Assessing the Role of Selenium in Endometrial Cancer Risk: A Mendelian Randomization Study.

Endometrial cancer is the most commonly diagnosed gynecological cancer in developed countries. Based on evidence from observational studies which suggest selenium inhibits the development of several cancers (including lung and prostate cancer), selenium supplementation has been touted as a potential cancer preventative agent. However, randomized controlled trials have not reported benefit for selenium supplementation in reducing cancer risk. For endometrial cancer, limited observational studies have been conducted assessing whether selenium intake, or blood selenium levels, associated with reduced risk, and no randomized controlled trials have been conducted. We performed a two-sample Mendelian randomization analysis to examine the relationship between selenium levels (using a composite measure of blood and toenail selenium) and endometrial cancer risk, using summary statistics for four genetic variants associated with selenium levels at genome-wide significance levels (P < 5 × 10-8), from a study of 12,906 endometrial cancer cases and 108,979 controls, all of European ancestry. Inverse variance weighted (IVW) analysis indicated no evidence of a causal role for selenium levels in endometrial cancer development (OR per unit increase in selenium levels Z-score = 0.99, 95% CI = 0.87-1.14). Similar results were observed for sensitivity analyses robust to the presence of unknown pleiotropy (OR per unit increase in selenium levels Z-score = 0.98, 95% CI 0.89-1.08 for weighted median; OR per unit increase in selenium levels Z-score = 0.90, 95% CI = 0.53-1.50 for MR-Egger). In conclusion, these results do not support the use of selenium supplementation to prevent endometrial cancer.This work was supported by a National Health and Medical Research Council (NHMRC) Project Grant (APP1109286). PFK is supported by an Australian Government Research Training Program PhD Scholarship and QIMR Berghofer Postgraduate Top-Up Scholarship, TAO’M is supported by an NHMRC Early Career Fellowship (APP1111246), ABS is supported by an NHMRC Senior Research Fellowship (APP1061779)

Genome-Wide Association Studies of Endometrial Cancer: Latest Developments and Future Directions.

Endometrial cancer, the most commonly diagnosed cancer of the female reproductive tract in developed countries, has a heritable component. To date, 16 genetic risk regions have been robustly discovered by genome-wide association studies (GWAS) of endometrial cancer. Post-GWAS analyses including expression quantitative trait loci analysis and laboratory-based functional studies have been successful in identifying genes and pathways involved in endometrial carcinogenesis. Mendelian randomization analysis studies have confirmed factors causal for endometrial cancer risk, including increased body mass index and early onset of menarche. In this review, we summarize findings from GWAS and post-GWAS analyses of endometrial cancer. We discuss clinical implications of these findings, current knowledge gaps, and future directions for the study of endometrial cancer genetics.TAO’M is supported by a National Health and Medical Research Council (NHMRC) Early Career Fellowship (APP1111246), PFK is supported by an Australian Government Research Training Program PhD Scholarship and QIMR Berghofer Postgraduate Top-Up Scholarship, ABS is supported by an NHMRC Senior Research Fellowship (APP1061779)

Rapid Pathogen-Induced Apoptosis: A Mechanism Used by Dendritic Cells to Limit Intracellular Replication of Legionella pneumophila

Dendritic cells (DCs) are specialized phagocytes that internalize exogenous antigens and microbes at peripheral sites, and then migrate to lymphatic organs to display foreign peptides to naïve T cells. There are several examples where DCs have been shown to be more efficient at restricting the intracellular replication of pathogens compared to macrophages, a property that could prevent DCs from enhancing pathogen dissemination. To understand DC responses to pathogens, we investigated the mechanisms by which mouse DCs are able to restrict replication of the intracellular pathogen Legionella pneumophila. We show that both DCs and macrophages have the ability to interfere with L. pneumophila replication through a cell death pathway mediated by caspase-1 and Naip5. L. pneumophila that avoided Naip5-dependent responses, however, showed robust replication in macrophages but remained unable to replicate in DCs. Apoptotic cell death mediated by caspase-3 was found to occur much earlier in DCs following infection by L. pneumophila compared to macrophages infected similarly. Eliminating the pro-apoptotic proteins Bax and Bak or overproducing the anti-apoptotic protein Bcl-2 were both found to restore L. pneumophila replication in DCs. Thus, DCs have a microbial response pathway that rapidly activates apoptosis to limit pathogen replication

The Archaeology and Remote Sensing of Santa Elena’s Four Millennia of Occupation

In this study, we present the results of a comprehensive, landscape-scale remote sensing project at Santa Elena on Parris Island, South Carolina. Substantial occupation at the site extends for over 4000 years and has resulted in a complex array of features dating to different time periods. In addition, there is a 40-year history of archaeological research at the site that includes a large-scale systematic shovel test survey, large block excavations, and scattered test units. Also, modern use of the site included significant alterations to the subsurface deposits. Our goals for this present work are threefold: (1) to explicitly present a logical approach to examine sites with long-term occupations; (2) to examine changes in land use at Santa Elena and its implications for human occupation of this persistent place; and (3) to use the remote sensing program and past archaeological research to make substantive suggestions regarding future research, conservation, and management of the site. Our research provides important insight into the distribution of cultural features at this National Historic Landmark. While the majority of archaeological research at the site has focused on the Spanish period, our work suggests a complex and vast array of archaeological features that can provide insight into over 4000 years of history in the region. At a gross level, we have identified possible Late Archaic structures, Woodland houses and features, Late Prehistoric and early Historic council houses, and a suite of features related to the Spanish occupation which builds on our previous research at the site. In addition to documenting possible cultural features at the site, our work illustrates the value of multiple remote sensing techniques used in conjunction with close-interval shovel test data

