Institute Dinvestigacio Biomedica Of Girona

Girona, Spain

Institute Dinvestigacio Biomedica Of Girona

Girona, Spain
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Allemani C.,London School of Hygiene and Tropical Medicine | Weir H.K.,Centers for Disease Control and Prevention | Carreira H.,London School of Hygiene and Tropical Medicine | Harewood R.,London School of Hygiene and Tropical Medicine | And 19 more authors.
The Lancet | Year: 2015

Background Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. Methods Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75 000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. Findings 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. Interpretation International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems. Funding Canadian Partnership Against Cancer (Toronto, Canada), Cancer Focus Northern Ireland (Belfast, UK), Cancer Institute New South Wales (Sydney, Australia), Cancer Research UK (London, UK), Centers for Disease Control and Prevention (Atlanta, GA, USA), Swiss Re (London, UK), Swiss Cancer Research foundation (Bern, Switzerland), Swiss Cancer League (Bern, Switzerland), and University of Kentucky (Lexington, KY, USA). © 2015 Allemani et al. Open Access article distributed under the terms of CC BY.


Menke A.,Johns Hopkins University | Muntner P.,University of Alabama at Birmingham | Fernandez-Real J.M.,Institute Dinvestigacio Biomedica Of Girona | Fernandez-Real J.M.,CIBER ISCIII | And 2 more authors.
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2012

Background and Aims: Elevated iron biomarkers are associated with diabetes and other cardiometabolic abnormalities in the general population. It is unclear whether they are associated with an increased risk of all-cause or cause-specific mortality. The purpose of the current analysis was to evaluate the association of ferritin and transferrin saturation levels with all-cause, cardiovascular, and cancer mortality in the general US adult population. Methods and Results: A prospective cohort study was conducted with 12,258 adults participating in the Third National Health and Nutrition Examination Survey (NHANES III), a nationally representative sample of the US population. Study participants were recruited in 1988-1994 and followed through December 31, 2006 for all-cause, cardiovascular disease, and cancer mortality. The multivariable-adjusted hazard ratios (95% confidence interval) for all-cause mortality comparing the fourth versus the second quartiles of ferritin and transferrin saturation were 1.09 (0.82-1.44; p-trend across quartiles = 0.92) and 1.08 (0.82-1.43; p-trend across quartiles = 0.62), respectively, for men, 1.43 (0.63-3.23; p-trend across quartiles = 0.31) and 1.48 (0.70-3.11; p-trend across quartiles = 0.60), respectively, for premenopausal women, and 1.03 (0.79-1.34; p-trend across quartiles = 0.95) and 1.17 (0.92-1.49; p-trend across quartiles = 0.63), respectively, for postmenopausal women. Quartile of ferritin and transferrin saturation also showed no association between biomarkers of iron status and mortality. Conclusions: In a large nationally representative sample of US adults, within the spectrum of normal iron metabolism, ferritin and transferrin saturation were not associated with risk of mortality among people who were not taking iron supplements and did not have a baseline history of cardiovascular disease or cancer. © 2010 Elsevier B.V.


Ortega F.J.,Institute Dinvestigacio Biomedica Of Girona | Ortega F.J.,CIBER ISCIII | Mercader J.M.,Barcelona Supercomputing Center | Moreno-Navarrete J.M.,Institute Dinvestigacio Biomedica Of Girona | And 17 more authors.
Diabetes Care | Year: 2014

