The inflammatory food index and its association with weight gain and incidence of diabetes: Longitudinal Study of Adult Health (ELSA-Brasil).

BACKGROUND AND AIMS: Diet plays a central role in regulating inflammation and is closely related to the development of chronic diseases. We aimed to develop an inflammatory food index (IFI) based on the relationship of food items with biomarkers of inflammation and to evaluate its association with weight gain and type 2 diabetes. METHODS AND RESULTS: A sample of 9909 participants of the ELSA-Brasil study was analyzed. Standardized measurements including interviews, anthropometry, and laboratory exams were performed at baseline and follow-up. A baseline food frequency questionnaire was used to derive IFI scores using reduced rank regression (RRR). The inflammatory pattern derived included 11 pro-inflammatory food groups: processed meat, red meat, pork, sugary soda, and hot dogs. The anti-inflammatory pattern included seven food groups: fruits, nuts, and wine. The IFI score, adjusted through logistic regression for multiple sociodemographic, behavioral, and clinical covariates, including body mass index, predicted the development of a large weight gain (tertile 3 vs. 1: OR = 1.30; 95%CI 1.08-1.55). The score, adjusted for sociodemographic factors through proportional hazard models, predicted incident diabetes (tertile 3 vs. 1: HR = 1.26; 95%CI 1.04-1.52). CONCLUSION: These findings support the hypothesis that subclinical inflammation caused by a pro-inflammatory food pattern, characterized mainly by greater ultra-processed food consumption, underlies weight gain and the development of type 2 diabetes. This study was registered at clinicaltrials.com as NCT02320461.

Lifetime risk of developing diabetes and years of life lost among those with diabetes in Brazil.

BACKGROUND: Given the paucity of studies for low- or middle-income countries, we aim to provide the first ever estimations of lifetime risk of diabetes, years of life spent and lost among those with diabetes for Brazilians. Estimates of Brazil´s diabetes burden consist essentially of reports of diabetes prevalence from national surveys and mortality data. However, these additional metrics are at times more meaningful ways to characterize this burden. METHODS: We joined data on incidence of physician-diagnosed diabetes from the Brazilian risk factor surveillance system, all-cause mortality from national statistics, and diabetes mortality rate ratios from ELSA-Brasil, an ongoing cohort study. To calculate lifetime risk of developing diabetes, we applied an illness-death state model. To calculate years of life lost for those with diabetes and years lived with the disease, we additionally calculated the mortality rates for those with diabetes. RESULTS: A 35-year-old white adult had a 23.4% (95% CI = 22.5%-25.5%) lifetime risk of developing diabetes by age 80 while a same-aged black/brown adult had a 30.8% risk (95% confidence interval (CI) = 29.6%-33.2%). Men diagnosed with diabetes at age 35 would live 32.9 (95% CI = 32.4-33.2) years with diabetes and lose 5.5 (95% CI = 5.1-6.1) years of life. Similarly-aged women would live 38.8 (95% CI = 38.3-38.9) years with diabetes and lose 2.1 (95% CI = 1.9-2.6) years of life. CONCLUSIONS: Assuming maintenance of current rates, one-quarter of young Brazilians will develop diabetes over their lifetimes, with this number reaching almost one-third among young, black/brown women. Those developing diabetes will suffer a decrease in life expectancy and will generate a considerable cost in terms of medical care.

Cancer Cell Fitness Is Dynamic.

Several phenotypes that impact the capacity of cancer cells to survive and proliferate are dynamic. Here we used the number of cells in colonies as an assessment of fitness and devised a novel method called Dynamic Fitness Analysis (DynaFit) to measure the dynamics in fitness over the course of colony formation. DynaFit is based on the variance in growth rate of a population of founder cells compared with the variance in growth rate of colonies with different sizes. DynaFit revealed that cell fitness in cancer cell lines, primary cancer cells, and fibroblasts under unhindered growth conditions is dynamic. Key cellular mechanisms such as ERK signaling and cell-cycle synchronization differed significantly among cells in colonies after 2 to 4 generations and became indistinguishable from randomly sampled cells regarding these features. In the presence of cytotoxic agents, colonies reduced their variance in growth rate when compared with their founder cell, indicating a dynamic nature in the capacity to survive and proliferate in the presence of a drug. This finding was supported by measurable differences in DNA damage and induction of senescence among cells of colonies. The presence of epigenetic modulators during the formation of colonies stabilized their fitness for at least four generations. Collectively, these results support the understanding that cancer cell fitness is dynamic and its modulation is a fundamental aspect to be considered in comprehending cancer cell biology and its response to therapeutic interventions. SIGNIFICANCE: Cancer cell fitness is dynamic over the course of the formation of colonies. This dynamic behavior is mediated by asymmetric mitosis, ERK activity, cell-cycle duration, and DNA repair capacity in the absence or presence of a drug.