Assessing the Role of Selenium in Endometrial Cancer Risk: A Mendelian Randomization Study

Endometrial cancer is the most commonly diagnosed gynecological cancer in developed countries. Based on evidence from observational studies which suggest selenium inhibits the development of several cancers (including lung and prostate cancer), selenium supplementation has been touted as a potential cancer preventative agent. However, randomized controlled trials have not reported benefit for selenium supplementation in reducing cancer risk. For endometrial cancer, limited observational studies have been conducted assessing whether selenium intake, or blood selenium levels, associated with reduced risk, and no randomized controlled trials have been conducted. We performed a two-sample Mendelian randomization analysis to examine the relationship between selenium levels (using a composite measure of blood and toenail selenium) and endometrial cancer risk, using summary statistics for four genetic variants associated with selenium levels at genome-wide significance levels (P &lt; 5 × 10−8), from a study of 12,906 endometrial cancer cases and 108,979 controls, all of European ancestry. Inverse variance weighted (IVW) analysis indicated no evidence of a causal role for selenium levels in endometrial cancer development (OR per unit increase in selenium levels Z-score = 0.99, 95% CI = 0.87–1.14). Similar results were observed for sensitivity analyses robust to the presence of unknown pleiotropy (OR per unit increase in selenium levels Z-score = 0.98, 95% CI 0.89–1.08 for weighted median; OR per unit increase in selenium levels Z-score = 0.90, 95% CI = 0.53–1.50 for MR-Egger). In conclusion, these results do not support the use of selenium supplementation to prevent endometrial cancer

Confirmatory factor analysis of the Infant Feeding Styles Questionnaire in Latino families

Parent feeding practices affect risk of obesity in children. Latino children are at higher risk of obesity than the general population, yet valid measure of feeding practices, one of which is the Infant Feeding Styles Questionnaire (IFSQ), have not been formally validated in Spanish

Milk- and solid-feeding practices and daycare attendance are associated with differences in bacterial diversity, predominant communities, and metabolic and immune function of the infant gut microbiome

The development of the infant intestinal microbiome in response to dietary and other exposures may shape long-term metabolic and immune function. We examined differences in the community structure and function of the intestinal microbiome between four feeding groups, exclusively breastfed infants before introduction of solid foods (EBF), non-exclusively breastfed infants before introduction of solid foods (non-EBF), EBF infants after introduction of solid foods (EBF+S), and non-EBF infants after introduction of solid foods (non-EBF+S), and tested whether out-of-home daycare attendance was associated with differences in relative abundance of gut bacteria. Bacterial 16S rRNA amplicon sequencing was performed on 49 stool samples collected longitudinally from a cohort of 9 infants (5 male, 4 female). PICRUSt metabolic inference analysis was used to identify metabolic impacts of feeding practices on the infant gut microbiome. Sequencing data identified significant differences across groups defined by feeding and daycare attendance. Non-EBF and daycare-attending infants had higher diversity and species richness than EBF and non-daycare attending infants. The gut microbiome of EBF infants showed increased proportions of Bifidobacterium and lower abundance of Bacteroidetes and Clostridiales than non-EBF infants. PICRUSt analysis indicated that introduction of solid foods had a marginal impact on the microbiome of EBF infants (24 enzymes overrepresented in EBF+S infants). In contrast, over 200 bacterial gene categories were overrepresented in non-EBF+S compared to non-EBF infants including several bacterial methyl-accepting chemotaxis proteins (MCP) involved in signal transduction. The identified differences between EBF and non-EBF infants suggest that breast milk may provide the gut microbiome with a greater plasticity (despite having a lower phylogenetic diversity) that eases the transition into solid foods

Development and validation of the Infant Feeding Style Questionnaire

This study describes and validates the Infant Feeding Style Questionnaire (IFSQ), a self-report instrument designed to measure feeding beliefs and behaviors among mothers of infants and young children. Categorical confirmatory factor analysis was used to estimate latent factors for five feeding styles, laissez-faire, restrictive, pressuring, responsive and indulgent, and to validate that items hypothesized a priori as measures of each style yielded well-fitting models. Models were tested and iteratively modified to determine the best fitting model for each of 13 feeding style sub-constructs, using a sample of 154 low-income African-American mothers of infants aged 3-20 months in North Carolina. With minor changes, models were confirmed in an independent sample of 150 African-American first-time mothers, yielding a final instrument with 39 questions on maternal beliefs, 24 questions on behaviors and an additional 20 behavioral items pertaining to solid feeding for infants over 6 months of age. Internal reliability measures for the sub-constructs ranged from 0.75 to 0.95. Several sub-constructs, responsive to satiety cues, pressuring with cereal, indulgent pampering and indulgent soothing, were inversely related to infant weight-for-length z-score, providing initial support for the validity of this instrument for assessing maternal feeding beliefs and behaviors that may influence infant weight outcomes