Carlos III Health Institute

Majadahonda, Spain

Carlos III Health Institute

Majadahonda, Spain
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Albein-Urios N.,University of Granada | Verdejo-Roman J.,University of Granada | Asensio S.,University Cardenal Herrera | Soriano-Mas C.,CEU Cardenal Herrera University | And 3 more authors.
Addiction Biology | Year: 2014

Cocaine dependence is associated with pronounced elevations of negative affect and deficient regulation of negative emotions. We aimed to investigate the neural substrates of negative emotion regulation in cocaine-dependent individuals (CDI), as compared to non-drug-using controls, using functional magnetic resonance imaging (fMRI) during a re-appraisal task. Seventeen CDI abstinent for at least 15 days and without other psychiatric co-morbidities and 18 intelligence quotient-matched non-drug-using controls participated in the study. Participants performed the re-appraisal task during fMRI scanning: they were exposed to 24 blocks of negative affective or neutral pictures that they should Observe (neutral pictures), Maintain (sustain the emotion elicited by negative pictures) or Suppress (regulate the emotion elicited by negative pictures through previously trained re-appraisal techniques). Task-related activations during two conditions of interest (Maintain>Observe and Suppress>Maintain) were analyzed using the general linear model in SPM8 software. We also performed psychophysiological interaction (PPI) seed-based analyses based on one region from each condition: the dorsolateral prefrontal cortex (dlPFC - Maintain>Observe) and the inferior frontal gyrus (IFG - Suppress>Maintain). Results showed that cocaine users had increased right dlPFC and bilateral temporoparietal junction activations during Maintain>Observe, whereas they showed decreased right IFG, posterior cingulate cortex, insula and fusiform gyrus activations during Suppress>Maintain. PPI analyses showed that cocaine users had increased functional coupling between the dlPFC and emotion-related regions during Maintain>Observe, whereas they showed decreased functional coupling between the right IFG and the amygdala during Suppress>Maintain. These findings indicate that CDI have dysfunctional corticolimbic activation and connectivity during negative emotion experience and re-appraisal. © 2012 Society for the Study of Addiction.

Albein-Urios N.,University of Granada | Martinez-Gonzalez J.M.,Centro Provincial Of Drogodependencias | Lozano O.,University of Huelva | Moreno-Lopez L.,University of Granada | And 4 more authors.
Drug and Alcohol Dependence | Year: 2013

Background: Individuals with cocaine dependence and co-occurring personality disorders are more likely to have increased impulsivity, dysfunctional beliefs, executive dysfunction and brain structural abnormalities by virtue of the conjoint impact of both pathologies. Methods: We recruited 32 cocaine dependent patients with comorbid Cluster B personality disorders, 44 cocaine dependent patients without comorbidities and 34 non-drug-using controls. They completed the UPPS-P impulsivity scale, the Personality Belief Questionnaire, and executive function tests of working memory, attention/response inhibition and shifting. A subsample (n= 61) was also scanned using Magnetic Resonance Imaging. We used univariate ANOVAs for group comparisons, and tested the association between impulsivity, executive control and personality dysfunction and diagnoses using correlation and multivariate logistic regression analyses. Results: Cocaine dependent patients with personality disorders had elevated negative urgency and borderline beliefs, decreased inhibition and attention regulation, and reduced temporal pole gray matter with respect to the rest of the sample. Trait and cognitive measures correctly classified 73% of comorbid patients (60% sensitivity and 82% specificity). Conclusion: The co-occurrence of cocaine dependence and personality disorders is associated with negative-mood impulsivity and beliefs, executive dysfunction and temporal pole attrition. © 2013 Elsevier Ireland Ltd.

News Article | December 1, 2016

Researchers of the Sarcoma research group of the Bellvitge Biomedical Research Institute (IDIBELL), led by Dr. Òscar Martínez-Tirado, have first described the methylation profile of Ewing's sarcoma (ES), a cancer of bone and soft tissues that mainly affects children and teenagers. Their analysis has unveiled the potential of the PTRF gene as a prognostic marker of the disease and as a possible future therapeutic target in conjunction with the new genomic editing tools available. "This is the first time that the methylation profile of Ewing's sarcoma has been described," explains Dr. Òscar Martínez-Tirado, lead author of the study. DNA methylation is a type of epigenetic modification capable of controlling gene expression, that is, it can activate or deactivate genes that enhance to or block characteristics and processes in individuals, including the development of tumors. Using bioinformatic tools, the research team looked for common elements that allowed them to relate the set of differentially hypomethylated or hypermethylated genes they found in the tumor samples. The researchers identified a group of 12 genes related to the structure of the cell membrane; Among them, the precursor of the protein PTRF particularly called their attention by its relation with the caveolae, small invaginations that are present in the membrane of some cells; the IDIBELL group has extensive experience in the study of these structures and their relationship with ES. The team correlated the presence of PTRF in samples from 67 patients. "Initially, we saw that those patients who express PTRF have a better survival, therefore, we could consider this protein as a potential marker of prognosis of the disease," concludes Martinez-Tirado. Normal cells with caveolae express both the PTRF protein and caveolin-1 (CAV1), another protein related to caveolae formation. In contrast, tumor cells in ES do not have caveolae, nor express PTRF. "This made us think about the possibility of exogenously reintroducing the precursor gene PTRF into the study cell lines", explains the researcher. "In those that also expressed CAV1, the reintroduction of PTRF triggered caveolae formation. For tumor cells, this modification of the structure is so stressful that it destroys them". In addition, researchers have shown that the formation of the caveolae in these cells activates a known cell death signaling pathway promoted by the p53 protein. Current epigenetic drugs are rather nonspecific, but new CRISPR genomic editing tools have the potential to be used to demethylate specific genes from a tumor cell in the future. "If we are able to specifically act on the PTRF promoter gene so that the protein is expressed at normal levels, we would induce cell death and therefore we would have a promising new personalized therapeutic option for ES." This has been a highly collaborative work, both at the research level, as researchers by two groups from IDIBELL's epigenetics and cancer biology program, Germans Trias Institute, Institute of biomedicine of Seville, University Hospital la Paz, Children's University Hospital Niño Jesús, San Juan de Dios Hospital, Vall d'Hebron University Hospital and Virgen del Rocío University Hospital have collaborated, as well as at a financial level level, given that the project is funded by the Carlos III Health Institute, the AECC and the Alba Pérez Foundation.

