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Crespo M.,Autonomous University of Barcelona | Crespo M.,Vall dHebron Institute of Research VHIR | Navarro J.,Autonomous University of Barcelona | Navarro J.,Vall dHebron Institute of Research VHIR | And 10 more authors.
Enfermedades Infecciosas y Microbiologia Clinica | Year: 2016

Introduction: Limited data is available regarding the hepatic safety of maraviroc in patients co-infected with HIV and HCV and/or HBV. Our objective was to compare the hepatic safety profile and fibrosis progression in HIV-mono-infected patients and co-infected with HCV and/or HBV treated with maraviroc. Methods: Retrospective multicentre cohort study of HIV-infected patients receiving treatment with a maraviroc-containing regimen in 27 hospitals in Spain. Results: A total of 667 patients were analyzed, of whom 313 were co-infected with HCV (n = 282), HBV (n = 14), or both (n = 17). Maraviroc main indications were salvage therapy (52%) and drug toxicity (20%). Grade 3-4 hypertransaminasaemia (AST/ALT >5 times ULN) per 100 patient-years of maraviroc exposure, was 5.84 (95% CI, 4.04-8.16) and 1.23 (95% CI, 0.56-2.33) in co-infected and HIV-mono-infected patients, respectively (incidence rate ratio, 4.77; 95% CI, 2.35-10.5). However, the degree of aminotransferase abnormalities remained stable throughout the study in both groups, and no significant between-group differences were seen in the cumulative proportion of patients showing an increase in AST/ALT levels greater than 3.5 times baseline levels. No between-group differences were seen in liver fibrosis over time. With a maraviroc median exposure of 20 months (IQR, 12-41), two patients (0.3%) discontinued maraviroc because of grade 4 hepatitis, and other 2 died due to complications associated to end-stage-liver disease. Conclusions: Maraviroc-containing regimens showed a low incidence of hepatitis in a large Spanish cohort of HIV-infected patients, including more than 300 patients co-infected with HCV and/or HBV. Co-infection did not influence the maximum liver enzyme level or the fibrosis progression throughout the study. © 2016 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica.


Oro D.,Hospital Clinic Universitari | Yudina T.,Catalan Institute of Nanoscience and Nanotechnology | Fernandez-Varo G.,Hospital Clinic Universitari | Fernandez-Varo G.,University of Barcelona | And 11 more authors.
Journal of Hepatology | Year: 2016

Background & Aims Cerium oxide nanoparticles (CeO2NPs) have proven to behave as free radical scavengers and/or anti-inflammatory agents. The aim of the study was to determine whether CeO2NPs display hepatoprotective properties in experimental chronic liver disease. Methods Systemic and hepatic effects of nanoparticles were assessed in CCl4-treated rats receiving CeO2NPs or vehicle twice weekly for two weeks and CCl4 treatment was continued for 8 additional weeks. Thereafter, mean arterial pressure and portal pressure (PP) were assessed and serum samples obtained to measure standard hepatic and renal function tests. Organ and subcellular distribution of NPs were assessed using mass spectrometry (ICP-MS) and transmission electron microscopy. Liver samples were obtained to evaluate steatosis, α-SMA expression, macrophage infiltration, apoptosis and mRNA expression of oxidative stress, inflammatory or vasoactive related genes. Results Most CeO2NPs were located in the liver and it reduced hepatic steatosis, ameliorated systemic inflammatory biomarkers and improved PP without affecting mean arterial pressure. In addition, a marked reduction in mRNA expression of inflammatory cytokines (TNFα, IL1β, COX-2, iNOS), ET-1 and messengers related to oxidative (Epx, Ncf1, Ncf2) or endoplasmic reticulum (Atf3, Hspa5) stress signaling pathways was observed in the liver of rats receiving CeO2NPs. This was associated with reduced macrophage infiltration and reduced abundance of caspase-3, α-SMA and inflammatory cytokines. Conclusions CeO2NPs administration to CCl4-treated rats protects against chronic liver injury by reducing liver steatosis and portal hypertension and markedly attenuating the intensity of the inflammatory response, thereby suggesting that CeO2NPs may be of therapeutic value in chronic liver disease. © 2015 European Association for the Study of the Liver.


