tbuckley/cabot-search huggingface dataset:
The Nuclear Receptor Constitutive Androstane Receptor/NR1I3 Enhances the Profibrotic Effects of Transforming Growth Factor β and Contributes to the Development of Experimental Dermal Fibrosis
Authors: Jérôme Avouac, Katrin Palumbo‐Zerr, Nadira Ruzehaji, Michal Tomcik, Pawel Zerr, Clara Dees, Alfiya Distler, Christian Beyer, Holm Schneider, Oliver Distler, Georg Schett, Yannick Allanore, Jörg H. W. Distler
Journal: Arthritis & Rheumatology (2014)

Nuclear receptors regulate cell growth, differentiation, and homeostasis. Selective nuclear receptors promote fibroblast activation, which leads to tissue fibrosis, the hallmark of systemic sclerosis (SSc). This study was undertaken to investigate the effects of constitutive androstane receptor (CAR)/NR1I3, an orphan nuclear receptor, on fibroblast activation and experimental dermal fibrosis.CAR expression was quantified by quantitative polymerase chain reaction, Western blotting, immunohistochemistry, and immunofluorescence. CAR expression was modulated by small molecules, small interfering RNA, forced overexpression, and site-directed mutagenesis. The effects of CAR activation were analyzed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor type I (TβRI-CA).Up-regulation of CAR was detected in the skin and in dermal fibroblasts in SSc patients. Stimulation of healthy fibroblasts with TGFβ induced the expression of CAR messenger RNA and protein in a Smad-dependent manner. Pharmacologic activation or overexpression of CAR in healthy fibroblasts significantly increased the stimulatory effects of TGFβ on collagen synthesis and myofibroblast differentiation, and amplified the stimulatory effects of TGFβ on COL1A2 transcription activity. Treatment with CAR agonist increased the activation of canonical TGFβ signaling in murine models of SSc and exacerbated bleomycin-induced and TβRI-CA-induced fibrosis with increased dermal thickening, myofibroblast counts, and collagen accumulation.Our findings indicate that CAR is up-regulated in SSc and regulates TGFβ signaling. Activation of CAR increases the profibrotic effects of TGFβ in cultured fibroblasts and in different preclinical models of SSc. Thus, inactivation of CAR might be a novel approach to target aberrant TGFβ signaling in SSc and in other fibrotic diseases.
Flow detection and calcium signalling in vascular endothelial cells
Authors: Joji Ando, Kimiko Yamamoto
Journal: Cardiovascular Research (2013)

Blood vessels alter their morphology and function in response to changes in blood flow, and their responses are based on blood flow detection by the vascular endothelium. Endothelial cells (ECs) covering the inner surface of blood vessels sense shear stress generated by flowing blood and transmit the signal into the interior of the cell, which evokes a cellular response. The EC response to shear stress is closely linked to the regulation of vascular tone, blood coagulation and fibrinolysis, angiogenesis, and vascular remodelling, and it plays an important role in maintaining the homoeostasis of the circulatory system. Impairment of the EC response to shear stress leads to the development of vascular diseases such as hypertension, thrombosis, aneurysms, and atherosclerosis. Rapid progress has been made in elucidating shear stress mechanotransduction by using in vitro methods that apply controlled levels of shear stress to cultured ECs in fluid-dynamically designed flow-loading devices. The results have revealed that shear stress is converted into intracellular biochemical signals that are mediated by a variety of membrane molecules and microdomains, including ion channels, receptors, G-proteins, adhesion molecules, the cytoskeleton, caveolae, the glycocalyx, and primary cilia, and that multiple downstream signalling pathways become activated almost simultaneously. Nevertheless, neither the shear-stress-sensing mechanisms nor the sensor molecules that initially sense shear stress are yet known. Their identification would contribute to a better understanding of the pathophysiology of the vascular diseases that occur in a blood flow-dependent manner and to the development of new treatments for them.
Developmental changes in long-opening behavior of L-type Ca2+ channels in embryonic chick heart cells.
Authors: N Tohse, J Mészáros, N Sperelakis
Journal: Circulation Research (1992)

