tbuckley/cabot-search huggingface dataset:
5-HT release from platelets and activation of 5-HT2B play a crucial role for development of fibrosis in systemic sclerosis
Authors: C. Dees, A. Akhmetshina, N. Busch, J. Zwerina, M. Bader, G. Schett, O. Distler, J. H W Distler
Journal: Annals of the Rheumatic Diseases (2010)

Purpose Systemic sclerosis (SSc) is characterised by progressive vascular disease and organ fi brosis.Tryptophanhydroxylase-1 (tph-1) is the rate-limiting enzyme for the synthesis of 5-hydroxytryptamine (5-HT).After synthesis, 5-HT is stored in large amounts within platelets and can be released upon activation.The aim of the present study was to investigate the role of 5-HT release upon platelet activation and whether 5-HT signalling is involved in the pathogenesis of SSc.Methods Dermal fi broblasts from SSc patients and healthy individuals were stimulated with 5-HT and incubated with selective inhibitors of different 5-HT receptors.Expression of 5-hydroxytryptamine (serotonin) receptor 2B (5-HT2B) in human sections was analysed by immunohistochemistry.The role of platelet-derived 5-HT and of the 5-HT2B receptor was evaluated in the mouse model of bleomycin-induced dermal fi brosis and in tight-skin-1 (tsk-1) mice.Results Stimulation of SSc and healthy dermal fi broblasts with 5-HT signifi cantly increased dose-dependently mRNA and protein levels of collagen by up to 3.1±0.14-fold(p<0.05 for each), which was signifi cantly reduced upon incubation with the selective 5-HT2B inhibitor SB 204741.The expression of 5-HT2B protein was strongly increased in the skin of SSc patients compared to healthy volunteers.In the mouse models of bleomycin-induced fi brosis and tsk-1, the concentration of 5-HT in lesional skin signifi cantly increased from 3.2±0.2 to 5.8±0.5 ng/mg and from 3.5±0.4 to 4.8±0.2ng/ mg, respectively, as analysed by ELISA.Treatment with clopidogrel signifi cantly reduced the 5-HT content of the skin in both models.Along with reduced levels of 5-HT, treatment with clopidogrel decreased dermal thickening upon bleomycin-challenge and prevented also hypodermal thickening in tsk-1 mice.Also selective depletion of 5-HT from platelets by knockdown of tph-1 signifi cantly ameliorated dermal fi brosis in mice lacking tph-1 with a mean reduction in dermal thickening of 61±6% (p<0.05).Mice lacking 5-HT2B were completely on August 25,
Immune Thrombocytopenia in Patients with Chronic Lymphocytic Leukemia Is Associated with Stereotyped B-cell Receptors
Authors: Carlo Visco, Francesco Maura, Giacomo Tuana, Luca Agnelli, Marta Lionetti, Sonia Fabris, Elisabetta Novella, Ilaria Giaretta, Gianluigi Reda, Wilma Barcellini, Luca Baldini, Antonino Neri, Francesco Rodeghiero, Agostino Cortelezzi
Journal: Clinical Cancer Research (2012)

