tbuckley/cabot-search huggingface dataset:
The Pathogenesis of Venous Thromboembolism: Evidence for Multiple Interrelated Causes
Authors: Jan-Leendert P. Brouwer, Nic J.G.M. Veeger, Hanneke C. Kluin-Nelemans, Jan van der Meer
Journal: Annals of Internal Medicine (2006)

Venous thromboembolism (VTE) is thought to result from interactions between multiple genetic and environmental risk factors.To assess the contribution of multiple thrombophilic defects and exogenous risk factors to the absolute risk for VTE.Retrospective family cohort study.Single university hospital.468 relatives of 91 probands with a symptomatic hereditary deficiency of protein S, protein C, or antithrombin.All relatives were tested for 10 thrombophilic deficiencies and defects in addition to the index deficiency and were assessed for exogenous risk factors (surgery, trauma, immobilization, use of oral contraceptives, and pregnancy). The authors compared annual incidences and relative risks for VTE in deficient and nondeficient relatives.Annual incidences of VTE in relatives with 0, 1, and 2 or more additional thrombophilic deficiencies or defects were 1.16 (95% CI, 0.60 to 2.03), 1.75 (CI, 1.17 to 2.53), and 2.64 (CI, 1.67 to 3.96) per 100 person-years, respectively, compared with 0.06 (CI, 0.002 to 0.33) per 100 person-years in nondeficient relatives without additional deficiencies or defects. Adjusted relative risks were 16.3 (CI, 2.0 to 131.0), 50.3 (6.5 to 389.7), and 102.8 (12.5 to 843.4). Of deficient relatives, 38% with no additional defect, 57% with 1 additional defect, and 81% with 2 or more additional defects had VTE at age 65 years compared with 5% of nondeficient relatives (P < 0.001). In deficient relatives with additional deficiencies or defects, exogenous risk factors increased the risk for VTE from 1.20% to 2.51% per year (relative risk, 2.1 [CI, 1.1 to 4.2]).This was a retrospective study without the ability to distinguish interactions between specific thrombophilic deficiencies and defects.Additional thrombophilic defects and exogenous risk factors increase the risk for VTE in persons with hereditary deficiencies of protein S, protein C, or antithrombin and provide evidence that multiple genetic and environmental risk factors contribute to VTE.
Influence of awareness of the recording of breathing on respiratory pattern in healthy humans
Authors: JN Han, K Stegen, M Cauberghs, KP Van de Woestijne
Journal: European Respiratory Journal (1997)

This study was designed to test whether awareness of the measurement of breathing influences the breathing pattern in healthy subjects under routine laboratory conditions. Seventy four subjects (40 females and 34 males), aged 21-63 yrs, were studied under three different conditions whilst their breathing was being recorded for 5 min by means of inductance plethysmography (Respitrace): 1) subjects were misled into believing that their breathing was not being recorded but that they had to wait for 5 min whilst equipment was calibrated; 2) subjects were instructed that their breathing pattern was being recorded for 5 min; 3) the subject's breathing was recorded for 5 min with mouthpiece and pneumotachograph. The first two conditions were randomized. The Respitrace was calibrated by means of multiple linear regression carried out during the 5 min period of quiet breathing through a mouthpiece. Awareness of the recording of breathing caused prolongation of inspiratory (tI) and expiratory time (tE). Breathing through the mouthpiece resulted in an increase of tI, tE and tidal volume (VT). The breathing irregularities (sighs and end-expiratory pauses) decreased when subjects were aware of the recording of breathing and nearly disappeared when subjects breathed through the mouthpiece. The end-tidal carbon dioxide concentration was not significantly different between the three conditions. Mouthpiece breathing often induced some respiratory discomfort and even anxiety, particularly in females. Awareness by the subject that his or her breathing was being recorded altered the spontaneous breathing pattern, mainly the breathing frequency. In addition, use of a mouthpiece markedly increased tidal volume, particularly in females in whom mouthpiece breathing induced more complaints than in males.
Dietary fish oil effects on biliary lipid secretion and cholesterol gallstone formation in the African green monkey
Authors: Martin W. Scobey, Fred L. Johnson, John S. Parks, Lawrence L. Rudel
Journal: Hepatology (1991)