In the early (3-day) stage of development, long-lasting openings of the L-type Ca2+ channels (mode 2) occur in embryonic chick heart cells. Since mode-2 behavior is infrequently observed in adult heart cells of other species, in the present study, developmental change in behavior of the Ca2+ channel was examined in young (3-day) and old (17-day) embryonic chick heart cells. In the whole-cell voltage clamp, the L-type Ca2+ current carried by Ca2+ ions was smaller in amplitude and had a faster inactivation in 17-day cells than in 3-day cells. The peak current density was 8.1 +/- 0.2 microA/cm2 (mean +/- SEM, n = 5) and 5.1 +/- 0.3 microA/cm2 (n = 5) in 3-day and 17-day cells, respectively. When the charge carrier was Ba2+, the L-type Ca2+ channel current density was also smaller in 17-day cells (22.7 +/- 1.8 microA/cm2) than in 3-day cells (28.3 +/- 2.1 microA/cm2). In single-channel recordings, the mode-2 behavior was infrequent in 17-day cells compared with 3-day cells. High-open probability sweeps (with an open probability of greater than 0.25), reflecting mode-2 behavior, accounted for 20.2% and 3.7% in 3-day and 17-day cells, respectively. The ensemble-averaged currents in 17-day cells was 37% of that current in 3-day cells. In addition, decay of the averaged current appeared to be faster in 17-day cells than in 3-day cells. All data from the single-channel analysis agreed with the data from the whole-cell voltage clamp.(ABSTRACT TRUNCATED AT 250 WORDS)
Clinical response, drug survival and predictors thereof in 432 ankylosing spondylitis patients after switching tumour necrosis factor α inhibitor therapy: results from the Danish nationwide DANBIO registry
Authors: Bente Glintborg, Mikkel Østergaard, Niels Steen Krogh, Ulrik Tarp, Natalia Manilo, Anne Gitte Rasmussen Loft, Annette Hansen, Annette Schlemmer, Victoria Fana, Hanne M Lindegaard, Henrik Nordin, Claus Rasmussen, Leif Ejstrup, Dorte Vendelbo Jensen, Peter Mosborg Petersen, Merete Lund Hetland
Journal: Annals of the Rheumatic Diseases (2012)

To investigate frequencies and reasons for switching, treatment responses and drug survival in patients with ankylosing spondylitis (AS) switching tumour-necrosis-factor-α inhibitor (TNFi) treatment in routine clinical care.AS patients were identified in the Danish nationwide DANBIO registry. Disease activity, treatment responses (50% or 20 mm reduction in Bath AS Disease Activity Index (BASDAI)), duration and rates of drug survival and predictors thereof were studied in patients receiving ≥2 different biological drugs.Of 1436 AS patients starting TNFi treatment, 432 patients (30%) switched to a second and 137 (10%) to a third biological drug. Compared with non-switchers, switchers were more frequently women (33%/22%), had shorter disease duration (3 years/5 years) and higher BASDAI (62(52-76) mm/56(43-69) mm (median(interquartile-range))), Bath AS Functional Index (BASFI) (54(39-71) mm/47(31-65) mm) and visual-analogue-scale (VAS) global, pain and fatigue scores when they started the first TNFi (all p<0.01). Main reason for switching was lack of response (56%). During the first, second and third treatment BAS- and VAS scores had decreased after 6 months' treatment (all p<0.05). Median drug survivals were 3.1, 1.6 and 1.8 years respectively (p<0.001). After 2 years of treatment 52% of switchers and 63% of non-switchers had achieved response (number needed to treat 1.9 and 1.6, respectively, p=0.01). Drug survivals were similar regardless of the reason for switching. Male gender and low BASFI predicted drug survival of the second TNFi.Nearly one-third of AS patients in clinical practice switched biological treatment. Response rates and drug survivals were lower among switchers, however, half of switchers achieved treatment response.
Local Anesthetic Anchoring to Cardiac Sodium Channels
Authors: Ronald A. Li, Robert G. Tsushima, Klaus Himmeldirk, David S. Dime, Peter H. Backx
Journal: Circulation Research (1999)

