tbuckley/cabot-search huggingface dataset:
Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats
Authors: Marc Mejias, Ester Garcia-Pras, Carolina Tiani, Rosa Miquel, Jaime Bosch, Mercedes Fernandez
Journal: Hepatology (2008)

Portal hypertension, the most important complication in patients with cirrhosis of the liver, is a serious and life-threatening disease for which there are few therapeutic options. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of this study was to determine the effects of sorafenib-a potent inhibitor of proangiogenic vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-beta), and Raf kinases-on splanchnic, intrahepatic, systemic, and portosystemic collateral circulations in two different experimental models of portal hypertension: rats with prehepatic portal hypertension induced by partial portal vein ligation and rats with intrahepatic portal hypertension and secondary biliary cirrhosis induced by bile duct ligation. Such a comprehensive approach is necessary for any translational research directed toward defining the efficacy and potential clinical application of new therapeutic agents. Sorafenib administered orally once a day for 2 weeks in experimental models of portal hypertension and cirrhosis effectively inhibited VEGF, PDGF, and Raf signaling pathways, and produced several protective effects by inducing an approximately 80% decrease in splanchnic neovascularization and a marked attenuation of hyperdynamic splanchnic and systemic circulations, as well as a significant 18% decrease in the extent of portosystemic collaterals. In cirrhotic rats, sorafenib treatment also resulted in a 25% reduction in portal pressure, as well as a remarkable improvement in liver damage and intrahepatic fibrosis, inflammation, and angiogenesis. Notably, beneficial effects of sorafenib against tissue damage and inflammation were also observed in splanchnic organs.Taking into account the limitations of translating animal study results into humans, we believe that our findings will stimulate consideration of sorafenib as an effective therapeutic agent in patients suffering from advanced portal hypertension.
Determination and validation of a predictive model for Clostridium difficile diarrhea in hospitalized oncology patients
Authors: None Hornbuckle, A. Chak, H.M. Lazarus, G.S. Cooper, L.A. Kutteh, R. Gucalp, S. Carlisle, J. Sparano, P. Parker, R.A. Salata
Journal: Annals of Oncology (1998)
Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana
Authors: Michael C. Thigpen, Poloko M. Kebaabetswe, Lynn A. Paxton, Dawn K. Smith, Charles E. Rose, Tebogo M. Segolodi, Faith L. Henderson, Sonal R. Pathak, Fatma A. Soud, Kata L. Chillag, Rodreck Mutanhaurwa, Lovemore Ian Chirwa, Michael Kasonde, Daniel Abebe, Evans Buliva, Roman J. Gvetadze, Sandra Johnson, Thom Sukalac, Vasavi T. Thomas, Clyde Hart, Jeffrey A. Johnson, C. Kevin Malotte, Craig W. Hendrix, John T. Brooks
Journal: New England Journal of Medicine (2012)

Preexposure prophylaxis with antiretroviral agents has been shown to reduce the transmission of human immunodeficiency virus (HIV) among men who have sex with men; however, the efficacy among heterosexuals is uncertain.
Evaluation of a large-scale tuberculosis contact investigation in the Netherlands
Authors: K. Borgen, B. Koster, H. Meijer, V. Kuyvenhoven, M. van der Sande, F. Cobelens
Journal: European Respiratory Journal (2008)

The aim of the present study was to evaluate yield and effectiveness of a large-scale contact investigation around a supermarket employee with infectious tuberculosis. Supermarket customers were screened by tuberculin skin test (TST) and/or radiography, depending on individual characteristics. The number of recent infections was estimated based on historical reference data after correction for false-positive TST results. TST screening of 15,518 subjects yielded 12 cases of tuberculosis disease as a direct result of the investigation (1,293 screenings per case identified). Radiographical screening of 5,945 subjects yielded no cases. There were 359 (2.6%) positive TSTs; 117 (34%) were estimated to be due to recent exposure. The number of customers screened in order to find one case of recent infection was 114, varying from 43 for customers who visited the supermarket twice per week or more, to 4,148 for customers who visited less than once per month. In conclusion, although this patient probably transmitted Mycobacterium tuberculosis to at least 117 customers, the contact investigation was inefficient, as large numbers of customers had to be screened and the majority of identified tuberculosis infections were probably not related to the index case. The efficiency could have been improved by omitting radiographical screening and limiting tuberculin skin test screening to customers who reported frequent supermarket visits.
Effects of exacerbation risk on symptoms and clinical characteristics in patients with bronchiectasis
Authors: Ozge Ozalp, Deniz Inal-Ince, Ebru Calik, Naciye Vardar-Yagli, Melda Saglam, Sema Savci, Hulya Arikan, Meral Bosnak-Guclu, Lutfi Coplu
Journal: European Respiratory Journal (2012)