Mata F.,Monash University | Verdejo-Roman J.,University of Granada | Soriano-Mas C.,Carlos III Health Institute | Soriano-Mas C.,Bellvitge Biomedical Research Institute IDIBELL | And 2 more authors.
Appetite | Year: 2015

This study was aimed to examine if adolescent obesity is associated with alterations of insula function as indexed by differential correlations between insula activation and perception of interoceptive feedback versus external food cues. We hypothesized that, in healthy weight adolescents, insula activation will positively correlate with interoceptive sensitivity, whereas in excess weight adolescents, insula activation will positively correlate with sensitivity towards external cues. Fifty-four adolescents (age range 12-18), classified in two groups as a function of BMI, excess weight (n = 22) and healthy weight (n = 32), performed the Risky-Gains task (sensitive to insula function) inside an fMRI scanner, and completed the heartbeat perception task (measuring interoceptive sensitivity) and the Dutch Eating Behaviour Questionnaire (measuring external eating as well as emotional eating and restraint) outside the scanner. We found that insula activation during the Risky-Gains task positively correlated with interoceptive sensitivity and negatively correlated with external eating in healthy weight adolescents. Conversely, in excess weight adolescents, insula activation positively correlated with external eating and negatively correlated with interoceptive sensitivity, arguably reflecting obesity related neurocognitive adaptations. In excess weight adolescents, external eating was also positively associated with caudate nucleus activation, and restrained eating was negatively associated with insula activation. Our findings suggest that adolescent obesity is associated with disrupted tuning of the insula system towards interoceptive input. © 2015 Elsevier Ltd.

Prados-Torres A.,University of Zaragoza | Prados-Torres A.,Carlos III Health Institute | Prados-Torres A.,Aragon Health science Institute IACS | Calderon-Larranaga A.,University of Zaragoza | And 7 more authors.
Journal of Clinical Epidemiology | Year: 2014

Objectives The aim of this review was to identify studies on patterns of associative multimorbidity, defined as the nonrandom association between diseases, focusing on the main methodological features of the studies and the similarities among the detected patterns. Study Design and Setting Studies were identified through MEDLINE and EMBASE electronic database searches from their inception to June 2012 and bibliographies. Results The final 14 articles exhibited methodological heterogeneity in terms of the sample size, age and recruitment of study participants, the data source, the number of baseline diseases considered, and the statistical procedure used. A total of 97 patterns composed of two or more diseases were identified. Among these, 63 patterns were composed of three or more diseases. Despite the methodological variability among studies, this review demonstrated relevant similarities for three groups of patterns. The first one comprised a combination of cardiovascular and metabolic diseases, the second one was related with mental health problems, and the third one with musculoskeletal disorders. Conclusion The existence of associations beyond chance among the different diseases that comprise these patterns should be considered with the aim of directing future lines of research that measure their intensity, clarify their nature, and highlight the possible causal underlying mechanisms. © 2014 Elsevier Inc. All rights reserved.

Hu-Lieskovan S.,University of California at Los Angeles | Robert L.,University of California at Los Angeles | Moreno B.H.,University of California at Los Angeles | Moreno B.H.,Carlos III Health Institute | Ribas A.,University of California at Los Angeles
Journal of Clinical Oncology | Year: 2014

Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non-BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials. © 2014 by American Society of Clinical Oncology.

