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Valencia, Spain

Cortes M.,Institute Investigacion Sanitaria | Pareja E.,Institute Investigacion Sanitaria | Garcia-Canaveras J.C.,Institute Investigacion Sanitaria | Donato M.T.,Institute Investigacion Sanitaria | And 4 more authors.
Journal of Hepatology | Year: 2014

Background & Aims Early allograft dysfunction (EAD) dramatically influences graft and patient outcome after orthotopic liver transplantation and its incidence is strongly determined by donor liver quality. Nevertheless, objective biomarkers, which can assess graft quality and anticipate organ function, are still lacking. This study aims to investigate whether there is a preoperative donor liver metabolomic biosignature associated with EAD. Methods A comprehensive metabolomic profiling of 124 donor liver biopsies collected before transplantation was performed by mass spectrometry coupled to liquid chromatography. Donor liver grafts were classified into two groups: showing EAD and immediate graft function (IGF). Multivariate data analysis was used to search for the relationship between the metabolomic profiles present in donor livers before transplantation and their function in recipients. Results A set of liver graft dysfunction-associated biomarkers was identified. Key changes include significantly increased levels of bile acids, lysophospholipids, phospholipids, sphingomyelins and histidine metabolism products, all suggestive of disrupted lipid homeostasis and altered histidine pathway. Based on these biomarkers, a predictive EAD model was built and further evaluated by assessing 24 independent donor livers, yielding 91% sensitivity and 82% specificity. The model was also successfully challenged by evaluating donor livers showing primary non-function (n = 4). Conclusions A metabolomic biosignature that accurately differentiates donor livers, which later showed EAD or IGF, has been deciphered. The remarkable metabolomic differences between donor livers before transplant can relate to their different quality. The proposed metabolomic approach may become a clinical tool for donor liver quality assessment and for anticipating graft function before transplant. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Source

Del Rey M.J.,Institute Investigacion | Izquierdo E.,Institute Investigacion | Usategui A.,Institute Investigacion | Gonzalo E.,Institute Investigacion | And 3 more authors.
Arthritis Care and Research | Year: 2010

Objective: Hypoxia is a prominent feature in rheumatoid arthritis (RA) synovium. However, its contribution to the pathogenesis of RA remains unclear. We undertook this study to systematically characterize the changes in gene expression induced by hypoxia in synovial fibroblasts. Methods We used microarray expression profiling in paired normoxic and hypoxic cultures of healthy synovial fibroblasts (HSFs) and RA synovial fibroblasts (RASFs). We used Student's paired t-test with Benjamini and Hochberg multiple testing correction to determine statistical significance. Validation of microarray data was performed by quantitative real-time reverse transcription-polymerase chain reaction analysis of selected genes. Biologic pathways differentially modulated by hypoxia in RASFs or HSFs were identified using unsupervised Ingenuity Pathways Analysis. Results Hypoxia induced significant changes in the expression of a large group of genes in both HSFs and RASFs. In RASFs, we observed a lower number of hypoxia-regulated genes and partial differences in their functional categories. The number of differentially expressed genes in RASFs compared with HSFs was significantly increased by hypoxia. Multiple gene sets involved in energy metabolism, intracellular signal transduction, angiogenesis, and immune and inflammatory pathways were significantly modified, the last in both proinflammatory and antiinflammatory directions. Conclusion These data demonstrate that hypoxia induces significant changes in gene expression in HSFs and RASFs and identify differences between RASF and HSF profiles. The hypoxia-induced gene expression program in synovial fibroblasts identifies new factors and pathways relevant to understanding their contribution to the pathogenesis of chronic arthritis. Copyright © 2010 by the American College of Rheumatology. Source

Arranz A.,ETH Zurich | Dong D.,CAS Institute of Automation | Zhu S.,Xidian University | Savakis C.,B.S.R.C. Alexander Fleming | And 4 more authors.
Scientific Reports | Year: 2014

