Navarra Institute for Health Research

Navarra, Spain

Navarra Institute for Health Research

Navarra, Spain

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Toledo E.,Public University of Navarra | Salas-Salvado J.,University of Cambridge | Donat-Vargas C.,Public University of Navarra | Buil-Cosiales P.,Nutricion Institute Salud Carlos III | And 16 more authors.
JAMA Internal Medicine | Year: 2015

IMPORTANCE Breast cancer is the leading cause of female cancer burden, and its incidence has increased by more than 20%worldwide since 2008. Some observational studies have suggested that the Mediterranean dietmay reduce the risk of breast cancer. OBJECTIVE To evaluate the effect of 2 interventions with Mediterranean diet vs the advice to follow a low-fat diet (control) on breast cancer incidence. DESIGN, SETTING, AND PARTICIPANTS The PREDIMED study is a 1:1:1 randomized, single-blind, controlled field trial conducted at primary health care centers in Spain. From 2003 to 2009, 4282 women aged 60 to 80 years and at high cardiovascular disease risk were recruited after invitation by their primary care physicians. INTERVENTIONS Participants were randomly allocated to a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). MAIN OUTCOMES AND MEASURES Breast cancer incidencewas a prespecified secondary outcome of the trial for women without a prior history of breast cancer (n = 4152). RESULTS After a median follow-up of 4.8 years, we identified 35 confirmed incident cases of breast cancer. Observed rates (per 1000 person-years) were 1.1 for the Mediterranean diet with extra-virgin olive oil group, 1.8 for the Mediterranean diet with nuts group, and 2.9 for the control group. The multivariable-adjusted hazard ratios vs the control group were 0.32 (95%CI, 0.13-0.79) for the Mediterranean diet with extra-virgin olive oil group and 0.59 (95% CI, 0.26-1.35) for the Mediterranean diet with nuts group. In analyses with yearly cumulative updated dietary exposures, the hazard ratio for each additional 5%of calories from extra-virgin olive oil was 0.72 (95%CI, 0.57-0.90). CONCLUSIONS AND RELEVANCE This is the first randomized trial finding an effect of a long-term dietary intervention on breast cancer incidence. Our results suggest a beneficial effect of a Mediterranean diet supplemented with extra-virgin olive oil in the primary prevention of breast cancer. These results come from a secondary analysis of a previous trial and are based on few incident cases and, therefore, need to be confirmed in longer-term and larger studies. Copyright © 2015 American Medical Association. All rights reserved.


PubMed | d CEFA Monkole, h Monkole Hospital, Public University of Navarra, Hospital Of La Santa Creu I Sant Pau and Navarra Institute for Health Research
Type: | Journal: AIDS care | Year: 2016

In the Democratic Republic of Congo no previous studies have assessed the factors associated with different patterns of condom use and with multiple sexual partners, and the association between condom use simultaneously taking into account multiple sexual partnerships, and HIV infection. We carried out a prospective case-control study. From December 2010 until June 2012, 1630 participants aged 15-49 getting HIV Voluntary Counseling and Testing in a hospital in Kinshasa were selected. Cases were new HIV diagnosis and controls were HIV-negative participants detected along the study period. We recruited 274 cases and 1340 controls that were interviewed about HIV-related knowledge, attitudes and behaviours. Among cases there was a high prevalence of multiple lifetime and concurrent sexual partnerships (89.8% and 20.4%, respectively) and most cases never used condoms with only 1.5% using them consistently. Condom use and multiple partnerships were associated with male, single and high-educated participants. An association was found between multiple lifetime partners and any condom use (OR=2.99; 95%CI: 2.14-4.19) but not with consistent use. Both having two or more multiple concurrent sexual partners or not using condoms were variables similarly and highly associated to HIV risk. The association found between having two or more concurrent sexual partners and HIV was slightly higher (OR=3.58, 95%CI:2.31-5.56) than the association found between never condom use and HIV (OR=3.38, 95%CI:1.15-9.93). We found a high prevalence of multiple lifetime sexual partners and an extremely high prevalence of inconsistent condom use, both strongly associated with HIV seropositivity. Local programmes would benefit from comprehensive interventions targeting all behavioural and sociocultural determinants.


