tbuckley/cabot-search huggingface dataset:
Vascular Matrix Metalloproteinase-2–Dependent Cleavage of Calcitonin Gene-Related Peptide Promotes Vasoconstriction
Authors: Carlos Fernandez-Patron, Ken G. Stewart, Yunlong Zhang, Erkki Koivunen, Marek W. Radomski, Sandra T. Davidge
Journal: Circulation Research (2000)

Abstract —Matrix metalloproteinase (MMP)-2 has been historically associated with the process of vascular remodeling through the cleavage of extracellular matrix proteins. However, we recently found that MMP-2 also cleaves the endothelium-derived peptide big endothelin-1, ET-1[1–38] and yields the novel vasoconstrictor ET-1[1–32]. We therefore investigated the effects of MMP-2 inhibitors as potential vasodilators. MMP inhibition with ortho-phenanthroline (0.3 to 30 μmol/L) induced vasorelaxation of isolated rat mesenteric arteries (maximum of relaxation=74.5±27.6% at 30 μmol/L). However, phosphoramidon (0.3 to 30 μmol/L), which inhibits some metalloenzymes, but not MMP-2, did not dilate the arteries. Selective inhibition of endogenous MMP-2 with the novel tissue-permeable cyclic peptide CTTHWGFTLC (CTT, 10 μmol/L) also caused vasorelaxation (by 85±6%), whereas STTHWGFTLS (10 μmol/L), an inactive CTT analogue, did not dilate the arteries. Interestingly, the vasorelaxation that results from MMP-2 inhibition was endothelium-independent. Thus, we examined whether MMP-2 acted on peptides derived from the smooth muscle or the perivascular nerves. Recombinant human MMP-2 cleaved calcitonin gene-related peptide (CGRP) specifically at the Gly 14 -Leu 15 peptide bond and reduced the vasodilatory potency of CGRP by 20-fold. Inhibition of MMP-2 increased the amount of intact CGRP in arteries and enhanced vasorelaxation induced by anandamide, which stimulates CGRP release. Vasorelaxation in response to MMP-2 inhibition was abolished by CGRP[8–37], a selective CGRP receptor antagonist, and by capsaicin, which depletes arterial perivascular nerves of CGRP. We conclude that vascular MMP-2 cleaves endogenous CGRP and promotes vasoconstriction. These data suggest a novel mechanism of regulating the vasoactive and, possibly, the neurohormonal actions of CGRP and establish MMP-2 as a modulator of vascular function.
Dose of Non-Heat-Treated Factor VIII Concentrate and HIV-1 RNA Levels
Authors: J. B. Montoro
Journal: JAMA (1997)

<h3>To the Editor.</h3> —Dr O'Brien and colleagues<sup>1</sup>determined the influence of human immunodeficiency virus type 1 (HIV-1) RNA levels on the long-term incidence of the acquired immunodeficiency syndrome (AIDS) and survival in patients with hemophilia and HIV-1 infection. Levels of HIV-1 RNA strongly predicted time to development of AIDS. They found no association between HIV-1 RNA levels and the dose of non-heat-treated factor concentrate. Recent epidemiologic studies have found that the use of lower doses of factor concentrates was associated with an increased risk of progression to AIDS and mortality in patients with hemophilia.<sup>2,3</sup>This fact should justify the inclusion of the dose in the Cox proportional hazard models. Moreover, examining the data shown by O'Brien et al in their Table 1 using a test for linear trend rather than the Mantel-Haenszel ϰ<sup>2</sup>test used by the authors, the<i>P</i>value for the comparison between RNA level
Definition and Clinical Importance of Haplotypes
Authors: Dana C. Crawford, Deborah A. Nickerson
Journal: Annual Review of Medicine (2004)

