Limited Genomics Training Among Physicians Remains a Barrier to Genomics-Based Implementation of Precision Medicine.

The field of precision medicine has undergone significant growth over the past 10 years. Despite increasing applications of clinical genetic and genomic testing, studies consistently report limited knowledge of genetics and genomics among healthcare providers. This study explored barriers to the implementation of precision medicine by surveying physicians working in a large academic medical center. We assessed prior training in genetics, use of genetic testing in the clinic, desire for additional resources in genetics and genomic medicine and perceived barriers to successful integration of precision medicine. Only 20% of respondents reported moderate or extensive training in genetics. Physicians with limited or no training in genetics were less likely to have ordered a genetic test for any purpose. Furthermore, 41% of physicians responded that their lack of training identifying appropriate genetic tests and how to interpret genetic testing results was the most significant barrier to ordering genetic testing for their patients. These findings suggest that future efforts to realize the promise of precision medicine should focus on the integration of training programs for non-genetics trained healthcare providers.

Serum levels of L1-ORF1p and airflow limitation.

In a population-based study, higher circulating levels of L1-ORF1p were associated with lower lung function levels and increased risk for airflow limitation among former smokers http://bit.ly/2ZEIjNv.

Precision prevention: A focused response to shifting paradigms in healthcare.

IMPACT STATEMENT: The study of LINE-1 retroelements and their role in the pathogenesis of diseases of the lung such as COPD and lung cancer may provide valuable diagnostic and therapeutic tools to identify pre-emptively individuals at risk of pulmonary disease progression. Limited information is presently available on the role of LINE-1 in the regulation of disease phenotypes and the development of novel therapeutics designed to curtail LINE-1-mediated pathogenesis. Successful implementation of precision prevention strategies may help to spare those impacted by obstructive pulmonary disease from continued deterioration, while realizing significant cost savings and improved quality of healthcare.

Driving the precision medicine highway: community health workers and patient navigators.

The general public is currently bombarded with direct-to-consumer advertising, real time "medical" guidance through the internet, access to digital devices that capture health information, and science-based adds that promote foods, cosmetics, and dietary supplements. Unfortunately, much of this information relies on terminology and concepts not well-understood by consumers, particularly those with lower levels of health and genomic literacy. Such constraints align with the limitations of the American public to obtain and process the basic medical information needed to make appropriate healthcare decisions. Low levels of health and genomic literacy render the American public ill-equipped to make informed decisions, use and interpret genomic information, or appreciate the benefits afforded by genomics-based technologies. We propose that coordinated expansion of the roles of community health workers and patient navigators within the precision medicine space can be effectively used to disseminate the knowledge required for the public to benefit from precision medicine advances in healthcare. A well-organized and trained community health worker and patient navigator workforce will provide a voice for the disadvantaged, especially among recent immigrants likely to be experiencing social isolation, language barriers, and economic deprivation. Armed with this knowledge, community health workers and patient navigators can advance the precision medicine agenda and empower disadvantaged communities to take advantage of major advances in the precision medicine era.

Genetics and epigenetics of pediatric leukemia in the era of precision medicine.

Pediatric leukemia represents a heterogeneous group of diseases characterized by germline and somatic mutations that manifest within the context of disturbances in the epigenetic machinery and genetic regulation. Advances in genomic medicine have allowed finer resolution of genetic and epigenetic strategies that can be effectively used to risk-stratify patients and identify novel targets for therapy. This review discusses the genetic and epigenetic mechanisms of leukemogenesis, particularly as it relates to acute lymphocytic leukemias, the mechanisms of epigenetic control of leukemogenesis, namely DNA methylation, histone modifications, microRNAs, and LINE-1 retroelements, and highlights opportunities for precision medicine therapeutics in further guiding disease management. Future efforts to broaden the integration of advances in genomic and epigenomic science into the practice of pediatric oncology will not only identify novel therapeutic strategies to improve clinical outcomes but also improve the quality of life for this unique patient population. Recent findings in precision therapeutics of acute lymphocytic leukemias over the past three years, along with some provocative areas of epigenetics research, are reviewed here.

The aryl hydrocarbon receptor agonist benzo(a)pyrene reactivates LINE-1 in HepG2 cells through canonical TGF-ß1 signaling: implications in hepatocellular carcinogenesis.

