<.001 for both procedures) and the presence of two or more comorbidities (P(trend)<.001 for colonoscopy and P(trend) =.03 for sigmoidoscopy). Compared with those who were endoscopied and did not have a perforation, the risk of death was statistically significantly increased for those who had a perforation after either colonoscopy (OR = 9.0, 95% CI = 3.0 to 27.3) or sigmoidoscopy (OR = 8.8, 95% CI = 1.6 to 48.5). The risk of perforation after colonoscopy, especially for screening procedures, declined during the 8-year study period.The risk of perforation after colonoscopy is approximately double that after sigmoidoscopy, but this difference appears to be decreasing. These observations should be useful to clinicians making screening and diagnostic decisions for individual patients and to policy officials setting guidelines for colorectal cancer screening programs.
Combined blockade of granulocyte-macrophage colony stimulating factor and interleukin 17 pathways potently suppresses chronic destructive arthritis in a tumour necrosis factor α-independent mouse model
Authors: C Plater-Zyberk, L A B Joosten, M M A Helsen, M I Koenders, P A Baeuerle, W B van den Berg
Journal: Annals of the Rheumatic Diseases (2008)

A pathogenic role for granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)17 in rheumatoid arthritis (RA) has been suggested. In previously published work, the therapeutic potentials of GM-CSF and IL17 blockade in arthritis have been described. In the present study, the simultaneous blockade of both pathways in a mouse model for chronic arthritis was investigated to identify whether this double blockade provides a superior therapeutic efficacy.A chronic relapsing arthritis was induced in C57Bl/6 wild type (WT) and C57Bl/6 genetically deficient for IL17 receptor (IL17R knockout (KO)) mice by intra-articular injection of Streptococcal cell wall (SCW) fragments into knees on days 0, 7, 14 and 21. Treatments (intraperitoneal) were given weekly starting on day 14. Animals were analysed for inflammation, joint damage and a range of inflammatory mediators.Joint swelling and cartilage damage were significantly reduced in the IL17R KO mice and in WT mice receiving anti-GM-CSF neutralising mAb 22E9 compared to isotype control antibodies. The therapeutic effect was significantly more pronounced in mice where IL17 and GM-CSF pathways were inhibited (eg, IL17R KO mice treated with 22E9 mAb). Tumour necrosis factor (TNF)alpha blockade had essentially no effect.Our data further support the therapeutic potentials of GM-CSF and IL17 blockade in a RA model that is no longer responsive to an established TNFalpha antagonist, moreover, our results suggest that concomitant inhibition of both pathways may provide the basis for a highly effective treatment of chronic RA in patients that are resistant to treatment by TNFalpha inhibitors.
Depletion of luminal iron alters the gut microbiota and prevents Crohn's disease-like ileitis
Authors: T. Werner, S. J. Wagner, I. Martinez, J. Walter, J.-S. Chang, T. Clavel, S. Kisling, K. Schuemann, D. Haller
Journal: Gut (2010)

<h3>Background</h3> Iron replacement therapy is a common treatment in patients with anaemia and Crohn9s disease, but oral iron supplements are less tolerated. The pathogenesis of Crohn9s disease is attributed to intestinal bacteria and environmental factors that trigger disease in a genetically predisposed host. The aim of this study was to characterise the interrelationship between luminal iron sulfate, systemic iron, the gut microbiota and the development of chronic ileitis in a murine model of Crohn9s disease. <h3>Methods</h3> Wild type (WT) and heterozygous TNF<sup>ΔARE/WT</sup> mice were fed with an iron sulfate containing or iron sulfate free diet in combination with intraperitoneal control injections or iron injections for 11 weeks. <h3>Results</h3> TNF<sup>ΔARE/WT</sup> mice develop severe inflammation of the distal ileum but remained completely healthy when transferred to an iron sulfate free diet, even if iron was systemically repleted. Absence of luminal iron sulfate reduced cellular markers of endoplasmic reticulum (ER) stress responses and pro-apoptotic mechanisms in the ileal epithelium. Phenotype or reactivity of major effector intraepithelial CD8αβ<sup>+</sup> T cells were not altered in the absence of luminal iron. Interestingly, ER stress mechanisms sensitised the small intestinal epithelial cell (IEC) line Mode-K to cytotoxic function of effector T cells from TNF<sup>∆ARE/WT</sup> mice. Pyrosequencing of 16S rRNA tags of the caecal microbiota revealed that depletion of luminal iron sulfate induced significant compositional alterations, while total microbial diversity (Shannon9s diversity index) and number of total operational taxonomic units were not affected. <h3>Conclusion</h3> This study showed that an iron sulfate free diet in combination with systemic iron repletion prevents the development of chronic ileitis in a murine model of Crohn9s disease. Luminal iron may directly affect IEC function or generate a pathological milieu in the intestine that triggers epithelial cell stress-associated apoptosis through changes in microbial homeostasis. These results suggest that oral replacement therapy with iron sulfate may trigger inflammatory processes associated with progression of Crohn9s disease-like ileitis.
ApoE mimetic peptide decreases Aβ production in vitro and in vivo
Authors: S Sakura Minami, Antoinette Cordova, John R Cirrito, Joseph A Tesoriero, Lenard W Babus, Gary C Davis, Sivanesan Dakshanamurthy, R Scott Turner, Daniel TS Pak, G William Rebeck, Mikell Paige, Hyang-Sook Hoe
Journal: Molecular Neurodegeneration (2010)