Aim: Exacerbations may deteriorate symptoms and clinical features in patients with bronchiectasis. The purpose of this study was to investigate effects of exacerbation risk on muscle strength, exercise capacity, dyspnea, fatigue, and quality of life in patients with bronchiectasis.

Methods: Fifteen low risk patients (0 exacerbation per year) and 15 high risk patients (≥1 exacerbations per year) participated in this study. Lung function, quadriceps muscle strength (hand held dynamometer), dyspnea (modified Medical Research Council dyspnea scale, MRC), fatigue (Fatigue Severity Scale, FSS), exercise capacity (six-minute walk test, 6MWT), and cough specific (Leicester Cough Questionnaire, LCQ) and general (Nottingham Health Profile, NHP) were determined.

Results : No significant difference was found in lung function between the groups (p>0.05). Number of females was significantly higher in high risk group as compared to low risk group (p<0.05). Quadriceps muscle strength, 6MWT distance, and LCQ physical score were significantly lower; and MRC, FSS score, and NHP energy, emotional reactions, pain, physical mobility, and total scores were significantly higher in high risk bronchiectasis patients than those of low risk patients (p<0.05).

Conclusion: High risk of having exacerbations adversely effects quadriceps strength; exercise capacity, dyspnea and fatigue perception, and cough specific and general health in patients with bronchiectasis. Number of exacerbations in the previous year may be a determinant of characteristics and function in bronchiectasis.
Mechanisms of cervical spine injury in rugby union: a systematic review of the literature
Authors: Daniel Kuster, Alastair Gibson, Rami Abboud, Tim Drew
Journal: British Journal of Sports Medicine (2012)

Background Severe cervical spine injury in rugby union (rugby) exerts a major impact on the individual who sustains the injury and on the broader society. Since the late 1970s, authors of rugby case report studies have postulated that the underlying mechanism of cervical spine injury is hyperflexion of the neck. However, this is in conflict with findings from more recent experimental studies. These have shown that it is more likely that the majority of cervical spine injuries occur due to buckling of the cervical spinal column. Objective To investigate the primary mechanism of cervical spine injury in rugby. Methods A comprehensive and systematic review of the literature was undertaken. Six key factors were identified and subsequently used to investigate the two principally postulated mechanisms of cervical spine injury: hyperflexion and buckling. Results Facet dislocations, in particular bilateral facet dislocations, were identified as the most common types of cervical spine injury in rugby. Trauma occurred most often at lower cervical spinal levels, notably the C4/5 and C5/6 motion segments. Experimental studies demonstrate that bilateral facet dislocations occurring at the lower cervical spinal levels are primarily produced via buckling. Conclusion Our analysis of key factors for cervical spine injury in rugby shows that it is unlikely that the majority of injuries occur after hyperflexion of the neck. It appears more likely that they are the result of buckling of the cervical spinal column.
Flow Rate–Modulated Dissolution of Fibrin With Clot-Embedded and Circulating Proteases
Authors: Erzsébet Komorowicz, Krasimir Kolev, István Léránt, Raymund Machovich
Journal: Circulation Research (1998)

