Faculty Bibliography

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

BACKGROUND: Normal metabolism generates several volatile organic compounds (VOCs) that are excreted in the breath (e.g. alkanes). In patients with lung cancer, induction of high-risk cytochrome p450 genotypes may accelerate catabolism of these VOCs, so that their altered abundance in breath may provide biomarkers of lung cancer. METHODS: VOCs in 1.0 L alveolar breath were analyzed in 193 subjects with primary lung cancer and 211 controls with a negative chest CT. Subjects were randomly assigned to a training set or to a prediction set in a 2:1 split. A fuzzy logic model of breath biomarkers of lung cancer was constructed in the training set and then tested in subjects in the prediction set by generating their typicality scores for lung cancer. RESULTS: Mean typicality scores employing a 16 VOC model were significantly higher in lung cancer patients than in the control group (p<0.0001 in all TNM stages). The model predicted primary lung cancer with 84.6% sensitivity, 80.0% specificity, and 0.88 area under curve (AUC) of the receiver operating characteristic (ROC) curve. Predictive accuracy was similar in TNM stages 1 through 4, and was not affected by current or former tobacco smoking. The predictive model achieved near-maximal performance with six breath VOCs, and was progressively degraded by random classifiers. Predictions with fuzzy logic were consistently superior to multilinear analysis. If applied to a population with 2% prevalence of lung cancer, a screening breath test would have a negative predictive value of 0.985 and a positive predictive value of 0.163 (true positive rate =0.277, false positive rate =0.029). CONCLUSIONS: A two-minute breath test predicted lung cancer with accuracy comparable to screening CT of chest. The accuracy of the test was not affected by TNM stage of disease or tobacco smoking. Alterations in breath VOCs in lung cancer were consistent with a non-linear pathophysiologic process, such as an off-on switch controlling high-risk cytochrome p450 activity. Further research is needed to determine if detection of lung cancer with this test will reduce mortality

The 81-kDa malate synthase (MS; Rv 1837c) and the 27-kDa MPT51 (Rv 3803c) of Mycobacterium tuberculosis are immunodominant antigens recognized by serum antibodies from approximately 80% of human immunodeficiency virus-negative smear-positive tuberculosis patients from India. We now provide evidence that the use of the MS/MPT51-based serodiagnostic assay can serve as an adjunct to sputum microscopy in the rapid diagnosis of pulmonary tuberculosis

Epidemiological studies using pollutant gases (e.g., SO2) and particle characteristics (e.g., elemental carbon) indicate that products of fossil fuel combustion are important contributors to particulate matter (PM)-associated hospital admissions and mortality. Coal is one of the world's most important fossil fuels, providing 40% of electricity worldwide. Besides individuals exposed to PM in ambient air, coal mining can cause adverse health effects in workers exposed to coal dusts at the workplace. Among the respiratory diseases, coal workers' pneumoconiosis (CWP) has received the most attention because of its clear occupational association. The field of CWP research is one of the few areas in occupational health in which considerable epidemiological data are available. This offers a good opportunity to focus on the relationship between epidemiological data and physico-chemical and/or biological characteristics of coals. The objective of this review is to assess whether some physico-chemical parameters play a role in the observed regional differences in the prevalence of CWP among various coalmine regions. We mainly concentrate on the chemical interaction of two minerals, pyrite (FeS2) and calcite (CaCO3) in the coals and their role in causing occupational lung diseases (e.g., pneumoconiosis) and other environmental problems (e.g., acid mine drainage). Therefore, understanding the chemical interaction of the two minerals in the coal may lead to the identification of the causal components in coal dusts as well as in PM. Examples from U.S.A. coals are used to illustrate the chemical interaction and geological distribution of iron and calcium minerals in various coalmine regions and how the differences in levels of these types of minerals contribute to the observed regional differences in the prevalence of CWP. Molecular mechanisms leading to the CWP development are also discussed, particular in the aspects of oxidative stress and inflammation