Research Center Medica Aplicada

Pamplona, Spain

Research Center Medica Aplicada

Pamplona, Spain

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Martinez-Lopez J.,Hospital Universitario 12 Of Octubre | Lahuerta J.J.,Hospital Universitario 12 Of Octubre | Pepin F.,Sequenta | Gonzalez M.,Hospital Universitario Of Salamanca Ibsal | And 20 more authors.
Blood | Year: 2014

We assessed the prognostic value of minimal residual disease (MRD) detection in multiple myeloma(MM) patients using a sequencing-based platform in bone marrow samples from 133 MM patients in at least very good partial response (VGPR) after front-line therapy. Deep sequencing was carried out in patients in whom a high-frequency myeloma clone was identified and MRD was assessed using the IGH-VDJH, IGH-DJH, and IGK assays. The results were contrasted with those of multiparametric flow cytometry (MFC) and allelespecific oligonucleotide polymerase chain reaction (ASO-PCR). The applicability of deep sequencing was 91%. Concordance between sequencing and MFC and ASO-PCR was 83% and 85%, respectively. Patients who were MRD- by sequencing had a significantly longer time to tumor progression (TTP) (median 80 vs 31 months; P <.0001) and overall survival (median not reached vs 81 months; P = .02), compared with patients who were MRD1.When stratifying patients by different levels of MRD, the respective TTP medians were: MRD ≥10-3 27 months, MRD 10-3 to 10-5 48 months, and MRD <10 -5 80 months (P = .003 to .0001). Ninety-two percent of VGPR patients were MRD1. In complete response patients, the TTP remained significantly longer for MRD- compared with MRD+ patients (131 vs 35 months; P 5 .0009). © 2014 by The American Society of Hematology.


Corrales F.J.,Research Center Medica Aplicada | Mora M.I.,Research Center Medica Aplicada
Journal of Proteome Research | Year: 2012

We analyzed embryo-maternal interactions in the bovine uterus on day 8 of development. Proteomic profiles were obtained by two-dimensional difference gel electrophoresis from 8 paired samples of uterine fluid (UF) from the same animal with and without embryos in the uterus. Results were contrasted with UF obtained after artificial insemination. We detected 50 differential protein spots (t test, p < 0.05). Subsequent protein characterization by nano-LC-ESI-MS/MS enabled us to identify 38 proteins, obtaining for first time the earliest evidence of involvement of the down-regulated NFkB system in cattle as a pregnancy signature pathway. Embryos enhanced the embryotrophic ability of UF and decreased uterine protein, while blood progesterone was unaltered. Twinfilin, hepatoma-derived growth factor, and synaptotagmin-binding cytoplasmic RNA interacting protein have not previously been identified in the mammalian uterus. TNFα and IL-1B were localized to embryos by immunocytochemistry, and other proteins were validated by Western blot in UF. Glycosylated- TNFα, IL-1B, insulin, lactotransferrin, nonphosphorylated-peroxiredoxin, albumin, purine nucleoside phosphorylase, HSPA5, and NFkB were down-regulated, while phosphorylated-peroxiredoxin, annexin A4, and nonglycosylated-TNFα were up-regulated. The embryonic signaling agents involved could be TNFα and IL-1B, either alone or in a collective dialogue with other proteins. Such molecules might explain the immune privilege during early bovine development. © 2011 American Chemical Society.


Corrales F.J.,Research Center Medica Aplicada | Mora M.I.,Research Center Medica Aplicada | Pello-Palma J.,University of Oviedo | Moreno J.F.,Sexing Technologies
Journal of Proteome Research | Year: 2013

The bovine endometrium recognizes early embryos and reacts differently depending on the developmental potential of the embryo. However, it is unknown whether the endometrium can distinguish embryonic sex. Our objective was to analyze sexual dimorphism in the uterus in response to male and female embryos. Differentially expressed (DE) proteins, different levels of hexoses, and other embryotrophic differences were analyzed in uterine fluid (UF). Proteomic analysis of day-8 UF recovered from heifers after the transfer of day-5 male or female embryos identified 23 DE proteins. Regulated proteasome/immunoproteasome protein subunits indicated differences in antigen processing between UF carrying male embryos (male-UF) or female embryos (female-UF). Several enzymes involved in glycolysis/gluconeogenesis and antioxidative/antistress responses were up-regulated in female-UF. Fructose concentration was increased in female-UF versus male-UF, while glucose levels were similar. In vitro cultures with molecules isolated from male-UF were found to improve male embryo development compared to female embryos cultured with molecules isolated from female-UF. We postulated that, in vivo, male embryos induce changes in the endometrium to help ensure their survival. In contrast, female embryos do not appear to induce these changes. © 2013 American Chemical Society.


