Polyunsaturated Fatty Acids and Early-Life Cardiometabolic Disease Risk

Background: Polyunsaturated fatty acid (PUFA) intake is low throughout Latin America, but sociodemographic patterning and dietary sources of PUFA status in the region are poorly characterized. PUFA may be related to the development of early-life risk factors for cardiometabolic diseases, which have reached epidemic proportions in Latin America. However, the relations between these nutrients and cardiometabolic risk in children are poorly understood. Objectives: To identify sociodemographic, anthropometric, and dietary correlates of PUFA status in Mesoamerica (aim 1), and to examine the relations of n-3 and n-6 PUFA with metabolic syndrome (MetS) (aim 2) and development of adiposity in children (aim 3). Methods: Aims 1 and 2 were completed using data from the Nine Mesoamerican Countries Metabolic Syndrome (NiMeCoMeS) study, a cross-sectional investigation of school-age children and their parents from the capital cities of Guatemala, Honduras, El Salvador, Nicaragua, Costa Rica, Belize, Panama, the Dominican Republic, and the city of Tuxtla Gutíerrez in Chiapas, Mexico. Researchers collected information on sociodemographic characteristics; food intake and the type of cooking oil used in the home were measured by food frequency questionnaire. PUFA concentrations were quantified in adipose tissue by gas chromatography. In aim 1, we assessed correlates of adipose tissue PUFA biomarkers by estimating percent mean differences in each PUFA between levels of predictors using multivariable-adjusted linear regression models. In aim 2, we examined associations between PUFA and MetS in parents, and between PUFA and a continuous metabolic risk score in children. We estimated prevalence ratios of MetS in adults and mean differences in metabolic score in children across quartiles of PUFA using multivariable-adjusted Poisson and linear regression models, respectively. Aim 3 was conducted in the context of a cohort of children from Santiago, Chile who were recruited in infancy and followed through adolescence. PUFA were quantified in serum at 5 and 10 y of age. Body mass index (BMI) was measured at 5, 10, and 16 y. We compared the change in BMI-for-age Z scores through 16 y of age between PUFA quartiles at 5 or 10 y and between quartiles of PUFA change from 5 to 10 y by fitting growth curves from multivariable linear mixed models with restricted cubic splines. Results: Country of origin was the strongest predictor of all essential and long-chain PUFA biomarkers. The type of cooking oil used in the home was the strongest dietary correlate of PUFA status. Among adults, MetS prevalence was inversely associated with adipose tissue alpha-linolenic acid (ALA) and gamma-linolenic acid (GLA), and positively associated with eicosapentaenoic acid (EPA), dihomo-gamma-linolenic acid (DGLA), and the Δ6-desaturase activity index. Among children, metabolic risk score was positively associated with docosapentaenoic acid (DPA). Serum concentrations of some long-chain n-3 PUFA in middle childhood were associated with less weight gain through adolescence whereas the n-6 PUFA arachidonic acid (AA) and estimated Δ5-desaturase activity are related to increased weight gain. Conclusions and significance: PUFA status within Latin America is heterogeneous and is related to the type of vegetable oil used for cooking. ALA is inversely associated with MetS among adults but long-chain n-3 PUFA do not appear to be protective against MetS in children or adults. However, they may be protective against development of adiposity in middle childhood. These results suggest that PUFA are related to cardiometabolic risk in early life and could serve as modifiable targets for intervention.PHDEpidemiological ScienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/144058/1/kflanna_1.pd

Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice

Pancreatic cancer is almost invariably associated with mutations in the KRAS gene, most commonly KRASG12D, that result in a dominant-active form of the KRAS GTPase. However, how KRAS mutations promote pancreatic carcinogenesis is not fully understood, and whether oncogenic KRAS is required for the maintenance of pancreatic cancer has not been established. To address these questions, we generated two mouse models of pancreatic tumorigenesis: mice transgenic for inducible KrasG12D, which allows for inducible, pancreas-specific, and reversible expression of the oncogenic KrasG12D, with or without inactivation of one allele of the tumor suppressor gene p53. Here, we report that, early in tumorigenesis, induction of oncogenic KrasG12D reversibly altered normal epithelial differentiation following tissue damage, leading to precancerous lesions. Inactivation of KrasG12D in established precursor lesions and during progression to cancer led to regression of the lesions, indicating that KrasG12D was required for tumor cell survival. Strikingly, during all stages of carcinogenesis, KrasG12D upregulated Hedgehog signaling, inflammatory pathways, and several pathways known to mediate paracrine interactions between epithelial cells and their surrounding microenvironment, thus promoting formation and maintenance of the fibroinflammatory stroma that plays a pivotal role in pancreatic cancer. Our data establish that epithelial KrasG12D influences multiple cell types to drive pancreatic tumorigenesis and is essential for tumor maintenance. They also strongly support the notion that inhibiting KrasG12D, or its downstream effectors, could provide a new approach for the treatment of pancreatic cancer