tbuckley/cabot-search huggingface dataset:
Cysteinyl Leukotrienes Promote Human Airway Smooth Muscle Migration
Authors: Krishnan Parameswaran, Gerard Cox, Katherine Radford, Luke J. Janssen, Roma Sehmi, Paul M. O'Byrne
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Cysteinyl leukotrienes promote airway smooth muscle (ASM) contraction and proliferation. Little is known about their role in ASM migration. We investigated this using cultured human ASMs (between the second and fifth passages) obtained from the large airways of resected nonasthmatic lung. Platelet-derived growth factor-BB (1 ng/ml) promoted significant (3.5-fold) ASM migration of myocytes across collagen-coated 8-μm polycarbonate membranes in Transwell culture plates. Leukotriene E4 (10−7, 10−8, 10−9 M) did not demonstrate a chemotactic effect; it did promote chemokinesis. Priming by leukotriene E4 (10−7 M) significantly augmented the directional migratory response to platelet-derived growth factor (1.5-fold, p < 0.05). This was blocked by montelukast (10−6 M), demonstrating the effect to be mediated by the cysteinyl leukotriene receptor. The "priming effect" was also partially attenuated by prostaglandin E2 (10−7 M). Whereas both the chemokinetic and the chemotactic "primed" responses were equally attenuated by a p38 mitogen-activated protein kinase inhibitor (SB203580, 25 μM) and by a Rho-kinase inhibitor (Y27632, 10 μM), the chemotactic response showed greater inhibition than chemokinesis by a phosphatidylinositol-3 kinase inhibitor (LY294002, 50 μM). These experiments suggest that cysteinyl leukotrienes play an augmentary role in human ASM migration. The phosphatidylinositol-3 kinase pathway is a key signaling mechanism in the chemotactic migration of ASM cells in response to cysteinyl leukotrienes.
Nurse Practitioner Care Improves Renal Outcome in Patients with CKD
Authors: Mieke J. Peeters, Arjan D. van Zuilen, Jan A.J.G. van den Brand, Michiel L. Bots, Marjolijn van Buren, Marc A.G.J. ten Dam, Karin A.H. Kaasjager, Gerry Ligtenberg, Yvo W.J. Sijpkens, Henk E. Sluiter, Peter J.G. van de Ven, Gerald Vervoort, Louis-Jean Vleming, Peter J. Blankestijn, Jack F.M. Wetzels
Journal: Journal of the American Society of Nephrology (2013)

Treatment goals for patients with CKD are often unrealized for many reasons, but support by nurse practitioners may improve risk factor levels in these patients. Here, we analyzed renal endpoints of the Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of Nurse Practitioners (MASTERPLAN) study after extended follow-up to determine whether strict implementation of current CKD guidelines through the aid of nurse practitioners improves renal outcome. In total, 788 patients with moderate to severe CKD were randomized to receive nurse practitioner support added to physician care (intervention group) or physician care alone (control group). Median follow-up was 5.7 years. Renal outcome was a secondary endpoint of the MASTERPLAN study. We used a composite renal endpoint of death, ESRD, and 50% increase in serum creatinine. Event rates were compared with adjustment for baseline serum creatinine concentration and changes in estimated GFR were determined. During the randomized phase, there were small but significant differences between the groups in BP, proteinuria, LDL cholesterol, and use of aspirin, statins, active vitamin D, and antihypertensive medications, in favor of the intervention group. The intervention reduced the incidence of the composite renal endpoint by 20% (hazard ratio, 0.80; 95% confidence interval, 0.66 to 0.98; P=0.03). In the intervention group, the decrease in estimated GFR was 0.45 ml/min per 1.73 m(2) per year less than in the control group (P=0.01). In conclusion, additional support by nurse practitioners attenuated the decline of kidney function and improved renal outcome in patients with CKD.
Selective activation of STAT5 unveils its role in stem cell self-renewal in normal and leukemic hematopoiesis
Authors: Yuko Kato, Atsushi Iwama, Yuko Tadokoro, Kazuya Shimoda, Mayu Minoguchi, Shizuo Akira, Minoru Tanaka, Atsushi Miyajima, Toshio Kitamura, Hiromitsu Nakauchi
Journal: The Journal of Experimental Medicine (2005)

