Applying an Exposome-Wide (ExWAS) Approach to Cancer Research

Traditional research approaches, including genome-wide association studies (GWAS), epigenome-wide association studies (EWAS) and Gene × Environment (G × E) studies are limited in their ability to handle the multiplicity of chemical and non-chemical toxicants to which people are exposed in the real world, over their life course, their impact on epigenomics and other biological systems, and their relationship to cancer onset, progression, and outcomes. Exposome-wide association study (ExWAS) provides a new approach for conceptualizing the roles and relationships of multiple chemical and non-chemical exposures in the etiology and progression of cancer at key developmental periods, over the life course, and across generations. ExWAS challenges us to consider the influence of both internal and external environment, chemical and non-chemical stressors, risk and protective factors, and spatial and temporal dimensions of exposures in our models of cancer incidence, outcomes, and disparities. Applying an ExWAS approach to cancer and cancer disparities research supports robust computational models and methods that will allow for analysis of the dynamic and complex interactions between genetics, epigenetics, and exposomics factors. In the coming months, we will spatially and temporally align environmental exposures with SCCS participant data from time of enrollment forward to move us closer to identifying complete exposure pathways that lead to cancer. In the future, we hope to link external sources of exposure to biomarkers of exposure, biomarkers of disease, disease phenotypes, and population level disparities

Using an external exposome framework to examine pregnancy-related morbidities and mortalities: Implications for health disparities research

© 2015 by the authors; licensee MDPI, Basel, Switzerland. Objective: We have conducted a study to assess the role of environment on the burden of maternal morbidities and mortalities among women using an external exposome approach for the purpose of developing targeted public health interventions to decrease disparities. Methods: We identified counties in the 48 contiguous USA where observed low birthweight (LBW) rates were higher than expected during a five-year study period. The identification was conducted using a retrospective space-time analysis scan for statistically significant clusters with high or low rates by a Discrete Poisson Model. Results: We observed statistically significant associations of LBW rate with a set of predictive variables. However, in one of the two spatiotemporal models we discovered LBW to be associated with five predictive variables (teen birth rate, adult obesity, uninsured adults, physically unhealthy days, and percent of adults who smoke) in two counties situated in Alabama after adjusting for location changes. Counties with higher than expected LBW rates were similarly associated with two environmental variables (ozone and fine particulate matter). Conclusions: The county-level predictive measures of LBW offer new insights into spatiotemporal patterns relative to key contributory factors. An external framework provides a promising place-based approach for identifying “hotspots” with implications for designing targeted interventions and control measures to reduce and eliminate health disparities

The Public Health Exposome: A Population-Based, Exposure Science Approach to Health Disparities Research

The lack of progress in reducing health disparities suggests that new approaches are needed if we are to achieve meaningful, equitable, and lasting reductions. Current scientific paradigms do not adequately capture the complexity of the relationships between environment, personal health and population level disparities. The public health exposome is presented as a universal exposure tracking framework for integrating complex relationships between exogenous and endogenous exposures across the lifespan from conception to death. It uses a social-ecological framework that builds on the exposome paradigm for conceptualizing how exogenous exposures “get under the skin”. The public health exposome approach has led our team to develop a taxonomy and bioinformatics infrastructure to integrate health outcomes data with thousands of sources of exogenous exposure, organized in four broad domains: natural, built, social, and policy environments. With the input of a transdisciplinary team, we have borrowed and applied the methods, tools and terms from various disciplines to measure the effects of environmental exposures on personal and population health outcomes and disparities, many of which may not manifest until many years later. As is customary with a paradigm shift, this approach has far reaching implications for research methods and design, analytics, community engagement strategies, and research training

3D characterization of CdSe nanoparticles attached to carbon nanotubes

The crystallographic structure of CdSe nanoparticles attached to carbon nanotubes has been elucidated by means of high resolution transmission electron microscopy and high angle annular dark field scanning transmission electron microscopy tomography. CdSe rod-like nanoparticles, grown in solution together with carbon nanotubes, undergo a morphological transformation and become attached to the carbon surface. Electron tomography reveals that the nanoparticles are hexagonal-based with the (001) planes epitaxially matched to the outer graphene layer.Comment: 7 pages, 8 figure

Diurnal Immune Cell Migration Patterns Characterized in the Spaceflight Environment

Daily diurnal immune rhythm shapes biological pathways of organisms and closely aligns with optimizing energy usage in response to environmental light-dark cycles. Immune mobilization depends on diurnal signals to regulate immunity. In spaceflight, disrupted circadian rhythms and immune systems are noted. However, crosstalk between these systems has not been fully characterized. To fill this knowledge gap, we utilized a ground-based model of spaceflight to phenotype diurnal immunity in mice. For this, 24-week-old male and female mice were exposed to a combination of single-housed, acute 15cGy 5-ion GCRsim irradiation and continuous hindlimb unloading for 2 weeks on a light:dark [12hr:12hr] cycle throughout. Blood was collected at 24 hours and 2 weeks post irradiation and flow cytometrically profiled. Additionally, ribo-depleted, bulk RNA sequencing characterized unique, diurnal and sex-specific biosignatures. This work expands our understanding of diurnal immunity which is important to consider for personalized medicine directives for astronauts. This work was supported in part by the NASA Human Research Program (HRP) Human Factors Behavioral Performance Element Grant 18 18FLAG 2 0028 to AER and Embry-Riddle Start-up grant to Dr. Amber Paul

