tbuckley/cabot-search huggingface dataset:
Thrombin Regulates Expression of Monocyte Chemoattractant Protein-1 in Vascular Smooth Muscle Cells
Authors: Ulrich O. Wenzel, Bruno Fouqueray, Giuseppe Grandaliano, Yong-Soo Kim, Costantinos Karamitsos, Anthony J. Valente, Hanna E. Abboud
Journal: Circulation Research (1995)

Abstract Thrombin, a serine protease generated at sites of vascular injury, plays a role in the pathogenesis of atherosclerosis and restenosis after angioplasty. Adherence of monocytes to the endothelium and migration into the subendothelial space is an important early event in the pathogenesis of atherosclerosis. Monocyte chemoattractant protein 1 (MCP-1) may be an important mediator of monocyte recruitment to the tissue in this and other diseases. We have characterized the expression of MCP-1 in vascular smooth muscle cells (VSMCs) isolated from human renal artery and studied its regulation by thrombin. Serum-deprived cells release monocyte chemotactic activity that is neutralized (80%) by an MCP-1 antibody. The antibody recognized a 13- and 15-kD protein in smooth muscle cell–conditioned medium. Thrombin stimulates MCP-1 gene expression in a concentration- and time-dependent manner. An increase over basal levels was observed with concentrations of thrombin as low as 0.05 U/mL. The maximal effect occurred at 5 U/mL. The stimulatory effect was detected within 1 hour, reached a maximum at 3 hours, and was still present at 8 to 24 hours after the addition of thrombin. A concentration- and time-dependent effect of thrombin on MCP-1 gene expression was also found in rat VSMCs. The thrombin protease inhibitor hirudin blocked thrombin-induced MCP-1 expression. Thrombin stimulated the release of MCP-1 protein in conditioned medium of human VSMCs as measured by radioimmunoassay and chemotactic assay. Thrombin also increased monocyte chemotactic activity in short-term organ cultures of rat aortic rings and in first passage cells. The effect of thrombin on MCP-1 was mimicked by a thrombin receptor–activating peptide (NH 2 -Ser-Phe-Leu-Leu-Arg-Asn-Pro-COOH). These data describe an important biological activity of thrombin in VSMCs and provide a novel mechanism whereby locally released thrombin may contribute to the pathogenesis of atherosclerosis or restenosis after angioplasty.
P139 Survival of Idiopathic Pulmonary Arterial Hypertension BMPR2 Mutation Carriers Vs BMPR2 Non Carriers
Authors: CM Treacy, D Taboada Buasso, N Doughty, NW Morrell, J Pepke-Zaba
Journal: Thorax (2012)

