Système rénine-angiotensine et cancers urologiques / Renin-angiotensin system and urological cancers.

International audienceIntroduction: A controversy animates the literature on the potential role of the rennin-angiotensin system (RAS) in tumorogenesis. The objective of this review was to determine the involvement of this pathway in cancer, and more specifically in urological cancers. Material and Method: We made a systematic review of articles referenced in Pubmed, using the following keywords alone or combined: cancer, renin, angiotensin, VEGF, AT1R, antagonists of angiotensin-2 receptors, inhibitors of angiotensinogen converting. Results: Many types of cancers overexpress AT1-R in their tumoral tissues (breast, stomach, bladder, astrocytoma, glioblastoma, ovary, uterus, pancreas, kidney, prostate, adrenal gland). Ang-II can induce VEGF-A expression and promote neoangiogenesis, but also can trigger different molecular pathways involved in cell proliferation or inhibit apoptosis. Several xenograft murin models demonstrated anti-tumoral efficacy of RAS blockers, alone or using combined therapies, targeting angiogenesis and slowing down tumor growth. Retrospective studies in patients have also revealed a better progression-free survival and a better response to therapies in those treated with RAS blockers. Conclusion: Many data seem to demonstrate the involvement of the RAS in carcinogenesis, as well as anti-tumoral effect of RAS blockers in addition to anti-cancer treatments. Clinical data are now expected to confirm these experimental findings

How the Selfish Brain Organizes its Supply and Demand

During acute mental stress, the energy supply to the human brain increases by 12%. To determine how the brain controls this demand for energy, 40 healthy young men participated in two sessions (stress induced by the Trier Social Stress Test and non-stress intervention). Subjects were randomly assigned to four different experimental groups according to the energy provided during or after stress intervention (rich buffet, meager salad, dextrose-infusion and lactate-infusion). Blood samples were frequently taken and subjects rated their autonomic and neuroglycopenic symptoms by standard questionnaires. We found that stress increased carbohydrate intake from a rich buffet by 34 g (from 149 ± 13 g in the non-stress session to 183 ± 16 g in the stress session; P < 0.05). While these stress-extra carbohydrates increased blood glucose concentrations, they did not increase serum insulin concentrations. The ability to suppress insulin secretion was found to be linked to the sympatho-adrenal stress-response. Social stress increased concentrations of epinephrine 72% (18.3 ± 1.3 vs. 31.5 ± 5.8 pg/ml; P < 0.05), norepinephrine 148% (242.9 ± 22.9 vs. 601.1 ± 76.2 pg/ml; P < 0.01), ACTH 184% (14.0 ± 1.3 vs. 39.8 ± 7.7 pmol/l; P < 0.05), cortisol 131% (5.4 ± 0.5 vs. 12.4 ± 1.3 μg/dl; P < 0.01) and autonomic symptoms 137% (0.7 ± 0.3 vs. 1.7 ± 0.6; P < 0.05). Exogenous energy supply (regardless of its character, i.e., rich buffet or energy infusions) was shown to counteract a neuroglycopenic state that developed during stress. Exogenous energy did not dampen the sympatho-adrenal stress-responses. We conclude that the brain under stressful conditions demands for energy from the body by using a mechanism, which we refer to as “cerebral insulin suppression” and in so doing it can satisfy its excessive needs

Prenatal Organochlorine Compound Exposure, Rapid Weight Gain, and Overweight in Infancy

Background: Although it has been hypothesized that fetal exposure to endocrine-disrupting chemicals may increase obesity risk, empirical data are limited, and it is uncertain how early in life any effects may begin. Objectives: We explored whether prenatal exposure to several organochlorine compounds (OCs) is associated with rapid growth in the first 6 months of life and body mass index (BMI) later in infancy. Methods: Data come from the INMA (Infancia y Medio-Ambiente) Child and Environment birth cohort in Spain, which recruited 657 women in early pregnancy. Rapid growth during the first 6 months was defined as a change in weight-for-age z-scores > 0.67, and elevated BMI at 14 months, as a z-score ≥ the 85th percentile. Generalized linear models were used to estimate the risk of rapid growth or elevated BMI associated with 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (DDE), hexachlorobenzene, β-hexachlorohexane, and polychlorinated biphenyls in first-trimester maternal serum. Results: After multivariable adjustment including other OCs, DDE exposure above the first quartile was associated with doubling of the risk of rapid growth among children of normal-weight (BMI < 25 kg/m2), but not overweight, mothers. DDE was also associated with elevated BMI at 14 months (relative risk per unit increase in log DDE = 1.50; 95% confidence interval, 1.11–2.03). Other OCs were not associated with rapid growth or elevated BMI after adjustment. Conclusions: In this study we found prenatal DDE exposure to be associated with rapid weight gain in the first 6 months and elevated BMI later in infancy, among infants of normal-weight mothers. More research exploring the potential role of chemical exposures in early-onset obesity is needed.This work was supported by grants from the Spanish Ministry of Health (FIS-PI041436), Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041), the Generalitat de Catalunya-CIRIT (Consejo Interdepartamental de Investigación e Innovación Tecnológica) (1999SGR 00241), and the Fundació Roger Torne

Child Fitness and Father’s BMI Are Important Factors in Childhood Obesity: A School Based Cross-Sectional Study