Abstract Purpose: To assess biologic features related to the development of immune thrombocytopenia (ITP) in patients with chronic lymphocytic leukemia (CLL). Experimental Design: We retrospectively analyzed 463 patients with CLL with available immunoglobulin heavy-chain variable (IGHV) gene status and B-cell receptor (BCR) configuration [heavy-chain complementary-determining region 3 (HCDR3)], of whom thirty-six developed ITP, according to previously defined criteria. Most of them had available cytogenetic analysis. Results: We observed a significant association between ITP occurrence and IGHV unmutated gene status (P &amp;lt; 0.0001), unfavorable cytogenetic lesions (P = 0.005), and stereotyped HCDR3 (P = 0.006). The more frequent stereotyped HCDR3 subsets were #1 (IGHV1-5-7/IGHD6-19/IGHJ4; 16 of 16 unmutated) and #7 (IGHV1-69 or IGHV3-30/IGHD3-3/IGHJ6; 13 of 13 unmutated), both being significantly more represented among patients developing ITP (P = 0.003 and P = 0.001, respectively). Moreover, restricting the analysis to unmutated patients, subset #7 confirmed its independent significant association with the occurrence of ITP (P = 0.013). Both unmutated IGHV mutational status, del(11)(q23) and stereotyped BCR were significantly associated with shorter time to ITP development (P &amp;lt; 0.0001, P = 0.02, and P = 0.005, respectively) than other patients. Conclusion: Our data suggest that patients with CLL and peculiar BCR conformations are at higher risk of developing secondary ITP and that stereotyped BCR may be involved in the pathogenesis of this complication. Clin Cancer Res; 18(7); 1870–8. ©2012 AACR.
Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials
Authors: Kazem Rahimi, Neeraj Bhala, Pieter Kamphuisen, Jonathan Emberson, Sara Biere-Rafi, Vera Krane, Michele Robertson, John Wikstrand, John McMurray
Journal: PLoS Medicine (2012)

A systematic review and meta-analysis conducted by Kazem Rahimi and colleagues re-evaluates the hypothesis, generated in previous studies, that statins may reduce the risk of venous thromboembolic events. Their meta-analysis does not support the previous findings.
Eniluracil Treatment Completely Inactivates Dihydropyrimidine Dehydrogenase in Colorectal Tumors
Authors: Fareeda Y. Ahmed, Stephen J. Johnston, James Cassidy, Terry O'Kelly, Norman Binnie, Graeme I. Murray, Albert H. van Gennip, Nico G.G.M. Abeling, Sidonie Knight, Howard L. McLeod
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To determine the effect of eniluracil on colorectal tumor dihydropyrimidine dehydrogenase (DPD) activity. PATIENTS AND METHODS: Patients who were to undergo primary colorectal tumor resection received oral eniluracil 10 mg/m 2 twice daily for 3 days before surgery. Mononuclear cells were obtained before the start of eniluracil and on the morning of surgery, to measure DPD activity, protein, and mRNA. Plasma uracil was also measured at these two time points to assess the effect of eniluracil on pyrimidine accumulation. DPD activity, protein, and mRNA were also assessed in colorectal tumors and adjacent normal mucosa of patients who received eniluracil and untreated control patients. RESULTS: DPD activity in tumors from 10 untreated patients ranged from 30 to 92 pmol/min/mg of protein. In contrast, there was no detectable tumor DPD activity in 10 patients who received eniluracil. A similar pattern was observed in mononuclear cells, where median pretherapy activity was 366.5 pmol/min/mg of protein (range, 265 to 494 pmol/min/mg of protein) and was undetectable immediately before surgery. Plasma uracil changed from a median less than 0.2 μmol/L before therapy to 27.76 μmol/L before surgery. No difference in DPD protein or mRNA was observed between pretherapy and presurgery mononuclear cell samples or between treated and untreated tumor samples. CONCLUSION: This study provides definitive evidence that eniluracil completely inactivates DPD activity in human solid tumors. The increased plasma uracil and decreased DPD activity are consistent with systemic inactivation of the enzyme. The mechanism of inactivation is at the catalytic level, because no changes in DPD protein or mRNA were observed. Treatment with eniluracil will eliminate DPD activity as a source of pharmacokinetic fluorouracil variability or resistance in human colorectal cancer.
Erythropoietin and Erythropoietin Receptor Expression in Head and Neck Cancer: Relationship to Tumor Hypoxia
Authors: Murat O. Arcasoy, Khalid Amin, Shu-Chuan Chou, Zishan A. Haroon, Mahesh Varia, James A. Raleigh
Journal: Clinical Cancer Research (2005)