Abstract —The efficiency of plasmin, miniplasmin, and neutrophil leukocyte elastase in fibrin digestion is well characterized in static systems. Since in vivo the components of the fibrinolytic system are permanently exposed to flow, we have developed two in vitro models and studied the effect of shear forces on fibrin dissolution with these proteases. Cylindrical nonocclusive fibrin clots are perfused at various flow rates through their preformed axial channel, and dissolution of fibrin is followed by measuring the absorbance of degradation products released into the circulating fluid phase. In one experimental setting, fibrin surface is degraded with enzymes applied in the recirculating fluid phase; in another setting, clots containing gel-embedded proteases are perfused with enzyme-free buffer. As shear rate at fibrin surface is changed from 25 to 500 s −1 , the rate of product release by recirculated enzymes increases 2.8-, 2.9-, and 4-fold for plasmin, miniplasmin, and porcine pancreatic elastase, respectively. Buffer-perfused fibrin containing gel-embedded plasmin or miniplasmin is disintegrated by shear forces at a relatively early stage of dissolution, and this disassembly is related to the formation of fragment Y (150 kDa) and fragment D (100 kDa) fibrin degradation products. Fibrin clots degraded by incorporated polymorphonuclear leukocyte elastase, which yields different degradation products, do not disassemble abruptly, even at the highest shear rate (500 s −1 ). Our results suggest that fibrin surface degradation is accelerated with increasing shear rate and that plasmin or miniplasmin embedded in the clot promotes the release of particular clot remnants into the circulating phase, whereas polymorphonuclear leukocyte elastase does not.
Estrogen Replacement Therapy After Localized Breast Cancer: Clinical Outcome of 319 Women Followed Prospectively
Authors: Rena Vassilopoulou-Sellin, Lina Asmar, Gabriel N. Hortobagyi, Mary Jean Klein, Marsha McNeese, Sonja E. Singletary, Richard L. Theriault
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To determine whether estrogen replacement therapy (ERT) alters the development of new or recurrent breast cancer in women previously treated for localized breast cancer. PATIENTS AND METHODS: Potential participants (n = 319) in a trial of ERT after breast cancer were observed prospectively for at least 2 years whether they enrolled onto the randomized trial or not. Of 319 women, 39 were given estrogen and 280 were not given hormones. Tumor size, number of lymph nodes, estrogen receptors, menopausal status at diagnosis, and disease-free interval at the initiation of the observation period were comparable for the trial participants (n = 62) versus nonparticipants (n = 257) and for women on ERT (n = 39) versus controls (n = 280). Cancer events were ascertained for both groups. RESULTS: Patient and disease characteristics were comparable for the trial participants versus nonparticipants, as well as for the women on ERT versus the controls. One patient in the ERT group developed a new lobular estrogen receptor–positive breast cancer 72 months after the diagnosis of a ductal estrogen receptor–negative breast cancer and 27 months after initiation of ERT. In the control group, there were 20 cancer events: 14 patients developed new or recurrent breast cancer at a median time of 139.5 months after diagnosis and six patients developed other cancers at a median time of 122 months. CONCLUSION: ERT does not seem to increase breast cancer events in this subset of patients previously treated for localized breast cancer. Results of randomized trials are needed before any changes in current standards of care can be proposed.
Proteolytic degradation of intestinal mucosal extracellular matrix after lamina propria T cell activation.
Authors: S L Pender, P Lionetti, S H Murch, N Wathan, T T MacDonald
Journal: Gut (1996)

BACKGROUND: Proteoglycans, consisting of glycosaminoglycan (GAG) side chains covalently linked to a protein core, are a major component of the extracellular matrix of the intestinal lamina propria. AIMS: This study investigated the effects of lamina propria T cell activation on the proteoglycan component of the matrix. METHODS: The high degree of sulphation of GAGs means that they are polyanionic and thus can be visualised in tissue sections by means of colloidal-gold labelled cationic probes. RESULTS: In human fetal small intestine there is a dense meshwork of anionic residues in the lamina propria and basement membrane. When explants of human fetal small intestine are cultured ex vivo, and resident lamina propria T cells are activated with pokeweed mitogen, mucosal destruction occurs within three days. This is associated with the rapid loss of anionic sites from the lamina propria. Dermatan sulphate proteoglycan is lost from the tissue and is present at increased concentrations in the organ culture supernatants, indicating that T cell activation has led to solubilisation of lamina propria proteoglycans. Tissue destruction and loss of anionic residues are inhibited in a dose dependent fashion by dexamethasone, and by the protease inhibitor, alpha 2 macroglobulin. CONCLUSIONS: Proteolytic degradation of the lamina propria may therefore be a mechanism by which T cell hypersensitivity injures the intestinal mucosa.
The Effect of Oligonucleotides to c <i>-myb</i> on Vascular Smooth Muscle Cell Proliferation and Neointima Formation After Porcine Coronary Angioplasty
Authors: Julian Gunn, Cathy M. Holt, Sheila E. Francis, Lynda Shepherd, Malcolm Grohmann, Christopher M. H. Newman, David C. Crossman, David C. Cumberland
Journal: Circulation Research (1997)