Advances in genotyping and sequencing technologies, coupled with the development of sophisticated statistical methods, have afforded investigators novel opportunities to define the role of sequence variation in the development of common human diseases. At the forefront of these investigations is the use of dense maps of single-nucleotide polymorphisms (SNPs) and the haplotypes derived from these polymorphisms. Here we review basic concepts of high-density genetic maps of SNPs and haplotypes and how they are typically generated and used in human genetic research. We also provide useful examples and tools available for researchers interested in incorporating haplotypes into their studies. Finally, we discuss the latest concepts for the analysis of haplotypes related to human disease, including haplotype blocks, the International HapMap Project, and the future directions of these resources.
Tumor necrosis factor expression in human epithelial tumor cell lines.
Authors: D R Spriggs, K Imamura, C Rodriguez, E Sariban, D W Kufe
Journal: Journal of Clinical Investigation (1988)

Tumor necrosis factor (TNF) is a monokine with in vitro cytotoxicity for some but not all tumor cells. The basis for sensitivity and resistance to the antitumor effects of this agent remains unclear. The present studies have monitored the effects of TNF on 14 epithelial tumor cell lines. Eleven of these cell lines were resistant to the growth inhibitory effects of TNF (50% inhibitory concentration greater than 1,000 U/ml). 12 of the 14 tumor cell lines has detectable levels of high affinity cell surface TNF binding sites, thus suggesting that resistance was not often due to the absence of cell surface TNF receptors. Northern blot analysis demonstrated that three of the eleven resistant cell lines expressed detectable levels of TNF mRNA. Furthermore, both sensitive and resistant epithelial tumor cells had the capacity to express TNF transcripts in the presence of the protein synthesis inhibitor, cycloheximide. Finally, the presence of TNF expression at the RNA level is shown to be associated with the production of a TNF-like protein in the resistant Ov-D ovarian carcinoma cells. These findings suggest that certain human epithelial tumor cell lines inherently resistant to TNF also express this cytokine.
Altered Pulmonary Vascular Reactivity in Mice with Excessive Erythrocytosis
Authors: Jo Hasegawa, Klaus F. Wagner, Dörte Karp, Dechun Li, Junpei Shibata, Matthias Heringlake, Ludger Bahlmann, Reinhard Depping, Joachim Fandrey, Peter Schmucker, Stefan Uhlig
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Pulmonary vascular remodeling during chronic hypoxia may be the result of either oxygen deprivation or erythrocytosis. To separate experimentally the effects of hypoxia and erythrocytosis, we analyzed transgenic mice that constitutively overexpress the human erythropoietin gene in an oxygen-independent manner. These mice are characterized by polycythemia but have normal blood pressure, heart rate, and cardiac output. In transgenic mice, pulmonary artery pressure (PAP) was increased in vivo but was reduced in blood-free perfused lungs. The thromboxane receptor agonist U46619 caused a smaller rise in PAP in isolated transgenic lungs than in lungs from wild-type mice. The transgenic pulmonary vasculature was characterized by elevated prostacyclin production, stronger endothelial nitric oxide synthase expression, and reduced pulmonary vascular smooth muscle thickness. The fact that transgenic polycythemic mice have marked pulmonary hypertension in vivo but not in vitro suggests that their pulmonary hypertension is due to the increased blood viscosity, thus supporting an independent role of polycythemia in the development of pulmonary hypertension. In addition, our findings indicate that the lungs of transgenic animals adapt to the high PAP by elevated synthesis of vasodilators and reduced vascular smooth muscle thickness that tend to reduce vascular tone and vascular responsiveness.
Rosette-forming ability of thymus-derived lymphocytes in cell-mediated immunity. I. Delayed hypersensitivity and in vitro cytotoxicity.
Authors: B E Elliott, J S Haskill, M A Axelrad
Journal: The Journal of Experimental Medicine (1975)