Aryl-hydrocarbon receptor binding and the incidence of type 2 diabetes: the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

BACKGROUND: Persistent organic pollutants (POPs) may cause diabetes, in part through aryl hydrocarbon receptor (AhR) binding. Ensuing mitochondrial dysfunction is postulated to mediate this effect. We aim to investigate the association of POPs with incident diabetes indirectly by bio-assaying AhR ligand bioactivity and intracellular ATP level induced by participant serum samples. METHODS: In incident case-cohort analyses of one ELSA-Brasil center, 1605 eligible subjects without diabetes at baseline had incident diabetes ascertained by self-report, medication use, OGTT or HbA1c at follow-up 4 years later. We assayed AhR ligand bioactivity (AhRL) and intracellular ATP content, the latter reflecting the presence of mitochondria-inhibiting substances (MIS), following incubation of recombinant mouse Hepa1c1c7 cells with participant sera for 71 incident diabetes cases and 472 randomly selected controls. RESULTS: In multiply-adjusted proportional hazards regression analyses, those with above-median AhRL and below-median MIS-ATP had 69 and 226% greater risk of developing diabetes (HR = 1.69; 95%CI 1.01-2.83 and 3.26; 1.84-5.78), respectively. A strong interaction was seen between the two exposures (HRhigh AhRL/low MIS-ATP vs. low AhRL/high MIS-ATP = 8.15; 2.86-23.2). CONCLUSION: The markedly increased incidence of diabetes seen in those with both higher AhR ligand bioactivity and increased mitochondrial inhibition supports the hypothesis that widespread POPs exposure contributes to the diabetes epidemic.

A nationwide analysis of the excess death attributable to diabetes in Brazil.

BACKGROUND: Data on mortality burden and excess deaths attributable to diabetes are sparse and frequently unreliable, particularly in low and middle-income countries. Estimates in Brazil to date have relied on death certificate data, which do not consider the multicausal nature of deaths. Our aim was to combine cohort data with national prevalence and mortality statistics to estimate the absolute number of deaths that could have been prevented if the mortality rates of people with diabetes were the same as for those without. In addition, we aimed to estimate the increase in burden when considering undiagnosed diabetes. METHODS: We estimated self-reported diabetes prevalence from the National Health Survey (PNS) and overall mortality from the national mortality information system (SIM). We estimated the diabetes mortality rate ratio (rates of those with vs without diabetes) from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), an ongoing cohort study. Joining estimates from these three sources, we calculated for the population the absolute number and the fraction of deaths attributable to diabetes. We repeated our analyses considering both self-reported and unknown diabetes, the latter estimated based on single point-in-time glycemic determinations in ELSA-Brasil. Finally, we compared results with diabetes-related mortality information from death certificates. RESULTS: In 2013, 65 581 deaths, 9.1% of all deaths between the ages of 35-80, were attributable to known diabetes. If cases of unknown diabetes were considered, this figure would rise to 14.3%. In contrast, based on death certificates only, 5.3% of all death had diabetes as the underlying cause and 10.4% as any mentioned cause. CONCLUSIONS: In this first report of diabetes mortality burden in Brazil using cohort data to estimate diabetes mortality rate ratios and the prevalence of unknown diabetes, we showed marked underestimation of the current burden, especially when unknown cases of diabetes are also considered.

Intermediate hyperglycaemia to predict progression to type 2 diabetes (ELSA-Brasil): an occupational cohort study in Brazil.