Although the concept of a leukemic stem cell system has recently been well accepted, its nature and the underlying molecular mechanisms remain obscure. Constitutive activation of signal transducers and activators of transcription 3 (STAT3) and STAT5 is frequently detected in various hematopoietic tumors. To evaluate their role in normal and leukemic stem cells, we took advantage of constitutively active STAT mutants to activate STAT signaling selectively in hematopoietic stem cells (HSCs). Activation of STAT5 in CD34- c-Kit+ Sca-1+ lineage marker- (CD34- KSL) HSCs led to a drastic expansion of multipotential progenitors and promoted HSC self-renewal ex vivo. In sharp contrast, STAT3 was demonstrated to be dispensable for the HSC maintenance in vivo, and its activation facilitated lineage commitment of HSCs in vitro. In a mouse model of myeloproliferative disease (MPD), sustained STAT5 activation in CD34- KSL HSCs but not in CD34+ KSL multipotential progenitors induced fatal MPD, indicating that the capacity of STAT5 to promote self-renewal of hematopoietic stem cells is crucial to MPD development. Our findings collectively establish a specific role for STAT5 in self-renewal of normal as well as leukemic stem cells.
The inhibiting effect of soft paraffin on the Kobner response in psoriasis
Authors: J.S. COMAISH, J.S. GREENER
Journal: British Journal of Dermatology (1976)

White soft paraffin has been shown to inhibit the development of the isomorphic response (Köbner phenomenon) in psoriasis. The possible reasons for this are discussed and it is suggested that this finding has implications which should lead to a greater understanding of the nature of psoriasis.
Central and Peripheral Mechanisms of T-Lymphocyte Activation and Vascular Inflammation Produced by Angiotensin II–Induced Hypertension
Authors: Paul J. Marvar, Salim R. Thabet, Tomasz J. Guzik, Heinrich E. Lob, Louise A. McCann, Connie Weyand, Frank J. Gordon, David G. Harrison
Journal: Circulation Research (2010)

Rationale : We have previously found that T lymphocytes are essential for development of angiotensin II–induced hypertension; however, the mechanisms responsible for T-cell activation in hypertension remain undefined. Objective : We sought to study the roles of the CNS and pressure elevation in T-cell activation and vascular inflammation caused by angiotensin II. Methods and Results : To prevent the central actions of angiotensin II, we created anteroventral third cerebral ventricle (AV3V) lesions in mice. The elevation in blood pressure in response to angiotensin II was virtually eliminated by AV3V lesions, as was activation of circulating T cells and the vascular infiltration of leukocytes. In contrast, AV3V lesioning did not prevent the hypertension and T-cell activation caused by the peripheral acting agonist norepinephrine. To determine whether T-cell activation and vascular inflammation are attributable to central influences or are mediated by blood pressure elevation, we administered hydralazine (250 mg/L) in the drinking water. Hydralazine prevented the hypertension and abrogated the increase in circulating activated T cells and vascular infiltration of leukocytes caused by angiotensin II. Conclusions : We conclude that the central and pressor effects of angiotensin II are critical for T-cell activation and development of vascular inflammation. These findings also support a feed-forward mechanism in which modest degrees of blood pressure elevation lead to T-cell activation, which in turn promotes inflammation and further raises blood pressure, leading to severe hypertension.
Statistics in Clinical Practice
Authors: T. Johnson
Journal: BMJ (1995)

David Coggon BMJ Publishing Group, £10.95, pp 116 ISBN 0 7279 0907 X

Over the past 20 years the BMJ has established a fine reputation for publishing papers and books that present basic statistical techniques to a clinical readership. The first book, T D V Swinscow's Statistics at Square One (now in its 8th edition), teaches simple data presentation, the basis of probability and inference, and applications of the more popular statistical tests. Statistics with Confidence (edited by Gardner and Altman, 1989) emphasises the importance of estimation, with details of the calculation of confidence intervals as well as simple statistical guidelines and checklists to aid authors and readers alike; both books were based on a …
Leptin and the risk of Barrett's oesophagus
Authors: B J Kendall, G A Macdonald, N K Hayward, J B Prins, I Brown, N Walker, N Pandeya, A C Green, P M Webb, D C Whiteman
Journal: Gut (2007)