Effector cells in delayed hypersensitivity and in vitro cytotoxicity were studied in lymph node cells from animals immunized with sheep erythrocytes (SRBC) in complete Freund's adjuvant. Delayed hypersensitivity response (DHR) was assayed by the increase in foot pad swelling after the intrafoot pad injection of immune cells plus antigen. Cell-mediated cytotoxicity against SRBC was assayed by a microcytotoxicity test with sheep fibroblasts as target cells. Effector cells were antigen specific, sensitive to anti-theta serum plus complement (C), and insensitive to anti-Ig serum plus C. A nonrosette-forming (non-RFC) small lymphocyte effector T cell and a rosette-forming medium lymphocyte effector T cell were isolated by velocity sedimentation. The small lymphocyte non-RFC required a longer time than the medium lymphocyte RFC effector cell to produce maximum activity. Buoyant density failed to distinguish medium lymphocyte effector cells in DHR and in vitro cytotoxicity.
Efficacy and safety of AZD5069, a CXCR2 antagonist, in adult bronchiectasis
Authors: I Pavord, A De Soyza, J S Elborn, D Smith, H Wray, M Puu, B Larsson, R Stockley
Journal: European Respiratory Journal (2013)

Rationale:   CXCR2 antagonist AZD5069 may be useful for neutrophilic airway diseases, including bronchiectasis. This early phase study assessed the effects of AZD5069 on sputum neutrophil numbers, a range of biomarkers, other variables and safety in bronchiectasis patients (pts).   Methods:   Pts with radiological bronchiectasis entered a randomised, double-blind, parallel-group, multicentre study (NCT01255592) of oral AZD5069 80 mg (n=26) or placebo (PBO; n=26) twice daily for 4 weeks. The primary outcome was relative change in absolute sputum neutrophil count.   Results:   Table 1 summarises baseline demographics and effects of treatment. AZD5069 reduced neutrophil counts by 69% vs PBO (p=0.004). There were no clinically relevant effects on secondary variables. Biomarkers (sputum IL-6, GRO-α; serum GRO-α, IL-1β, IL-8) increased with AZD5069 vs PBO (p≤0.001), but this was not considered to affect AZD5069 efficacy (since effect on the primary target was confirmed by reduced sputum neutrophils). More pts receiving AZD5069 reported adverse events (23 vs 16). Incidence of infections was similar with AZD5069 and PBO but infections led to more study discontinuations with AZD5069 (4 vs 0).   Conclusions: AZD5069 resulted in a statistically significant reduction in sputum neutrophils vs PBO. Clinical status was not improved in this short-term study.
Hemodynamic and Anatomic Correlation of Electrocardiogram in Double-Outlet Right Ventricle
Authors: EHUD KRONGRAD, DONALD G. RITTER, WILLIAM H. WEIDMAN, JAMES W. DUSHANE
Journal: Circulation (1972)

Scalar electrocardiograms of 31 patients with double-outlet right ventricle (19 with and 12 without pulmonary stenosis) were correlated with the hemodynamic and anatomic findings. Atrioventricular conduction defects, intraventricular conduction delay, and counterclockwise frontal-plane loops were found less often than formerly reported. Counterclockwise frontal-plane loops were found with, as well as without, pulmonary stenosis. The presence or absence of left ventricular hypertrophy did not correlate with the severity of pulmonary vascular obstructive disease. Electrocardiographic evidence of left atrial enlargement was difficult to interpret. Additional intracardiac malformations could not be appreciated from the electrocardiographic findings. The predictive value of the electrocardiogram for the diagnosis of double-outlet right ventricle was considered to be low. In patients with double-outlet right ventricle without pulmonary stenosis, the electrocardiogram was not helpful in predicting the severity of pulmonary vascular obstructive disease.
Maintenance of Brain Monoamine Oxidase B Inhibition in Smokers After Overnight Cigarette Abstinence
Authors: Joanna S. Fowler, Gene-Jack Wang, Nora D. Volkow, Dinko Franceschi, Jean Logan, Naomi Pappas, Colleen Shea, Robert R. MacGregor, Victor Garza
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: The authors' goal was to replicate a previous finding that smokers have lower brain monoamine oxidase B (MAO-B) levels than comparison nonsmoking subjects and to determine if levels recover after overnight cigarette abstinence. METHOD: Brain MAO-B levels were measured by means of positron emission tomography in six smokers who were scanned twice: 11.3 hours (baseline) and 10 minutes after smoking one cigarette. RESULTS: Average MAO-B levels in smokers in the present study were similar to those found in the previous study and averaged 39% (SD=17) lower than those found in a comparison group of nonsmokers. Brain MAO-B levels did not differ between baseline levels and 10 minutes after smoking. CONCLUSIONS: This study reinforces the need to investigate whether MAO-B inhibition may account for some of the behavioral and epidemiological features of smoking.
Inhibiting Interactions of Lysine Demethylase LSD1 with Snail/Slug Blocks Cancer Cell Invasion
Authors: Giovanna Ferrari-Amorotti, Valentina Fragliasso, Roza Esteki, Zelia Prudente, Angela Rachele Soliera, Sara Cattelani, Gloria Manzotti, Giulia Grisendi, Massimo Dominici, Marco Pieraccioli, Giuseppe Raschellà, Claudia Chiodoni, Mario Paolo Colombo, Bruno Calabretta
Journal: Cancer Research (2012)

