tbuckley/cabot-search huggingface dataset:
S47 Effect of macitentan on haemodynamics in patients with pulmonary arterial hypertension: results from the long-term, randomised, placebo-controlled SERAPHIN trial: Abstract S47 Table 1.
Authors: G Coghlan, A Torbicki, N Galiè, LJ Rubin, L Perchenet, G Simonneau
Journal: Thorax (2013)

<h3>Introduction and objectives</h3> Macitentan, a novel dual endothelin receptor antagonist (ERA), significantly reduced morbidity and mortality in pulmonary arterial hypertension (PAH) patients in the SERAPHIN trial (NCT00660179), the first event-driven outcomes trial in PAH. A substudy in SERAPHIN investigated the effect of macitentan on patients9 cardiac haemodynamics. <h3>Methods</h3> 742 PAH patients were randomised to placebo, macitentan 3 mg, or macitentan 10 mg once-daily. Stable background PAH therapy, except injectable prostanoids and other ERAs, were allowed. At selected centres, patients underwent right heart catheterisation at randomisation and Month 6. Changes from baseline to Month 6 for mean right atrial pressure (mRAP), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI) and mixed venous oxygen saturation (SvO<sub>2</sub>) were calculated for all patients and stratified in an exploratory analysis for background PAH therapy and baseline WHO functional class I/II vs III/IV. Median treatment effects (95% CL) between placebo and macitentan are reported. <h3>Results</h3> 187 patients participated in the substudy (51% were treatment-naïve and 56% in WHO FC III/IV). Baseline median values for all patients on placebo (n = 68), macitentan 3 mg (n = 62) and 10 mg (n = 57) were: mRAP 7.0, 8.0, 7.0 mmHg; mPAP 52.0, 54.0, 52.3 mmHg; PVR 800, 785, 789 dyn·sec/cm<sup>5</sup>; CI 2.49, 2.23, 2.47 L/min/m<sup>2</sup>; and SvO<sub>2</sub> 66.0, 64.5, 66.5%, respectively. Overall, haemodynamic parameters improved at Month 6 with macitentan and worsened with placebo. Beneficial treatment effects with macitentan were statistically significant (P &lt; 0.05) for PVR and CI for both subgroups, except for PVR in treatment naïve patients treated with macitentan 3mg (Table). <h3>Conclusions</h3> Macitentan significantly improved cardio-pulmonary haemodynamics in PAH patients. Improvements in PVR and CI were consistent irrespective of background PAH therapy and baseline WHO FC.
Wine Drinking and Risks of Cardiovascular Complications After Recent Acute Myocardial Infarction
Authors: Michel de Lorgeril, Patricia Salen, Jean-Louis Martin, François Boucher, François Paillard, Joël de Leiris
Journal: Circulation (2002)

Scientific data on the clinical impact of moderate alcohol consumption after a recent acute myocardial infarction (AMI) are limited, and the specific effect of wine ethanol has not been studied.In survivors of a recent AMI, we analyzed the association between ethanol intake and the risk of recurrence. The patients were classified according to the amount of ethanol that they consumed regularly during follow-up. Major prognostic factors, including the severity of the prior AMI and drug treatment, were recorded and included in the analyses. Only patients with at least 2 reliable assessments of drinking (and dietary) habits were included (n=437). The average ethanol intake was 7.6% of the total energy intake, wherein wine ethanol represented 92% of the total. Among these patients, 104 cardiovascular complications occurred during a mean follow-up period of 4 years. In comparison with abstainers, the adjusted risk of complications was reduced by 59% (95% confidence interval: 17 to 80) in patients whose average ethanol intake was 7.7% of the total energy intake (about 2 drinks/day), and by 52% (95% confidence interval: 4 to 76) in those whose average ethanol intake was of 16% of energy (about 4 drinks/day).Whereas moderate wine drinking was associated with a significant reduction in the risk of complications in this homogenous population of coronary heart disease patients, further studies are required to confirm the data, define the clinical and biological profile of the patients who would most benefit from wine drinking after recent AMI, and examine whether the relations found are due to ethanol or other wine ingredients.
Differential regulation of T cell antigen responsiveness by isoforms of the src-related tyrosine protein kinase p59fyn.
Authors: D Davidson, L M Chow, M Fournel, A Veillette
Journal: The Journal of Experimental Medicine (1992)