OBJECTIVE: This study sought to identify the profile of circulating microRNAs (miRNAs) in type 2 diabetes (T2D) and its response to changes in insulin sensitivity. RESEARCH DESIGN AND METHODS: The circulating miRNA profile was assessed in a pilot study of 12 men: 6 with normal glucose tolerance (NGT) and 6 T2D patients. The association of 10 circulating miRNAs with T2D was cross-sectionally validated in an extended sample of 45 NGT vs. 48 T2D subjects (65 nonobese and 28 obese men) and longitudinally in 35 T2D patients who were recruited in a randomized, double-blinded, and placebo-controlled 3-month trial of metformin treatment. Circulating miRNAs were also measured in seven healthy volunteers before and after a 6-h hyperinsulinemic-euglycemic clamp and insulin plus intralipid/heparin infusion. RESULTS: Cross-sectional studies disclosed a marked increase of miR-140-5p, miR-142-3p, and miR-222 and decreased miR-423-5p, miR-125b, miR-192, miR-195, miR-130b, miR-532-5p, and miR-126 in T2D patients. Multiple linear regression analyses revealed that miR-140-5p and miR-423-5p contributed independently to explain 49.5% (P < 0.0001) of fasting glucose variance after controlling for confounders. A discriminant function of four miRNAs (miR-140-5p, miR-423-5p, miR-195, and miR-126) was specific for T2D with an accuracy of 89.2% (P < 0.0001). Metformin (but not placebo) led to significant changes in circulating miR-192 (49.5%; P = 0.022), miR-140-5p (-15.8%; P = 0.004), and miR-222 (-47.2%; P = 0.03), in parallel to decreased fasting glucose and HbA1c. Furthermore, while insulin infusion during clamp decreased miR-222 (-62%; P = 0.002), the intralipid/heparin mixture increased circulating miR-222 (163%; P = 0.015) and miR-140-5p (67.5%; P = 0.05). CONCLUSIONS: This study depicts the close association between variations in circulating miRNAs and T2D and their potential relevance in insulin sensitivity. © 2014 by the American Diabetes Association.


Rodriguez-Cuenca S.,University of Cambridge | Carobbio S.,University of Cambridge | Velagapudi V.R.,VTT Technical Research Center of Finland | Barbarroja N.,VTT Technical Research Center of Finland | And 6 more authors.
Molecular and Cellular Biology | Year: 2012

Optimal lipid storage and mobilization are essential for efficient adipose tissue. Nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) regulates adipocyte differentiation and lipid deposition, but its role in lipolysis and dysregulation in obesity is not well defined. This investigation aimed to understand the molecular impact of dysfunctional PPARγ on the lipolytic axis and to explore whether these defects are also confirmed in common forms of human obesity. For this purpose, we used the P465L PPARγ mouse as a model of dysfunctional PPARγ that recapitulates the human pparγ mutation (P467L). We demonstrated that defective PPARγ impairs catecholamine-induced lipolysis. This abnormal lipolytic response is exacerbated by a state of positive energy balance in leptin-deficient ob/ob mice. We identified the protein kinase A (PKA) network as a PPARγ-dependent regulatory node of the lipolytic response. Specifically, defective PPARγ is associated with decreased basal expression of prkaca (PKAcatα) and d-akap1, the lipase genes Pnplaz (ATGL) and Lipe (HSL), and lipid droplet protein genes fsp27 and adrp in vivo and in vitro. Our data indicate that PPARγ is required for activation of the lipolytic regulatory network, dysregulation of which is an important feature of obesity-induced insulin resistance in humans. © 2012, American Society for Microbiology.


Moreno-Navarrete J.M.,Institute Dinvestigacio Biomedica Of Girona | Ortega F.,Institute Dinvestigacio Biomedica Of Girona | Sabater M.,Institute Dinvestigacio Biomedica Of Girona | Ricart W.,Institute Dinvestigacio Biomedica Of Girona | Fernandez-Real J.M.,Institute Dinvestigacio Biomedica Of Girona
International Journal of Obesity | Year: 2010

Obesity and increased fat mass are associated with increased adipocyte proliferation. Telomere length can serve as a biomarker of a cell's biological (vs chronological) age. To gain insight in the physiology of adipose tissue, we aimed to investigate telomere length in subcutaneous adipose tissue in relation to age and obesity. Telomere length was measured in 72 subcutaneous adipose tissue samples from 21 nonobese and 51 obese subjects. Telomere length of subcutaneous adipose tissue cells was negatively associated with body mass index (BMI), systolic blood pressure and fasting triglycerides. After controlling for age, fasting glucose, triglycerides and smoking status, BMI (P=0.009) contributed independently to 16% of telomere length variance. Interestingly, formerly obese patients (n=10) had shorter telomere length than never-obese subjects (n12) of similar age, sex and BMI (7.1±1.3 vs 9.08±1.8 kb, P=0.01). In summary, adipose tissue cells from obese subjects show a shorter telomere length. The shorter telomere length of formerly obese subjects suggests that this is an established, irreversible feature of obesity that could contribute to its comorbidities. © 2010 Macmillan Publishers Limited All rights reserved.