Sangro B.,Liver Unit | Sangro B.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas | Prieto J.,Liver Unit | Prieto J.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas | Prieto J.,Research Center Medica Aplicada
Current Opinion in Molecular Therapeutics | Year: 2010

In contrast to the large quantity of preclinical evidence for efficacy, few gene therapy agents have reached clinical development for the treatment of primary and secondary liver cancer. This review discusses the published clinical trials that have explored the feasibility, safety and efficacy of gene therapy strategies for the treatment of liver cancer. Strategies include restoration of tumor suppressor genes, genetic prodrug-activating therapy, genetic immunotherapy and oncolytic virotherapy. In these trials, transgene expression of varying degrees has been detected. Globally, gene therapy has proven to be safe, with none of the agents tested reaching the MTD. Although none of the phase II trials provided significant response rates, objective remissions have occasionally been observed and proof-of-concept for the ability of gene therapy to produce significant tumor cell killing has been determined. Insufficient delivery following intravascular administration and short-lived transgene expression are likely to be the cause of this limited antitumor efficacy. The development of new gene therapy vectors with improved characteristics will increase the probability of success of gene therapy for the treatment of liver cancer. © 2010 Thomson Reuters (Scientific) Ltd.


Garcia-Osta A.,Cell Medica | Cuadrado-Tejedor M.,Cell Medica | Garcia-Barroso C.,Cell Medica | Oyarzabal J.,Cell Medica | And 2 more authors.
ACS Chemical Neuroscience | Year: 2012

Alzheimers disease (AD) is the most common form of dementia among the elderly. In AD patients, memory loss is accompanied by the formation of beta-amyloid plaques and the appearance of tau in a pathological form. Given the lack of effective treatments for AD, the development of new management strategies for these patients is critical. The continued failure to find effective therapies using molecules aimed at addressing the anti-beta amyloid pathology has led researchers to focus on other non-amyloid-based approaches to restore memory function. Promising non-amyloid related candidate targets include phosphosdiesterases (PDEs), and indeed, Rolipram, a specific PDE4 inhibitor, was the first compound found to effectively restore cognitive deficits in animal models of AD. More recently, PDE5 inhibitors have also been shown to effectively restore memory function. Accordingly, inhibitors of other members of the PDE family may also improve memory performance in AD and non-AD animal models. Hence, in this review, we will summarize the data supporting the use of PDE inhibitors as cognitive enhancers and we will discuss the possible mechanisms of action underlying these effects. We shall also adopt a medicinal chemistry perspective that leads us to propose the most promising PDE candidates on the basis of inhibitor selectivity, brain distribution, and mechanism of action. © 2012 American Chemical Society.


PubMed | Hospital Clinico Universitario, University of Navarra, Hospital Universitari Bellvitge, Bioinformatics Unit and 2 more.
Type: Journal Article | Journal: European journal of haematology | Year: 2016

The aim of this study was to assess differences in the gene expression profile of peripheral blood cells between patients with early recurrent thrombosis vs. patients without recurrent events after withdrawal of anticoagulant therapy for a first episode of unprovoked deep vein thrombosis (uDVT), to identify novel predictors of recurrence.In the discovery population (N=32), a microarray RNA assay followed by RT-PCR confirmation were performed. In the validation population (N=44) a multiple RT-PCR-based strategy was applied to assess genes differentially expressed in the discovery population.The sex-adjusted Linear Model for Microarray Data analysis showed 102 genes differentially expressed (P<0.01) in the discovery population. Nineteen of them underwent further confirmation in the validation population. The gene encoding for Acyl-CoA Synthetase Family Member 2 (ACSF2) was underexpressed in recurrent DVT patients in both, the discovery (P=0.007) and validation populations (P=0.004). In the receiver operator characteristic (ROC) analysis, the areas under the curve of ACSF2 expression were 0.77 and 0.80, respectively.For the first time an association between ACSF2 expression and the risk of recurrent DVT is suggested. Should this association be confirmed in larger prospective studies, ACSF2 could become useful for the selection of patients requiring extended anticoagulant therapy.