Local anesthetics inhibit Na+ channels in a variety of tissues, leading to potentially serious side effects when used clinically. We have created a series of novel local anesthetics by connecting benzocaine (BZ) to the sulfhydryl-reactive group methanethiosulfonate (MTS) via variable-length polyethylether linkers (L) (MTS-LX-BZ [X represents 0, 3, 6, or 9]). The application of MTS-LX-BZ agents modified native rat cardiac as well as heterologously expressed human heart (hH1) and rat skeletal muscle (rSkM1) Na+ channels in a manner resembling that of free BZ. Like BZ, the effects of MTS-LX-BZ on rSkM1 channels were completely reversible. In contrast, MTS-LX-BZ modification of heart and mutant rSkM1 channels, containing a pore cysteine at the equivalent location as cardiac Na+ channels (ie, Y401C), persisted after drug washout unless treated with DTT, which suggests anchoring to the pore via a disulfide bond. Anchored MTS-LX-BZ competitively reduced the affinity of cardiac Na+ channels for lidocaine but had minimal effects on mutant channels with disrupted local anesthetic modification properties. These results establish that anchored MTS-LX-BZ compounds interact with the local anesthetic binding site (LABS). Variation in the linker length altered the potency of channel modification by the anchored drugs, thus providing information on the spatial relationship between the anchoring site and the LABS. Our observations demonstrate that local anesthetics can be anchored to the extracellular pore cysteine in cardiac Na+ channels and dynamically interact with the intracellular LABS. These results suggest that nonselective agents, such as local anesthetics, might be made more selective by linking these agents to target-specific anchors.
Autologous stem cell transplantation for primary refractory Hodgkin’s disease: results and clinical variables affecting outcome
Authors: M. Constans, A. Sureda, M.J. Terol, R. Arranz, M.D. Caballero, A. Iriondo, I. Jarque, E. Carreras, J.M. Moraleda, D. Carrera, A. León, A. López, C. Albó, J. Díaz-Mediavilla, P. Fernández-Abellán, J.C. García-Ruiz, F. Hernández-Navarro, R. Mataix, J. Petit, M.J. Pascual, J. Rifón, J. García-Conde, J.M. Fernández-Rañada, M.V. Mateos, J. Sierra, E. Conde
Journal: Annals of Oncology (2003)
EphrinB Ligands Recruit GRIP Family PDZ Adaptor Proteins into Raft Membrane Microdomains
Authors: Katja Brückner, Juan Pablo Labrador, Peter Scheiffele, Anne Herb, Peter H Seeburg, Rüdiger Klein
Journal: Neuron (1999)

Transmembrane ephrinB proteins have important functions during embryonic patterning as ligands for Eph receptor tyrosine kinases and presumably as signal-transducing receptor-like molecules. Consistent with "reverse" signaling, ephrinB1 is localized in sphingo-lipid/cholesterol-enriched raft microdomains, platforms for the localized concentration and activation of signaling molecules. Glutamate receptor–interacting protein (GRIP) and a highly related protein, which we have termed GRIP2, are recruited into these rafts through association with the C-terminal PDZ target site of ephrinB1. Stimulation of ephrinB1 with soluble EphB2 receptor ectodomain causes the formation of large raft patches that also contain GRIP proteins. Moreover, a GRIP-associated serine/threonine kinase activity is recruited into ephrinB1–GRIP complexes. Our findings suggest that GRIP proteins provide a scaffold for the assembly of a multiprotein signaling complex downstream of ephrinB ligands.
Gene Therapy With Inducible Nitric Oxide Synthase Protects Against Myocardial Infarction via a Cyclooxygenase-2–Dependent Mechanism
Authors: Qianhong Li, Yiru Guo, Yu-Ting Xuan, Charles J. Lowenstein, Susan C. Stevenson, Sumanth D. Prabhu, Wen-Jian Wu, Yanqing Zhu, Roberto Bolli
Journal: Circulation Research (2003)

