SPH Environmental Health Papers and Presentations

Genetic and Epigenetic Somatic Alterations in Head and Neck Squamous Cell Carcinomas Are Globally Coordinated but Not Locally Targeted

Thu, 11 Mar 2010 00:00:00 GMT

Genetic and Epigenetic Somatic Alterations in Head and Neck Squamous Cell Carcinomas Are Globally Coordinated but Not Locally Targeted Poage, Graham M.; Christensen, Brock C.; Houseman, E. Andres; McClean, Michael D.; Wiencke, John K.; Posner, Marshall R.; Clark, John R.; Nelson, Heather H.; Marsit, Carmen J.; Kelsey, Karl T. BACKGROUND. Solid tumors, including head and neck squamous cell carcinomas (HNSCC), arise as a result of genetic and epigenetic alterations in a sustained stress environment. Little work has been done that simultaneously examines the spectrum of both types of changes in human tumors on a genome-wide scale and results so far have been limited and mixed. Since it has been hypothesized that epigenetic alterations may act by providing the second carcinogenic hit in gene silencing, we sought to identify genome-wide DNA copy number alterations and CpG dinucleotide methylation events and examine the global/local relationships between these types of alterations in HNSCC. METHODOLOGY/PRINCIPAL FINDINGS. We have extended a prior analysis of 1,413 cancer-associated loci for epigenetic changes in HNSCC by integrating DNA copy number alterations, measured at 500,000 polymorphic loci, in a case series of 19 primary HNSCC tumors. We have previously demonstrated that local copy number does not bias methylation measurements in this array platform. Importantly, we found that the global pattern of copy number alterations in these tumors was significantly associated with tumor methylation profiles (p<0.002). However at the local level, gene promoter regions did not exhibit a correlation between copy number and methylation (lowest q=0.3), and the spectrum of genes affected by each type of alteration was unique. CONCLUSION/SIGNIFICANCE. This work, using a novel and robust statistical approach demonstrates that, although a "second hit" mechanism is not likely the predominant mode of action for epigenetic dysregulation in cancer, the patterns of methylation events are associated with the patterns of allele loss. Our work further highlights the utility of integrative genomics approaches in exploring the driving somatic alterations in solid tumors.

Growth of a Human Mammary Tumor Cell Line Is Blocked by Galangin, a Naturally Occurring Bioflavonoid, and Is Accompanied by Down-Regulation of Cyclins D3, E, and A

Mon, 27 Mar 2006 00:00:00 GMT

Growth of a Human Mammary Tumor Cell Line Is Blocked by Galangin, a Naturally Occurring Bioflavonoid, and Is Accompanied by Down-Regulation of Cyclins D3, E, and A Murray, Tessa J; Yang, Xinhai; Sherr, David H INTRODUCTION. This study was designed to determine if and how a non-toxic, naturally occurring bioflavonoid, galangin, affects proliferation of human mammary tumor cells. Our previous studies demonstrated that, in other cell types, galangin is a potent inhibitor of the aryl hydrocarbon receptor (AhR), an environmental carcinogen-responsive transcription factor implicated in mammary tumor initiation and growth control. Because some current breast cancer therapeutics are ineffective in estrogen receptor (ER) negative tumors and since the AhR may be involved in breast cancer proliferation, the effects of galangin on the proliferation of an ER-, AhRhigh line, Hs578T, were studied. METHODS. AhR expression and function in the presence or absence of galangin, a second AhR inhibitor, α-naphthoflavone (α-NF), an AhR agonist, indole-3-carbinol, and a transfected AhR repressor-encoding plasmid (FhAhRR) were studied in Hs578T cells by western blotting for nuclear (for instance, constitutively activated) AhR and by transfection of an AhR-driven reporter construct, pGudLuc. The effects of these agents on cell proliferation were studied by 3H-thymidine incorporation and by flow cytometry. The effects on cyclins implicated in mammary tumorigenesis were evaluated by western blotting. RESULTS. Hs578T cells were shown to express high levels of constitutively active AhR. Constitutive and environmental chemical-induced AhR activity was profoundly suppressed by galangin as was cell proliferation. However, the failure of α-NF or FhAhRR transfection to block proliferation indicated that galangin-mediated AhR inhibition was either insufficient or unrelated to its ability to significantly block cell proliferation at therapeutically relevant doses (IC50 = 11 μM). Galangin inhibited transition of cells from the G0/G1 to the S phases of cell growth, likely through the nearly total elimination of cyclin D3. Expression of cyclins A and E was also suppressed. CONCLUSION. Galangin is a strong inhibitor of Hs578T cell proliferation that likely mediates this effect through a relatively unique mechanism, suppression of cyclin D3, and not through the AhR. The results suggest that this non-toxic bioflavonoid may be useful as a chemotherapeutic, particularly in combination with agents that target other components of the tumor cell cycle and in situations where estrogen receptor-specific therapeutics are ineffective.