Apolipoprotein E (apoE) is postulated to affect brain Abeta levels through multiple mechanisms--by altering amyloid precursor protein (APP) processing, Abeta degradation, and Abeta clearance. We previously showed that an apoE-derived peptide containing a double repeat of the receptor-binding region was similarly effective in increasing APP processing in vivo. Here, we further examined whether peptides containing tandem repeats of the apoE receptor-binding region (amino acids 141-149) affected APP trafficking, APP processing, and Abeta production.We found that peptides containing a double or triple tandem repeat of the apoE receptor-binding region, LRKLRKRLL, increased cell surface APP and decreased Abeta levels in PS1-overexpressing PS70 cells and in primary neurons. This effect was potentiated by a sequential increase in the number of apoE receptor-binding domain repeats (trimer > dimer > monomer). We previously showed that the apoE dimer increased APP CTF in vivo; to determine whether the dimer also affected secreted APP or Abeta levels, we performed a single hippocampal injection of the apoE dimer in wild-type mice and analyzed its effect on APP processing. We found increased sAPPalpha and decreased Abeta levels at 24 hrs after treatment, suggesting that the apoE dimer may increase alpha-secretase cleavage.These data suggest that small peptides consisting of tandem repeats of the apoE receptor-binding region are sufficient to alter APP trafficking and processing. The potency of these peptides increased with increasing repeats of the receptor binding domain of apoE. In addition, in vivo administration of the apoE peptide (dimer) increased sAPPalpha and decreased Abeta levels in wild-type mice. Overall, these findings contribute to our understanding of the effects of apoE on APP processing and Abeta production both in vitro and in vivo.
Papillary muscle dysfunction attenuates ischemic mitral regurgitation in patients with localized basal inferior left ventricular remodeling
Authors: Takeshi Uemura, Yutaka Otsuji, Toshiro Kumanohoso, Kunitsugu Takasaki, Toshinori Yuasa, Woo-Shik Kim, Akira Kisanuki, Shinichi Minagoe, Robert A. Levine, Chuwa Tei
Journal: Journal of the American College of Cardiology (2003)
Primary chemotherapy in the treatment of inflammatory breast carcinoma: a study of 230 cases from the Institut Gustave-Roussy.
Authors: J Rouëssé, S Friedman, D Sarrazin, H Mouriesse, T Le Chevalier, R Arriagada, M Spielmann, A Papacharalambous, F May-Levin
Journal: Journal of Clinical Oncology (1986)

We report the largest series of induction chemotherapy for inflammatory breast carcinoma (IBC). Results of two chemotherapy protocols with radiation therapy (RT) (170 patients) are compared with results with radiation alone (60 patients) in the treatment of this disease. From 1973 to 1975, 60 patients (control, group C) received RT (45 Gy and 20 to 30 Gy boost) and hormonal manipulation. From 1976 to 1980, 91 patients (group A) were treated with induction chemotherapy: Adriamycin (Adria Laboratories, Columbus, Ohio), vincristine, and methotrexate (AVM) and RT on a cyclical schedule; and maintenance chemotherapy: vincristine, cyclophosphamide, and 5-fluorouracil (5-FU) (VCF). From 1980 to 1982, 79 patients (group B) received induction chemotherapy, Adriamycin, vincristine, cyclophosphamide, methotrexate, and 5-FU (AVCMF) and RT on a cyclical schedule and VCF maintenance. Hormonal manipulation was performed in all groups. Disease-free survival at 4 years was 15% for group C, 32% for group A, and 54% for group B (P less than .005 group C v group A, less than .00001 group C v group B, and less than .01 group A v group B). Total survival at 4 years was 42% for group C, 53% for group A, and 74% for group B (P = .17 group C v group A, less than .00001 group C v group B, and less than .001 group A v group B). Clinical assessment of tumor aggressiveness, nodal status, type of chemotherapy administered, and early response to chemotherapy (by third course) were all prognostic factors. There is an important, highly statistically significant benefit in terms of both disease-free survival and total survival observed in patients treated with the addition of chemotherapy compared with radiation alone in IBC.
Enhanced G <sub>i</sub> Signaling Selectively Negates β <sub>2</sub> -Adrenergic Receptor (AR)– but Not β <sub>1</sub> -AR–Mediated Positive Inotropic Effect in Myocytes From Failing Rat Hearts
Authors: Rui-Ping Xiao, Sheng-Jun Zhang, Khalid Chakir, Pavel Avdonin, Weizhong Zhu, Richard A. Bond, C. William Balke, Edward G. Lakatta, Heping Cheng
Journal: Circulation (2003)