Although the inducible isoform of NO synthase (iNOS) mediates late preconditioning (PC), it is unknown whether iNOS gene transfer can replicate the cardioprotective effects of late PC, and the role of this protein in myocardial ischemia is controversial. Thus, the cDNA for human iNOS was cloned behind the Rous sarcoma virus (RSV) promoter to create adenovirus (Ad) 5/iNOS lacking E1, E2a, and E3 regions. Intramyocardial injection of Ad5/iNOS in mice increased local iNOS protein expression and activity and markedly reduced infarct size. The infarct-sparing effects of Ad5/iNOS were at least as powerful as those of ischemic PC. The increased iNOS expression was associated with increased cyclooxygenase-2 (COX-2) protein expression and prostanoid levels. Pretreatment with the COX-2-selective inhibitor NS-398 completely abrogated the infarct-sparing actions of Ad5/iNOS, demonstrating that COX-2 is an obligatory downstream effector of iNOS-dependent cardioprotection. We conclude that gene transfer of iNOS (an enzyme commonly thought to be detrimental) affords powerful cardioprotection the magnitude of which is equivalent to that of late PC. This is the first report that upregulation of iNOS, in itself, is sufficient to reduce infarct size. The results provide proof-of-principle for gene therapy against ischemia/reperfusion injury, which increases local myocardial NO synthase levels without the need for continuous intravenous infusion of NO donors and without altering systemic hemodynamics. The data also reveal the existence of a close coupling between iNOS and COX-2, whereby induction of the former enzyme leads to secondary induction of the latter, which in turn mediates the cytoprotective effects of iNOS. We propose that iNOS and COX-2 form a stress-responsive functional module that mitigates ischemia/reperfusion injury.
Hantavirus epidemic In Europe, 1993
Authors: J. Clement, P. McKenna, P. Colson, Ph Damoiseaux, C. Penalba, P. Halin, D. Lombart, BernardLe Guenno, MarieAlice Camprasse, JeanCharles Guilbaut, Pascale Lanoux, Bruno Hoen, PierreE. Rollin, Daniel Coudrier, Pierre Sureau
Journal: The Lancet (1994)
The Use of Radiation As a Component of Breast Conservation Therapy in National Comprehensive Cancer Network Centers
Authors: Thomas A. Buchholz, Richard L. Theriault, Joyce C. Niland, Melissa E. Hughes, Rebecca Ottesen, Stephen B. Edge, Michael A. Bookman, Jane C. Weeks
Journal: Journal of Clinical Oncology (2006)

