Institute dInvestigacio Germans Trias i Pujol

Institute dInvestigacio Germans Trias i Pujol

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De Souza-Galvao M.L.,Hospital Universitari Vall dHebron | De Souza-Galvao M.L.,IDIAP Jordi Gol Research Foundation | De Souza-Galvao M.L.,University of Barcelona | Latorre I.,University of Barcelona | And 15 more authors.
BMC Infectious Diseases | Year: 2014

Background: The aim of the study was to assess the correlation between the tuberculin skin test (TST) and in vitro interferon-gamma released assays (IGRAs) with risk factors for the spread of infection in smear positive pulmonary tuberculosis (TB) contacts.Methods: We recruited prospective contacts with smear positive pulmonary TB cases. We looked at human immunodeficiency virus (HIV) infection and other conditions of immunosuppression, presence of BCG vaccination and the degree of exposure to the index case. Patients underwent the TST, chest radiography, sputum analysis when necessary, and IGRA assays (QFN-G-IT and T-SPOT.TB). Presence of cough, diagnostic delay (days between first symptoms and TB diagnostic), contact conditions: room size (square meters) and index of overcrowding (square meters per person) were investigated in the index case.Results: 156 contacts (119 adults, 37 children) of 66 TB patients were enrolled, 2.4 (1-14) contacts per TB case. The positivity of the TST did not correlate with the risk factors studied: presence of cough (p = 0.929); delayed diagnosis (p = 0.244); room size (p = 0.462); overcrowding (p = 0.800). Both QFN-G-IT and T-SPOT.TB, showed significant association with cough (p = 0.001, and p = 0.007) and room size (p = 0.020, and p = 0.023), respectively.Conclusions: Both IGRA associated better than TST with certain host-related risk factors involved in the transmission of disease, such as the presence of cough. © 2014 de Souza-Galvão et al.; licensee BioMed Central Ltd.

Karachaliou N.,Quiron Dexeus Hospital Universitario | Rosell R.,Hospital Germans Trias i Pujol | Rosell R.,Molecular Oncology Research MORe Foundation | Morales-Espinosa D.,Institute dInvestigacio Germans Trias i Pujol | Viteri S.,Quiron Dexeus Hospital Universitario
Expert Review of Anticancer Therapy | Year: 2014

Over a short period of time, translational research has described a new clinically relevant molecular subset of non-small-cell lung cancer (NSCLC) that is defined by EGFR mutations or EML4-ALK fusions. Today, patients with metastatic disease can achieve survival rates at least double that of patients with wild-type tumors. Through the rational dissection of the mechanisms of drug sensitivity and resistance, promising strategies have been defined to further improve the outcomes of patients with NCSLC. This review adds to a growing body of knowledge into mechanisms of resistance that can be interrogated in NSCLC patients with EGFR mutations or EML4-ALK fusions, as well as strategies to overcome resistance to TKIs. © 2014 Informa UK, Ltd.

PubMed | University of Lleida, Hospital Germans Trias i Pujol and Institute dInvestigacio Germans Trias i Pujol
Type: Journal Article | Journal: European journal of immunology | Year: 2016

Autoreactive B lymphocytes play a key role as APCs in diaebetogenesis. However, it remains unclear whether B-cell tolerance is compromised in NOD mice. Here, we describe a new B lymphocyte transgenic NOD mouse model, the 116C-NOD mouse, where the transgenes derive from an islet-infiltrating B lymphocyte of a (8.3-NODxNOR) F1 mouse. The 116C-NOD mouse produces clonal B lymphocytes with pancreatic islet beta cell specificity. The incidence of T1D in 116C-NOD mice is decreased in both genders when compared with NOD mice. Moreover, several immune selection mechanisms (including clonal deletion and anergy) acting on the development, phenotype, and function of autoreactive B lymphocytes during T1D development have been identified in the 116C-NOD mouse. Surprisingly, a more accurate analysis revealed that, despite their anergic phenotype, 116C B cells express some costimulatory molecules after activation, and induce a T-cell shift toward a Th17 phenotype. Furthermore, this shift on T lymphocytes seems to occur not only when both T and B cells contact, but also when helper T (Th) lineage is established. The 116C-NOD mouse model could be useful to elucidate the mechanisms involved in the generation of Th-cell lineages.