Myocardial contractile response to beta1- and beta2-adrenergic receptor (AR) stimulation is severely impaired in chronic heart failure, in which G(i) signaling and the ratio of beta2/beta1 are often increased. Because beta2-AR but not beta1-AR couples to G(s) and G(i) with the G(i) coupling negating the G(s)-mediated contractile response, we determined whether the heart failure-associated augmentation of G(i) signaling contributes differentially to the defects of these beta-AR subtypes and, if so, whether inhibition of G(i) or selective activation of beta2-AR/G(s) by ligands restores beta2-AR contractile response in the failing heart.Cardiomyocytes were isolated from 18- to 24-month-old failing spontaneously hypertensive (SHR) or age-matched Wistar-Kyoto (WKY) rat hearts. In SHR cardiomyocytes, either beta-AR subtype-mediated inotropic effect was markedly diminished, whereas G(i) proteins and the beta2/beta1 ratio were increased. Disruption of G(i) signaling by pertussis toxin (PTX) enabled beta2- but not beta1-AR to induce a full positive inotropic response in SHR myocytes. Furthermore, screening of a panel of beta2-AR ligands revealed that the contractile response mediated by most beta2-AR agonists, including zinterol, salbutamol, and procaterol, was potentiated by PTX, indicating concurrent G(s) and G(i) activation. In contrast, fenoterol, another beta2-AR agonist, induced a full positive inotropic effect in SHR myocytes even in the absence of PTX.We conclude that enhanced G(i) signaling is selectively involved in the dysfunction of beta2- but not beta1-AR in failing SHR hearts and that disruption of G(i) signaling by PTX or selective activation of beta2-AR/G(s) signaling by fenoterol restores the blunted beta2-AR contractile response in the failing heart.
A novel cause for primordial dwarfism revealed: defective tRNA modification
Authors: Liudmila Filonava, Adrian Gabriel Torres, Lluis Ribas de Pouplana
Journal: Genome biology (2015)

A mutation in the WDR4 gene, coding for a tRNA-modifying enzyme, leads to reduced levels of guanosine methylation in tRNA in patients with primordial dwarfism. See related Research article: http://www.genomebiology.com/2015/16/1/210 .
S100B Interaction With the Receptor for Advanced Glycation End Products (RAGE)
Authors: J.N. Tsoporis, S. Izhar, H. Leong-Poi, J.-F. Desjardins, H.J. Huttunen, T.G. Parker
Journal: Circulation Research (2009)

Rationale : Post–myocardial infarction ventricular remodeling is associated with the expression of a variety of factors including S100B that can potentially modulate myocyte apoptosis. Objective : This study was undertaken to investigate the expression and function of S100B and its receptor, the receptor for advanced glycation end products (RAGE) in both postinfarction myocardium and in a rat neonatal myocyte culture model. Methods and Results : In a rat model of myocardial infarction following coronary artery ligation, we demonstrate in periinfarct myocytes, upregulation of RAGE, induction of S100B, and release into plasma with consequent myocyte apoptosis. Using a coimmunoprecipitation strategy, we demonstrate a direct interaction between S100B and RAGE. In rat neonatal cardiac myocyte cultures, S100B at concentrations ≥50 nmol/L induced myocyte apoptosis, as evidenced by increased terminal DNA fragmentation, TUNEL, cytochrome c release from mitochondria to cytoplasm, phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p53, increased expression and activity of proapoptotic caspase-3, and decreased expression of antiapoptotic Bcl-2. Transfection of a full-length cDNA of RAGE or a dominant-negative mutant of RAGE resulted in increased or attenuated S100B-induced myocyte apoptosis, respectively. Inhibition of ERK1/2 by U0126/PD-98059 or overexpression of a dominant negative p53 comparably inhibited S100B-induced myocyte apoptosis. Conclusions : These results suggest that interaction of RAGE and its ligand S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53 signaling. This receptor-mediated mechanism is uniquely amenable to therapeutic intervention.
V158F polymorphism of FCGR3A gene in the etiopathogenesis of sarcoidosis
Authors: Marlena Typiak, Krzysztof Rebala, Adam Sternau, Maria Dudziak, Jan Marek Slominski, Anna Dubaniewicz
Journal: European Respiratory Journal (2013)