<h3>Background:</h3> Obesity is associated with increased risks of Barrett’s oesophagus and oesophageal adenocarcinoma. Alterations in serum leptin and adiponectin, obesity-related cytokines, have been linked with several cancers and have been postulated as potential mediators of obesity-related carcinogenesis; however, the relationship with Barrett’s oesophagus remains unexplored. <h3>Methods:</h3> Serum leptin and adiponectin concentrations were measured on two subsets of participants within a case–control study conducted in Brisbane, Australia. Cases were people aged 18–79 years with histologically confirmed Barrett’s oesophagus newly diagnosed between 2003 and 2006. Population controls, frequency matched by age and sex to cases, were randomly selected from the electoral roll. Phenotype and medical history data were collected through structured, self-completed questionnaires. Odds ratios (OR) and 95% CI were calculated using multivariable logistic regression analysis. <h3>Results:</h3> In the pilot analysis (51 cases, 67 controls) risks of Barrett’s oesophagus were highest among those in the highest quartile of serum leptin (OR 4.6, 95% CI 0.6 to 33.4). No association was seen with adiponectin. In the leptin validation study (306 cases, 309 controls), there was a significant threefold increased risk of Barrett’s oesophagus among men in the highest quartile of serum leptin (OR 3.3, 95% CI 1.7 to 6.6) and this persisted after further adjustment for symptoms of gastro-oesophageal reflux (OR 2.4, 95% CI 1.1 to 5.2). In contrast, the risk of Barrett’s oesophagus among women decreased with increasing serum leptin concentrations. <h3>Conclusions:</h3> High serum leptin is associated with an increased risk of Barrett’s oesophagus among men but not women. This association is not explained simply by higher body mass or gastro-oesophageal reflux among cases. The mechanism remains to be determined.
The invariant chain is required for intracellular transport and function of major histocompatibility complex class II molecules.
Authors: E A Elliott, J R Drake, S Amigorena, J Elsemore, P Webster, I Mellman, R A Flavell
Journal: The Journal of Experimental Medicine (1994)

The major histocompatibility complex (MHC) class II-associated invariant chain (Ii) is thought to act as a chaperone that assists class II during folding, assembly, and transport. To define more precisely the role of Ii chain in regulating class II function, we have investigated in detail the biosynthesis, transport, and intracellular distribution of class II molecules in splenocytes from mice bearing a deletion of the Ii gene. As observed previously, the absence of Ii chain caused significant reduction in both class II-restricted antigen presentation and expression of class II molecules at the cell surface because of the intracellular accumulation of alpha and beta chains. Whereas much of the newly synthesized MHC molecules enter a high molecular weight aggregate characteristic of misfolded proteins, most of the alpha and beta chains form dimers and acquire epitopes characteristic of properly folded complexes. Although the complexes do not bind endogenously processed peptides, class II molecules that reach the surface are competent to bind peptides added to the medium, further demonstrating that at least some of the complexes fold properly. Similar to misfolded proteins, however, the alpha and beta chains are poorly terminally glycosylated, suggesting that they fail to reach the Golgi complex. As demonstrated by double label confocal and electron microscope immunocytochemistry, class II molecules were found in a subcompartment of the endoplasmic reticulum and in a population of small nonlysosomal vesicles possibly corresponding to the intermediate compartment or cis-Golgi network. Thus, although alpha and beta chains can fold and form dimers on their own, the absence of Ii chain causes them to be recognized as "misfolded" and retained in the same compartments as bona fide misfolded proteins.
Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting
Authors: Razelle Kurzrock, Hagop M. Kantarjian, Jorge E. Cortes, Neil Singhania, Deborah A. Thomas, Edward F. Wilson, John J. Wright, Emil J. Freireich, Moshe Talpaz, Saïd M. Sebti
Journal: Blood (2003)
Antitussive Drugs—Past, Present, and Future
Authors: P.V. Dicpinigaitis, A.H. Morice, S.S. Birring, L. McGarvey, J.A. Smith, B.J. Canning, C.P. Page
Journal: Pharmacological Reviews (2014)

Cough remains a serious unmet clinical problem, both as a symptom of a range of other conditions such as asthma, chronic obstructive pulmonary disease, gastroesophageal reflux, and as a problem in its own right in patients with chronic cough of unknown origin. This article reviews our current understanding of the pathogenesis of cough and the hypertussive state characterizing a number of diseases as well as reviewing the evidence for the different classes of antitussive drug currently in clinical use. For completeness, the review also discusses a number of major drug classes often clinically used to treat cough but that are not generally classified as antitussive drugs. We also reviewed a number of drug classes in various stages of development as antitussive drugs. Perhaps surprising for drugs used to treat such a common symptom, there is a paucity of well-controlled clinical studies documenting evidence for the use of many of the drug classes in use today, particularly those available over the counter. Nonetheless, there has been a considerable increase in our understanding of the cough reflex over the last decade that has led to a number of promising new targets for antitussive drugs being identified and thus giving some hope of new drugs being available in the not too distant future for the treatment of this often debilitating symptom.
Pulmonary hypertension in advanced sarcoidosis: epidemiology and clinical characteristics
Authors: A. F. Shorr, D. L. Helman, D. B. Davies, S. D. Nathan
Journal: European Respiratory Journal (2005)