<h3>Introduction</h3> Idiopathic pulmonary arterial hypertension (IPAH) is a devastating condition charactericed by the narrowing and obliteration of small pulmonary arteries, leading to elevated pulmonary arterial pressure and ultimately to right heart failure and death. Even with treatment, IPAH survival is poor with 3 year survival reported to be 63% on epoprostenol (Mclaughlin, Circulation 2002). Pulmonary arterial hypertension (PAH) can be heritable, with mutations found in the bone morphogenetic protein type 2 receptor (BMPR2) gene found in &gt; 70% of familial cases, (Lane, Nat Genet 2000). There are previous conflicting reports of worse survival in heritable PAH, but this has not previously been determined in the UK patient population. <h3>Methods</h3> This study examined the retrospective database of 76 IPAH cases diagnosed between 2001–2006. 32 patients were screened for BMPR2 mutation. 13 were BMPR2+ve. Non-screened (NS) IPAH were included in the survival analysis (n=44). Survival time was taken from the time of initial diagnostic right heart catherisation. Demographics, treatment, 6MWT, time to transplant and World Health Organization (WHO) classification were compared. Physicians were blinded to the BMPR2 status at time of treatment. <h3>Results</h3> All three cohorts presented at baseline with no significant difference in functional class, 6MWT, hemodynamics except age, cardiac index (CI), right atrial pressure (RAP) and treatment modalities. Patients with BMPR2 mutation were significantly younger. Of the BMPR+ve group, 6 patients were transplanted compared to zero in the BMPR-ve group. The NS IPAH cohort had 2 patients transplanted and fewer patients were treated with prostanoids. Time to transplant was shorter in the BMPR2 mutation carriers, 2.65 years, vs. 3.1years in the NS IPAH group. <h3>Conclusion</h3> Survival for the first 5 years from diagnosis was similar in IPAH and heritable PAH. The BMPR2 +ve patients presented younger with severe disease and were treated more aggressively with 6 patients undergoing transplant in the 5 year period. BMPR2 mutation frequency was 41% from our cohort of 33 which is higher than previously reports of 20–30% (Morrell, Proc Am Thorac Soc, 2006). Survival for IPAH continues to be poor even with improvements in treatment. Patients with BMPR2 mutations present with severe disease earlier and time to lung transplant is shorter.
Influence of Ambient Air Pollutant Sources on Clinical Encounters for Infant Bronchiolitis
Authors: Catherine J. Karr, Paul A. Demers, Mieke W. Koehoorn, Cornel C. Lencar, Lillian Tamburic, Michael Brauer
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: Data regarding the influence of ambient air pollution on infant bronchiolitis are few.Objectives: We evaluated the impact of several air pollutants and their sources on infant bronchiolitis.Methods: Infants in the Georgia Air Basin of British Columbia with an inpatient or outpatient clinical encounter for bronchiolitis (n = 11,675) were matched on day of birth to as many as 10 control subjects. Exposure to particulate matter with a diameter of 2.5 μm or less (PM2.5), PM10, NO2/NO, SO2, CO, and O3 were assessed on the basis of a regional monitoring network. Traffic exposure was assessed using regionally developed land use regression (LUR) models of NO2, NO, PM2.5, and black carbon as well as proximity to highways. Exposure to wood smoke and industrial emissions was also evaluated. Risk estimates were derived using conditional logistic regression and adjusted for infant sex and First Nations (Canadian government term for recognized aboriginal groups) status and for maternal education, age, income-level, parity, smoking during pregnancy, and initiation of breastfeeding.Measurements and Main Results: An interquartile increase in lifetime exposure to NO2, NO, SO2, CO, wood-smoke exposure days, and point source emissions score was associated with increased risk of bronchiolitis (e.g., adjusted odds ratio [ORadj] NO2, 95% confidence interval [CI], 1.12, 1.09–1.16; ORadj wood smoke, 95% CI, 1.08, 1.04–1.11). Infants who lived within 50 meters of a major highway had a 6% higher risk (1.06, 0.97–1.17). No adverse effect of increased exposure to PM10, PM2.5, or black carbon, was observed. Ozone exposure was negatively correlated with the other pollutants and negatively associated with the risk of bronchiolitis.Conclusions: Air pollutants from several sources may increase infant bronchiolitis requiring clinical care. Traffic, local point source emissions, and wood smoke may contribute to this disease.
Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring
Authors: Ryoichi Mori, Tanya J. Shaw, Paul Martin
Journal: The Journal of Experimental Medicine (2008)

Previous studies of tissue repair have revealed osteopontin (OPN) to be up-regulated in association with the wound inflammatory response. We hypothesize that OPN may contribute to inflammation-associated fibrosis. In a series of in vitro and in vivo studies, we analyze the effects of blocking OPN expression at the wound, and determine which inflammatory cells, and which paracrine factors from these cells, may be responsible for triggering OPN expression in wound fibroblasts. Delivery of OPN antisense oligodeoxynucleotides into mouse skin wounds by release from Pluronic gel decreases OPN protein levels at the wound and results in accelerated healing and reduced granulation tissue formation and scarring. To identify which leukocytic lineages may be responsible for OPN expression, we cultured fibroblasts in macrophage-, neutrophil-, or mast cell–conditioned media (CM), and found that macrophage- and mast cell–secreted factors, specifically platelet-derived growth factor (PDGF), induced fibroblast OPN expression. Correspondingly, Gleevec, which blocks PDGF receptor signaling, and PDGF-Rβ–neutralizing antibodies, inhibited OPN induction by macrophage-CM. These studies indicate that inflammation-triggered expression of OPN both hinders the rate of repair and contributes to wound fibrosis. Thus, OPN and PDGF are potential targets for therapeutic modulation of skin repair to improve healing rate and quality.
Synthesis of Factor VIII Antigen by Cultured Guinea Pig Megakaryocytes
Authors: Ralph Nachman, Richard Levine, Eric A. Jaffe
Journal: Journal of Clinical Investigation (1977)