Recent observations suggest that the src-related tyrosine protein kinase p59fyn may be involved in antigen-induced T lymphocyte activation. As a result of alternative splicing, p59fyn exists as two isoforms that differ exclusively within a short sequence spanning the end of the Src Homology 2 (SH2) region and the beginning of the tyrosine protein kinase domain. While one p59fyn isoform (fynB) is highly expressed in brain, the alternative product (fynT) is principally found in T lymphocytes. To further understand the role of p59fyn in T cell activation and to test the hypothesis that p59fynT serves a tissue-specific function in T lymphocytes, we have examined the effects of expression of activated versions (tyrosine 528 to phenylalanine 528 mutants) of either form of p59fyn on the physiology of an antigen-specific mouse T cell hybridoma. Our results demonstrated that the two forms of fyn, expressed in equivalent amounts, efficiently enhanced antibody-induced T cell receptor (TCR)-mediated signals. In contrast, only p59fynT increased interleukin 2 production in response to antigen stimulation. This finding implies that the distinct p59fyn isoform expressed in T lymphocytes regulates the coupling of TCR stimulation by antigen/major histocompatibility complex to lymphokine production.
Prognostic Factors and Clinical Outcomes in Children and Adolescents With Metastatic Rhabdomyosarcoma—A Report From the Intergroup Rhabdomyosarcoma Study IV
Authors: John C. Breneman, Elizabeth Lyden, Alberto S. Pappo, Michael P. Link, James R. Anderson, David M. Parham, Stephen J. Qualman, Moody D. Wharam, Sarah S. Donaldson, Harold M. Maurer, William H. Meyer, K. Scott Baker, Charles N. Paidas, William M. Crist
Journal: Journal of Clinical Oncology (2002)

To identify risk factors associated with outcomes in children with metastatic rhabdomyosarcoma (RMS) treated on the fourth Intergroup Rhabdomyosarcoma Study (IRS-IV).Patients with metastatic RMS were treated with one of two regimens that incorporated a window of either ifosfamide and etoposide (IE) with vincristine, dactinomycin, and cyclophosphamide (VAC) or vincristine, melphalan (VM) and VAC. Study end points were failure-free survival (FFS) and overall survival (OS). Clinical factors including age, histology, sites of primary and metastatic disease, and number of sites of metastatic disease were correlated with those end points.One hundred twenty-seven patients were eligible for analysis. The estimated 3-year OS and FFS for all patients were 39% and 25%, respectively. By univariate analysis, 3-year OS was significantly influenced by histology (47% for embryonal v 34% for all others, P =.026) and increasing number of metastatic sites (P =.028). By multivariate analysis, the presence of two or fewer metastatic sites was the only significant predictor (P =.007 and.006, respectively). The combination of embryonal histology with two or fewer metastatic sites identified a subgroup with 3-year FFS of 40% and OS of 47%.Children with group IV RMS treated on the IRS-IV study had improved OS and FFS if they had two or fewer metastatic sites and embryonal histology. This favorable subset of patients has outcomes approaching those observed in selected patients with localized, nonmetastatic disease. Thus, these patients might not be appropriate candidates for regimens that include experimental agents with substantial toxicities or unproven antitumor activity.
Inhibition of STAT3 dimerization and acetylation by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo
Authors: Gautam Sethi, Snehajyoti Chatterjee, Peramaiyan Rajendran, Feng Li, Muthu K Shanmugam, Kwong Fai Wong, Alan Prem Kumar, Parijat Senapati, Amit K Behera, Kam Man Hui, Jeelan Basha, Nagashayana Natesh, John M Luk, Tapas K Kundu
Journal: Molecular Cancer (2014)