Rodriguez-Ortigosa C.M.,University of Navarra | Rodriguez-Ortigosa C.M.,Research Center Medica Aplicada | Celay J.,University of Navarra | Olivas I.,University of Navarra | And 12 more authors.
Gastroenterology | Year: 2014

Background & Aims Bile salts inhibit their own production by inducing the nuclear receptor small heterodimer partner (SHP) (encoded by NR0B2), which contributes to repression of the gene encoding cholesterol 7α-hydroxylase (CYP7A1), a key enzyme for the control of bile salt synthesis. On the other hand, bile salts stimulate hepatic synthesis of nitric oxide. We investigated the role of nitric oxide signaling in the control of CYP7A1 expression and the involvement in this process of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which participates in intracellular propagation of nitric oxide signals.Methods We studied the effects of inhibitors of nitric oxide synthesis (L-NG-nitroarginine methyl ester [L-NAME]) or protein nitrosylation (via dithiothreitol) on bile salt homeostasis in male Wistar rats placed on a cholate-rich diet for 5 days and in cultured primary hepatocytes. S-nitrosylation of GAPDH was assessed using a biotin-switch assay. Interacions of SHP with other proteins and with the Cyp7a1 promoter sequence were studied using immunoprecipitation and chromatin immunoprecipitation (ChIP) assays. We reduced the GAPDH levels in H35 cells with small interfering RNAs. GAPDH nitrosylation was assessed in normal and cholestatic rat and human livers.Results Rats placed on cholate-rich diets and given L-NAME had increased intrahepatic and biliary levels of bile salts, and deficiency in repression of CYP7A1 (at the messenger RNA and protein levels) in liver tissue, despite preserved induction of SHP. In cultured hepatocytes, L-NAME or dithiothreitol blocked cholate-induced down-regulation of CYP7A1 without impairing SHP up-regulation. In hepatocytes, cholate promoted S-nitrosylation of GAPDH and its translocation to the nucleus, accompanied by S-nitrosylation of histone deacetylase 2 (HDAC2) and Sirtuin 1 (SIRT1), deacetylases that participate, respectively, in the formation of Cyp7a1 and Shp repressor complexes. Knockdown of GAPDH prevented repression of CYP7A1 by cholate, and blocking nuclear transport of nitrosylated GAPDH reduced cholate-induced nitrosylation of HDAC2 and SIRT1; this effect was accompanied by abrogation of Cyp7a1 repression. Cholate induced binding of SHP to HDAC2 and its recruitment to the Cyp7a1 promoter; these processes were inhibited by blocking nitric oxide synthesis. Levels of nitrosylated GAPDH and nitrosylated HDAC2 were increased in cholestatic human and rat livers reflecting increased concentrations of bile salts in these conditions.Conclusions In rat liver, excess levels of bile salts activate a GAPDH-mediated transnitrosylation cascade that provides feedback inhibition of bile salt synthesis. © 2014 by the AGA Institute.


PubMed | Research Center Medica Aplicada, Hospital Universitario Of Salamanca and Hospital Clinic Institute Dinvestigacions Biomediques August Pi I Sunyer Idibaps
Type: | Journal: Bone marrow transplantation | Year: 2016