Even though in vivo imaging approaches have witnessed several new and important developments, specimens that exhibit high light scattering properties such as Drosophila melanogaster pupae are still not easily accessible with current optical imaging techniques, obtaining images only from subsurface features. This means that in order to obtain 3D volumetric information these specimens need to be studied either after fixation and a chemical clearing process, through an imaging window-thus perturbing physiological development-, or during early stages of development when the scattering contribution is negligible. In this paper we showcase how Optical Projection Tomography may be used to obtain volumetric images of the head eversion process in vivo in Drosophila melanogaster pupae, both in control and headless mutant specimens. Additionally, we demonstrate the use of Helical Optical Projection Tomography (hOPT) as a tool for high throughput 4D-imaging of several specimens simultaneously. Source

Celis R.,Arthritis Unit | Planell N.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas | Fernandez-Sueiro J.L.,Complejo Hospitalario Universitario | Sanmarti R.,Arthritis Unit | And 4 more authors.
Arthritis Research and Therapy | Year: 2012

Introduction: Psoriatic arthritis (PsA) is an autoantibody-negative immune-mediated disease in which synovial lymphoid neogenesis (LN) occurs. We determined whether LN is associated with specific patterns of inflammatory cytokine expression in paired synovial tissue (ST) and fluid (SF) samples and their potential correlation with the clinical characteristics of PsA.Methods: ST and paired SF samples were obtained from the inflamed knee of PsA patients. ST samples were immunostained with CD3 (T cell), CD20 (B cell), and MECA-79 (high endothelial vessels). Total ST mRNA was extracted, and the gene expression of 21 T-cell-derived and proinflammatory cytokines were measured with quantitative real-time PCR. SF concentrations of Th1, Th2, Th17, and proinflammatory cytokines were determined with the Quantibody Human Th17 Array. Clinical and biologic data were collected at inclusion and after a median of 27 months of follow-up.Results: Twenty (43.5%) of 46 patients had LN. Only two genes showed differences (Wilcoxon test, P < 0.06) in ST between LN-positive and LN-negative patients: interleukin-23A (IL-23A) (P = 0.058) and transforming growth factor-beta (TGF-β1) (P = 0.050). IL-23A expression was higher, and TGF-β1 expression was lower in LN-positive patients. ST IL-15 mRNA showed a nonsignificant trend toward higher expression in LN-positive patients, and SF IL-15 protein levels were significantly higher in LN-positive patients (P = 0.002). In all PsA patients, IL-23A mRNA expression correlated with C-reactive protein (CRP) (r = 0.471; P = 0.001) and swollen-joint count (SJC) (r = 0.350; P = 0.018), whereas SF levels of IL-6 and CC chemokine-ligand 20 (CCL-20) correlated with CRP levels (r = 0.377; P = 0.014 and r = 0.501; P < 0.0001, respectively).Conclusions: These findings suggest differences in the cytokine profile of PsA patients with LN, with a higher expression of IL-23A and IL-15 and a lower expression of TGF-β1. In the entire group of patients, IL-23 ST expression and CCL20 SF levels strongly correlated with markers of disease activity. This cytokine pattern was not accompanied by gross clinical or biologic differences between LN-positive and -negative patients. Taken together, these results suggest a role of the IL-17/IL-23 cytokine axis in synovial LN in PsA. © 2012 Cañete et al.; licensee BioMed Central Ltd. Source

Fiuza-Luces C.,European University at Madrid | Fiuza-Luces C.,Institute Investigacion | Garatachea N.,University of Zaragoza | Berger N.A.,Case Western Reserve University | And 2 more authors.
Physiology | Year: 2013

The concept of a "polypill" is receiving growing attention to prevent cardiovascular disease. Yet similar if not overall higher benefits are achievable with regular exercise, a drug-free intervention for which our genome has been haped over evolution. Compared with drugs, exercise is available at low cost and relatively free of adverse effects. We summarize epidemiological evidence on the preventive/therapeutic benefits of exercise and on the main biological mediators involved. © 2013 Int. Union Physiol. Sci./Am. Physiol. Soc. Source

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