BACKGROUND: The burden of diabetes is increasing worldwide and diabetes can be prevented with intervention in people with impaired glucose tolerance (IGT). Intermediate hyperglycaemia defined without an oral glucose tolerance test as impaired fasting glucose (IFG) and high HbA1c are also used to characterise risk. We aimed to assess the prognostic properties of five definitions of intermediate hyperglycaemia (also known as prediabetes) on the basis of their ability to predict who will progress to diabetes. METHODS: The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is an occupational cohort study of active or retired civil servants, aged 35-74 years, recruited from public universities and research institutes in six state capital cities in Brazil. We excluded participants who provided insufficient information to ascertain diabetes status, those without information on relevant covariates, and those with diabetes. We classified type 2 diabetes on the basis of self-report, medication use, measures of fasting plasma glucose (FPG), 2 h plasma glucose, and HbA1c. We used five laboratory definitions of intermediate hyperglycaemia: IGT (2 h plasma glucose ≥7·8 mmol/L [≥140 mg/dL]); IFG based on American Diabetes Association (ADA) criteria (FPG ≥5·5 mmol/L [≥100 mg/dL]); IFG based on WHO criteria (FPG ≥6·1 mmol/L [≥110 mg/dL]); HbA1c based on ADA criteria (HbA1c ≥39 mmol/mol [5·7%]); and HbA1c based on International Expert Committee criteria, IEC-HbA1c, (HbA1c ≥42 mmol/mol [6·0%]). We estimated risk of each definition using Cox regression and overall predictability (area under the receiver operating characteristic curve [AUC]) using logistic regression. FINDINGS: We recruited 15 105 participants from Aug 18, 2008, to Dec 20, 2010, and followed up for a mean of 3·7 (SD 0·63) years. Diabetes incidence rate was 2·0 per 100 person-years (95% CI 1·8-2·1). Among the 11 199 eligible participants, 6563 (59%) presented with some form of intermediate hyperglycaemia. ADA-IFG (4870/11 199 [43·5%), IEC-HbA1c (1005 [9·0%]), and ADA-HbA1c (2299 [20·5%]) poorly predicted diabetes (3·5-3·6 per 100 person-years). WHO-IFG (1140 [10·2%]) and IGT (2245 [20·0%]) predicted greater conversion (7·5 per 100 person-years and 5·8 per 100 person-years, respectively). All definitions presented either low sensitivity or specificity. Combinations of tests improved prognostic properties, with the combination of IGT or WHO-IFG showing the best, but still insufficient, predictability (sensitivity 67·7%, 95% CI 64·5-70·1; specificity 77·9%, 77·1-78·7). The AUC for the three underlying glycaemic tests was 65·0% (95% CI 63·0-66·9) for HbA1c, 74·6% (72·7-76·4) for FPG, and 77·1% (75·4-78·8) for 2 h plasma glucose, whereas the AUC for a score composed of clinical information was 71·6% (69·8-73·3). When this score was combined with results of an oral glucose tolerance test, the AUC reached 82·4% (80·9-83·9). INTERPRETATION: IFG based on WHO criteria and IGT predict diabetes progression better than do the other three definitions of intermediate hyperglycaemia, but their sensitivity is low. IFG based on ADA criteria has better sensitivity than the others, but classifies almost half of adults as having intermediate hyperglycaemia and poorly predicts diabetes. Combining glycaemic results with clinical information improves prognostic properties of those at risk. FUNDING: The Brazilian Ministry of Health (Science and Technology Department), the Brazilian Ministry of Science, Technology and Innovation (Financiadora de Estudos e Projetos and Conselho Nacional de Desenvolvimento Científico e Tecnológico), and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES).

Transcriptional characterization of immunological infiltrates and their relation with glioblastoma patients overall survival.

Introduction: Several cell populations from the peripheral immune system interact to create a complex immunologic status during glioblastoma growth and response to therapy. The aim of this study was to integrate the impact of different immune cell populations present in glioblastoma tumor microenvironment on overall survival. Methodology: Gene expression and clinical data were generated by The Cancer Genome Atlas and previously reported meta-signatures representing cells of the immune system were used. The relationship between meta-signatures was evaluated through Pearson's correlation analyses. Survival analyses were performed through Kaplan-Meier plots and Cox regression model. Results and discussion: Meta-signatures corresponding to infiltrating immune cells with immunosuppressive roles, such as macrophages, NK and NK T cells, MDSCs and Tregs, correlated with poorer patient prognosis. Meta-signatures related to CD8+ T cells predicted improved survival only in patients with low immunosuppressive meta-signatures. By clustering the meta-signatures we found that the cluster containing high meta-signatures of macrophages, MDSCs and Tregs demonstrated the worst prognosis. Conclusion: Integrating the information provided by transcriptional signatures of immunological aspects is fundamental in understanding the impact of the immune system on patient survival. We found a predictive impact on survival with positive role for CD8 and negative roles for macrophages, MDSC, Tregs, NK and NK-T in glioblastoma patients. Understanding these regulatory and stimulatory factors of patients' immune system is essential to delineate an effective strategy to increase the anti-tumor immune response and to generate potential clinical benefits.

Mesenchymal stem cells from different murine tissues have differential capacity to metabolize extracellular nucleotides.

Mesenchymal stem cells (MSCs) have shown a great potential for cell-based therapy and many different therapeutic purposes. Despite the recent advances in the knowledge of MSCs biology, their biochemical and molecular properties are still poorly defined. Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) and ecto-5'-nucleotidase (eNT/CD73) are widely expressed enzymes that hydrolyze extracellular nucleotides, generating an important cellular signaling cascade. Currently, studies have evidenced the relationship between the purinergic system and the development, maintenance, and differentiation of stem cells. The objective of this study is to identify the NTPDases and eNT/CD73 and compare the levels of nucleotide hydrolysis on MSCs isolated from different murine tissues (bone marrow, lung, vena cava, kidney, pancreas, spleen, skin, and adipose tissue). MSCs from all tissues investigated expressed the ectoenzymes at different levels. In MSCs from pancreas and adipose tissue, the hydrolysis of triphosphonucleosides was significantly higher when compared to the other cells. The diphosphonucleosides were hydrolyzed at a higher rate by MSC from pancreas when compared to MSC from other tissues. The differential nucleotide hydrolysis activity and enzyme expression in these cells suggests that MSCs play different roles in regulating the purinergic system in these tissues. Overall MSCs are an attractive adult-derived cell population for therapies, however, the fact that ecto-nucleotide metabolism can affect the microenvironment, modulating important events, such as immune response, makes the assessment of this metabolism an important part of the characterization of MSCs to be applied therapeutically.