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been linked with proliferation, survival, invasion and angiogenesis of a variety of human cancer cells, including hepatocellular carcinoma (HCC). Thus, novel agents that can suppress STAT3 activation have potential for both prevention and treatment of HCC. Here we report, garcinol, a polyisoprenylated benzophenone, could suppress STAT3 activation in HCC cell lines and in xenografted tumor of HCC in nude mice model.Different HCC cell lines have been treated with garcinol and the inhibition of STAT3 activation, dimerization and acetylation have been checked by immunoblotting, immuno-fluorescence, and DNA binding assays. Xenografted tumor model has been generated in nude mice using HCC cell line and effect of garcinol in the inhibition of tumor growth has been investigated.Garcinol could inhibit both constitutive and interleukin (IL-6) inducible STAT3 activation in HCC cells. Computational modeling showed that garcinol could bind to the SH2 domain of STAT3 and suppress its dimerization in vitro. Being an acetyltransferase inhibitor, garcinol also inhibits STAT3 acetylation and thus impairs its DNA binding ability. The inhibition of STAT3 activation by garcinol led to the suppression of expression of various genes involved in proliferation, survival, and angiogenesis. It also suppressed proliferation and induced substantial apoptosis in HCC cells. Remarkably, garcinol inhibited the growth of human HCC xenograft tumors in athymic nu/nu mice, through the inhibition of STAT3 activation.Overall, our results suggest that garcinol exerts its anti-proliferative and pro-apoptotic effects through suppression of STAT3 signaling in HCC both in vitro and in vivo.
Dose-Response Relationship to Inhaled Endotoxin in Normal Subjects
Authors: OLIVIER MICHEL, ANNE-MARIE NAGY, MARC SCHROEVEN, JEAN DUCHATEAU, JEAN NÈVE, PIERRE FONDU, ROGER SERGYSELS
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Exposure to endotoxin and to its purified derivative lipopolysaccharide (LPS) is related to several occupational pulmonary diseases and to severe domestic asthma. An inhalation of a given dose of pure LPS produces both a systemic and a bronchial inflammatory response. Information on the dose- response relationship to inhaled LPS in normal subjects is a prerequisite to define the safety threshold of exposure. In the present study, the clinical and inflammatory responses to rising doses of inhaled LPS was evaluated. Nine normal volunteers were challenged weekly by inhalation with saline, 0.5, 5, and 50 μ g LPS (Escherichia coli ). The response determinators are the clinical symptoms, fever, FEV1, blood polymorphonuclear neutrophils (PMNs) with their level of activation (measured by luminol enhanced-chemiluminescence), and both the blood and the urine concentrations of the C-reactive protein (CRP). To assess the bronchial inflammatory response, an induced sputum was obtained 6 h after each dose of LPS, and the total and differential cell counts as well as the MPO, ECP, and TNF- α concentrations were measured. Compared with the saline, an inhalation of 0.5 μ g LPS induces a significant decrease in the PMN luminol-enhanced chemiluminescence (p < 0.01), which could reflect a process of margination and/or extravascular sequestration of activated PMN. Inhalation of 5 μ g LPS is associated with a significant rise in blood CRP (p < 0.01) and PMNs (p < 0.001) and in sputum PMNs (p < 0.05), monocytes (p < 0.05), and MPO (p < 0.05). Inhalation of 50 μ g LPS was characterized by a significant increase in temperature (p < 0.01), blood PMNs (p < 0.001), blood and urine CRP (p < 0.01 and < 0.01), and sputum PMNs (p < 0.001), monocytes (p < 0.05), lymphocytes (p < 0.05), MPO (p < 0.01), TNF- α (p < 0.01), and ECP (p < 0.01) while five subjects develop symptoms. In normal subjects, the response to inhaled LPS is dose-related, the most sensitive markers of LPS-induced inflammation being the blood PMNs count with their level of activation, the blood CRP concentration, and the sputum PMNs count. The no-response threshold to an acute inhalation of LPS is less than 0.5 μ g.
Activation of somatostatin receptors attenuates pulmonary fibrosis
Authors: R Borie, A Fabre, F Prost, J Marchal-Somme, R Lebtahi, S Marchand-Adam, M Aubier, P Soler, B Crestani
Journal: Thorax (2007)