We studied two groups of adult male African green monkeys to assess the effects of dietary fish oil on biliary lipid secretion and cholesterol gallstone formation. One group was fed 0.8 mg cholesterol/kcal and 42% of calories as fat with half of the fat calories derived from lard; the other group was fed a similar diet except for the isocaloric substitution of menhaden oil for lard. After 21/2 to 3 yr, necropsies were performed and the presence of gallstones was determined. Gallbladder bile specimens were analyzed for cholesterol saturation index, as well as for bile acid species and biliary phospholipid fatty acid composition. Our results showed that 67% of animals fed the lard diet had cholesterol gallstones compared with only 22% of animals in the group fed the fish oil diet (p = 0.08). The cholesterol saturation index of gallbladder bile also tended to be higher in the lard-fed group (1.15 ± 0.11) compared with the fish oil-fed group (0.86 ± 0.09, p = 0.06). No differences between the two dietary groups were noted in the percentages of the various types of bile acids. However, a greater percentage of ω-3 fatty acids and a lesser percentage of 18:1, 18:2 and 20:4 fatty acids were found in the biliary phospholipids from the fish oil-fed group compared with the lard-fed group. Biliary lipid secretion rates were then measured during isolated recirculating liver perfusion performed with a constant sodium taurocholate infusion. A significantly greater biliary phospholipid secretion rate was noted in the fish oil-fed animals compared with the lard-fed animals, whereas bile acid and cholesterol secretion rates were similar between the diet groups. We conclude that the increased biliary phospholipid secretion observed in the fish oil-fed group produced a less lithogenic gallbladder bile, which in turn resulted in a less frequent occurrence of gallstones in that group. In addition the increased phospholipid secretion was probably favored by the enrichment of biliary phospholipids with relatively less hydrophobic ω-3 fatty acids. (Hepatology 1991;14:679-684.)
Tumor Transcriptome Reveals the Predictive and Prognostic Impact of Lysosomal Protease Inhibitors in Non–Small-Cell Lung Cancer
Authors: Russell D. Petty, Keith M. Kerr, Graeme I. Murray, Marianne C. Nicolson, Patrick H. Rooney, Donald Bissett, Elaina S.R. Collie-Duguid
Journal: Journal of Clinical Oncology (2006)

Insight into clinical response to platinum-based chemotherapy (PBC) in non-small-cell lung cancer (NSCLC).Matched tumor and nontumor lung tissues from PBC-treated NSCLC patients (four nonresponders and four responders) and tumor tissue from an independent test set (four nonresponders and four responders), were profiled using microarrays. Lysosomal protease inhibitors SerpinB3 and cystatin C were highly correlated with clinical response and were further evaluated by immunohistochemistry in PBC-treated patients (36 prechemotherapy and 13 postchemotherapy). Investigation of the pathogenic and prognostic significance of SerpinB3 was performed in 251 primary tumors, with 64 regional lymph node pairs, from chemotherapy-naïve NSCLC patients using immunohistochemistry.Bioinformatic analyses of gene expression in the training set identified a gene set (n = 17) that separated all patients in the training and test sets (n = 16) according to response in hierarchical clustering. Transcriptome profiling revealed that SerpinB3 mRNA was highly correlated with degree of response (r = -0.978; P < .0001) and was a clear outlier (nonresponders:responders > 50-fold). SerpinB3 protein expression was correlated with clinical response in PBC-treated NSCLC patients (P = .045). Expression of SerpinB3 and cystatin C, relative to the target, protease cathepsin B, was independently predictive of response (odds ratio, 17.8; 95% CI, 2.0 to 162.4; P = .01), with an accuracy of 72%. High SerpinB3 expression levels, invariably associated with chemoresistance, had contrasting prognostic impact in untreated squamous cell carcinomas (hazard ratio [HR], 0.43; 95% CI, 0.18 to 0.93) or adenocarcinomas (HR, 2.09; 95% CI, 1.03 to 4.72).This provides the first comprehensive molecular characterization of clinical responsiveness to PBC in NSCLC and reveals the predictive and prognostic impact of two lysosomal protease inhibitors, potentially representing novel targets for NSCLC therapeutics.
Stanozolol in treatment of leg ulcers due to cryofibrinogenaemia
Authors: V. Falanga, R.S. Kirsner, W.H. Eaglstein, M.H. Katz, F.A. Kerdel
Journal: The Lancet (1991)