Long interspersed nuclear element-1 (L1) is a genetic element that mobilizes throughout the mammalian genome via retrotransposition and damages host DNA via mutational insertions, chromosomal rearrangements, and reprogramming of gene expression. The cellular mechanisms responsible for aberrant L1 expression during cancer pathogenesis are unclear. Previously, we have shown that L1 reactivation in several human cell lines is dependent upon the activation of aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor member of the PAS superfamily of proteins. We also showed that ectopic expression of L1 reprograms the HepG2 genome leading to epithelial-to-mesenchymal transition (EMT). Here we present evidence that reactivation of L1 and modulation of EMT in HepG2 cells by the AhR ligand benzo(a)pyrene (BaP) is effected through the canonical TGF-ß1 signaling pathway. BaP increased TGF-ß1 mRNA, SMAD2 phosphorylation and decreased expression of E-Cadherin. The functional relevance of these interactions and the involvement of TGFBR1/ALK5 and SMAD2/3 were confirmed by siRNA interference. Furthermore, expression of L1-encoded ORF1p was positively correlated with the activation of TGF-ß1 signaling in human hepatocarcinoma samples at various stages of malignant progression. These results indicate that ligand-mediated AhR activation regulates L1 via canonical TGF-ß1 signaling and raise important questions about the molecular etiology of human hepatocarcinomas.

LINE-1 silencing by retinoblastoma proteins is effected through the nucleosomal and remodeling deacetylase multiprotein complex.

BACKGROUND: Long Interspersed Nuclear Element-1 (L1) is an oncogenic mammalian retroelement silenced early in development via tightly controlled epigenetic mechanisms. We have previously shown that the regulatory region of human and murine L1s interact with retinoblastoma (RB) proteins to effect retroelement silencing. The present studies were conducted to identify the corepressor complex responsible for RB-mediated silencing of L1. METHODS: Chromatin immunoprecipitation and silencing RNA technology were used to identify the repressor complex that silences L1 in human and murine cells. RESULTS: Components of the Nucleosomal and Remodeling Deacetylase (NuRD) multiprotein complex specifically enriched the L1 5'-untranslated DNA sequence in human and murine cells. Genetic ablation of RB proteins in murine cells destabilized interactions within the NuRD macromolecular complex and mediated nuclear rearrangement of Mi2-ß, an ATP-dependent helicase subunit with nucleosome remodeling activity. Depletion of Mi2-ß, RbAP46 and HDAC2 reduced the repressor activity of the NuRD complex and reactivated a synthetic L1 reporter in human cells. Epigenetic reactivation of L1 in RB-null cells by DNA damage was markedly enhanced compared to wild type cells. CONCLUSIONS: RB proteins stabilize interactions of the NuRD corepressor complex within the L1 promoter to effect L1 silencing. L1 retroelements may serve as a scaffold on which RB builds heterochromatic regions that regulate chromatin function.

Health status, perceptions and needs of Hispanics in rural Shelbyville, Kentucky.

This cross-sectional study was completed to characterize the health status, perceptions and needs of Hispanics in Shelbyville, KY, USA. Community Health Workers interviewed 668 Hispanic residents in Shelbyville, KY, USA. Data were collected from 2009 to 2010 and analyzed from 2011 until present. Hispanic immigrants from Mexico and other Central American countries completed the survey. The most common self-reported diseases were allergies, asthma, diabetes, lung disease and cardiovascular disease. High blood pressure and diabetes were the two most common diagnoses among insured, older females. Health education, disease prevention and nutrition were the top health concerns among participants. Deficits in health care infrastructure for this largely transient community may compromise their ability to meet health care needs and concerns. Similar issues may be faced by other disadvantaged Hispanic communities in the continental US and likely to be influenced by anticipated provisions of the Patient Protection and Affordable Care Act.

Culturally-Tailored Education Programs to Address Health Literacy Deficits and Pervasive Health Disparities among Hispanics in Rural Shelbyville, Kentucky.

OBJECTIVES: This investigation was conducted to evaluate the impact of culturally-tailored education on health knowledge among Hispanic residents of rural, Shelbyville, KY. DESIGN: The program identified specific pathways to address health literacy deficits and disparities identified through a community-wide health assessment completed in 2010. RESULTS: A total of 43 Hispanic males who shared deficiencies in community-wide health infrastructure were enrolled in the program. The curriculum included an introductory session followed by five, subject-specific, sessions offered on a weekly basis from February to April 2011. Pre/post-test assessments showed marked improvement in knowledge base for all participants after each session, most notably related to cardiovascular disease, diabetes and metabolic syndrome. The group reconvened in January 2012 for follow-up instruction on cardiovascular disease and diabetes, as well as global assessment of knowledge retention over a nine-month period. Comparisons of pre/post testing in cardiovascular disease and diabetes, as well as global health-related knowledge showed significant gains for all parameters. CONCLUSIONS: Health education programs that embrace perceptions of the community of their own health, and that integrate knowledge into culturally-sensitive education, significantly improved health knowledge among Hispanic residents in rural Kentucky. Such gains may translate into sustainable improvements in health literacy and help reduce health disparities.