Erythropoietin, an oxygen-regulated glycoprotein hormone, is a hematopoietic cytokine that stimulates erythropoiesis by binding to its cellular receptor [erythropoietin receptor (EPOR)]. The recombinant form of human erythropoietin is used to prevent or treat anemia in cancer patients. However, in a recent randomized, placebo-controlled trial involving patients receiving curative radiotherapy for squamous cell carcinoma of the head and neck, erythropoietin treatment was associated with poorer locoregional progression-free survival. The purpose of our study was to determine whether EPOR and its ligand erythropoietin are expressed in primary head and neck cancer. We also investigated the hypothesis that erythropoietin expression in malignant cells may be associated with the presence of tumor hypoxia, an important factor involved in resistance to radiation treatment, tumor aggressiveness, and poor prognosis.Twenty-one patients received an i.v. infusion of the hypoxia marker pimonidazole hydrochloride before multiple tumor biopsies. Contiguous sections from 74 biopsies were analyzed by immunohistochemistry for EPOR and erythropoietin expression and pimonidazole binding.EPOR expression was present in tumor cells in 97% of the biopsies. Coexpression of erythropoietin was observed in 90% of biopsies. Erythropoietin and pimonidazole adduct staining did not always colocalize within tumors, but there was a significant positive correlation between levels of microregional erythropoietin expression and pimonidazole binding.The coexpression of erythropoietin and EPOR in tumor cells suggests that erythropoietin may potentially function as an autocrine or paracrine factor in head and neck cancer. The expression of the hypoxia-inducible protein erythropoietin in tumor cells correlates with levels of tumor hypoxia.
Efficacy and safety of long-term low molecular weight heparin in patients with antiphospholipid syndrome
Authors: J. A. Vargas-Hitos, O. Ateka-Barrutia, S. Sangle, M. A. Khamashta
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> Evaluation of the effectiveness and safety of long-term low molecular weight heparin (LMWH) in patients with antiphospholipid syndrome (APS) that had not previously responded to or tolerated oral vitamin K antagonists. <h3>Methods</h3> 23 patients with confirmed diagnosis of APS were retrospectively recruited. All patients were receiving LMWH as a result of intolerance and/or lack of response to warfarin therapy. The type of LMWH, the duration of treatment, the reason for switching to LMWH and the adverse effects were recorded. Outcomes were classified as no improvement, partial improvement or total improvement after at least 1 year of using LMWH. <h3>Results</h3> The average duration of LMWH treatment was 36 months. Most of the patients were on treatment with enoxaparin (n=16, 69%) and were switched to LMWH from warfarin mainly because of thrombosis despite therapeutic international normalised ratio (n=9, 39%). Good quality of life with no evidence of recurrent thrombotic events was noted in nine patients (39%), whereas 11 (48%) showed partial clinical improvement but no evidence of recurrent thrombotic episodes. Osteoporosis was reported in five patients (23%), all of whom were also receiving treatment with corticosteroids. <h3>Conclusions</h3> Long-term LMWH may be a safe and effective alternative to warfarin for APS patients.
Nuclear Bile Acid Receptor FXR Protects against Intestinal Tumorigenesis
Authors: Salvatore Modica, Stefania Murzilli, Lorena Salvatore, Daniel R. Schmidt, Antonio Moschetta
Journal: Cancer Research (2008)