PubMed | University of Barcelona, Institute dInvestigacio Germans Trias i Pujol, FIDMAG Germanes Hospitalaries CIBERSAM, Hospital Germans Trias i Pujol and 3 more.
Type: | Journal: The International journal of biological markers | Year: 2016

Homologous recombination (HR) is frequently impaired in sporadic high-grade serous ovarian carcinoma (sHGSOC) due to deficiencies in BRCA1/2 genes, a situation associated with hypersensitivity to platinum compounds. Alterations in other genes can also cause HR deficiency. Preclinical data show that RAP80 is an HR-pathway-related gene that influences BRCA1 activity. RAP80 has been reported to affect outcome in some solid neoplasms. This study investigates the role of RAP80 in sHGSOC survival.mRNA expression of RAP80 was analyzed in tumor samples from 35 patients who postoperatively received standard platinum-based chemotherapy. The effects of RAP80 expression on progression-free survival (PFS) and overall survival (OS) were examined by means of Cox regressions. The clinical variables known to have prognostic value (FIGO stage, residual disease at surgery, and debulking surgery) were included as covariates in the analysis. BRCA1 was analyzed given the moderate correlations with RAP80.Median follow-up, PFS and OS were 61.3, 20.2 and 62.8 months, respectively. Low RAP80 expression levels were associated with shorter PFS (HR = 1.449, p = 0.007) and OS (HR = 1.331, p = 0.047).This is the first study to show a potential prognostic role of RAP80 expression in patients with HGSOC. The results suggest that HR deficiency due to low RAP80 expression is not associated with hypersensitivity to platinum compounds in sHGSOC.

Arif S.,King's College London | Moore F.,Free University of Colombia | Marks K.,King's College London | Bouckenooghe T.,Free University of Colombia | And 12 more authors.
Diabetes | Year: 2011

OBJECTIVE - CD4 T-cells secreting interleukin (IL)-17 are implicated in several human autoimmune diseases, but their role in type 1 diabetes has not been defined. To address the relevance of such cells, we examined IL-17 secretion in response to β-cell autoantigens, IL-17A gene expression in islets, and the potential functional consequences of IL-17 release for β-cells. RESEARCH DESIGN AND METHODS - Peripheral blood CD4 T-cell responses to β-cell autoantigens (proinsulin, insulinoma-associated protein, and GAD65 peptides) were measured by IL-17 enzyme-linked immunospot assay in patients with new-onset type 1 diabetes (n = 50). mRNA expression of IL-17A and IFNG pathway genes was studied by qRT-PCR using islets obtained from subjects who died 5 days and 10 years after diagnosis of disease, respectively, and from matched control subjects. IL-17 effects on the function of human islets, rat β-cells, and the rat insulinoma cell line INS-1E were examined. RESULTS - A total of 27 patients (54%) showed IL-17 reactivity to one or more peptides versus 3 of 30 (10%) control subjects (P = 0.0001). In a single case examined close to diagnosis, islet expression of IL17A, RORC, and IL22 was detected. It is noteworthy that we show that IL-17 mediates significant and reproducible enhancement of IL-1β/interferon (IFN)-γ-induced and tumor necrosis factor (TNF)-α/IFN-γ-induced apoptosis in human islets, rat β-cells, and INS-1E cells, in association with significant upregulation of β-cell IL17RA expression via activation of the transcription factors STAT1 and nuclear factor (NF)-κB. CONCLUSIONS - Circulating IL-17+ β-cell-specific autoreactive CD4 T-cells are a feature of type 1 diabetes diagnosis. We disclose a novel pathway to β-cell death involving IL-17 and STAT1 and NF-κB, rendering this cytokine a novel disease biomarker and potential therapeutic target. © 2011 by the American Diabetes Association.