<h3>Background and aim:</h3> Somatostatin analogues may have antifibrotic properties in the lung. The aim of this study was to evaluate the expression of the five somatostatin receptors sst1 to sst5 in normal and fibrotic mouse lung and the action of SOM230 (pasireotide), a new somatostatin analogue with a long half-life, in bleomycin induced lung fibrosis and in human lung fibroblasts in vitro. <h3>Methods:</h3> After intratracheal injection of bleomycin, C57Bl6 male mice received one daily subcutaneous injection of SOM230 or saline. The lungs were evaluated on days 3, 7 and 14 after administration of bleomycin. <h3>Results:</h3> We found that all somatostatin receptors were expressed in the normal mouse lung. The sst2 receptor mRNA expression was increased after bleomycin. SOM230 improved mice survival (69% vs 44%; p = 0.024), reduced lung collagen content at day 14 and decreased lung collagen-1 mRNA at day 7. SOM230 reduced bronchoalveolar lavage inflammatory cell influx at day 3, decreased lung connective tissue growth factor mRNA and transforming growth factor (TGF) β mRNA and increased lung hepatocyte growth factor and keratinocyte growth factor mRNA. The sst2 receptor was strongly expressed in the human lung (normal or fibrotic), particularly by fibroblasts. In vitro, SOM230 reduced BrdU incorporation by control human lung fibroblasts cultured under basal conditions or with TGFβ, and reduced alpha-1 collagen-1 mRNA expression in TGFβ stimulated fibroblasts. <h3>Conclusion:</h3> We conclude that SOM230 attenuates bleomycin induced pulmonary fibrosis in mice and human lung fibroblasts activation. This study points to a potential new approach for treating pulmonary fibrotic disorders.
Azacitidine might be beneficial in a subgroup of older AML patients compared to intensive chemotherapy: a single centre retrospective study of 227 consecutive patients
Authors: Lieke H van der Helm, Ellen RM Scheepers, Nic JGM Veeger, Simon MGJ Daenen, André B Mulder, Eva van den Berg, Edo Vellenga, Gerwin Huls
Journal: Journal of Hematology & Oncology (2013)

Treatment options in older acute myeloid leukaemia (AML) patients include intensive chemotherapy, best supportive care (BSC), and hypomethylating agents. Currently, limited data is available on hypomethylating agents in older AML patients in unselected patient populations.To compare the effectiveness of azacitidine with conventional therapy, we collected data of 227 consecutive AML patients (≥60 years) who were treated with azacitidine (N = 26), intensive chemotherapy (N = 90), or BSC (N = 97).Azacitidine-treated patients were older and had more comorbidities, but lower white blood cell- and bone marrow blast counts compared with intensive chemotherapy patients. Complete or partial response was achieved in 42% of azacitidine-treated patients and in 73% of intensive chemotherapy patients (P = 0.005). However, the overall survival (OS) was similar (1-year-OS 57% versus 56%, P = 0.93; 2-year-OS 35% versus 35%, P = 0.92), and remained similar after correction for risk factors in a multivariate analysis. Patients treated with BSC had an inferior OS (1-year- and 2-year-OS 16% and 2%, P < 0.001). Compared to intensive chemotherapy, azacitidine-treated patients spent less days in the hospital (median in first three months 0.5 versus 56, P < 0.001), and needed less red blood cell and platelet transfusions (median per month 2.7 versus 7, P < 0.001 and 0.3 versus 5, P < 0.001) in the first three months.Azacitidine treatment is associated with a comparable OS but higher tolerability in a subgroup of older AML patients compared with intensive chemotherapy. Patients receiving BSC had a poor prognosis.
Endothelium-Dependent Contractions Are Associated With Both Augmented Expressionof Prostaglandin H Synthase-1 and Hypersensitivity to Prostaglandin H <sub>2</sub> in the SHR Aorta
Authors: Tong Ge, Helen Hughes, Didier C. Junquero, Kenneth K. Wu, Paul M. Vanhoutte, Chantal M. Boulanger
Journal: Circulation Research (1995)