Five consecutive patients with cryofibrinogenaemia in association with painful leg ulcers and intravascular dermal thrombi were treated with stanozolol, an androgenic steroid with fibrinolytic properties. In all patients treatment was followed by rapid and striking pain relief and healing of the ulcers. Cryofibrinogenaemia was not detected on subsequent laboratory evaluation, and dermal intravascular thrombi had resolved on repeat histological examination.
Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells
Authors: Nabila Seddiki, Brigitte Santner-Nanan, Jeff Martinson, John Zaunders, Sarah Sasson, Alan Landay, Michael Solomon, Warwick Selby, Stephen I. Alexander, Ralph Nanan, Anthony Kelleher, Barbara Fazekas de St. Groth
Journal: The Journal of Experimental Medicine (2006)

Abnormalities in CD4+CD25+Foxp3+ regulatory T (T reg) cells have been implicated in susceptibility to allergic, autoimmune, and immunoinflammatory conditions. However, phenotypic and functional assessment of human T reg cells has been hampered by difficulty in distinguishing between CD25-expressing activated and regulatory T cells. Here, we show that expression of CD127, the α chain of the interleukin-7 receptor, allows an unambiguous flow cytometry–based distinction to be made between CD127lo T reg cells and CD127hi conventional T cells within the CD25+CD45RO+RA− effector/memory and CD45RA+RO− naive compartments in peripheral blood and lymph node. In healthy volunteers, peripheral blood CD25+CD127lo cells comprised 6.35 ± 0.26% of CD4+ T cells, of which 2.05 ± 0.14% expressed the naive subset marker CD45RA. Expression of FoxP3 protein and the CD127lo phenotype were highly correlated within the CD4+CD25+ population. Moreover, both effector/memory and naive CD25+CD127lo cells manifested suppressive activity in vitro, whereas CD25+CD127hi cells did not. Cell surface expression of CD127 therefore allows accurate estimation of T reg cell numbers and isolation of pure populations for in vitro studies and should contribute to our understanding of regulatory abnormalities in immunopathic diseases.
Neuropeptides activate TRPV1 in rheumatoid arthritis fibroblast-like synoviocytes and foster IL-6 and IL-8 production
Authors: Riccardo Terenzi, Eloisa Romano, Mirko Manetti, Francesca Peruzzi, Francesca Nacci, Marco Matucci-Cerinic, Serena Guiducci
Journal: Annals of the Rheumatic Diseases (2013)

Neurogenic inflammation is caused by neuropeptides which are released by peripheral neurons and induce inflammatory signals. Two of the main neuropeptides involved are substance P (SP) and calcitonin gene related peptide (CGRP),1 both acting through several molecular mechanisms including activation of transient receptor potential vanilloid (TRPV) cation channels, particularly TRPV1 (also called vanilloid receptor type 1 or capsaicin (CAP) receptor).2 ,3 SP and CGRP have been found increased in synovial fluid from rheumatoid arthritis (RA) patients4 ,5 and may induce the production of interleukin (IL)-6 and IL-8 in RA synoviocytes,6 suggesting that neuropeptides may have a role in joint inflammation during RA. Interestingly, TRPV cation channels are expressed in various non-neuronal cell types and, recently, they have been found expressed in human synoviocytes.7 