Purpose Benchmark data regarding quality measures of breast cancer management are needed. We investigated rates of radiation use after breast conservation therapy (BCT) for patients treated for ductal carcinoma-in-situ (DCIS) or invasive breast cancer at National Comprehensive Cancer Network (NCCN) centers. Patients and Methods We studied 3,333 consecutive patients treated between 1997 and 2002 with BCT for DCIS (n = 587) or for stage I or II breast cancer (n = 2,746) in eight NCCN centers. Results The overall rate of radiation therapy use was 91%, with a lower frequency of radiation use in DCIS versus invasive breast cancers (82% v 94%; odds ratio [OR] = 0.31; P &lt; .0001). In a multivariable analysis of the patients with DCIS, the only factor significantly associated with lower rates of radiation use was low/intermediate grade (OR = 0.19; P = .0003). For patients with invasive breast cancer, significant factors were presence of comorbidity (OR = 0.53; P = .0005), tubular histology (OR = 0.39; P = .02), type of health insurance (P = .0072), and the NCCN institution (P = .0005). The model also showed lower rates of radiation use in patients with stage II disease who did not receive systemic therapy (OR = 0.01; P = .0001), younger patients who did not receive systemic therapy (P = .003); and older patients with stage I disease (P &lt; .0001). Conclusion Radiation use as a component of BCT was high for patients seen at NCCN centers; however, there was variability in practice patterns noted across institutions. Radiation was most commonly omitted in patients with favorable disease characteristics, patients with comorbidities, and patients who also did not receive guideline-recommended systemic treatment.
Effect of introduction of integrated out of hours care in England: observational study
Authors: Val Lattimer, Joanne Turnbull, Abigail Burgess, Heidi Surridge, Karen Gerard, Judith Lathlean, Helen Smith, Steve George
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objectives</b> To quantify service integration achieved in the national exemplar programme for single call access to out of hours care through NHS Direct, and its effect on the wider health system. <b>Design</b> Observational before and after study of demand, activity, and trends in the use of other health services. <b>Participants</b> 34 general practice cooperatives with NHS Direct partners (exemplars): four were case exemplars; 10 control cooperatives. <b>Setting</b> England. <b>Main outcome measures</b> Extent of integration; changes in demand, activity, and trends in emergency ambulance transports; attendances at emergency departments, minor injuries units, and NHS walk-in centres; and emergency admissions to hospital in the first year. <b>Results</b> Of 31 distinct exemplars, 21 (68%) integrated all out of hours call management. Nine (29%) achieved single call access for all patients. In the only case exemplar where direct comparison was possible, a higher proportion of telephone calls were handled by cooperative nurses before integration than by NHS Direct afterwards (2622/6687 (39%) <i>v</i> 2092/7086 (30%): P &lt; 0.0001). Other case exemplars did not achieve 30%. A small but significant downturn in overall demand for care seen in two case exemplars was also seen in the control cooperatives. The number of emergency ambulance transports increased in three of the four case exemplars after integration, reaching statistical significance in two (5%, −0.02% to 10%, P = 0.06; 6%, 1% to 12%, P = 0.02; 7%, 3% to 12%, P = 0.001). This was always accompanied by a significant reduction in the number of calls to the integrated service. <b>Conclusion</b> Most exemplars achieved integration of call management but not single call access for patients. Most patients made at least two telephone calls to contact NHS Direct, and then waited for a nurse to call back. Evidence for transfer of demand from case exemplars to 999 ambulance services may be amenable to change, but NHS Direct may not have sufficient capacity to support national implementation of the programme.
Relationship between the functional exon 3 deleted growth hormone receptor polymorphism and symptomatic osteoarthritis in women
Authors: K M J A Claessen, M Kloppenburg, H M Kroon, J Bijsterbosch, A M Pereira, J A Romijn, T van der Straaten, R G H H Nelissen, A Hofman, A G Uitterlinden, B J Duijnisveld, N Lakenberg, M Beekman, J B van Meurs, P E Slagboom, N R Biermasz, I Meulenbelt
Journal: Annals of the Rheumatic Diseases (2013)

Several studies suggest a role of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in the pathophysiology of primary osteoarthritis (OA). A common polymorphism of the GH receptor (exon 3 deletion, d3-GHR) is associated with increased GH/IGF-1 activity.To study associations between the d3-GHR polymorphism and symptomatic OA.In the GARP (Genetics, osteoARthritis and Progression) study, we compared the d3-GHR polymorphism between OA patients and controls. GARP patients were genotyped for seven single nucleotide polymorphisms encompassing the d3-GHR gene, using rs4590183 as proxy for d3-GHR (pairwise r(2)=1). Binary logistic regression models with robust SEs were performed, stratified by sex. For replication, rs4590183 was tested in three additional cohorts. Fixed- and random-effects combined analyses were performed.In female GARP patients with severe familial OA, d3-GHR was associated with OA (adjusted OR 1.36 (95% CI 1.01 to 1.83), p=0.043), independently of age and body mass index. Combined analysis of all studies showed suggestive evidence for association between d3-GHR and OA (OR=1.17 (95% CI 1.04 to 1.30), p=0.008). Evidence was strongest in hip OA cases, without any evidence for heterogeneity.In women, the d3-GHR polymorphism was associated with symptomatic OA, especially at the hip site.
Re: Risk of Malignant Progression in Barrett's Esophagus Patients: Results from a Large Population-Based Study
Authors: M. Rugge, M. Fassan, F. Cavallini, G. Zaninotto
Journal: JNCI Journal of the National Cancer Institute (2012)