Pulmonary hypertension (PH) is a predictor of poor outcome in sarcoidosis. Little is known about the epidemiology of PH in sarcoidosis. The current authors reviewed the records of patients with sarcoidosis listed for lung transplantation in the USA between January 1995 and December 2002. PH was defined as a mean pulmonary artery pressure of >25 mmHg and severe PH as a mean pulmonary artery pressure of > or =40 mmHg. The cohort included 363 patients of whom 73.8% had PH. Neither spirometric testing nor the need for corticosteroids was associated with PH. Subjects with PH required more supplemental oxygen (2.7+/-1.8 L.min(-1) versus 1.6+/-1.4 L.min(-1)). The cardiac index was lower in individuals with PH, whereas the pulmonary capillary wedge pressure was higher. In multivariate analysis, supplemental oxygen remained an independent predictor of PH, whereas the relationship between cardiac index and PH was no longer significant. As a screening test, the need for oxygen had a sensitivity and specificity of 91.8% and 32.6%, respectively. Pulmonary hypertension is common in advanced sarcoidosis. The need for oxygen correlates with pulmonary hypertension. Since pulmonary hypertension is associated with poor outcomes and because simple clinical criteria fail to identify patients with sarcoidosis and pulmonary hypertension, more aggressive screening for this should be considered.
Involvement of both major histocompatibility complex class II alpha and beta chains in CD4 function indicates a role for ordered oligomerization in T cell activation.
Authors: R König, X Shen, R N Germain
Journal: The Journal of Experimental Medicine (1995)

CD4 is a membrane glycoprotein on T lymphocytes that binds to the same peptide:major histocompatibility complex (MHC) class II molecule recognized by the antigen-specific receptor (TCR), thereby stabilizing interactions between the TCR and peptide;MHC class II complexes and promoting the localization of the src family tyrosine kinase p56lck into the receptor complex. Previous studies identified a solvent-exposed loop on the class II beta 2 domain necessary for binding to CD4 and for eliciting CD4 coreceptor activity. Here, we demonstrate that a second surface-exposed segment of class II is also critical for CD4 function. This site is in the alpha 2 domain, positioned in single class II heterodimers in such a way that it cannot simultaneously interact with the same CD4 molecule as the beta 2 site. The ability of mutations at either site to diminish CD4 function therefore indicates that specifically organized CD4 and/or MHC class II oligomers play a critical role in coreceptor-dependent T cell activation.
Challenges of Existing Pediatric Dyslipidemia Guidelines
Authors: Julia Steinberger, Aaron S. Kelly
Journal: Circulation (2008)

E xisting guidelines for screening and managing lipopro- tein abnormalities in children and adolescents are based on a consensus document published over 15 years ago by the National Cholesterol Education Program (NCEP) Expert Panel on Blood Cholesterol Levels in Children and Adolescents. 1 This document was based on evidence that elevated levels of low-density lipoprotein (LDL) cholesterol are highly correlated with development of atherosclerotic cardiovascular disease (ASCVD) in adults and on pathological data suggesting that dyslipidemia in children and adolescents was associated with early arterial plaque development.The panel recommended 2 strategies to address abnormal lipoprotein levels in children: a population-based approach (dietary recommendations) and a targeted screening approach (selective screening based on family history of ASCVD and/or parental hypercholesterolemia).The guidelines recommended dietary and lifestyle interventions for children with elevated LDL cholesterol levels.They proposed that drug therapy only be considered when LDL cholesterol levels are Ն190 mg/dL or Ն160 mg/dL with concomitant ASCVD risk factors (Ն2) or with a family history of ASCVD.
Thalidomide: Emerging Role in Cancer Medicine
Authors: Paul Richardson, Teru Hideshima, Kenneth Anderson
Journal: Annual Review of Medicine (2002)