No previous study has investigated the possible link among SP, CGRP and TRPV channels in the inflammation process driven by RA synoviocytes. The aim of our work was to investigate whether SP, CGRP and CAP, a potent activator (agonist) of TRPV1, can increase IL-6 and IL-8 production by RA and healthy fibroblast-like synoviocytes, and whether neuropeptides may modulate TRPV1 expression in RA and healthy cells. Synoviocytes were obtained from knee-biopsy of three patients with active RA diagnosed according to the American College of Rheumatology 1987 revised criteria undergoing surgical joint replacement. Patients had not received any disease-modifying antirheumatic drug treatment. Healthy synoviocytes were collected from knee-biopsy of three subjects who underwent surgical intervention after accidental trauma. Synoviocytes (passage 2–4) were cultured at confluence, serum-starved for 24 h and incubated for …
Dyspnea and Decreased Variability of Breathing in Patients with Restrictive Lung Disease
Authors: Thomas Brack, Amal Jubran, Martin J. Tobin
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Patients with restrictive lung disease are typically dyspneic and have an increase in overall respiratory center drive, as a result of increased lung elasticity. When we subjected healthy volunteers to external elastic loads, their variability of breathing was lessened. Accordingly, we hypothesized that patients with restrictive lung disease display decreased variability of breathing and, also, that decreased variability of breathing is related to dyspnea. Breathing pattern was measured nonobtrusively over 1 hour in 10 patients with restrictive lung disease and in 7 healthy subjects. On a separate occasion, dyspnea was measured while all subjects copied different tidal volumes and frequencies. Compared with healthy subjects, the random fraction of breath variability was reduced in patients with restrictive lung disease: 27 times for expiratory time, 12 times for tidal volume, and 6 times for inspiratory time (p < 0.01 in each instance). Conversely, the nonrandom, correlated fraction for tidal volume was increased almost 3-fold in the patients (p < 0.01). Small variations from average resting tidal volume caused marked increases in dyspnea in patients, and the relationship was parabolic (r 2 = 0.97; p < 0.001). In conclusion, patients with restrictive lung disease adopt a tightly constrained breathing pattern, probably as a strategy for avoiding dyspnea.
Regulation of the acute phase and immune responses in viral disease. Enhanced expression of the beta 2-interferon/hepatocyte-stimulating factor/interleukin 6 gene in virus-infected human fibroblasts.
Authors: P B Sehgal, D C Helfgott, U Santhanam, S B Tatter, R H Clarick, J Ghrayeb, L T May
Journal: The Journal of Experimental Medicine (1988)

We have defined the expression of the mRNA for, and secretion of, IFN-beta 2/hepatocyte-stimulating factor/IL-6 (IFN-beta 2/IL-6) in human diploid fibroblasts (FS-4 strain) infected with different RNA- and DNA-containing viruses. RNA blot-hybridization analyses carried out 6-8 h after the beginning of infection showed that the RNA-containing Sendai virus (paramyxoviridae) enhanced IFN-beta 2/IL-6 mRNA levels 10-fold, followed, in decreasing order, by encephalomyocarditis (EMC, picornaviridae), vesicular stomatitis (VSV, rhabdoviridae), Newcastle disease virus (NDV, paramyxoviridae), and influenza A (Flu, myxoviridae) viruses. The DNA-containing pseudorabies virus (PR, herpesviridae) enhanced IFN-beta 2/IL-6 mRNA levels sixfold, while the effect of adenovirus type 5 (Ad5, adenoviridae) was considerably less and comparable with that of NDV or Flu. A rabbit antiserum raised against E. coli-derived human IFN-beta 2/IL-6 was used in immunoprecipitation experiments to monitor the secretion of 35S-methionine-pulse-labeled IFN-beta 2/IL-6 proteins by fibroblasts up to 7 h after the beginning of infection. Enhanced levels of secretion of IFN-beta 2/IL-6 (2-14-fold) were observed in every instance evaluated (Sendai, EMC, VSV, Flu, PR, Ad5 viruses). A biological consequence of enhanced secretion of IFN-beta 2/IL-6 was the ability of media from infected FS-4 cell cultures to enhance by 8-15-fold the synthesis and secretion of a typical acute phase plasma protein (alpha 1-antichymotrypsin) by human hepatoma Hep3B2 cells. These observations make it likely that IFN-beta 2/IL-6 mediates, in part, the host response to acute virus infections.
Physical activity and obesity editorial: is exercise pointless or was it a pointless exercise?
Authors: Kamal R Mahtani, Jim McManus, David Nunan
Journal: British Journal of Sports Medicine (2015)

In their editorial, Malhotra et al 1 highlighted the important health benefits of physical activity in cardiovascular disease, type 2 diabetes, dementia and cancer, but dismissed any benefit for weight loss in obesity. However, the poor use of existing evidence to underpin this dismissal and the resultant press release generated headlines that could send a misleading message to patients and the public.