Immunoprecipitates containing guinea pig Factor VIII antigen were prepared from guinea pig plasma with a cross-reacting rabbit anti-human Factor VIII. Monospecific antisera to guinea pig Factor VIII antigen were produced in rabbits by using these washed immunoprecipitates as immunogens. The resulting antisera to guinea pig Factor VIII antigen detected Factor VIII antigen in guinea pig plasma and inhibited the von Willebrand factor activity in guinea pig plasma. This antibody also detected Factor VIII antigen in a solubilized protein mixture prepared from isolated cultured guinea pig megakaryocytes. Cultured guinea pig megakaryocytes were labeled with radio-active leucine. By radioautography, 96.2% of the radio-activity was present in megakaryocytes. The radio-active Factor VIII antigen present in the solubilized cell protein mixture was isolated by immunoprecipitation and characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The results demonstrate that cultured guinea pig megakaryocytes synthesize Factor VIII antigen which contains the same polypeptide subunit (mol wt 200,000) present in guinea pig plasma Factor VIII antigen.
Inhalation of nitric oxide modulates methacholine-induced bronchoconstriction in the rabbit
Authors: M Högman, C Frostell, H Arnberg, G Hedenstierna
Journal: European Respiratory Journal (1993)

Nitric oxide (NO) accounts for the major effects of endothelium-derived relaxing factor. We investigated whether NO, added to the inspired gas, could exert a bronchodilatory action similar to the pulmonary vasodilation described when administering NO during lung vascular constriction. New Zealand White rabbits were intubated and mechanically-ventilated with 30% oxygen during neuroleptanaesthesia. Methacholine (MCh) was nebulized at increasing concentrations from 0.5 to 4.0 mg.ml-1, with or without inhalation of 80 parts per million (ppm) NO. The technique of rapid airway occlusion during constant-flow inflation was used for measuring respiratory mechanics, i.e. resistance and compliance of the respiratory system. Methacholine nebulization without NO inhalation raised the resistance from 51 +/- 6 (mean +/- 95% confidence interval) to 107 +/- 52 cmH2O.l-1.s at Mch 4 mg.ml-1. During NO inhalation, nebulization of MCh showed no significant increase in resistance. Arterial oxygen tension (PaO2) and compliance fell to the same extent during methacholine challenge, whether NO was inhaled or not. Closure of small airways may be a mechanism that causes the decrease in PaO2 and compliance observed. This suggests that 80 ppm NO added to the inspired gas modulates the response in central airway tone to nebulized MCh in this rabbit model. However, it appears to have less effect on peripheral airways.
Ascorbate Attenuates Atrial Pacing-Induced Peroxynitrite Formation and Electrical Remodeling and Decreases the Incidence of Postoperative Atrial Fibrillation
Authors: Cynthia A. Carnes, Mina K. Chung, Tomohiro Nakayama, Hitomi Nakayama, Reshma S. Baliga, Shengfu Piao, Anne Kanderian, Steven Pavia, Robert L. Hamlin, Patrick M. McCarthy, John A. Bauer, David R. Van Wagoner
Journal: Circulation Research (2001)

Atrial fibrillation (AF), the most common chronic arrhythmia, increases the risk of stroke and is an independent predictor of mortality. Available pharmacological treatments have limited efficacy. Once initiated, AF tends to self-perpetuate, owing in part to electrophysiological remodeling in the atria; however, the fundamental mechanisms underlying this process are still unclear. We have recently demonstrated that chronic human AF is associated with increased atrial oxidative stress and peroxynitrite formation; we have now tested the hypothesis that these events participate in both pacing-induced atrial electrophysiological remodeling and in the occurrence of AF following cardiac surgery. In chronically instrumented dogs, we found that rapid (400 min −1 ) atrial pacing was associated with attenuation of the atrial effective refractory period (ERP). Treatment with ascorbate, an antioxidant and peroxynitrite decomposition catalyst, did not directly modify the ERP, but attenuated the pacing-induced atrial ERP shortening following 24 to 48 hours of pacing. Biochemical studies revealed that pacing was associated with decreased tissue ascorbate levels and increased protein nitration (a biomarker of peroxynitrite formation). Oral ascorbate supplementation attenuated both of these changes. To evaluate the clinical significance of these observations, supplemental ascorbate was given to 43 patients before, and for 5 days following, cardiac bypass graft surgery. Patients receiving ascorbate had a 16.3% incidence of postoperative AF, compared with 34.9% in control subjects. In combination, these studies suggest that oxidative stress underlies early atrial electrophysiological remodeling and offer novel insight into the etiology and potential treatment of an enigmatic and difficult to control arrhythmia. The full text of this article is available at http://www.circresaha.org.
Inhibition of Pituitary-Induced Nodular Hyperplasia in Mammary Glands of C3H Mice Fed a Phenylalanine-Deficient Diet&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: Y. H. Hui, K. B. DeOme, G. M. Briggs
Journal: JNCI Journal of the National Cancer Institute (1971)