Abstract Bile acids have been considered intestinal tumor promoters, and because they are natural ligands for the nuclear receptor FXR, we examined the role of FXR in intestinal tumorigenesis. Using gain- and loss-of-function studies, we found that FXR suppresses intestinal tumorigenesis in vivo. Loss of FXR in the ApcMin/+ and in the chronic colitis mouse models of intestinal tumorigenesis resulted in early mortality and increased tumor progression via promotion of Wnt signaling by infiltrating neutrophils and macrophages and tumor necrosis factor α production. Treatment with the bile acid binding resin cholestyramine did not modify the intestinal tumor susceptibility of FXR−/− mice, indicating that loss of FXR and not merely elevated bile acid concentrations increases susceptibility to tumorigenesis. Activation of FXR induced a proapoptotic program in the differentiated normal colonic epithelium as well as transformed colonocytes. Our data suggest that it is unlikely that the tumor-promoting activity of bile acids occurs as a function of their ability to activate FXR. However, FXR activity is relevant to the pathogenesis of intestinal cancer. When FXR is absent in the intestine, there is a promotion of Wnt signaling with expansion of the basal proliferative compartment, and a concomitant reduction in the apical differentiated apoptosis-competent compartment. When FXR is activated in the intestine and in colon cancer cells, there is an induction of apoptosis and removal of genetically altered cells, which may otherwise progress to complete transformation. Thus, from a therapeutic standpoint, strategies aimed at reactivating FXR expression in colon tumors might be useful in treatment of colon cancer. [Cancer Res 2008;68(23):9589–94]
DNase1L2 suppresses biofilm formation by Pseudomonas aeruginosa and Staphylococcus aureus
Authors: L. Eckhart, H. Fischer, K.B. Barken, T. Tolker-Nielsen, E. Tschachler
Journal: British Journal of Dermatology (2007)

Background The formation of biofilms, which is an important step in bacterial colonization, can be inhibited by deoxyribonuclease (DNase)-mediated breakdown of extracellular DNA. We have recently demonstrated that epidermal keratinocytes strongly express DNase1-like 2 (DNase1L2) in a differentiation-associated manner. Objectives To determine whether enzymatically active DNase1L2 is present in human stratum corneum and whether it is able to suppress bacterial biofilm formation. Methods DNase1L2 was extracted from normal human stratum corneum, immunocaptured and incubated with plasmid DNA. DNA hydrolysis was monitored by gel electrophoresis and ethidium bromide staining. The effect of DNase1L2 on biofilm formation was assayed by cultivation of Pseudomonas aeruginosa and Staphylococcus aureus in the presence or absence of purified recombinant DNase1L2 in microtitre plates and subsequent quantification of biofilm-forming bacteria by crystal violet staining. Results DNase1L2 was found to be present in an enzymatically active form in the stratum corneum of human skin. In an in vitro assay, purified recombinant DNase1L2 efficiently suppressed the formation of biofilms by P. aeruginosa and S. aureus. Conclusions Our data suggest that DNase1L2 is a novel component of the innate antimicrobial defence of the epidermis.
FOOD ECONOMY IN WAR TIME.
Authors: Margaret Ashton, Winifred Portland, HenriettaO. Barnett, Horace Plunkett, Lauder Brunton, B. Seebohm Rowntree, Robert Hutchison, Beatrice Webb, F.E. Lacey, Basil Wilberforce Leigh, LyttonG. Sims Woodhead, Isabel Margesson, H. Beckett-Overy, Gilbert Murray
Journal: The Lancet (1916)
The TEACCH program for children and adults with autism: A meta-analysis of intervention studies
Authors: Javier Virues-Ortega, Flávia M. Julio, Roberto Pastor-Barriuso
Journal: Clinical Psychology Review (2013)