Bassols J.,Institute Dinvestigacio Biomedica Of Girona | Moreno J.M.,Institute Dinvestigacio Biomedica Of Girona | Ortega F.,Institute Dinvestigacio Biomedica Of Girona | Ricart W.,Institute Dinvestigacio Biomedica Of Girona | Fernandez-Real J.M.,Institute Dinvestigacio Biomedica Of Girona
Obesity | Year: 2010

Herpes virus entry mediator (HVEM) is a member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF14), which serves as a receptor for herpes viruses and cytokines such as lymphotoxin-α (LT-α) and LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpes virus entry on T cells). We aimed to explore the associations of HVEM with human obesity. HVEM gene expression and protein levels were studied in total adipose tissue and in their fractions (isolated adipocytes and stromovascular cells (SVCs)) obtained from 81 subjects during elective surgical procedures. HVEM 241GA and 14AG gene polymorphisms were also studied and associated with obesity measures in 840 subjects. Visceral adipose tissue had significantly higher expression of HVEM than subcutaneous adipose tissue (P < 0.0001). Obese patients had significantly higher subcutaneous HVEM gene expression (P = 0.03) and protein levels (P = 0.01) than lean subjects. HVEM gene expression and protein levels were found in both isolated adipocytes and SVCs. These findings were confirmed in primary cultures from human preadipocytes, in which a significant increase in HVEM was observed during the differentiation process. HVEM 241GA and 14AG gene polymorphisms were associated with obesity, diastolic pressure, several inflammatory parameters (C-reactive protein and interleukin 18 (IL-18)), and circulating LIGHT concentrations. A sample of men with the G241A gene polymorphism also showed an increased serum titer of IgG antiherpes virus 1. These results provide evidences of an existing relationship between HVEM and obesity, which suggest that this TNF superfamily receptor could be involved in the pathogenesis of obesity and inflammation-related activity. © 2009 The Obesity Society.


Fernandez-Real J.M.,Institute Dinvestigacio Biomedica Of Girona | Moreno-Navarrete J.M.,Institute Dinvestigacio Biomedica Of Girona | Ortega F.,Institute Dinvestigacio Biomedica Of Girona | Ricart W.,Institute Dinvestigacio Biomedica Of Girona
Obesity | Year: 2011

Decreased serum creatinine concentration has been recently described to constitute a new risk factor of type 2 diabetes. Increased free radicals have been consistently associated with decreased serum creatinine and with cellular senescence. Telomere length is considered as a biological marker for senescence. We aimed to study the association of telomere length with serum creatinine. Telomere length of subcutaneous adipose tissue cells was measured in a sample of obese and nonobese subjects (n = 49). Telomere length of subcutaneous adipose tissue cells was positively associated with serum creatinine (r = 0.40, P = 0.004), i.e., the lower the telomere length, the lower the serum creatinine, but not with glomerular filtration rate (GFR). In addition, telomere length was negatively associated with BMI (r = 0.45, P = 0.001) and systolic blood pressure (r = 0.41, P = 0.003). In a multiple linear regression analysis, BMI (P = 0.005), systolic blood pressure (P = 0.01) and telomere length (P = 0.03) independently contributed to 37% of serum creatinine variance after controlling for sex and age. In conclusion, the association of serum creatinine with a marker of cellular senescence suggests an underlying mechanism influencing both decreased serum creatinine and increased risk of type 2 diabetes. © 2011 The Obesity Society.


Moreno M.,Institute Dinvestigacio Biomedica Of Girona | Ortega F.,Institute Dinvestigacio Biomedica Of Girona | Xifra G.,Institute Dinvestigacio Biomedica Of Girona | Ricart W.,Institute Dinvestigacio Biomedica Of Girona | And 2 more authors.
FASEB Journal | Year: 2015

To gain insight into the regulation of intracellular iron homeostasis in adipose tissue, we investigated the role of iron regulatory protein 1/cytosolic aconitase 1 (ACO1). ACO1 gene expression and activity increased in parallel to expression of adipogenic genes during differentiation of both murine 3T3-L1 cells and human preadipocytes. Lentiviral knockdown (KD) of Aco1 in 3T3-L1 preadipocytes led to diminished cytosolic aconitase activity and isocitrate dehydrogenase 1 (NADP+), soluble (Idh1) mRNA levels, decreased intracellular NADPH:NADP ratio, and impaired adipogenesis during adipocyte differentiation. In addition, Aco1 KD in fully differentiated 3T3-L1 adipocytes decreased lipogenic, Idh1, Adipoq, and Glut4 gene expression. A bidirectional cross-talk was found between intracellular iron levels and ACO1 gene expression and protein activity. Although iron in excess, known to increase reactive oxygen species production, and iron depletion both resulted in decreased ACO1 mRNA levels and activity, Aco1 KD led to reduced gene expression of transferrin receptor (Tfrc) and transferrin, disrupting intracellular iron uptake. In agreement with these findings, in 2 human independent cohorts (n = 85 and n = 38), ACO1 gene expression was positively associated with adipogenic markers in subcutaneous and visceral adipose tissue. ACO1 gene expression was also positively associated with the gene expression of TFRC while negatively linked to ferroportin (solute carrier family 40 (iron-regulated transporter), member 1) mRNA levels. Altogether, these results suggest that ACO1 activity is required for the normal adipogenic capacity of adipose tissue by connecting iron, energy metabolism, and adipogenesis. © FASEB.