The process of epithelial-mesenchymal transition (EMT) which is required for cancer cell invasion is regulated by a family of E-box-binding transcription repressors, which include Snail (SNAIL1) and Slug (SNAI2). Snail appears to repress the expression of the EMT marker E-cadherin by epigenetic mechanisms dependent on the interaction of its N-terminal SNAG domain with chromatin-modifying proteins including lysine-specific demethylase 1 (LSD1/KDM1A). We assessed whether blocking Snail/Slug-LSD1 interaction by treatment with Parnate, an enzymatic inhibitor of LSD1, or TAT-SNAG, a cell-permeable peptide corresponding to the SNAG domain of Slug, suppresses the motility and invasiveness of cancer cells of different origin and genetic background. We show here that either treatment blocked Slug-dependent repression of the E-cadherin promoter and inhibited the motility and invasion of tumor cell lines without any effect on their proliferation. These effects correlated with induction of epithelial and repression of mesenchymal markers and were phenocopied by LSD1 or Slug downregulation. Parnate treatment also inhibited bone marrow homing/engraftment of Slug-expressing K562 cells. Together, these studies support the concept that targeting Snail/Slug-dependent transcription repression complexes may lead to the development of novel drugs selectively inhibiting the invasive potential of cancer cells.
Incidence, Predictors, and Outcome of Thrombosis After Successful Implantation of Drug-Eluting Stents
Authors: Ioannis Iakovou
Journal: JAMA (2005)

m e n t s i n a n t i p l a t e l e t therapy, thrombotic events remain the primary cause of death after percutaneous coronary interventions. 1,2][10] We analyzed the incidence, predictors, and
Prognostic Importance of Histone Methyltransferase <i>MLL5</i> Expression in Acute Myeloid Leukemia
Authors: Frederik Damm, Tina Oberacker, Felicitas Thol, Ewa Surdziel, Katharina Wagner, Anuhar Chaturvedi, Michael Morgan, Karoline Bomm, Gudrun Göhring, Michael Lübbert, Lothar Kanz, Walter Fiedler, Brigitte Schlegelberger, Gerhard Heil, Richard F. Schlenk, Konstanze Döhner, Hartmut Döhner, Jürgen Krauter, Arnold Ganser, Michael Heuser
Journal: Journal of Clinical Oncology (2011)