Goni L.,University of Navarra | Cuervo M.,University of Navarra | Cuervo M.,CIBER ISCIII | Cuervo M.,Navarra Institute for Health Research | And 5 more authors.
Journal of Nutrition | Year: 2016

As obesity has become a major global public health challenge, a large number of studies have analyzed different strategies aimed at inducing a negative energy balance and, consequently, body weight loss. However, most existing weight loss programs are generally unsuccessful, so several interventions have been carried out to identify physiologic and behavioral factors concerning this variability in order to implement more personalized treatment. Nowadays, an individualized approach is being proposed through so-called personalized nutrition, whereby not only the phenotype but also the genotype is used for customized nutrition treatment. Regarding body weight regulation, ~70 polymorphisms have been identified in or near genes related to energy expenditure, appetite, adipogenesis, insulin resistance, and lipid metabolism. Although personalized nutrition refers mainly to genetic makeup, recent advances in the investigation of the epigenome and themicrobiome open the door to implementmore personalized recommendations for bodyweightmanagement. In this context, recent studies have demonstrated the existence of several epigeneticmarkers thatmay modify gene expression and could be involved in the outcome of weight loss interventions. Moreover, different studies have shown that dietary interventions could affect the composition of gut microbiota and have an impact on body weight. The integration of nutrigenetic, epigenetic, and metagenomic data may lead to the design of more personalized dietary treatments to prevent chronic diseases and to optimize the individual's response to dietary interventions. © 2016 American Society for Nutrition.


Lopez B.,University of Navarra | Lopez B.,Navarra Institute for Health Research | Ravassa S.,University of Navarra | Ravassa S.,Navarra Institute for Health Research | And 16 more authors.
Journal of the American College of Cardiology | Year: 2016

Background Excessive myocardial collagen cross-linking (CCL) determines myocardial collagen's resistance to degradation by matrix metalloproteinase (MMP)-1 and interstitial accumulation of collagen fibers with impairment of cardiac function. Objectives This study sought to investigate whether CCL and a newly identified biomarker of this alteration are associated with hospitalization for heart failure (HHF) or cardiovascular death in patients with HF and arterial hypertension in whom other comorbidities were excluded. Methods Endomyocardial biopsies and blood samples from 38 patients (invasive study), and blood samples from 203 patients (noninvasive study) were analyzed. Mean follow-ups were 7.74 ± 0.58 years and 4.72 ± 0.11 years, respectively. Myocardial CCL was calculated as the ratio between insoluble and soluble collagen. The ratio between the C-terminal telopeptide of collagen type I (CITP) and matrix metalloproteinase-1 (CITP:MMP-1) was determined in blood samples. Results Invasive study: CCL was increased (p < 0.001) in patients compared with controls. Patients were categorized according to normal or high CCL values. Patients with high CCL exhibited higher risk for subsequent HHF (log-rank test p = 0.022), but not for cardiovascular death. CITP:MMP-1 was inversely associated with CCL (r = -0.460; p = 0.005) in all patients. Receiver operating characteristic curves rendered a CITP:MMP-1 cutoff ≤1.968 (80% sensitivity and 76% specificity) for predicting high CCL. Noninvasive study: Patients were categorized according to CITP:MMP-1 ratio values as normal ratio (>1.968) or low ratio (≤1.968). Patients with a low ratio exhibited higher risk for HHF (log-rank test p = 0.014), which remained significant after adjustment for relevant covariables (adjusted hazard ratio: 2.22; 95% CI: 1.37 to 3.59, p = 0.001). In addition, CITP:MMP-1-based categorization yielded significant integrated discrimination and net reclassification improvements (p = 0.003 and p = 0.009, respectively) for HHF over relevant risk factors. CITP:MMP-1 was not associated with the risk of cardiovascular death. Conclusions Excessive myocardial CCL is associated with HHF in hypertensive patients with HF. In this population, the serum CITP:MMP-1 ratio identifies patients with increased CCL and high risk of HHF. © 2016 American College of Cardiology Foundation.