Moreno-Navarrete J.M.,Institute Dinvestigacio Biomedica Of Girona | Novelle M.G.,University of Santiago de Compostela | Catalan V.,University of Navarra | Ortega F.,Institute Dinvestigacio Biomedica Of Girona | And 9 more authors.
Diabetes Care | Year: 2014

OBJECTIVE: Circulating markers of iron overload are associated with insulin resistance. Less is known about the impact of iron overload on adipose tissue (AT). We hypothesized that gene expression markers of iron metabolism in AT could be associated with insulin action. RESEARCH DESIGN AND METHODS: The AT expression of ferroportin (SLC40A1), transferrin (TF), TF receptor (TFRC), ferritin (FT) heavy polypeptide 1 ( FTH1), and FT light polypeptide (FTL) was analyzed cross-sectionally in three independent cohorts and also after weight loss-induced changes in insulin sensitivity (clamp M value) in an independent fourth cohort. RESULTS: In human AT, TF mRNA and protein levels were decreased with obesity and insulin resistance in the three cohorts and were positively associated with adipogenic mRNAs and insulin action. Otherwise, FTL mRNA and protein and SLC40A1 transcripts were positively associated with BMI and negatively linked to adipogenic genes and insulin action. Bariatric surgery-induced weight loss led to increased TF and decreased TFRC, FTH1, FTL, and SLC40A1 in subcutaneous AT in parallel to improved insulin action. CONCLUSIONS: These results suggest that iron overload impacts on AT in association with insulin resistance. © 2014 by the American Diabetes Association.


Sabater M.,Institute Dinvestigacio Biomedica Of Girona | Moreno-Navarrete J.M.,Institute Dinvestigacio Biomedica Of Girona | Ortega F.J.,Institute Dinvestigacio Biomedica Of Girona | Pardo G.,Institute Dinvestigacio Biomedica Of Girona | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Objective: We aimed to study circulating pigment epithelium-derived factor (PEDF) in vivo in association with insulin resistance and in vitro in human adipocytes. Methods: Circulating PEDF (ELISA) and metabolic profile were assessed in 125 Caucasian men. PEDF levels were also assessed in an independent cohort of subjects (n = 33) to study the effects of changing insulin action. PEDF gene expression and secretion were measured during differentiation of human preadipocytes. Results: In all subjects, PEDF was positively associated with body mass index (r = 0.326; P < 0.0001), waist-to-hip ratio (r = 0.380; P < 0.0001), HbA1c, and fasting triglycerides and negatively with insulin sensitivity (r = -0.320; P < 0.0001). PEDF levels were significantly increased in subjects with altered glucose tolerance and type 2 diabetes. Of the inflammatory markers measured, PEDF levels were positively associated with serum soluble TNF-α receptor 1 and IL-10 in obese subjects. Interestingly, weight loss led to significantly decreased PEDF concentration from 34.8 ± 19.3 to 22.5 ± 14.2 μg/ml (P < 0.0001). Multiple linear regression analyses revealed that insulin sensitivity contributed independently to explain 14% of the variance in PEDF levels after controlling for the effects of body mass index, age, and log fasting triglycerides. Differences in PEDF observed after weight loss were related to changes in obesity, insulin resistance, and blood pressure measures. PEDF gene expression and secretion increased during differentiation of human preadipocytes. Conclusion: Circulating PEDF is associated with insulin sensitivity. The findings show, for the first time in humans, that PEDF concentrations decrease significantly after weight loss in association with blood pressure. PEDF seems to be involved in human adipocyte biology. Copyright © 2010 by The Endocrine Society.

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