The response evaluation after autologous stem-cell transplantation (ASCT) is usually performed at day +100 in patients with multiple myeloma (MM). A recent report suggests that improvement in the response can be observed beyond day +100. The aim of the present study has been to evaluate the rate of improved response and outcome beyond day +100 after ASCT, with and without maintenance therapy. One hundred and forty-four patients who underwent single ASCT with chemosensitive disease and achieved less than CR at day 100 post ASCT were evaluated. Seventy-four patients (51.4%) did not receive any maintenance with only one of them showing an upgrade in the response. The remaining 70 patients (48.6%) received maintenance therapy; eleven of them (15.7%) improved their response beyond day +100. The outcome of these patients was better than those who did not upgrade their response in both progression-free survival and overall survival (P=0.019 and P=0.031, respectively). In conclusion, the improvement in response beyond day +100 after ASCT in patients not receiving any therapy is exceedingly rare. A minority of patients receiving maintenance therapy after ASCT upgrades their response and this finding is associated with better outcome.Bone Marrow Transplantation advance online publication, 21 November 2016; doi:10.1038/bmt.2016.299.


Martin-Calvo N.,Public University of Navarra | Martinez-Gonzalez M.-A.,Public University of Navarra | Martinez-Gonzalez M.-A.,Institute Salud Carlos III | Bes-Rastrollo M.,Public University of Navarra | And 4 more authors.
Public Health Nutrition | Year: 2013

Objective: To assess the association between the consumption of sugar-sweetened carbonated beverages (SSCB) and obesity in children and adolescents from Navarra (Spain). Design: We used a matched case-control study design. The exposure, SSCB consumption (1 serving: 200 ml), was measured with a previously validated FFQ. Anthropometrical measures were taken using standardized protocols. The outcome, obesity, was defined as BMI above the age- and sex-specific 97th percentile according to the Spanish reference charts. In the analysis we used conditional logistic regression. Potential confounders were controlled using a multivariable model. Setting: Subjects were recruited in the paediatric departments of the Universidad de Navarra Clinic and the Navarra Hospital Complex, and in three primary health centres of Navarra. Controls were recruited when attending for a routine medical examination or vaccination. Subjects: One hundred and seventy-four obese children and 174 individually sex- and age-matched controls, 52.87% boys, with a mean age of 11.6 years. Exclusion criteria were dietary interventions, exposure to hormone treatment, development of secondary obesity due to endocrinopathy and serious intercurrent illness. Results: Independently of other factors, high consumption of SSCB (>4 servings/week) was significantly associated with obesity (OR = 3.46; 95% CI 1.24, 9.62; P = 0.01). Besides, each additional daily serving of SSCB was associated with a 69% relative increase in the risk of obesity (OR = 1.69; 95% CI 1.04, 2.73; P = 0.03). Conclusions: We found a strong and significant association between SSCB consumption and obesity risk. Our results suggest a monotonic dose-response linear shape for this association in children and adolescents (P for trend = 0.02). © The Authors 2014.


Montenegro-Miranda P.S.,Tytgat Institute for Liver and Intestinal Research | Paneda A.,Research Center Medica Aplicada | Bloemendaal L.T.,Tytgat Institute for Liver and Intestinal Research | Duijst S.,Tytgat Institute for Liver and Intestinal Research | And 3 more authors.
PLoS ONE | Year: 2013

Preclinical studies in mice and non-human primates showed that AAV serotype 5 provides efficient liver transduction and as such seems a promising vector for liver directed gene therapy. An advantage of AAV5 compared to serotype 8 already shown to provide efficient correction in a phase 1 trial in patients suffering from hemophilia B, is its lower seroprevalence in the general population. Our goal is liver directed gene therapy for Crigler-Najjar syndrome type I, inherited severe unconjugated hyperbilirubinemia caused by UGT1A1 deficiency. In a relevant animal model, the Gunn rat, we compared the efficacy of AAV 5 and 8 to that of AAV1 previously shown to be effective. Ferrying a construct driving hepatocyte specific expression of UGT1A1, both AAV8 and AAV1 provided an efficient correction of hyperbilirubinemia. In contrast to these two and to other animal models AAV5 failed to provide any correction. To clarify whether this unexpected finding was due to the rat model used or due to a problem with AAV5, the efficacy of this serotype was compared in a mouse and two additional rat strains. Administration of an AAV5 vector expressing luciferase under the control of a liver specific promoter confirmed that this serotype poorly performed in rat liver, rendering it not suitable for proof of concept studies in this species. © 2013 Montenegro-Miranda et al.

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