PubMed | University of Navarra, Navarra Institute for Health Research and CIBER ISCIII
Type: Journal Article | Journal: Oncogene | Year: 2016

Resisting death is a central hallmark of cancer cells. Tumors rely on a number of genetic mechanisms to avoid apoptosis, and alterations in mRNA alternative splicing are increasingly recognized to have a role in tumorigenesis. In this study, we identify the splicing regulator SLU7 as an essential factor for the preservation of hepatocellular carcinoma (HCC) cells viability. Compared with hepatocytes, SLU7 expression is reduced in HCC cells; however, further SLU7 depletion triggered autophagy-related cellular apoptosis in association with the overproduction of reactive oxygen species. Remarkably, these responses were not observed in primary human hepatocytes or in the well-differentiated HepaRG cell line. Mechanistically, we demonstrate that SLU7 binds the C13orf25 primary transcript in which the polycistronic oncomir miR-17-92 cluster is encompassed, and is necessary for its processing and expression. SLU7 knockdown altered the splicing of the C13orf25 primary transcript, and markedly reduced the expression of its miR-17, miR-20 and miR-92a constituents. This led to the upregulation of CDKN1A (P21) and BCL2L11 (BIM) expression, two bona fide targets of the miR-17-92 cluster and recognized mediators of its pro-survival and tumorigenic activity. Interestingly, altered splicing of miR-17-92 and downregulation of miR-17 and miR-20 were not observed upon SLU7 knockdown in non-transformed hepatocytes, but was found in other (HeLa, H358) but not in all (Caco2) non-hepatic tumor cells. The functional relevance of miR-17-92 dysregulation upon SLU7 knockdown was established when oxidative stress, autophagy and apoptosis were reversed by co-transfection of HCC cells with a miR-17 mimic. Together, these findings indicate that SLU7 is co-opted by HCC cells and other tumor cell types to maintain survival, and identify this splicing regulator as a new determinant for the expression of the oncogenic miR-17-92 cluster. This novel mechanism may be exploited for the development of antitumoral strategies in cancers displaying such SLU7-miR-17-92 crosstalk.


Moreno Benitez F.,Lobaton Clinic | Moreno Benitez F.,University of Cádiz | Espinazo Romeu M.,Lobaton Clinic | Espinazo Romeu M.,University of Cádiz | And 6 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2015

Background Allergen immunotherapy is a treatment modality which can be applied using different vaccines. The aim of this study was to quantify and compare the allergen content of different house dust mites (HDM)' sublingual treatments and to review the evidence on their efficacy. Methods Five sublingual allergen immunotherapy (SLIT) products were ordered and purchased at an ordinary pharmacy and masked for blinding before the study was started. Detection of Dermatophagoides pteronyssinus and Dermatophagoides farinae allergens Der p 1, Der f 1, Der p 2 and Der f 2 was carried out by immunoblotting and fluorescent multiplex. A literature search for meta-analyses and systematic reviews that included SLIT-HDM products was performed. Results Der p 1 concentrations ranged from 0.6 to 14.5 μg/ml; similar figures were found for Der f 1 that ranged from 0.2 to 12.4 μg/ml. Der p 2+ Der f 2 ranged from 0.2 to 1.5 μg/ml. Data on efficacy are scarce for most of the five products. Conclusions Substantial variations regarding allergen content were found among these five SLIT-HDM products. Therefore, it can be necessary to guarantee the quality of the SLIT-HDM products and to demonstrate their effectiveness before they are marketed. It seems necessary, for the moment, to take into account these characteristics of the products before prescribing. © 2015 The Authors. Allergy Published by John Wiley and Sons Ltd.


Yarza R.,University of Navarra | Vela S.,University of Navarra | Solas M.,University of Navarra | Solas M.,Navarra Institute for Health Research | And 2 more authors.
Frontiers in Pharmacology | Year: 2016

c-Jun N-terminal kinases (JNKs) are a family of protein kinases that play a central role in stress signaling pathways implicated in gene expression, neuronal plasticity, regeneration, cell death, and regulation of cellular senescence. It has been shown that there is a JNK pathway activation after exposure to different stressing factors, including cytokines, growth factors, oxidative stress, unfolded protein response signals or Aβ peptides. Altogether, JNKs have become a focus of screening strategies searching for new therapeutic approaches to diabetes, cancer or liver diseases. In addition, activation of JNK has been identified as a key element responsible for the regulation of apoptosis signals and therefore, it is critical for pathological cell death associated with neurodegenerative diseases and, among them, with Alzheimer's disease (AD). In addition, in vitro and in vivo studies have reported alterations of JNK pathways potentially associated with pathogenesis and neuronal death in AD. JNK's, particularly JNK3, not only enhance Aβ production, moreover it plays a key role in the maturation and development of neurofibrillary tangles. This review aims to explain the rationale behind testing therapies based on inhibition of JNK signaling for AD in terms of current knowledge about the pathophysiology of the disease. Keeping in mind that JNK3 is specifically expressed in the brain and activated by stress-stimuli, it is possible to hypothesize that inhibition of JNK3 might be considered as a potential target for treating neurodegenerative mechanisms associated with AD. © 2016 Yarza, Vela, Solas and Ramirez.