Proto-oncogenes, including c-myb, are expressed early after vascular injury. The application of antisense oligodeoxynucleotides (AS-ODNs) against these genes inhibits cell proliferation and neointima formation in small animals and in peripheral arteries. The aim of this study was to investigate the specificity of action of AS-ODN-c-myb in vitro and to assess its effect, when delivered locally, on neointima formation after percutaneous transluminal coronary angioplasty (PTCA) in porcine coronary arteries. AS-ODN-c-myb inhibited the proliferation of vascular smooth muscle cells (VSMCs) in vitro in a dose-dependent manner. There was a corresponding reduction in steady state levels of c-myb mRNA and protein. Expression of another early gene, c-fos, was unaffected. S1 nuclease analysis demonstrated intact full-length AS-ODN-c-myb retrieved from VSMCs in culture after 12 hours. A range of ODNs, related and unrelated to c-myb, with and without a GGGG sequence, inhibited VSMC proliferation. Phosphorothioated AS-ODN-c-myb was 30 times less potent than unphosphorothioated AS-ODN-c-myb. PTCA induced porcine coronary artery neointima formation. c-myb mRNA was maximally induced 18 hours after injury. Unmodified AS-ODN-c-myb, sense-ODN-c-myb, saline, or nothing was delivered immediately after balloon dilatation via a double-skinned porous balloon (Transport, SciMed). Fluorescence-labeled AS-ODN-c-myb was deposited throughout the vessel wall. Mean maximum intima/media cross-sectional area 4 weeks after PTCA was reduced with AS-ODN-c-myb by 79% compared with saline (P < .05), 82% compared with sense-ODN-c-myb, and 63% compared with nothing (P < .10). Conclusions are as follows: (1) c-myb is expressed in VSMCs after vascular injury. (2) AS-ODN-c-myb is retained intact in VSMCs, reducing their proliferation in vitro in dose-dependent fashion, with reduction in c-myb mRNA and protein, whereas sense-ODN-c-myb is not. (3) A range of ODNs can reduce VSMC proliferation by a non-sequence-specific mechanism. (4) Phosphorothioate protection of antisense molecules may reduce their efficacy. (5) Local delivery of unmodified AS-ODN-c-myb via the Transport catheter reduces neointima formation after porcine PTCA. (6) Local delivery of fluid may exacerbate neointimal thickening.
Smoking cessation with a 16 h nicotine patch: results in a group of hospital workers
Authors: CA Jimenez Ruiz, S Florez, A Ramos, L Ramos, S Solano, E Fornies
Journal: European Respiratory Journal (1997)

As part of a programme for the implementation of a Smoking Control Policy in our hospital, an open study, without randomization, of 65 hospital workers, who wanted to give up smoking, was carried out. The characteristics of smoking in each subject were recorded. The Fagerstrom Questionnaire was used to measure the degree of dependence on nicotine. The treatment consisted of the daily use of 16 h nicotine patches for 12 weeks. During the first 4 weeks, the patches contained 15 mg of nicotine, for the second 4 weeks, 10 mg, and for the last 4 weeks 5 mg (per patch and day). Five visits were scheduled during the 26 week study period: at the start of the study and after 4, 8, 12 and 26 weeks. The abstinence was checked by measuring carbon monoxide in end-expiratory air. The success rate was 31% after 12 weeks, and decreased to 29% after 26 weeks. In conclusion, the nicotine patches appeared safe and effective in this study.
A Comparison of the Prevalence of the Metabolic Syndrome Using Two Proposed Definitions
Authors: Earl S. Ford, Wayne H. Giles
Journal: Diabetes Care (2003)

OBJECTIVE—To compare the prevalence of the metabolic syndrome using two definitions: one proposed by the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) and one by the World Health Organization (WHO). RESEARCH DESIGN AND METHODS—We used data from a nationally representative sample of the noninstitutionalized civilian population of the U.S. from the Third National Health and Nutrition Examination Survey, a cross-sectional health examination survey (1988–1994). RESULTS—Among 8,608 participants aged ≥20 years, the age-adjusted prevalence was 23.9% using the ATP III definition and 25.1% using the WHO definition. Among all participants, 86.2% were classified as either having or not having the metabolic syndrome under both definitions. Estimates differed substantially for some subgroups, however. For example, in African-American men, the WHO estimate was 24.9%, compared with the ATP III estimate of 16.5%. CONCLUSIONS—A universally accepted definition of the metabolic syndrome is needed.
PSYCHIATRIC DISTURBANCE LEADING TO POTASSIUM DEPLETION, SODIUM DEPLETION, RAISED PLASMA-RENIN CONCENTRATION, AND SECONDARY HYPERALDOSTERONISM
Authors: H.P. Wolff, F. Krück, P. Vecsei, S. Roscher, J.J. Brown, G.O. Düsterdieck, A.F. Lever, J.I.S. Robertson
Journal: The Lancet (1968)
Ia antigen-bearing B cell tumor lines can present protein antigen and alloantigen in a major histocompatibility complex-restricted fashion to antigen-reactive T cells.
Authors: L H Glimcher, K J Kim, I Green, W E Paul
Journal: The Journal of Experimental Medicine (1982)