Cabal A.,Hopsital Universitario Miguel Servet | Strunk M.,CIBER ISCIII | Dominguez J.,Institute dInvestigacio Germans Trias i Pujol | Dominguez J.,Autonomous University of Barcelona | And 14 more authors.
BMC Microbiology | Year: 2014

Background: Different polymorphisms have been described as markers to classify the lineages of the Mycobacterium tuberculosis complex. The analysis of nine single nucleotide polymorphisms (SNPs) was used to describe seven SNPs cluster groups (SCGs). We attempted to classify those strains that could not been categorized into lineages by the genotyping methods used in the routine testing. Results: The M. tuberculosis complex isolates collected in 2010 in our region were analysed. A new method based on multiplex-PCRs and pyrosequencing to analyse these SNPs was designed. For the pyrosequencing assay nine SNPs that defined the seven SCGs were selected from the literature: 1977, 74092, 105139, 232574, 311613, 913274, 2460626, 3352929 and gyrA95. In addition, SNPs in katG463,mgtC182,Ag85C103 and RDRio deletion were detected. Conclusions: This work has permitted to achieve a better classification of Aragonian strains into SCGs and in some cases, to assign strains to its certain lineage. Besides, the description of a new pattern shared by two isolates "SCG-6c" reinforces the interest of SNPs to follow the evolution of M. tuberculosis complex. © 2014 Cabal et al.; licensee BioMed Central Ltd.

Monguio-Tortajada M.,Institute dInvestigacio Germans Trias i Pujol | Lauzurica R.,Hospital Universitari Germans Trias i Pujol | Borras F.E.,Institute dInvestigacio Germans Trias i Pujol | Borras F.E.,Hospital Universitari Germans Trias i Pujol
Frontiers in Immunology | Year: 2014

Organ transplantation is often the unique solution for organ failure. However, rejection is still an unsolved problem. Although acute rejection is well controlled, the chronic use of immunosuppressive drugs for allograft acceptance causes numerous side effects in the recipient and do not prevent chronic allograft dysfunction. Different alternative therapies have been proposed to replace the classical treatment for allograft rejection. The alternative therapies are mainly based in pre-infusions of different types of regulatory cells, including DCs, MSCs and Tregs. Nevertheless, these approaches lack full efficiency and have many problems related to availability and applicability. In this context, the use of extracellular vesicles, and in particular exosomes, may represent a cell-free alternative approach in inducing transplant tolerance and survival. Preliminary approaches in vitro and in vivo have demonstrated the efficient alloantigen presentation and immunomodulation abilities of exosomes, leading to alloantigen-specific tolerance and allograft acceptance in rodent models. Donor exosomes have been used alone, processed by recipient antigen-presenting cells (APCs) or administered together with suboptimal doses of immunosuppressive drugs, achieving specific allograft tolerance and infinite transplant survival. In this review we gathered the latest exosome-based strategies for graft acceptance and discuss the tolerance mechanisms involved in organ tolerance mediated by the administration of exosomes. We will also deal with the feasibility and difficulties that arise from the application of this strategy into the clinic. © 2014 Monguió-tortajada, Lauzurica-valdemoros and Borràs.

Perez-Cabezas B.,Autonomous University of Barcelona | Naranjo-Gomez M.,Autonomous University of Barcelona | Ruiz-Riol M.,Autonomous University of Barcelona | Bastos-Amador P.,Autonomous University of Barcelona | And 5 more authors.
Journal of Leukocyte Biology | Year: 2012