Vicent S.,University of Navarra | Vicent S.,Navarra Institute for Health Research | Perurena N.,University of Navarra | Govindan R.,University of Washington | And 2 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2015

The skeleton is a common site of metastases in lung cancer, an event associated with significant morbidities and poor outcomes. Current antiresorptive therapies provide limited benefit, and novel strategies of prevention and treatment are urgently needed. This review summarizes the latest advances and new perspectives on emerging experimental and clinical approaches to block this deleterious process. Progress propelled by preclinical models has led to a deeper understanding on the complex interplay of tumor cells in the osseous milieu, unveiling potential new targets for drug development. Improvements in early diagnosis through the use of sophisticated imaging techniques with bone serum biomarkers are also discussed in the context of identifying patients at risk and monitoring disease progression during the course of treatment. Copyright © 2015 by the American Thoracic Society.


Rodriguez-Perdigon M.,University of Navarra | Solas M.,University of Navarra | Solas M.,Navarra Institute for Health Research
Journal of Alzheimer's Disease | Year: 2016

In the present work, the involvement of JNK in insulin signaling alterations and its role in glutamatergic deficits in Alzheimer's disease (AD) has been studied. In postmortem cortical tissues, pJNK levels were increased, while insulin signaling and the expression of VGLUT1 were decreased. A significant correlation was found between reduced expression of insulin receptor and VGLUT1. The administration of a JNK inhibitor reversed the decrease in VGLUT1 expression found in a mice model of insulin resistance. It is suggested that activation of JNK in AD inhibits insulin signaling which could lead to a decreased expression of VGLUT1, therefore contributing to the glutamatergic deficit in AD. © 2016 - IOS Press and the authors. All rights reserved.


PubMed | Hospital Of Fuenlabrada, University of Barcelona, Hospital Regional Universitario Of Malaga, Navarra Institute for Health Research and 11 more.
Type: Journal Article | Journal: Journal of investigational allergology & clinical immunology | Year: 2016

Multiple sensitization is frequent among pollen-allergic patients. The goal of this study was to determine the diagnostic accuracy of the ImmunoCAP ISAC 112 (ISAC112) microarray in allergy to pollen from several taxa and its clinical utility in a Spanish population.Specific IgE was determined in 390 pollen-allergic patients using the ISAC112 microarray. Diagnostic accuracy (sensitivity, specificity, predictive values, and area under the ROC curve) was calculated for the diagnosis of allergy to pollen from grass (n=49), cypress (n=75), olive tree (n=33), plane tree (n=63), and pellitory of the wall (n=17) and compared with that of the singleplex ImmunoCAP immunoassay.The sensitivity of the ISAC112 microarray ranged from 68.2% for allergy to plane tree pollen to 93.9% for allergy to grass pollen. The specificity was >90%. The AUC for the diagnosis of allergy to plane tree pollen was 0.798, whereas the AUC for the remaining cases was 0.876. The accuracy of ISAC112 was higher than that of ImmunoCAP for plane tree pollen and similar for the remaining pollens. The frequency of sensitization to most species-specific allergenic components and profilins varied between the different geographical regions studied. A total of 73% of pollen-allergic patients were sensitized to species-specific components of more than 1 pollen type.The ISAC112 microarray is an accurate tool for the diagnosis of allergy to pollen from grass, cypress, olive tree, plane tree, and pellitory of the wall. The features of the ISAC112 microarray are similar or superior (in the case of plane tree pollen) to those of ImmunoCAP. This microarray is particularly useful for the etiologic diagnosis of pollinosis in patients sensitized to multiple pollen species whose pollination periods overlap.

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