Bhat’s article (1) and its accompanying editorial (2) addressed the screening and/or surveillance strategies for Barrett’s esophagus (BE). We agree that the incidence of Barrett’s adenocarcinoma (BAc) is lower than that previously claimed (1,3). Consistent with data, variable endoscopy/biopsy protocols and inconsistent endoscopist–pathologist interactions substantially affect the assessment and reported prevalence of this disease (4,5). Unequivocal definitions, educational programs, and audited interdisciplinary teamwork are needed to obtain more reliable information, as demonstrated by our seven-year experience with a multicenter BE registry (the Esofago di Barrett e Rischio di Adenocarcinoma [EBRA] in Northeast Italy) (4,5). This registry, which is restricted to the records of intestinalized-BE patients and excludes patients with cancers that were diagnosed within a year of enrollment, currently includes 841 patients, with a median followup of 44.6 months or 3 058 patient-years (6). The incidence of high-grade dysplasia (HGD) is 4.9 (95% confidence interval [CI] = 2.7 to 8.1) patients per 1 000 person-years, and the incidence of BAc is 2.3 (95% CI = 0.9 to 4.7) patients per 1 000 person-years. Among patients with low-grade dysplasia, 32.0 (95% CI = 12.7 to 65.3) per 1 000 patient-years will progress to HG-D or BAc. These prospectively collected data lie between the earlier “enthusiastic” figures and Bhat’s “pessimistic” findings. Interestingly, Bhat’s findings and our own experience with the EBRA consistently demonstrate that the BE planet has so far been only partially explored.
Effects of Sodium Sulfate on Fecal pH and Proliferation of Colonic Mucosa in Patients at High Risk for Colon Cancer
Authors: H. Kashtan, R. C. Gregoire, W. R. Bruce, K. Hay, H. S. Stern
Journal: JNCI Journal of the National Cancer Institute (1990)

Journal Article Effects of Sodium Sulfate on Fecal pH and Proliferation of Colonic Mucosa in Patients at High Risk for Colon Cancer Get access Hanoch Kashtan, Hanoch Kashtan Department of Surgery, Mount Sinai Hospital, University of TorontoToronto, Canada. Search for other works by this author on: Oxford Academic PubMed Google Scholar Roger C. Gregoire, Roger C. Gregoire Department of Surgery, Mount Sinai Hospital, University of TorontoToronto, Canada. Search for other works by this author on: Oxford Academic PubMed Google Scholar W. Robert Bruce, W. Robert Bruce Department of Medical Biophysics, University of TorontoToronto, Canada. Search for other works by this author on: Oxford Academic PubMed Google Scholar Kazy Hay, Kazy Hay Department of Surgery, Mount Sinai Hospital, University of TorontoToronto, Canada. Search for other works by this author on: Oxford Academic PubMed Google Scholar Hartley S. Stern Hartley S. Stern * Department of Surgery, Mount Sinai Hospital, University of TorontoToronto, Canada. * Correspondence to: Hartley S. Stern, M.D., Department of Surgery, Mount Sinai Hospital, 600 University Ave., Suite 1225, Toronto, ON, Canada M5G IX5. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 82, Issue 11, 6 June 1990, Pages 950–952, https://doi.org/10.1093/jnci/82.11.950 Published: 06 June 1990 Article history Received: 07 February 1990 Accepted: 14 March 1990 Published: 06 June 1990