To assess the prognostic importance of mixed lineage leukemia 5 (MLL5) expression in acute myeloid leukemia (AML).MLL5 transcript levels from 509 patients with AML who were treated in multicenter trials AML SHG 0199 and AML SHG 0295 and 48 healthy volunteers were analyzed by real-time reverse-transcription polymerase chain reaction in the context of other molecular markers (NPM1, FLT3, CEBPA, IDH1/IDH2, NRAS, KIT, MN1, BAALC, ERG, and WT1).Patients with high (n = 127) compared with low (n = 382) MLL5 expression had a higher complete response rate in multivariate analysis (odds ratio, 1.87; 95% CI, 1.08 to 3.24; P = .026). In multivariate analysis, high MLL5 expression was a favorable prognostic marker for overall survival (OS; hazard ratio [HR], 0.66; 95% CI, 0.49 to 0.89; P = .007) and relapse-free survival (RFS; HR, 0.72; 95% CI, 0.52 to 1.01; P = .057). Patient characteristics, cytogenetic aberrations, and gene mutations were similarly distributed between patients with high and low MLL5 expression except for a higher platelet count in those with high MLL5 expression. MLL5 expression independently predicted prognosis in cytogenetically normal AML patients (n = 268; OS: HR, 0.53; 95% CI, 0.33 to 086; P = .011; RFS: HR, 0.61; 95% CI, 0.38 to 0.99; P = .05) and in patients with core-binding factor leukemias (n = 81; OS: HR, 0.12; 95% CI, 0.02 to 0.91; P = .04; RFS: HR, 0.18; 95% CI, 0.04 to 0.77; P = .02). The prognostic importance of high MLL5 expression was independently validated in 167 patients treated in the AMLSG 07/04 trial (OS: HR, 0.5; 95% CI, 0.27 to 0.92; P = .023; RFS: HR, 0.49; 95% CI, 0.25 to 0.96; P = .033).High MLL5 expression levels are associated with a favorable outcome and may improve risk and treatment stratification in AML.
Natural Autoantibodies Cytotoxic for Thymus Cells and for Neuraminidase-Treated Leukemia Cells in the Sera of Normal AKR Mice 2
Authors: M. Schlesinger, J. G. Bekesi
Journal: JNCI Journal of the National Cancer Institute (1977)

The sera of normal AKR mice were found to contain two types of naturally occurring autoantibodies. 1) Autoan-tibodies cytotoxic for mouse thymus cells in the presence of guinea pig complement were of the IgM class and were heat-labile. They exerted a cytotoxic effect on syngeneic and allogeneic thymus cells but not on lymph node and spleen cells. Absorption experiments indicated that the antigen with which these autoantibodies react was present in all examined tissues of AKR mice. The concentration of the antigen was about eight times higher on thymus cells than on other types of lymphoid cells. The cytotoxicity of normal AKR sera on thymus cells could be inhibited by various simple sugars; D-mannose, α-methyl-D-mannopyranoside, and L-fucose were the most potent inhibitors of autoantibodies to thymus cells. 2) Autoantibodies reactive with neuraminidase-treated AKR leukemia cells were also IgM in nature, were heat-labile, and could be absorbed by various tissues of AKR mice. Neuraminidase-treated leukemia cells were more effective in absorbing these autoantibodies than were un-treated leukemia cells. The cytotoxic activity of these autoan-tibodies could be completely inhibited by D-galactose, lactose, and L-fucose and inhibited to a lesser extent by α-methyl-D-mannopyranoside.
Improved medical and surgical management of cervical spine disease in patients with rheumatoid arthritis over 10 years
Authors: J. D Hamilton
Journal: Annals of the Rheumatic Diseases (2000)

(1) To compare clinical outcome and symptomatology of rheumatoid cervical myelopathy between patients managed conservatively and surgically. (2) To determine if surgical outcome has improved since the series published from this unit in 1987. (3) To examine the role of magnetic resonance imaging (MRI) in the diagnosis of cervical myelopathy.Patients undergoing MRI of the cervical spine between 1991 and 1996 were identified. Case records were reviewed retrospectively.111 patients with RA underwent 124 MRI scans. The median age at onset of cervical spine symptoms was 58 years (range 16-87) with median disease duration of 16 years (range 1-59). 18 (16%) required surgery immediately after MRI. 93 (84%) were managed conservatively, 9 of whom (10%) later required surgery. 2/7 deaths in the conservative group were directly related to cervical myelopathy. Patients requiring surgery were more likely to report paraesthesia, weakness, unsteadiness and to exhibit extensor plantar reflexes, gait disturbance, and reduced power. MRI findings did not correlate with clinical features. When compared with the 1974-82 cohort, fewer patients had severe myelopathy (Ranawat grade IIIB) before surgery (34% versus 7%). Early postoperative mortality improved from 9% to 0% and surgical complication rate fell from 50% to 22%. 89% of patients in the 1991-96 cohort reported subjective improvement in overall function.In this series surgical outcome has improved. The major factor in this more favourable outcome is probably that patients presenting with rheumatoid cervical myelopathy are now referred for surgery at an earlier stage of disease. Clinical findings correlate poorly with MRI findings, therefore clinical history should remain the key to determining the need for MRI.
Forced expiratory volume in one second: not just a lung function test but a marker of premature death from all causes
Authors: R. P. Young, R. Hopkins, T. E. Eaton
Journal: European Respiratory Journal (2007)