Diel activity patterns of two distinct populations of Aedes aegypti in Miami, FL and Brownsville, TX

The diel biting activity of Aedes (Stegomyia) aegypti (L) populations was extensively investigated in the early 1900s to gain more information on the biology of Ae. aegypti, and this information was used to devise effective approaches to controlling populations of this species and protect the human population from widespread arbovirus outbreaks. However, few contemporary studies are available regarding the diel activity patterns of Ae. aegypti. To assess the diel activity patterns of Ae. aegypti in southern Florida and Texas, we conducted 96-h uninterrupted mosquito collections once each month from May through November 2019 in Miami, Florida, and Brownsville, Texas, using BG-Sentinel 2 Traps. The overall diel activity pattern in both cities was bimodal with morning and evening peak activity between 7:00 and 8:00 and between 19:00 and 20:00. There were significant daily, monthly, seasonal, and site-specific differences in activity patterns, but these differences did not affect the overall peak activity times. These differences suggest daily, monthly, seasonal, and site-specific variations in human exposure to Ae. aegypti. Our observations can be used in planning and executing Ae. aegypti vector control activities in southern Florida and southern Texas, specifically those targeting the adult mosquito populations

MultiCellDS: a standard and a community for sharing multicellular data

Cell biology is increasingly focused on cellular heterogeneity and multicellular systems. To make the fullest use of experimental, clinical, and computational efforts, we need standardized data formats, community-curated "public data libraries", and tools to combine and analyze shared data. To address these needs, our multidisciplinary community created MultiCellDS (MultiCellular Data Standard): an extensible standard, a library of digital cell lines and tissue snapshots, and support software. With the help of experimentalists, clinicians, modelers, and data and library scientists, we can grow this seed into a community-owned ecosystem of shared data and tools, to the benefit of basic science, engineering, and human health

MultiCellDS: a community-developed standard for curating microenvironment-dependent multicellular data

Exchanging and understanding scientific data and their context represents a significant barrier to advancing research, especially with respect to information siloing. Maintaining information provenance and providing data curation and quality control help overcome common concerns and barriers to the effective sharing of scientific data. To address these problems in and the unique challenges of multicellular systems, we assembled a panel composed of investigators from several disciplines to create the MultiCellular Data Standard (MultiCellDS) with a use-case driven development process. The standard includes (1) digital cell lines, which are analogous to traditional biological cell lines, to record metadata, cellular microenvironment, and cellular phenotype variables of a biological cell line, (2) digital snapshots to consistently record simulation, experimental, and clinical data for multicellular systems, and (3) collections that can logically group digital cell lines and snapshots. We have created a MultiCellular DataBase (MultiCellDB) to store digital snapshots and the 200+ digital cell lines we have generated. MultiCellDS, by having a fixed standard, enables discoverability, extensibility, maintainability, searchability, and sustainability of data, creating biological applicability and clinical utility that permits us to identify upcoming challenges to uplift biology and strategies and therapies for improving human health

C-type lectin receptor expression is a hallmark of neutrophils infiltrating the skin in epidermolysis bullosa acquisita

IntroductionInflammatory epidermolysis bullosa acquisita (EBA) is characterized by a neutrophilic response to anti-type VII collagen (COL7) antibodies resulting in the development of skin inflammation and blistering. The antibody transfer model of EBA closely mirrors this EBA phenotype.MethodsTo better understand the changes induced in neutrophils upon recruitment from peripheral blood into lesional skin in EBA, we performed single-cell RNA-sequencing of whole blood and skin dissociate to capture minimally perturbed neutrophils and characterize their transcriptome.ResultsThrough this approach, we identified clear distinctions between circulating activated neutrophils and intradermal neutrophils. Most strikingly, the gene expression of multiple C-type lectin receptors, which have previously been reported to orchestrate host defense against fungi and select bacteria, were markedly dysregulated. After confirming the upregulation of Clec4n, Clec4d, and Clec4e in experimental EBA as well as in lesional skin from patients with inflammatory EBA, we performed functional studies in globally deficient Clec4e−/− and Clec4d−/− mice as well as in neutrophil-specific Clec4n−/− mice. Deficiency in these genes did not reduce disease in the EBA model.DiscussionCollectively, our results suggest that while the upregulation of Clec4n, Clec4d, and Clec4e is a hallmark of activated dermal neutrophil populations, their individual contribution to the pathogenesis of EBA is dispensable

Live Imaging of Innate Immune Cell Sensing of Transformed Cells in Zebrafish Larvae: Parallels between Tumor Initiation and Wound Inflammation

Live imaging and genetic studies of the initial interactions between leukocytes and transformed cells in zebrafish larvae indicate an attractant role for H2O2 and suggest that blocking these early interactions reduces expansion of transformed cell clones