Prostaglandin H2 (PGH2 [endoperoxide]) is an immediate product of prostaglandin H (PGH) synthase activity (cyclooxygenase) and a likely candidate to mediate endothelium-dependent contractions evoked by acetylcholine in the aorta of the spontaneously hypertensive rat (SHR). Experiments were designed to investigate whether or not endothelium-dependent contractions were associated with an increased expression of PGH synthase, an augmented acetylcholine-induced release of PGH2, and/or a hypersensitivity of the smooth muscle to endoperoxides in SHR aorta compared with normotensive Wistar-Kyoto (WKY) aorta. In SHR aorta, endothelium-dependent contractions to acetylcholine were abolished by tenidap (10(-8) mol/L), a preferential PGH synthase-1 inhibitor, but slightly impaired by NS-398 (10(-6) mol/L), a preferential PGH synthase-2 inhibitor. PGH synthase-1 expression, which was evaluated by both reverse transcriptase-polymerase chain reaction and Western blotting, was about twofold greater in preparations with endothelium from SHR than from WKY rats. There was no difference in PGH synthase-1 expression between preparations with and those without endothelium in both strains. In SHR but not WKY aortas, acetylcholine (10(-5) mol/L, 5 minutes) caused a significant endothelium-dependent release of PGH2 as measured by gas chromatography/mass spectrometry. PGH2 evoked more potent contractions in rings without endothelium from SHR than from WKY rats, whereas the thromboxane analogue U46619 and prostaglandin F2 alpha caused a comparable response in both preparations. These results show that endothelium-dependent contractions to acetylcholine in SHR aorta are associated with a greater expression of PGH synthase-1, a significant release of PGH2, and a hypersensitivity of the smooth muscle to the endoperoxide.
Association of Bisphenol A With Diabetes and Other Abnormalities
Authors: Sarah Howard
Journal: JAMA (2009)

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
Thymus-derived Glucocorticoids Regulate Antigen-specific Positive Selection
Authors: Melanie S. Vacchio, Jonathan D. Ashwell
Journal: The Journal of Experimental Medicine (1997)

While it is generally believed that the avidity of the T cell antigen receptor (TCR) for self antigen/major histocompatibility complex (MHC) determines a thymocyte's fate, how the cell discriminates between a stimulus that causes positive selection (survival) and one that causes negative selection (death) is unknown. We have previously demonstrated that glucocorticoids are produced in the thymus, and that they antagonize deletion caused by TCR cross-linking. To examine the role of glucocorticoids during MHC-dependent selection, we examined thymocyte development in organ cultures in which corticosteroid biosynthesis was inhibited. Inhibition of glucocorticoid production in thymi from α/β-TCR transgenic mice resulted in the antigen- and MHC-specific loss of thymocytes that normally recognize self antigen/MHC with sufficient avidity to result in positive selection. Furthermore, inhibition of glucocorticoid production caused an increase in apoptosis only in CD+CD8+ thymocytes bearing transgenic TCRs that recognized self antigen/MHC. These results indicate that the balance of TCR and glucocorticoid receptor signaling influences the antigen-specific thymocyte development by allowing cells with low-to-moderate avidity for self antigen/MHC to survive.
Carbimazole and exercise tolerance in chronic airflow obstruction.
Authors: R J Butland, J A Pang, D M Geddes
Journal: Thorax (1982)

Ten patients with severe dyspnoea and chronic airflow obstruction entered a randomised double-blind crossover trial comparing the effect of carbimazole 80 mg daily for two months with that of placebo. Assessment of thyroid function, lung function, and exercise tolerance was performed monthly. The mean free thyroxine index after two months of carbimazole was significantly lower at 64.1 (+/- 10.5, SEM) than the 89.1 (+/- 3.8) while on placebo. Serum tri-iodothyronine was reduced and thyroid stimulating hormone raised while on the active drug. There was no significant difference in the 12-minute walking distance (TMD), the rating of perceived exertion during the TMD, the oxygen cost score, the dyspnoea grade, the resting arterialised capillary blood gas tensions or the resting minute ventilation. During a progressive exercise test to exhaustion on a cycle ergometer, there was no significant difference in the minute ventilation, heart rate, blood gas tensions at exhaustion, or the total work done. There were no symptoms or signs of hypothyroidism. Lung function (FEV1, FVC, TLC, KCO) was unchanged. Thus a 28% reduction in the free thyroxine index produced no symptomatic or objective benefit in exercise tolerance in patients with severe airflow obstruction. These results provide no support for the use of carbimazole in chronic airflow obstruction.
Aquaporin 1, Urea Transporters, and Renal Vascular Bundles
Authors: Thomas L. Pallone
Journal: Journal of the American Society of Nephrology (2007)

Early theories of urinary concentration focused upon export of sodium by the thick ascending limb of Henle as the “single effect” that, when multiplied along the medullary axis, generates high osmolarity to extract water from the collecting duct. To account for the presence of a urea gradient