Hu-Lieskovan S.,University of California at Los Angeles | Mok S.,University of California at Los Angeles | Homet Moreno B.,University of California at Los Angeles | Homet Moreno B.,Carlos III Health Institute | And 9 more authors.
Science Translational Medicine | Year: 2015

Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA4 antibody ipilimumab was terminated early because of substantial liver toxicities. MEK [MAPK (mitogen-activated protein kinase) kinase] inhibitors can potentiate the MAPK inhibition in BRAF mutant cells while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild-type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAFV600E-driven melanoma, SM1, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors, and improved in vivo cytotoxicity. Single-agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and major histocompatibility complex (MHC) expression and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested the combination of dabrafenib, trametinib, and anti-PD1 therapy in SM1 tumors, and observed superior antitumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAFV600E mutant metastatic melanoma. © 2015, American Association for the Advancement of Science. All rights reserved.

Bouza C.,Health Care Technology Assessment Agency | Lopez-Cuadrado T.,Carlos III Health Institute | Almendro N.,Health Care Technology Assessment Agency | Amate J.M.,Health Care Technology Assessment Agency
European Spine Journal | Year: 2015

Purpose: The study aims to evaluate the safety of balloon kyphoplasty in the treatment of painful osteoporotic vertebral compression fractures in Europe. Methods: Systematic review of the literature, until September 2013, and meta-analysis of randomized controlled trials performed in Europe assessing the safety of balloon kyphoplasty in patients with symptomatic osteoporotic vertebral fractures. Outcomes sought include cement leaks, serious clinical complications and new vertebral fractures. Results: Six randomized controlled trials fulfilled the inclusion criteria. These studies included data on 525 treated levels in 424 patients. Cement leakages were detected in 18.3 % (95 % CI 11.6, 23.0) of fractures intervened. In about 0.5 % (95 % CI 0.1, 1.1) of fractures leakages proved to be symptomatic. Serious clinical complications were recorded in 11.5 % (95 % CI 1.1, 21.7) of patients treated with balloon kyphoplasty with several of these cases requiring intensive treatment or postoperative surgery. New vertebral fractures were detected in 20.7 % (95 % CI 0.4, 40.9) of patients treated but rates showed an upward pattern when the follow-up period increased. In 54 % of such cases, the fractures were located in regions adjacent to the treated level. Conclusions: The safety profile and associated complications of balloon kyphoplasty shown in this analysis, based on the evidence provided by existing randomized controlled trials, can be of help to the practicing clinician who must contrast them with the potential benefits of the technique. These data represent an important step towards a balanced evaluation of the intervention though, a better reporting and more reliable data on long-term assessment of potential sequelae are needed. © 2014, Springer-Verlag Berlin Heidelberg.

Avellon A.,Carlos III Health Institute | Morago L.,Carlos III Health Institute | Garcia-Galera del Carmen M.,Carlos III Health Institute | Munoz M.,Carlos III Health Institute | Echevarria J.-M.,Carlos III Health Institute
Journal of Medical Virology | Year: 2015

Hepatitis E virus (HEV) acute infection is often diagnosed only by anti-HEV IgM ELISA methods, whose sensitivity varies, according to different reports. Reports assessing the specificity of commercial assays for anti-HEV IgG testing are scarce, and estimates of sensitivity and specificity are both controversial. The aim of this work is to assess the sensitivity of different commercial techniques for HEV genotype 3 antibody (anti-HEV) IgM and IgG detection in entirely specific sample panels including both high and low antibody concentrations. The anti-HEV IgM and IgG ELISA methods compared were: DSI, Mikrogen, Wantai, Euroimmun, MP, and The rapid test All Diag was also included in the anti-HEV IgM comparison. Our results show that low anti-HEV IgM concentrations were better detected by DSI, Mikrogen, and All Diag, these tests being the most sensitive in our study. Euroimmun, MP and gave concordant results, showing lower sensitivity than the others. Regarding anti-HEV IgG our results revealed similar anti-HEV IgG sensitivity. Furthermore, there was a striking overall lack of concordance among the results. We present a thorough review of previous comparative reports, with particular reference to the anti-HEV IgG comparison, since published results differ from ours. This discrepancy may be related to the improved versions of the tests for MP and that we employed. © 2015 Wiley Periodicals, Inc.

Perez-Sautu U.,Carlos III Health Institute
Euro surveillance : bulletin Européen sur les maladies transmissibles = European communicable disease bulletin | Year: 2014

The Y155H amino acid substitution in the neuraminidase gene (NA) has previously been associated with highly reduced inhibition by neuraminidase inhibitors in the seasonal H1N1 influenza A virus which circulated in humans before the 2009 pandemic. During the 2012/13 epidemic season in Spain, two A(H1N1) pdm09 viruses bearing the specific Y155H substitution in the NA were detected and isolated from two patients diagnosed with severe respiratory syndrome and pneumonia requiring admission to the intensive care unit. Contrary to what was observed in the seasonal A(H1N1) viruses, neither of the Y155H A(H1N1) pdm09 viruses described here showed a phenotype of reduced inhibition by NAIs as determined by the neuraminidase enzyme inhibition assay (MUNANA). High-throughput sequencing of the NA of both Y155H viruses showed that they were composed to >99% of H155 variants. We believe that this report can contribute to a better understanding of the biological significance of amino acid substitutions in the neuraminidase protein with regard to susceptibility of influenza viruses to neuraminidase inhibitors. This is of critical importance for optimal management of influenza disease patients.

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