The intervention program for autism known as Treatment and Education of Autistic and Related Communication Handicapped Children (TEACCH) is considered an emerging practice for autism. In the present study we used state-of-the-art meta-analytical procedures to examine the pooled clinical effects of TEACCH in a variety of outcomes. A total of 13 studies were selected for meta-analysis totaling 172 individuals with autism exposed to TEACCH. Standardized measures of perceptual, motor, adaptive, verbal and cognitive skills were identified as treatment outcomes. We used inverse-variance weighted random effects meta-analysis supplemented with quality assessment, sensitivity analysis, meta-regression, and heterogeneity and publication bias tests. The results suggested that TEACCH effects on perceptual, motor, verbal and cognitive skills were of small magnitude in the meta-analyzed studies. Effects over adaptive behavioral repertoires including communication, activities of daily living, and motor functioning were within the negligible to small range. There were moderate to large gains in social behavior and maladaptive behavior. The effects of the TEACCH program were not moderated by aspects of the intervention such as duration (total weeks), intensity (hours per week), and setting (home-based vs. center-based). While the present meta-analysis provided limited support for the TEACCH program as a comprehensive intervention, our results should be considered exploratory owing to the limited pool of studies available.
The Relationship Between Managed Care Insurance and Use of Lower-Mortality Hospitals for CABG Surgery
Authors: L C Erickson, D F Torchiana, E C Schneider, J W Newburger, E L Hannan
Journal: JAMA (2000)

Explicit information about the quality of coronary artery bypass graft (CABG) surgery has been available for nearly a decade in New York State; however, the extent to which managed care insurance plans direct enrollees to the lowest-mortality CABG surgery hospitals remains unknown.To compare the proportion of patients with managed care insurance and fee-for-service (FFS) insurance who undergo CABG surgery at lower-mortality hospitals.A retrospective cohort study of CABG surgery discharges from 1993 to 1996, using New York Department of Health databases and multivariate analysis to estimate the use of lower-mortality hospitals by patients with different types of health insurance.Cardiac surgical centers in New York, of which 14 were classified as lower-mortality hospitals (mean rate, 2.1%) and 17 were classified as higher-mortality hospitals (mean rate, 3.2%).A total of 58,902 adults older than 17 years who were hospitalized for CABG surgery. Patients were excluded if their CABG surgery was combined with any valve procedure or left ventricular aneurysm resection or if they were younger than 65 years and enrolled in Medicare FFS or Medicare managed care.Probability of a patient receiving CABG surgery at a lower-mortality hospital.Compared with patients with private FFS insurance (n = 18,905), patients with private managed care insurance (n=7169) and Medicare managed care insurance (n=880) were less likely to receive CABG surgery at a lower-mortality hospital (relative risk [RR] of surgery at a lower-mortality hospital compared with patients with private FFS insurance, 0.77; 95% confidence interval [CI], 0.74-0.81; P<.001; and RR, 0.61; 95% CI, 0.54-0.70; P<.001, respectively, after controlling for multiple potential confounding factors). Patients with Medicare FFS insurance used lower-mortality hospitals at rates more similar to those with private FFS insurance (n = 31,948; RR, 0.95; 95% CI, 0.91-0.98; P=.004).Patients in New York State with private managed care and Medicare managed care insurance were significantly less likely to use lower-mortality hospitals for CABG surgery compared with patients with private FFS insurance.
Interstitial lung disease associated with autoimmune thyroiditis (ILD-AT)
Authors: Igor Stepanyan, Marina Kovalevskaya, Evgenij Shmelev
Journal: European Respiratory Journal (2012)

