Publications

We used a spheroid model of colon carcinoma to analyze integrin dynamics as a function of the epithelial-mesenchymal transition (EMT), a process that provides a paradigm for understanding how carcinoma cells acquire a more aggressive phenotype. This EMT involves transcriptional activation of the beta6 integrin subunit and a consequent induction of alphavbeta6 expression. This integrin enhances the tumorigenic properties of colon carcinoma, including activation of autocrine TGF-beta and migration on interstitial fibronectin. Importantly, this study validates the clinical relevance of the EMT. Kaplan-Meier analysis of beta6 expression in 488 colorectal carcinomas revealed a striking reduction in median survival time of patients with high beta6 expression. Elevated receptor expression did not simply reflect increasing tumor stage, since log-rank analysis showed a more significant impact on the survival of patients with early-stage, as opposed to late-stage, disease. Cox regression analysis confirmed that this integrin is an independent variable for these tumors. These findings define the alphavbeta6 integrin as an important risk factor for early-stage disease and a novel therapeutic candidate for colorectal cancer.

Despite numerous published studies, debate continues regarding the risk of developing lung cancer among men exposed occupationally to asbestos, particularly those without radiographic or functional evidence of asbestosis. The beta-Carotene and Retinol Efficacy Trial (CARET), a study of vitamin supplementation for chemoprevention of lung cancer, has followed 4,060 heavily exposed US men for 9-17 years. Lung cancer incidence for 1989-2002 was analyzed using a stratified proportional hazards model. The study confirmed excessive rates of lung cancer among men with radiographic asbestosis. Comparison of study arms revealed a strong, unanticipated synergy between radiographic profusion category and the active intervention. In the large subgroup of men with normal lung parenchyma on chest radiograph at baseline, there was evidence of exposure-related lung cancer risk: Men with more than 40 years' exposure in high-risk trades had a risk approximately fivefold higher than men with 5-10 years, after adjustment for covariates. The effect in these men was independent of study intervention arm, but pleural plaques on the baseline radiograph and abnormal baseline flow rate were strong independent predictors of subsequent lung cancer. Residual confounding by subclinical asbestosis, exposure to unmeasured lung carcinogens, or differences in smoking are unlikely to explain these observations better than a carcinogenic effect of asbestos per se.

OBJECTIVE

As a past recipient of the Jean Spencer Felton Award for Excellence in Scientific Writing from the Western Occupational and Environmental Medicine Association, it is truly an honor to contribute to this festschrift. What stands out in my mind about Dr Felton is that he loved to delve into the history of occupational medicine and tried to apply the lessons of that history to the modern practice of the discipline. He once wrote that "The name Ramazzini marks the beginning of society's concern with the well-being and physical and emotional health of its workers from the shops of the crafts to the offices of the executives." This review of a common disease for which an occupational contribution is too frequently ignored is offered in the spirit of both the father of modern occupational medicine and one of his 20th-century acolytes.

CONCLUSIONS

The biological plausibility of the capacity of occupational exposures to irritating dusts, gases, and fumes to cause chronic obstructive pulmonary disease (COPD) is high. Epidemiological evidence from both worker cohort and community studies supports an increased risk of COPD associated with such exposures. The occupational contribution to the burden of COPD is sufficiently great that preventive interventions are warranted.

COUP-TFII is a central nuclear hormone receptor that tightly regulates the expression of numerous target lipid metabolism genes in vertebrates. However, it remains unclear how COUP-TFII itself is transcriptionally controlled since studies with its promoter and upstream region fail to recapitulate the gene's liver expression. In an attempt to identify liver enhancers in the vicinity of COUP-TFII, we employed a comparative genomic approach. Initial comparisons between humans and mice of the 3470-kb gene-poor region surrounding COUP-TFII revealed 2023 conserved noncoding elements. To prioritize a subset of these elements for functional studies, we performed further genomic comparisons with the orthologous pufferfish (Fugu rubripes) locus and uncovered two anciently conserved noncoding sequences (CNS) upstream of COUP-TFII (CNS-62kb and CNS-66kb). Testing these two elements using reporter constructs in liver cells (HepG2) revealed that CNS-66kb, but not CNS-62kb, yielded robust in vitro enhancer activity. In addition, an in vivo reporter assay using naked DNA transfer with CNS-66kb linked to luciferase displayed strong reproducible liver expression in adult mice, further supporting its role as a liver enhancer. Together, these studies further support the utility of comparative genomics to uncover gene regulatory sequences based on evolutionary conservation and provide the substrates to better understand the regulation and expression of COUP-TFII.

This study examines the relationships that exist between social isolation, support, and capital and nutritional risk in older black and white women and men. The paper reports on 1000 community-dwelling older adults aged 65 and older enrolled in the University of Alabama at Birmingham (UAB) Study of Aging, a longitudinal observational study of mobility among older black and white participants in the USA. Black women were at greatest nutritional risk; and black women and men were the groups most likely to be socially isolated and to possess the least amounts of social support and social capital. For all ethnic-gender groups, greater restriction in independent life-space (an indicator of social isolation) was associated with increased nutritional risk. For black women and white men, not having adequate transportation (also an indicator of social isolation) was associated with increased nutritional risk. Additionally, for black and white women and white men, lower income was associated with increased nutritional risk. For white women only, the perception of a low level of social support was associated with increased nutritional risk. For black men, not being married (an indicator of social support) and not attending religious services regularly, restricting activities for fear of being attacked, and perceived discrimination (indicators of social capital) were associated with increased nutritional risk. Black females had the greatest risk of poor nutritional health, however more indicators of social isolation, support, and capital were associated with nutritional risk for black men. Additionally, the indicators of social support and capital adversely affecting nutritional risk for black men differed from those associated with nutritional risk in other ethnic-gender groups. This research has implications for nutritional policies directed towards older adults.