The Latino Health Insurance Program: A Pilot Intervention for Enrolling Latino Families in Health Insurance Programs, East Boston, Massachusetts, 2006-2007

Tue, 15 Sep 2009 00:00:00 GMT

The Latino Health Insurance Program: A Pilot Intervention for Enrolling Latino Families in Health Insurance Programs, East Boston, Massachusetts, 2006-2007 Abreu, Milagros; Hynes, H. Patricia BACKGROUND. Thirteen percent of Latinos in Massachusetts lack health insurance, the highest rate of any ethnic or racial group. Families without health insurance are more likely to be in poor or fair health, to lack a regular medical provider, and to not have visited a medical provider in the past year. CONTEXT. The Latino Health Insurance Program is designed as a response both to the high rate of uninsurance among Latinos in Boston and to the multiple obstacles that keep Latino parents from applying for insurance for their families. METHODS. In 2006, we designed and implemented a culturally competent model of health insurance outreach, education, enrollment and maintenance, and referral for primary care and social services for Latino families. CONSEQUENCES. Year 1 results of the Latino Health Insurance Program are promising. Six community members were hired and trained as case managers. A total of 230 children and adults were enrolled or re-enrolled in health insurance programs and received other needed services. Retention was near 100% after 1 year. INTERPRETATION. The Latino Health Insurance Program may serve as a model health insurance access program that can be adapted by community-based organizations and also can be incorporated into public agency programs for Latinos and other immigrant and minority groups. The program continues to serve East Boston residents and was expanded in 2008.

Assessment of Neuropsychological Trajectories in Longitudinal Population-Based Studies of Children

Fri, 05 Dec 2008 00:00:00 GMT

Assessment of Neuropsychological Trajectories in Longitudinal Population-Based Studies of Children White, R F; Campbell, R; Echeverria, D; Knox, S S; Janulewicz, P This paper provides a strategy for the assessment of brain function in longitudinal cohort studies of children. The proposed strategy invokes both domain-specific and omnibus intelligence test approaches. In order to minimise testing burden and practice effects, the cohort is divided into four groups with one-quarter tested at 6-monthly intervals in the 0–2-year age range (at ages 6 months, 1.0, 1.5 and 2.0 years) and at annual intervals from ages 3–20 (one-quarter of the children at age 3, another at age 4, etc). This strategy allows investigation of cognitive development and of the relationship between environmental influences and development at each age. It also allows introduction of new domains of function when age-appropriate. As far as possible, tests are used that will provide a rich source of both longitudinal and cross-sectional data. The testing strategy allows the introduction of novel tests and new domains as well as piloting of tests when the test burden is relatively light. In addition to the recommended tests for each age and domain, alternative tests are described. Assessment methodology and knowledge about child cognitive development will change over the next 20 years, and strategies are suggested for altering the proposed test schedule as appropriate.