Aim.  To show some peculiarities of an orphan syndrome which is often misdiagnosed on practice.   Patients and methods.  8 cases of ILD-AT were revealed among about 5000 patients with various interstitial lung diseases during 25 years.   Results.  ILD-AT was diagnosed in 7 female patients (age 49-60 yrs) and 1 male (age 23 yrs). In 5 cases the onset of pulmonary and thyroid disease was simultaneous in 3 autoimmune thyroiditis (AT) appeared several years earlier than ILD. The average duration of disease was 8.6 yrs to the moment of ILD-AT was diagnosed (range 1-27 yrs). In all patients ILD-AT presented with constant dry cough, dyspnea and crackles in lungs. NSIP pattern was seen on HRCT scans of all patients. Spirometry found out restriction in 6 of 8 cases (FVC 52-20%) while FEV1/FVC ratio was not decreased and bronchodilator test was negative. DLCO was lowered up to 52.6-25.2% as well as PaO 2  arterial blood level (69-49 mm Hg) in all patients. Long term treatment with low dose corticosteroids (during 2-27 yrs) prevented disease progression. The level of thyroid peroxydase in serum initially elevated in all of patients returned to normal after treatment. The results of treatment were as much better as shorter was the disease duration.   Conclusions.  Appearance of constant dry cough and dyspnea should be the reason for chest HRCT, spirometry and DLCO measurement in patients with AT. Patients with interstitial lung disease of unknown origin should be tested for AT. In spite of rather favorable course ILD-AT should be diagnosed in time and treated long to avoid diffuse pulmonary fibrosis formation.
Home testing for HIV
Authors: ThierryE Mertens, GeorgeDavey Smith, EricVan Praag, Ian Campbell, Chris Castle, Hilary Curtis, Sue Lucas, Maura O'Donahue, John Townsend, None HIV Testing Working Party, UK NGO AIDS Consortium, NoahJamie Robinson, Bertran Auvert, Daan Mulder, Richard Hayes, StevenD Pinkerton, PaulR Abramson, SheilaM Gore, A.Graham Bird
Journal: The Lancet (1994)
Inhibition of type I natural killer T cells by retinoids or following sulfatide‐mediated activation of type II natural killer T cells attenuates alcoholic liver disease in mice
Authors: Igor Maricic, Huiming Sheng, Idania Marrero, Ekihiro Seki, Tatiana Kisseleva, Som Chaturvedi, Natasha Molle, Stephanie A. Mathews, Bin Gao, Vipin Kumar
Journal: Hepatology (2014)

Innate immune mechanisms leading to liver injury subsequent to chronic alcohol ingestion are poorly understood. Natural killer T (NKT) cells, enriched in the liver and comprised of at least two distinct subsets, type I and II, recognize different lipid antigens presented by CD1d molecules. We have investigated whether differential activation of NKT cell subsets orchestrates inflammatory events leading to alcoholic liver disease (ALD). We found that after chronic plus binge feeding of Lieber‐DeCarli liquid diet in male C57BL/6 mice, type I, but not type II, NKT cells are activated, leading to recruitment of inflammatory Gr‐1 high CD11b + cells into the liver. A central finding is that liver injury after alcohol feeding is dependent upon type I NKT cells. Thus, liver injury is significantly inhibited in Jα18 −/− mice deficient in type I NKT cells as well as after their inactivation by sulfatide‐mediated activation of type II NKT cells. Furthermore, we have identified a novel pathway involving all‐trans retinoic acid (ATRA) and its receptor (RARγ) signaling that inhibits type I NKT cells and, consequently, ALD. A semiquantitative polymerase chain reaction analysis of hepatic gene expression of some of the key proinflammatory molecules shared in human disease indicated that their up‐regulation in ALD is dependent upon type I NKT cells. Conclusions : Type I, but not type II, NKT cells become activated after alcohol feeding. Type I NKT cell‐induced inflammation and neutrophil recruitment results in liver tissue damage whereas type II NKT cells protect from injury in ALD. Inhibition of type I NKT cells by retinoids or by sulfatide prevents ALD. Given that the CD1d pathway is highly conserved between mice and humans, NKT cell subsets might be targeted for potential therapeutic intervention in ALD. (H epatology 2015;61:1357–1369)
Translating pharmacogenomics discoveries into the clinic: an implementation framework
Authors: R Huang, Eric R Gamazon
Journal: Genome Medicine (2013)

The implementation of pharmacogenomics-guided care has the potential to improve clinical outcomes; however, the adoption of pharmacogenomics into clinical practice remains slow. This is partly due to the lack of a standardized framework for translating key findings into diagnostic tests. A recent study describes a comprehensive system developed by the Coriell Personalized Medicine Collaborative for facilitating the translation of genomic findings into clinical practice, and its application for seven commonly prescribed drugs. See related Research paper, http://genomemedicine.com/content/5/10/93