Cooperative events between DC subsets involve cell contact and soluble factors. Upon viral challenge, murine pDCs induce cDC cooperation through CD40-CD40L interactions and IL-15 secretion, whereas in humans, the same effect is mediated by IFN-α. Conversely, during bacterial infections, pDC maturation may be induced by activated cDCs, although no mechanisms had been described so far. Here, we investigate how human pDCs are "conditioned" by cDCs. Blood-borne DC subsets (cDCs and pDCs) were sorted from healthy donors. IL-3-maintained pDCs were cocul-tured with LPS-activated, poly (I:C)-activated, or control cDCs [cDCLPS, cDCP(I:C), cDCCTRL]. Coculture experiments showed that cDCLPS-conditioned pDCs up-regulated maturation markers, such as CD25 and CD86, whereas SNs contained higher amounts of IL-6 and CCL19 compared with control conditions. Gene-expression analyses on sorted cDCLPS or cDCP(I:C) conditioned pDCs confirmed the induction of several genes, including IL-6 and CCL19 and remarkably, several Notch target genes. Further studies using the γ-secretase/Notch inhibitor DAPT and soluble Notch ligands resulted in a significantly reduced expression of canonical Notch target genes in conditioned pDCs. DAPT treatment also hampered the secretion of CCL19 (but not of IL-6) by cDCLPS conditioned pDCs. These results reveal the involvement of γ-secretase-mediated mechanisms, including the Notch pathway, in the cell contact-dependent communication between human DC subsets. The resulting partial activation of pDCs after encountering with mature cDCs endows pDCs with an accessory function that may contribute to T cell recruitment and activation. © Society for Leukocyte Biology.

PubMed | Institute dInvestigacio Germans Trias i Pujol, Institute Universitari dInvestigacio en Atencio Primaria Jordi Gol Jordi Gol and Autonomous University of Barcelona
Type: Journal Article | Journal: Medicina clinica | Year: 2016

Although cardiovascular risk factors (CVRF) are well known, their degree of control is not optimal. The aim of this study is to assess the evolution and control of CVRFs after 5 years of monitoring a population-based cohort and their association with the incidence of peripheral arterial disease (PAD).Prospective cohort study recruited between 2006-2008. Second phase between 2011-2012. An ankle brachial index was determined for all participants in both phases. Demographic variables, CVRF and previous cardiovascular events, blood pressure, total cholesterol and its fractions (HDL, LDL), triglycerides, glucose and glycosylated hemoglobin levels in diabetic patients and the cardiovascular risk score according to the REGICOR table were recorded.A total of 2,125 individuals were analyzed. We observed an increase in the prevalence of hypertension (HT) (15.4%), diabetes (DM) (8.2%) and hypercholesterolemia (20.4%), with no changes in obesity and smoking. The cardiovascular risk determined on the basis of the REGICOR table remained at around 5.5%. We observed an increased control of CVRF throughout the follow-up period, except in the case of DM and obesity. In the multivariate analysis, uncontrolled HT 2-folded the risk of onset of PAD (odds ratio [OR] 2.3; 95% confidence interval [95% CI] 1.3-4.1), whereas smoking 5-folded this risk (OR 5.0; 95% CI 2.5-10.2).Smoking and uncontrolled HT increase the risk of onset of PAD in this population. Despite the increase in drug treatments, the control of CVRFs continues to be suboptimal.

PubMed | Institute dInvestigacio Germans Trias i Pujol
Type: Journal Article | Journal: Journal of leukocyte biology | Year: 2012

cDCs and pDCs differ in multiple aspects. Among those, antigen capture is a recognized feature of cDCs, whereas pDCs display poor capacity to capture cell-derived antigens. However, animal models of organ transplantation suggested a role for pDCs in tolerance induction via phagocytosis of donor antigens. In a transplantation setting, microvesicles, such as apoptotic bodies and exosomes secreted by the graft, may be potential sources of alloantigen. Here, we tested the capacity of human pDCs to capture exosomes and apoptotic bodies from Jurkat T cells. Exosomes and apoptotic bodies were indeed captured by pDCs, although required longer times of incubation when compared with the highly endocytic cDCs. In cDCs and pDCs, exosome capture was more efficient than apoptotic bodies. Endocytosis inhibitors clearly impaired exosome capture by cDCs, although this could not be verified in pDCs as a result of cellular toxicity. Functionally, capture of Jurkat-derived exosomes did not induce nor prevent pDC maturation, and exosome-loaded pDCs induced T cell proliferation, suggesting a link between capture and presentation. Thus, exosomes and apoptotic bodies may be sources of antigen for human pDCs.

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