Ulloa F.,University of Barcelona | Ulloa F.,CIBER ISCIII | Gonzalez-Junca A.,CIBER ISCIII | Gonzalez-Junca A.,Autonomous University of Barcelona | And 16 more authors.
PLoS ONE | Year: 2015

Glioblastoma (GBM) is the most prevalent adult brain tumor, with virtually no cure, and with a median overall survival of 15 months from diagnosis despite of the treatment. SNARE proteins mediate membrane fusion events in cells and are essential for many cellular processes including exocytosis and neurotransmission, intracellular trafficking and cell migration. Here we show that the blockade of the SNARE protein Syntaxin 1 (Stx1) function impairs GBM cell proliferation. We show that Stx1 loss-of-function in GBM cells, through ShRNA lentiviral transduction, a Stx1 dominant negative and botulinum toxins, dramatically reduces the growth of GBM after grafting U373 cells into the brain of immune compromised mice. Interestingly, Stx1 role on GBM progression may not be restricted just to cell proliferation since the blockade of Stx1 also reduces in vitro GBM cell invasiveness suggesting a role in several processes relevant for tumor progression. Altogether, our findings indicate that the blockade of SNARE proteins may represent a novel therapeutic tool against GBM. © 2015 Ulloa et al.


Morata J.,Institute Of Biologia Molecular Of Barcelona Ibmb | Bejar S.,Institute Of Biologia Molecular Of Barcelona Ibmb | Talavera D.,University of Manchester | Riera C.,Vall dHebron Institute of Research VHIR | And 5 more authors.
PLoS ONE | Year: 2013

At present we know that phenotypic differences between organisms arise from a variety of sources, like protein sequence divergence, regulatory sequence divergence, alternative splicing, etc. However, we do not have yet a complete view of how these sources are related. Here we address this problem, studying the relationship between protein divergence and the ability of genes to express multiple isoforms. We used three genome-wide datasets of human-mouse orthologs to study the relationship between isoform multiplicity co-occurrence between orthologs (the fact that two orthologs have more than one isoform) and protein divergence. In all cases our results showed that there was a monotonic dependence between these two properties. We could explain this relationship in terms of a more fundamental one, between exon number of the largest isoform and protein divergence. We found that this last relationship was present, although with variations, in other species (chimpanzee, cow, rat, chicken, zebrafish and fruit fly). In summary, we have identified a relationship between protein divergence and isoform multiplicity co-occurrence and explained its origin in terms of a simple gene-level property. Finally, we discuss the biological implications of these findings for our understanding of inter-species phenotypic differences. © 2013 Morata et al.


Cuadros T.,Vall dHebron Institute of Research VHIR | Trilla E.,Hospital Vall dHebron | Vila M.R.,Vall dHebron Institute of Research VHIR | De Torres I.,Hospital Vall dHebron | And 12 more authors.
European Journal of Cancer | Year: 2013

Aim of the study: To correlate hepatitis A virus cellular receptor (HAVCR)/kidney injury molecule-1 (KIM-1) expression in clear cell renal cell carcinoma (ccRCC) tumours with patient outcome and study the consequences of HAVCR/KIM-1 ectodomain shedding. Methods: HAVCR/KIM-1 expression in ccRCC, oncocytomes, papillary carcinomas and unaffected tissue counterparts was evaluated. Minimal change disease and pre-clamping normal and ccRCC tissue biopsies were included. Tissue microarrays from 98 ccRCC tumours were analysed. Tumour registry data and patient outcome were retrospectivelly collected. Deletions in HAVCR/KIM-1 ectodomain and lentiviral infection of 786-O cells with HAVCR/KIM-1 mutated constructs to determine their subcellular distribution and invasive capacity were performed. Results: HAVCR/KIM-1 was expressed in ccRCC, papillary tumours and in tubule cells of adjacent and distal unaffected counterparts of ccRCC tumours. The latest was not related to ischemic or tumour-related paracrine effects since pre-clamping normal biopsies were positive for HAVCR/KIM-1 and unaffected counterparts of papillary tumours were negative. HAVCR/KIM-1 analyses in patients and the invasive capacity of HAVCR/KIM-1 shedding mutants in cell lines demonstrated that: (i) relative low HAVCR/KIM-1 membrane levels correlate with activated shedding in ccRCC patients and mutant cell lines; (ii) augmented shedding directly correlates with higher invasiveness and tumour malignancy. Concluding statements: Constitutive expression of HAVCR/KIM-1 in kidney might constitute a susceptibility trait for ccRCC tumour development. Enhanced HAVCR/KIM-1 ectodomain shedding promotes invasive phenotype in vitro and more aggressive tumours in vivo. © 2013 Elsevier Ltd. All rights reserved.