The clinical utility of spirometric screening of asymptomatic smokers for early signs of air flow limitation has recently come under review. The current authors propose that reduced forced expiratory volume in one second (FEV 1 ) is more than a measure of airflow limitation, but a marker of premature death with broad utility in assessing baseline risk of chronic obstructive pulmonary disease (COPD), lung cancer, coronary artery disease and stroke, collectively accounting for 70–80% of premature death in smokers. Reduced FEV 1 identifies undiagnosed COPD, has comparable utility to that of serum cholesterol in assessing cardiovascular risk and defines those smokers at greatest risk of lung cancer. As such, reduced FEV 1 should be considered a marker that identifies smokers at greatest need of medical intervention. Smoking cessation has been shown to attenuate FEV 1 decline and, if achieved before the age of 45–50 yrs, may not only preserve FEV 1 within normal values but substantially reduce cardiorespiratory complications of smoking. Recent findings suggest inhaled drugs (bronchodilators and corticosteroids), and possibly statins, may be effective in reducing morbidity and mortality in patients with chronic obstructive pulmonary disease. The current authors propose that spirometry has broad utility in identifying smokers who are at greatest risk of cardiorespiratory complications and greatest benefit from targeted preventive strategies, such as smoking cessation, prioritised screening and effective pharmacotherapy.
Beta 2-microglobulin-dependent T cells are dispensable for allergen-induced T helper 2 responses.
Authors: Y Zhang, K H Rogers, D B Lewis
Journal: The Journal of Experimental Medicine (1996)

CD4+ and CD8+ alpha/beta+ T cells of the T helper cell (Th)2 phenotype produce the cytokines IL-4, IL-5, and IL-13 that promote IgE production and eosinophilic inflammation. IL-4 may play an important role in mediating the differentiation of antigenically naive alpha/beta+ T cells into Th2 cells. Murine NK1.1+ (CD4+ or CD4-CD8-) alpha/beta+ T cells comprise a beta 2-microglobulin (beta 2m)-dependent cell population that rapidly produces IL-4 after cell activation in vitro and in vivo and has been proposed as a source of IL-4 for Th2 cell differentiation. alpha/beta+ CD8+ T cells, most of which require beta 2m for their development, have also been proposed as positive regulators of allergen-induced Th2 responses. We tested whether beta 2m-dependent T cells were essential for Th2 cell-mediated allergic reactions by treating wild-type, beta 2m-deficient (beta 2m -/-), and IL-4-deficient (IL-4 -/-) mice of the C57BL/6 genetic background with ovalbumin (OVA), using a protocol that induces robust allergic pulmonary disease in wild-type mice. OVA-treated beta 2m -/- mice had circulating levels of total and OVA-specific IgE, pulmonary eosinophilia, and expression of IL-4, IL-5, and IL-13 mRNA in bronchial lymph node tissue similar to that of OVA-treated wild-type mice. In contrast, these responses in OVA-treated IL-4 -/- mice were all either undetectable or markedly reduced compared with wild-type mice, confirming that IL-4 was required in this allergic model. These results indicate that the NK1.1+ alpha/beta+ T cell population, as well as other beta 2m-dependent populations, such as most peripheral alpha/beta+ CD8+ T cells, are dispensable for the Th2 pulmonary response to protein allergens.