BACKGROUND: This study examines obesity and factors associated with obesity in children aged 11-13 years in the UK. METHODS: 1147 children from ten secondary schools participated in a health survey that included blood samples, fitness test and anthropometric measures. Factors associated with obesity were examined using multilevel logistic regression. FINDINGS: Of the children examined (490 male; 657 female) a third were overweight, 1 in 6 had elevated blood pressure, more than 1 in 10 had high cholesterol, 58% consumed more fat than recommended, whilst 37% were classified as unfit. Children in deprived areas had a higher proportion of risk factors; for example, they had higher blood pressure (20% (deprived) compared to 11% (non-deprived), difference: 9.0% (95%CI: 4.7%-13.4%)). Obesity is associated with risk factors for heart disease and diabetes. Maintaining fitness is associated with a reduction in the risk factors for heart disease (high blood pressure and cholesterol) but not on risk factors for diabetes (insulin levels). In order of importance, the main risk factors for childhood obesity are being unfit, having an obese father, and being large at birth. CONCLUSION: The high proportion of children with risk factors suggests future interventions need to focus on community and policy change to shift the population norm rather than targeting the behaviour of high risk individuals. Interventions need to focus on mothers' lifestyle in pregnancy, fathers' health, as well as promoting fitness among children. Obesity was not associated with deprivation. Therefore, strategies should be adopted in both deprived and non deprived areas

Angiotensin-2 receptors (AT1-R and AT2-R), new prognostic factors for renal clear-cell carcinoma?

International audienceBackground: The growth factor Angiotensin-2 signals through Angiotensin receptor type 1 (AT1-R) in a broad range of cell types and tumours and through the type-2 receptor (AT2-R) in a more restricted group of cell types. Although numerous forms of cancer have been shown to overexpress AT1-R, expression of AT1-R and AT2-R by human renal clear-cell carcinoma (RCCC) is not well understood. In this study, the expression of both angiotensin receptors was quantified in a retrospective series of RCCC and correlated with prognostic factors.Methods: Angiotensin receptor type 1 and AT2-R expressions were quantified on tumour tissues by immunohistochemistry (IHC), western blot and quantitative reverse transcriptase PCR (qRT–PCR). IHC results were correlated to Fuhrman's grade and patient progression-free survival (PFS).Results: A total of 84 RCCC were analysed. By IHC, AT1-R and AT2-R were expressed to a greater level in high-grade tumours (AT1-R: P<0.001, AT2-R: P<0.001). Univariate analysis showed a correlation between PFS and AT1-R or AT2-R expression (P=0.001). By multivariate analysis, only AT2-R expression correlated with PFS (HR 1.021, P=0.006) and cancer stage (P<0.001). By western blot, AT1-R and AT1-R were also found to be overexpressed in higher Fuhrman's grade (P<0.01 and P=0.001 respectively). By qRT–PCR, AT1-R but not AT2-R mRNA were downregulated (P=0.001 and P=0.118, respectively).Conclusion: Our results show that AT1-R and AT2-R proteins are overexpressed in the most aggressive forms of RCCC and that AT2-R expression correlates with PFS. AT1-R or AT2-R blockage could, therefore, offer novel directions for anti-RCCC therapy

Meal-induced inflammation: postprandial insights from the Personalised REsponses to DIetary Composition Trial (PREDICT) study in 1000 participants

Background: Meal-induced metabolic changes trigger an acute inflammatory response, contributing to chronic inflammation and associated diseases. Objectives: We aimed to characterize variability in postprandial inflammatory responses using traditional (IL-6) and novel [glycoprotein acetylation (GlycA)] biomarkers of inflammation and dissect their biological determinants with a focus on postprandial glycemia and lipemia. Methods: Postprandial (0–6 h) glucose, triglyceride (TG), IL-6, and GlycA responses were measured at multiple intervals after sequential mixed-nutrient meals (0 h and 4 h) in 1002 healthy adults aged 18–65 y from the PREDICT (Personalised REsponses to DIetary Composition Trial) 1 study, a single-arm dietary intervention study. Measures of habitual diet, blood biochemistry, gut microbiome composition, and visceral fat mass (VFM) were also collected. Results: The postprandial changes in GlycA and IL-6 concentrations were highly variable between individuals. Participants eliciting an increase in GlycA and IL-6 (60% and 94% of the total participants, respectively) had mean 6-h increases of 11% and 190%, respectively. Peak postprandial TG and glucose concentrations were significantly associated with 6-h GlycA (r = 0.83 and r = 0.24, respectively; both P &lt; 0.001) but not with 6-h IL-6 (both P &gt; 0.26). A random forest model revealed the maximum TG concentration was the strongest postprandial TG predictor of postprandial GlycA and structural equation modeling revealed that VFM and fasting TG were most strongly associated with fasting and postprandial GlycA. Network Mendelian randomization demonstrated a causal link between VFM and fasting GlycA, mediated (28%) by fasting TG. Individuals eliciting enhanced GlycA responses had higher predicted cardiovascular disease risk (using the atherosclerotic disease risk score) than the rest of the cohort. Conclusions: The variable postprandial increases in GlycA and their associations with TG metabolism highlight the importance of modulating TG in concert with obesity to reduce GlycA and associated low-grade inflammation–related diseases. This trial was registered at clinicaltrials.gov as NCT03479866