A mutant Ahr allele protects the embryonic kidney from hydrocarbon-induced deficits in fetal programming.

BACKGROUND: The use of experimental model systems has expedited the elucidation of pathogenetic mechanisms of renal developmental disease in humans and the identification of genes that orchestrate developmental programming during nephrogenesis. OBJECTIVES: We conducted studies to evaluate the role of AHR polymorphisms in the disruption of renal developmental programming by benzo(a)pyrene (BaP). METHODS: We used metanephric cultures of C57BL/6J (C57) mice expressing the Ahr(b-1) allele and B6.D2N-Ahr(d)/J (D2N) mice expressing a mutant allele deficient in ligand binding (Ahr(d)) to investigate molecular mechanisms of renal development. Deficits in fetal programming were evaluated in the offspring of pregnant mice treated with BaP during nephrogenesis. RESULTS: Hydrocarbon challenge of metanephri from C57 mice altered Wilms' tumor suppressor gene (Wt1) mRNA splice variant ratios and reduced mRNAs of the Wt1 transcriptional targets syndecan-1 (Sdc1) paired box gene 2 (Pax2), epidermal growth factor receptor (Egfr), and retinoic acid receptor, alpha (Rarα). These changes correlated with down-regulation of effectors of differentiation [secreted frizzled-related sequence protein 1 (Sfrp1), insulin-like growth factor 1 receptor (Igf1r), wingless-related MMTV-integration site 4 (Wnt4), Lim homeobox protein 1 (Lhx1), E-cadherin]. In contrast, metanephri from D2N mice were spared hydrocarbon-induced changes in Wt1 splice variant ratios and deficits of differentiation. We observed similar patterns of dysmorphogenesis and progressive loss of renal function at postnatal weeks 7 and 52 in the offspring of pregnant C57 but not D2N mice gavaged with 0.1 or 0.5 mg/kg BaP on gestation days 10-13. CONCLUSIONS: These findings support a functional link between AHR and WT1 in the regulation of renal morphogenesis and raise important questions about the contribution of human AHR polymorphisms to the fetal origins of adult-onset kidney disease.

Environmental risk factors of disease in the Cameron Park Colonia, a Hispanic community along the Texas-Mexico border.

OBJECTIVES: This report summarizes the results of a cross-sectional study in Cameron Park in 2000-2001 to identify disease prevalence and health concerns among colonia residents and to identify environmental exposures to potentially adverse environmental conditions. RESULTS: Asthma and allergies were among the most prevalent respiratory diseases reported in both adults and children of Cameron Park. Other diseases affecting the community in higher numbers included diabetes and heart disease/high blood pressure. Among children, the most prevalent health conditions were asthma, followed by lung diseases, allergies, and to a lesser degree, skin rashes. CONCLUSIONS: These data can be useful in developing education and intervention programs to address the public health and medical issues impacting residents in the Cameron Park Colonia of Texas.

Embracing the local: enriching scientific research, education, and outreach on the Texas-Mexico border through a participatory action research partnership.

Cameron Park, Texas, is a colonia (an isolated, unincorporated rural settlement without municipal improvements) on the Texas-Mexico border in the Lower Rio Grande Valley, in Cameron County near Brownsville, Texas. Cameron Park has a population of 5,961 residents, 99.3% of whom are Hispanic. The annual median income is 16,934 US dollars, about one-half of the state median. Fifty-eight percent of families generally and 68% of those with children younger than 5 years have incomes below poverty level. Cameron Park resides geographically in a region where agriculture has been, and continues to be, a dominant industry, a fact consistent with the intensive use of pesticides and increased potential for air, water, and ground contamination. The practice of good environmental health is extremely difficult under these conditions. In 1999 the Texas A&M University Center for Housing and Urban Development's Colonias Program and the Center for Environmental and Rural Health teamed up to create an environmental health education and outreach program called the Cameron Park Project (CPP). The CPP focused on how to reduce potential environmental exposures associated with human illness by providing residents with scientifically sound information on positive health practices and how to deal with environmental hazards. In this article we discuss the research methodology used in the CPP, a methodology specifically chosen to address four challenges presented by colonias to conducting valid and reliable research.