Genetic, infectious factors, as well as autoimmunity are considered in an etiopathogenesis of sarcoidosis (SA). We found a higher concentration of circulating immune complexes (ICs) with mycobacterial heat shock proteins from patients with sarcoidosis. This immunocomplexemia may be caused by a function disorder of receptors for Fc fragment of immunoglobulin G (FcγR), especially FcγRIIIa, encoded by FCGR3A gene because of V158F polymorphism of FCGR3A , which causes decreased affinity of FcγRIIIa to ICs with their following decreased clearance. Thus, we genotyped 77 SA patients and 143 healthy controls using polymerase chain reaction with sequence specific primers. We showed a significantly higher presence of 158F allele and 158FF homozygotes, and lower occurrence of 158FV heterozygotes in Stage I of SA (n=23), in comparison to controls. In contrast, in Stage II of SA (n=54), we revealed an increase in 158VV homozygotes when compared to controls. Additionally, we found a significant increase of 158FF homozygotes in Stage I vs II. We also showed an opposite occurrence of FCGR3A alleles in Stage I and II of SA with an increase of 158F allele in Stage I and 158V in Stage II of sarcoidosis. Hence, V158F polymorphism of FCGR3A gene may cause immunocomplexemia in our SA patients and lead either to development of Stage I (allele 158F and genotype 158FF), or to chronic course of the disease in Stage II (allele 158V and genotype 158VV). Therefore, it may serve as a prognostic biomarker of a clinical course of the disease. Funding: grant 5160/B/P01/2010/39, grant MN-31.
Low Water Intake and Risk for New-Onset Hyperglycemia
Authors: Ronan Roussel, Léopold Fezeu, Nadine Bouby, Beverley Balkau, Olivier Lantieri, François Alhenc-Gelas, Michel Marre, Lise Bankir
Journal: Diabetes Care (2011)

OBJECTIVE Water intake alters vasopressin secretion. Recent findings reveal an independent association between plasma copeptin, a surrogate for vasopressin, and risk of diabetes. RESEARCH DESIGN AND METHODS Participants were 3,615 middle-aged men and women, with normal baseline fasting glycemia (FG), who were recruited in a 9-year follow-up study. Odds ratios (ORs) and 95% CIs for the incidence of hyperglycemia (FG ≥6.1 mmol/L or treatment for diabetes) were calculated according to daily water intake classes based on a self-administered questionnaire. RESULTS During follow-up, there were 565 incident cases of hyperglycemia. After adjustment for confounding factors, ORs (95% CIs) for hyperglycemia associated with classes of water intake (&amp;lt;0.5 L, n = 677; 0.5 to &amp;lt;1.0 L, n = 1,754; and &amp;gt;1.0 L, n = 1,184) were 1.00, 0.68 (0.52–0.89), and 0.79 (0.59–1.05), respectively (P = 0.016). CONCLUSIONS Self-reported water intake was inversely and independently associated with the risk of developing hyperglycemia.
Glucagon-Like Peptide 1 Reduces Endothelial Dysfunction, Inflammation, and Oxidative Stress Induced by Both Hyperglycemia and Hypoglycemia in Type 1 Diabetes
Authors: Antonio Ceriello, Anna Novials, Emilio Ortega, Silvia Canivell, Lucia La Sala, Gemma Pujadas, Katherine Esposito, Dario Giugliano, Stefano Genovese
Journal: Diabetes Care (2013)

Hyperglycemia and hypoglycemia currently are considered risk factors for cardiovascular disease in type 1 diabetes. Both acute hyperglycemia and hypoglycemia induce endothelial dysfunction and inflammation, raising the oxidative stress. Glucagon-like peptide 1 (GLP-1) has antioxidant properties, and evidence suggests that it protects endothelial function.The effect of both acute hyperglycemia and acute hypoglycemia in type 1 diabetes, with or without the simultaneous infusion of GLP-1, on oxidative stress (plasma nitrotyrosine and plasma 8-iso prostaglandin F2alpha), inflammation (soluble intercellular adhesion molecule-1 and interleukin-6), and endothelial dysfunction has been evaluated.Both hyperglycemia and hypoglycemia acutely induced oxidative stress, inflammation, and endothelial dysfunction. GLP-1 significantly counterbalanced these effects.These results suggest a protective effect of GLP-1 during both hypoglycemia and hyperglycemia in type 1 diabetes.