Batlle M.,University of Barcelona | Ferri L.,University of Barcelona | Ferri L.,Catholic University of the Sacred Heart | Andrade C.,University of Barcelona | And 7 more authors.
BioMed Research International | Year: 2015

Brain injury triggers a progressive inflammatory response supported by a dynamic astroglia-microglia interplay. We investigated the progressive chronic features of the astroglia-microglia cross talk in the perspective of neuronal effects in a rat model of hippocampal excitotoxic injury. N-Methyl-D-aspartate (NMDA) injection triggered a process characterized within 38 days by atrophy, neuronal loss, and fast astroglia-mediated S100B increase. Microglia reaction varied with the lesion progression. It presented a peak of tumor necrosis factor-α (TNF-α) secretion at one day after the lesion, and a transient YM1 secretion within the first three days. Microglial glucocorticoid receptor expression increased up to day 5, before returning progressively to sham values. To further investigate the astroglia role in the microglia reaction, we performed concomitant transient astroglia ablation with L-α-aminoadipate and NMDA-induced lesion. We observed a striking maintenance of neuronal death associated with enhanced microglial reaction and proliferation, increased YM1 concentration, and decreased TNF-α secretion and glucocorticoid receptor expression. S100B reactivity only increased after astroglia recovery. Our results argue for an initial neuroprotective microglial reaction, with a direct astroglial control of the microglial cytotoxic response. We propose the recovery of the astroglia-microglia cross talk as a tissue priority conducted to ensure a proper cellular coordination that retails brain damage. © 2015 Montserrat Batlle et al.


Ramirez-Estrada S.,Vall Dhebron University Hospital | Borgatta B.,Vall Dhebron University Hospital | Borgatta B.,Vall Dhebron Institute Of Research Vhir | Rello J.,Autonomous University of Barcelona | Rello J.,Research Center Biomedica en Red enfermedad Respiratoria eReS
Infection and Drug Resistance | Year: 2016

Ventilator-associated pneumonia is the most common infection in intensive care unit patients associated with high morbidity rates and elevated economic costs; Pseudomonas aeruginosa is one of the most frequent bacteria linked with this entity, with a high attributable mortality despite adequate treatment that is increased in the presence of multiresistant strains, a situation that is becoming more common in intensive care units. In this manuscript, we review the current management of ventilator-associated pneumonia due to P. aeruginosa, the most recent antipseudomonal agents, and new adjunctive therapies that are shifting the way we treat these infections. We support early initiation of broad-spectrum antipseudomonal antibiotics in present, followed by culture-guided monotherapy de-escalation when susceptibilities are available. Future management should be directed at blocking virulence; the role of alternative strategies such as new antibiotics, nebulized treatments, and vaccines is promising. © 2016 Ramírez-Estrada et al.


Akizu N.,Institute Biologia Molecular Of Barcelona Ibmb | Akizu N.,Scripps Research Institute | Garcia M.A.,Institute Biologia Molecular Of Barcelona Ibmb | Estaras C.,Institute Biologia Molecular Of Barcelona Ibmb | And 6 more authors.
Open Biology | Year: 2016

The function of EZH2 as a transcription repressor is well characterized. However, its role during vertebrate development is still poorly understood, particularly in neurogenesis. Here, we uncover the role of EZH2 in controlling the integrity of the neural tube and allowing proper progenitor proliferation. We demonstrate that knocking down the EZH2 in chick embryo neural tubes unexpectedly disrupts the neuroepithelium (NE) structure, correlating with alteration of the Rho pathway, and reduces neural progenitor proliferation. Moreover, we use transcriptional profiling and functional assays to show that EZH2-mediated repression of p21WAF1/CIP1contributes to both processes. Accordingly, overexpression of cytoplasmic p21WAF1/CIP1induces NE structural alterations and p21WAF1/CIP1suppression rescues proliferation defects and partially compensates for the structural alterations and the Rho activity. Overall, our findings describe a new role of EZH2 in controlling the NE integrity in the neural tube to allow proper progenitor proliferation. © 2016 The Authors.


Rello J.,Autonomous University of Barcelona | Bunsow E.,Vall Dhebron Institute Of Research Vhir | Perez A.,Autonomous University of Barcelona
Expert Review of Clinical Pharmacology | Year: 2016

Introduction: Bacterial resistance to antibiotics is increasing worldwide, due to the emergence of multidrug-resistant strains. With this panorama, there is a serious danger that we may be entering the ‘post-antibiotic era’. Areas covered: We assess why so few new classes of antibiotics have been developed in the past years and discuss a variety of treatments that may be able to replace antimicrobials: monoclonal antibodies, bacteriophages, stem cells and anti-virulence agents such as liposomes. Expert commentary: There are a series of economic, scientific-research and regulatory reasons for the scarcity of new antimicrobials. New approaches are needed to combat infections. Innovative strategies like Eco-Evo drugs and innovative delivery methods such as aerosol or nanoparticle administration require a new management paradigm, in combination with rapid molecular diagnostic tests. Biopharma, clinical researchers, regulatory agencies, governments and investors must work together in the attempts to achieve effective treatment for infections caused by MDR organisms. © 2016 Informa UK Limited, trading as Taylor & Francis Group

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