Journal Article Inhibition of Pituitary-Induced Nodular Hyperplasia in Mammary Glands of C3H Mice Fed a Phenylalanine-Deficient Diet Get access Y. H. Hui, Y. H. Hui Department of Nutritional Sciences and Cancer Research Genetics Laboratory, University of California, Berkeley, California 94720 Search for other works by this author on: Oxford Academic PubMed Google Scholar K. B. DeOme, K. B. DeOme Department of Nutritional Sciences and Cancer Research Genetics Laboratory, University of California, Berkeley, California 94720 Search for other works by this author on: Oxford Academic PubMed Google Scholar G. M. Briggs G. M. Briggs Department of Nutritional Sciences and Cancer Research Genetics Laboratory, University of California, Berkeley, California 94720 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 46, Issue 5, May 1971, Pages 929–939, https://doi.org/10.1093/jnci/46.5.929 Published: 01 May 1971 Article history Received: 15 June 1970 Accepted: 21 January 1971 Published: 01 May 1971
Mutation in gelsolin gene in Finnish hereditary amyloidosis.
Authors: E Levy, M Haltia, I Fernandez-Madrid, O Koivunen, J Ghiso, F Prelli, B Frangione
Journal: The Journal of Experimental Medicine (1990)

Familial amyloidosis, Finnish type (FAF), is an autosomal dominant form of familial amyloid polyneuropathy. The novel amyloid fibril protein found in these patients is a degradation fragment of gelsolin, an actin-binding protein. We found a mutation (adenine for guanine) at nucleotide 654 of the gelsolin gene in genomic DNA isolated from five FAF patients. This site is polymorphic since the normal allele was also present in all the patients tested. This mutation was not found in two unaffected family members and 11 normal controls. The A for G transition causes an amino acid substitution (asparagine for aspartic acid) that was found at position 15 of the amyloid protein. The mutation and consequent amino acid substitution may lead to the development of FAF.
The diagnostic value of biomarkers (AshTest) for the prediction of alcoholic steato-hepatitis in patients with chronic alcoholic liver disease
Authors: Dominique Thabut, Sylvie Naveau, Frederic Charlotte, Julien Massard, Vlad Ratziu, Françoise Imbert-Bismut, Dominique Cazals-Hatem, Annie Abella, Djamila Messous, Fabienne Beuzen, Mona Munteanu, Julien Taieb, Richard Moreau, Didier Lebrec, Thierry Poynard
Journal: Journal of Hepatology (2006)
Low circulating levels of invariant natural killer T (iNKT) cells in patients with obstructive sleep apnoea syndrome and impaired functional response to hypoxia: Implications for cancer co-morbidity
Authors: Brian Kent, Gadintshware Gaoatswe, Michelle Corrigan, Walter McNicholas, Andrew Hogan, Donal O'Shea
Journal: European Respiratory Journal (2013)

Background  Recent epidemiological studies link obstructive sleep apnoea syndrome (OSAS) with increased cancer incidence and mortality. Invariant natural killer T (iNKT) cells are innate immune cells that play a key role in cancer immunity, with low circulating level of iNKT cells predicting worse prognosis in some forms of cancer. The relationship of OSAS severity with iNKT cell levels has not been examined.  Methods  We measured circulating iNKT cells by flow cytometry in 29 otherwise healthy male snorers being assessed by inpatient polysomnography for OSAS, and examined the relationship of OSAS severity and nocturnal hypoxaemia with iNKT levels, along with the impact of subsequent nCPAP. Using iNKT cell lines, we evaluated the effect of exposure to hypoxia for 24 hours on apoptosis and cytotoxicity.  Results  Patients with severe OSAS had markedly less iNKT cells (0.15%) compared to matched patients with moderate (0.22%) or no sleep apnoea (0.38%) (p0.005). The level of iNKT cells correlated inversely with apnoea-hypopnoea index (r=-0.6369; p  Conclusion  Patients with OSAS have significantly reduced levels of circulating iNKT cells, which increase with nCPAP. Furthermore, hypoxia leads to impaired iNKT cell function. These observations may partly contribute to increased cancer risk in OSAS.
Spontaneous Mammary Tumors Differ Widely in Their Inherent Sensitivity to Adoptively Transferred T Cells
Authors: Erika M. Wall, Katy Milne, Michele L. Martin, Peter H. Watson, Patty Theiss, Brad H. Nelson
Journal: Cancer Research (2007)