▪ Abstract Thalidomide—removed from widespread clinical use by 1962 because of severe teratogenicity—has antiangiogenic and immunomodulatory effects, including the inhibition of tumor necrosis alpha factor. It has now returned to practice as an effective oral agent in the management of various disease states including erythema nodosum leprosum, for which it was approved by the U.S. Food and Drug Administration in 1998, and more recently certain malignancies, including multiple myeloma. Although thalidomide's mechanism of action remains incompletely understood, considerable insight has been generated by extensive preclinical studies in multiple myeloma. Moreover, clinical trials have confirmed benefit in relapsed disease, and the role of thalidomide in treating newly diagnosed patients is currently under study. Its use in other tumors is under evaluation, with promise in renal cell carcinoma, prostate cancer, glioma, and Kaposi's sarcoma. Activity has also been demonstrated in chronic graft-versus-host disease and in symptom relief as part of palliative care.
The effect of carvedilol on enhanced ADP-ribosylation and red blood cell membrane damage caused by free radicals
Authors: T Habon
Journal: Cardiovascular Research (2001)

Objective: Previous studies have reported that the beta and alpha adrenoceptor blocker carvedilol has unique protective effects on free radical-induced myocardial injury. The aim of this study was to examine how carvedilol regulates reactive-oxygen-species-mediated signaling and decreases red blood cell membrane damage in heart perfusion and in a rheological model. Methods: The ischemia–reperfusion-induced oxidative cell damage, and changes in the intracellular signaling mediated by reactive oxygen species and peroxynitrite were studied on rat hearts in a Langendorff perfusion system (n=15). The effect of carvedilol on red blood cell suspension viscosity (hematocrit: 60%) incubated with free radical generator (phenazine methosulphate) was also investigated (n=10). The measurements were performed on a capillary viscosimeter. Results: In both studies a protective effect of carvedilol was found, as the decrease of red blood cell suspension viscosity and K+ concentration in the supernatant indicated. Carvedilol significantly decreased the ischemia–reperfusion-induced free radical production and the NAD+ catabolism and reversed the poly- and mono(ADP-ribosyl)ation. Carvedilol also decreased the lipid peroxidation and membrane damages as determined by free malondialdehyde production and the release of intracellular enzymes. The self ADP-ribosylation of isolated poly(ADP-ribose) polymerase was also significantly inhibited by carvedilol. Conclusion: Our results show that carvedilol can modulate the reactive-oxygen-species-induced signaling through poly- and mono(ADP-ribosyl)ation reactions, the NAD+ catabolism in postischemic perfused hearts and has a marked scavenger effect on free radical generator-induced red blood cell membrane damage. All these findings may play an important role in the beneficial effects of carvedilol treatment in different cardiovascular diseases.
Robust Gene Expression Signature from Formalin-Fixed Paraffin-Embedded Samples Predicts Prognosis of Non–Small-Cell Lung Cancer Patients
Authors: Yang Xie, Guanghua Xiao, Kevin R. Coombes, Carmen Behrens, Luisa M. Solis, Gabriela Raso, Luc Girard, Heidi S. Erickson, Jack Roth, John V. Heymach, Cesar Moran, Kathy Danenberg, John D. Minna, Ignacio I. Wistuba
Journal: Clinical Cancer Research (2011)

Abstract Purpose: The requirement of frozen tissues for microarray experiments limits the clinical usage of genome-wide expression profiling by using microarray technology. The goal of this study is to test the feasibility of developing lung cancer prognosis gene signatures by using genome-wide expression profiling of formalin-fixed paraffin-embedded (FFPE) samples, which are widely available and provide a valuable rich source for studying the association of molecular changes in cancer and associated clinical outcomes. Experimental Design: We randomly selected 100 Non–Small-Cell lung cancer (NSCLC) FFPE samples with annotated clinical information from the UT-Lung SPORE Tissue Bank. We microdissected tumor area from FFPE specimens and used Affymetrix U133 plus 2.0 arrays to attain gene expression data. After strict quality control and analysis procedures, a supervised principal component analysis was used to develop a robust prognosis signature for NSCLC. Three independent published microarray datasets were used to validate the prognosis model. Results: This study showed that the robust gene signature derived from genome-wide expression profiling of FFPE samples is strongly associated with lung cancer clinical outcomes and can be used to refine the prognosis for stage I lung cancer patients, and the prognostic signature is independent of clinical variables. This signature was validated in several independent studies and was refined to a 59-gene lung cancer prognosis signature. Conclusions: We conclude that genome-wide profiling of FFPE lung cancer samples can identify a set of genes whose expression level provides prognostic information across different platforms and studies, which will allow its application in clinical settings. Clin Cancer Res; 17(17); 5705–14. ©2011 AACR.