An evidence-based approach to clinical decision-making involves understanding the best type of evidence to use, how to appraise it, and assessing its usefulness in practice. Such an approach determines the risk of bias and ensures decisions are guided by accurate, meaningful evidence. The GRADE guidelines cite expert opinion alone as very low quality evidence, with a high risk of bias.2 Unfortunately, much of the evidence cited by Malhotra and colleagues was based on expert opinion or was not referenced. For example, when excluding a relationship between obesity and physical activity, the evidence cited was an opinion piece by Luke and Cooper,3 which has been criticised for ignoring observational and experimental studies that support a relation between physical activity and obesity. They give no reference for their claim that, according …
ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor
Authors: Christin Tse, Alexander R. Shoemaker, Jessica Adickes, Mark G. Anderson, Jun Chen, Sha Jin, Eric F. Johnson, Kennan C. Marsh, Michael J. Mitten, Paul Nimmer, Lisa Roberts, Stephen K. Tahir, Yu Xiao, Xiufen Yang, Haichao Zhang, Stephen Fesik, Saul H. Rosenberg, Steven W. Elmore
Journal: Cancer Research (2008)

Abstract Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1) is commonly associated with tumor maintenance, progression, and chemoresistance. We previously reported the discovery of ABT-737, a potent, small-molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable, which would limit chronic single agent therapy and flexibility to dose in combination regimens. Here we report the biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (Ki's of &amp;lt;1 nmol/L for Bcl-2, Bcl-xL, and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% to 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim), leading to the initiation of apoptosis within 2 hours posttreatment. In human tumor cells, ABT-263 induces Bax translocation, cytochrome c release, and subsequent apoptosis. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in small-cell lung cancer and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility both as a single agent and in combination regimens. [Cancer Res 2008;68(9):3421–8]
Manipulating the Bioenergetics of Alloreactive T Cells Causes Their Selective Apoptosis and Arrests Graft-Versus-Host Disease
Authors: Erin Gatza, Daniel R. Wahl, Anthony W. Opipari, Thomas B. Sundberg, Pavan Reddy, Chen Liu, Gary D. Glick, James L. M. Ferrara
Journal: Science Translational Medicine (2011)

Bioenergetic properties differentiate alloreactive T cells from other proliferating cells and can be exploited to arrest GVHD in mice.
XIAP gene expression and function is regulated by autocrine and paracrine TGF-β signaling
Authors: Céline Van Themsche, Parvesh Chaudhry, Valérie Leblanc, Sophie Parent, Eric Asselin
Journal: Molecular Cancer (2010)

Abstract Background X-linked inhibitor of apoptosis protein (XIAP) is often overexpressed in cancer cells, where it plays a key role in survival and also promotes invasiveness. To date however, the extracellular signals and intracellular pathways regulating its expression and activity remain incompletely understood. We have previously showed that exposure to each of the three TGF-β (transforming growth factor beta) isoforms upregulates XIAP protein content in endometrial carcinoma cells in vitro . In the present study, we have investigated the clinical relevance of TGF-β isoforms in endometrial tumours and the mechanisms through which TGF-β isoforms regulate XIAP content in uterine cancer cells. Methods TGF-β isoforms immunoreactivity in clinical samples from endometrial tumours was assessed using immunofluorescence. Two model cancer cell lines (KLE endometrial carcinoma cells and HeLa cervical cancer cells) and pharmacological inhibitors were used to investigate the signalling pathways regulating XIAP expression and activity in response to autocrine and paracrine TGF-β in cancer cell. Results We have found immunoreactivity for each TGF-β isoform in clinical samples from endometrial tumours, localizing to both stromal and epithelial/cancer cells. Blockade of autocrine TGF-β signaling in KLE endometrial carcinoma cells and HeLa cervical cancer cells reduced endogenous XIAP mRNA and protein levels. In addition, each TGF-β isoform upregulated XIAP gene expression when given exogenously, in a Smad/NF-κB dependent manner. This resulted in increased polyubiquitination of PTEN (phosphatase and tensin homolog on chromosome ten), a newly identified substrate for XIAP E3 ligase activity, and in a XIAP-dependent decrease of PTEN protein levels. Although each TGF-β isoform decreased PTEN content in a XIAP- and a Smad-dependent manner, decrease of PTEN levels in response to only one isoform, TGF-β3, was blocked by PI3-K inhibitor LY294002. Conclusions XIAP gene expression and function is positively regulated by exposure to the three TGF-β isoforms in a Smad-dependent manner, similar to constitutive XIAP gene expression which depends on autocrine TGF-β/Smad signalling.