Faculty Bibliography

Translational regulation is critical in cancer development and progression. Translation sustains tumor growth and development of a tumor vasculature, a process known as angiogenesis, which is activated by hypoxia. Here we first demonstrate that a majority of large advanced breast cancers overexpress translation regulatory protein 4E-BP1 and initiation factor eIF4G. Using model animal and cell studies, we then show that overexpressed 4E-BP1 and eIF4G orchestrate a hypoxia-activated switch from cap-dependent to cap-independent mRNA translation that promotes increased tumor angiogenesis and growth at the level of selective mRNA translation. Elevated levels of 4E-BP1 trigger hypoxia inhibition of cap-dependent mRNA translation at high-oxygen levels and, with eIF4G, increase selective translation of mRNAs containing internal ribosome entry sites (IRESs) that include key proangiogenic, hypoxia, and survival mRNAs. The switch from cap-dependent to cap-independent mRNA translation facilitates tumor angiogenesis and hypoxia responses in animal models

Asbestos and benzo(a)pyrene diol epoxide (BPDE) are pulmonary carcinogens with synergistic interaction in causing lung cancer. We used Affymetrix microarrays to study gene modulation in vitro using normal human bronchial epithelial cells exposed to chrysotile asbestos and/or BPDE for 4 or 24 h. Linear models were used to compare treated cells to controls at each time point to identify statistically significant up- or downregulation of genes. Profiles of genes regulated by chrysotile were dominated by cytokines, growth factors, and DNA damage. Profiles of genes with BPDE and chrysotile regulation were correlated with proliferation, DNA damage recognition and nucleotide-excision repair, cytokines, and apoptosis. Chemokines, growth-regulated oncogene-alpha (Gro-alpha, CXCL-1), and IL-8, were significantly increased, and these had previously been observed in bronchoalveolar lavage from asbestos workers or in animal models. Interestingly, the Hermansky-Pudlak gene, which is mutated in an autosomal recessive form of pulmonary fibrosis, was downregulated threefold by BPDE at 4 h. This is an interesting example of gene (Hermansky-Pudlak syndrome) and environment (BPDE) interaction. Transcription factors, including activating transcription factor 3 and Cbp/p300-interacting transactivator, were upregulated by chrysotile. Real Time PCR for IL-8, ATF-3, GADD45B, CXC Ligand 1, and CTGF compared to GAPDH validated microarray findings at 24 h. These in vitro findings in NHBE cells model environment-gene interaction for asbestos and BPDE, highlighting effects of inflammation, fibrosis, proliferation, and DNA damage recognition and repair

Computerized drug utilization review (DUR) can potentially reduce adverse drug events. We examined automated DUR for home healthcare patients with diabetes or hypertension. Sixty-eight percent of diabetes patients and 50.7% of hypertension patients triggered severe, moderate, or duplicative alerts. Among diabetes patients, 74.3% of duplicative alerts were trivial or inappropriate, compared with 3.9% among hypertension patients. Experts judged that 40.5% of high-risk diabetes patients and 53.6% of hypertension patients had alerts requiring nurse follow-up. Adequate follow-up was significantly lower for the former. The relationship between inappropriate alerts and poorer follow-up reinforces the need for more specific alert systems to focus clinicians' attention on clinically important alerts.