Publications

Large-scale gene expression studies provide significant insight into genes differentially regulated in disease processes such as cancer. However, these investigations offer limited understanding of multisystem, multicellular diseases such as atherosclerosis. A systems biology approach that accounts for gene interactions, incorporates nontranscriptionally regulated genes, and integrates prior knowledge offers many advantages. We performed a comprehensive gene level assessment of coronary atherosclerosis using 51 coronary artery segments isolated from the explanted hearts of 22 cardiac transplant patients. After histological grading of vascular segments according to American Heart Association guidelines, isolated RNA was hybridized onto a customized 22-K oligonucleotide microarray, and significance analysis of microarrays and gene ontology analyses were performed to identify significant gene expression profiles. Our studies revealed that loss of differentiated smooth muscle cell gene expression is the primary expression signature of disease progression in atherosclerosis. Furthermore, we provide insight into the severe form of coronary artery disease associated with diabetes, reporting an overabundance of immune and inflammatory signals in diabetics. We present a novel approach to pathway development based on connectivity, determined by language parsing of the published literature, and ranking, determined by the significance of differentially regulated genes in the network. In doing this, we identify highly connected "nexus" genes that are attractive candidates for therapeutic targeting and followup studies. Our use of pathway techniques to study atherosclerosis as an integrated network of gene interactions expands on traditional microarray analysis methods and emphasizes the significant advantages of a systems-based approach to analyzing complex disease.

Although a substantial number of hormones and drugs increase cellular cAMP levels, the global impact of cAMP and its major effector mechanism, protein kinase A (PKA), on gene expression is not known. Here we show that treatment of murine wild-type S49 lymphoma cells for 24 h with 8-(4-chlorophenylthio)-cAMP (8-CPT-cAMP), a PKA-selective cAMP analog, alters the expression of approximately 4,500 of approximately 13,600 unique genes. By contrast, gene expression was unaltered in Kin- S49 cells (that lack PKA) incubated with 8-CPT-cAMP. Changes in mRNA and protein expression of several cell-cycle regulators accompanied cAMP-induced G1-phase cell-cycle arrest of wild-type S49 cells. Within 2 h, 8-CPT-cAMP altered expression of 152 genes that contain evolutionarily conserved cAMP-response elements within 5 kb of transcriptional start sites, including the circadian clock gene Per1. Thus, cAMP through its activation of PKA produces extensive transcriptional regulation in eukaryotic cells. These transcriptional networks include a primary group of cAMP-response element-containing genes and secondary networks that include the circadian clock.

Codon volatility is defined as the proportion of a codon's point-mutation neighbors that encode different amino acids. The cumulative volatility of a gene in relation to its associated genome was recently reported to be an indicator of selection pressure. We used this approach to measure selection on all available full-length HIV-1 subtype B genomes in the Los Alamos HIV Sequence Database, and compared these estimates against those obtained via established likelihood- and distance-based comparative methods. Volatility failed to correlate with the results of any of the comparative methods demonstrating that it is not a reliable indicator of selection pressure.

BACKGROUND

Little is known about the participation of minorities in health behavior research. This manuscript assesses factors associated with participation among women in four racial/ethnic groups.

METHODS

A total of 2800 Asian/Pacific Islander (API), Black, Latina, and non-Latina White women recruited through the San Francisco Mammography Registry was invited in 2002 and 2003 to participate in a telephone survey about breast cancer prevention.

RESULTS

Minorities participated at lower rates (49% for APIs, 60% for Latinas, and 64% for Blacks) than Whites (77%). Increased participation was associated with younger age for Latinas (OR = 1.90, 95% CI 1.05-3.44) and Whites (OR = 1.77, CI 1.08-2.91), and with a family history of breast cancer for APIs (OR = 2.09, CI 1.24-3.52). Decreased participation was associated with having less than a high school education for APIs (OR = 0.47, CI 0.26-0.86), Blacks (OR = 0.29, CI 0.11-0.78), and Latinas (OR = 0.51, CI 0.28-0.94).

CONCLUSIONS

Results suggest minorities' participation in health behavior research does not match Whites' and should be enhanced.