Abstract Immunotherapy of cancer can lead to the selection of antigen loss variants, which provides strong rationale to target oncogenes that are essential for tumor growth or viability. To investigate this concept, we tagged the HER2/neu oncogene with epitopes from ovalbumin to confer recognition by T-cell receptor transgenic CD8+ (OT-I) and CD4+ (OT-II) T cells. Transgenic mice expressing neuOT-I/OT-II developed mammary adenocarcinomas at 6 to 10 months of age. Adoptively transferred naive OT-I cells (with or without OT-II cells) proliferated vigorously on encountering neuOT-I/OT-II-expressing tumors. This was followed by the complete regression of 37% of tumors, whereas others showed partial/stable responses (40%) or progressive disease (23%). Those tumors undergoing complete regression never recurred. In mice with multiple primary tumors, simultaneous regressions and nonregressions were often seen, indicating that immune evasion occurred at a local rather than systemic level. The majority of nonregressing tumors expressed NeuOT-I/OT-II and MHC class I, and many avoided rejection through a profound block to T-cell infiltration. Thus, T cells directed against an essential oncogene can permanently eradicate a subset of spontaneous, established mammary tumors. However, in other tumors, local barriers severely limit the therapeutic response. To maximize the efficacy of immunotherapy against spontaneous cancers, predictive strategies that take into account the heterogeneity of the tumor microenvironment will be required. [Cancer Res 2007;67(13):6442–50]
Intrapericardial Paclitaxel Delivery Inhibits Neointimal Proliferation and Promotes Arterial Enlargement After Porcine Coronary Overstretch
Authors: Dongming Hou, Pamela I. Rogers, Philip M. Toleikis, William Hunter, Keith L. March
Journal: Circulation (2000)

Catheter-based intrapericardial (IPC) delivery of therapeutic agents has recently been demonstrated. Paclitaxel is known to inhibit vascular smooth muscle cell proliferation. This study examined the effect of IPC instillation of paclitaxel on neointimal proliferation after balloon overstretch of porcine coronary arteries.Overstretch injury of coronary arteries was followed by IPC administration of micellar paclitaxel at low dose (LD, 10 mg; n=6) or high dose (HD, 50 mg; n=7) or of control micelles (50 mg, n=5). Animals were euthanized 28 days after balloon dilation. Arterial injury indices were no different among the groups. The neointimal area, maximal intimal thickness, and adventitial thickness were significantly reduced in both LD (0.47+/-0.04 mm(2), 0.43+/-0.03 mm, and 0.35+/-0.02 mm, respectively) and HD (0.51+/-0.06 mm(2), 0.42+/-0.03 mm, and 0. 38+/-0.03 mm, respectively) paclitaxel groups compared with the control group (0.79+/-0.07 mm(2), 0.56+/-0.02 mm, and 0.47+/-0.02 mm, respectively; P:<0.001). Meanwhile, the vessel circumference measured at the external elastic lamina of paclitaxel-treated vessels was significantly larger than the control circumference. Apoptotic cells were found in the neointima. The apoptotic cell percentage was not different between the control (1.72%) and LD (2. 31%) groups but was higher in the HD group (7.07%, P:<0.0001 versus control and LD groups). Immunostaining for matrix metalloproteinase-2 revealed concurrent reduction in the HD group compared with the control and LD groups.IPC space delivery of a single dose of paclitaxel significantly reduces vessel narrowing in this balloon-overstretch model. This effect is mediated by reduction of neointimal mass as well as positive vascular remodeling.
Inhibition of RhoA GTPase and the subsequent activation of PTP1B protects cultured hippocampal neurons against amyloid β toxicity
Authors: Pedro J Chacon, Rosa Garcia-Mejias, Alfredo Rodriguez-Tebar
Journal: Molecular Neurodegeneration (2011)

Amyloid beta (Aβ) is the main agent responsible for the advent and progression of Alzheimer's disease. This peptide can at least partially antagonize nerve growth factor (NGF) signalling in neurons, which may be responsible for some of the effects produced by Aβ. Accordingly, better understanding the NGF signalling pathway may provide clues as to how to protect neurons from the toxic effects of Aβ.We show here that Aβ activates the RhoA GTPase by binding to p75NTR, thereby preventing the NGF-induced activation of protein tyrosine phosphatase 1B (PTP1B) that is required for neuron survival. We also show that the inactivation of RhoA GTPase and the activation of PTP1B protect cultured hippocampal neurons against the noxious effects of Aβ. Indeed, either pharmacological inhibition of RhoA with C3 ADP ribosyl transferase or the transfection of cultured neurons with a dominant negative form of RhoA protects cultured hippocampal neurons from the effects of Aβ. In addition, over-expression of PTP1B also prevents the deleterious effects of Aβ on cultured hippocampal neurons.Our findings indicate that potentiating the activity of NGF at the level of RhoA inactivation and PTP1B activation may represent a new means to combat the noxious effects of Aβ in Alzheimer's disease.