Several Ia-positive BALB/c B cell tumor lines were screened for their ability to present alloantigen and protein antigens to alloreactive and antigen-reactive T cells. Of six Ia-positive tumor lines studied, three were found to be effective as antigen presenting cells (APC). Indeed, on a per cell basis, one of the stimulatory lines, A20.3, was substantially more effective than whole spleen cells. The other three lines, although Ia-positive, were nonstimulatory. A20.3 was chosen for further study. This tumor appeared to behave like the conventional APC because (a) the tumor cells presented alloantigen, (b) they presented protein antigen in an MHC-restricted fashion to both primed donor T cells and to long-term continuous T cell lines, (c) alloantigen presentation was blocked by the inclusion of an anti-Ia antibody in the culture system, and (d) A20.3 cells could be effectively pulsed with antigen, although the continuous presence of antigen in the culture system resulted in a superior response. The addition of an exogenous source of interleukin 1 proved necessary to obtain an alloreactive but not an antigen-specific T cell response, although its inclusion did enhance the magnitude of antigen-stimulated proliferation. These tumor cells should prove useful in studying the biochemical events that occur during antigen processing and the requirements for T cell triggering by processed antigen in association with Ia molecules.
Gene expression changes as markers of early lapatinib response in a panel of breast cancer cell lines
Authors: Fiona O’Neill, Stephen F Madden, Sinead T Aherne, Martin Clynes, John Crown, Padraig Doolan, Robert O’Connor
Journal: Molecular Cancer (2012)

Abstract Background Lapatinib, a tyrosine kinase inhibitor of HER2 and EGFR and is approved, in combination with capecitabine, for the treatment of trastuzumab-refractory metastatic breast cancer. In order to establish a possible gene expression response to lapatinib, a panel of breast cancer cell lines with varying sensitivity to lapatinib were analysed using a combination of microarray and qPCR profiling. Methods Co-inertia analysis (CIA), a data integration technique, was used to identify transcription factors associated with the lapatinib response on a previously published dataset of 96 microarrays. RNA was extracted from BT474, SKBR3, EFM192A, HCC1954, MDAMB453 and MDAMB231 breast cancer cell lines displaying a range of lapatinib sensitivities and HER2 expression treated with 1 μM of lapatinib for 12 hours and quantified using Taqman RT-PCR. A fold change ≥ ± 2 was considered significant. Results A list of 421 differentially-expressed genes and 8 transcription factors (TFs) whose potential regulatory impact was inferred in silico , were identified as associated with lapatinib response. From this group, a panel of 27 genes (including the 8 TFs) were selected for qPCR validation. 5 genes were determined to be significantly differentially expressed following the 12 hr treatment of 1 μM lapatinib across all six cell lines. Furthermore, the expression of 4 of these genes (RB1CC1, FOXO3A, NR3C1 and ERBB3) was directly correlated with the degree of sensitivity of the cell line to lapatinib and their expression was observed to “switch” from up-regulated to down-regulated when the cell lines were arranged in a lapatinib-sensitive to insensitive order. These included the novel lapatinib response-associated genes RB1CC1 and NR3C1. Additionally, Cyclin D1 (CCND1), a common regulator of the other four proteins, was also demonstrated to observe a proportional response to lapatinib exposure. Conclusions A panel of 5 genes were determined to be differentially expressed in response to lapatinib at the 12 hour time point examined. The expression of these 5 genes correlated directly with lapatinib sensitivity. We propose that the gene expression profile may represent both an early measure of the likelihood of sensitivity and the level of response to lapatinib and may therefore have application in early response detection.