Faculty Bibliography

Striking regional differences in the prevalence of coal workers' pneumoconiosis (CWP) have been observed but not fully understood. This study investigated the early biological responses of primary lung cells to treatment with coal dusts from various seams. High-density oligoarray technology (GeneChip, Affymetrix, Santa Clara, CA) was used to compile gene expression profiles of primary human bronchial epithelial cells to low concentrations (2 microg/cm(2)) of coals for 6 h or 24 h of treatment. Data showed that a total of 1050 out of 12,000 genes on the chip were altered by 2 coal dusts. The coal from the Pennsylvania (PA) coal-mine region with a high prevalence of CWP altered 908 genes, many more than the coal from Utah (UT) with a low prevalence of CWP, which affected 356 genes. Many genes decreased their expression levels in response to the PA coal at 6 h and/or 24 h of treatment. For example, transferrin receptor, a gene known to control cellular iron uptake, was downregulated in the cells treated with the iron-containing PA coal in order to protect cells from iron overload. The UT coal without bioavailable iron had no such effect. The downregulation patterns of genes were confirmed by reverse-transcription polymerase chain reaction (RT-PCR). This study is one of the first in profiling gene expressions of primary bronchial epithelial cells treated with coals from various seams, which may set stages for future studies on specific genes

STUDY OBJECTIVES: To evaluate volatile organic compounds (VOCs) in the breath as tumor markers in lung cancer. Alkanes and monomethylated alkanes are oxidative stress products that are excreted in the breath, the catabolism of which may be accelerated by polymorphic cytochrome p450-mixed oxidase enzymes that are induced in patients with lung cancer. DESIGN: Combined case-control and cross-sectional study. SETTING: Five academic pulmonary medicine services in the United States and the United Kingdom. Patients and participants: One hundred seventy-eight bronchoscopy patients and 41 healthy volunteers. INTERVENTION: Breath samples were analyzed by gas chromatography and mass spectroscopy to determine alveolar gradients (ie, the abundance in breath minus the abundance in room air) of C4-C20 alkanes and monomethylated alkanes. MEASUREMENTS: Patients with primary lung cancer (PLC) were compared to healthy volunteers, and a predictive model was constructed using forward stepwise discriminant analysis of the alveolar gradients. This model was cross-validated with a leave-one-out jackknife technique and was tested in two additional groups of patients who had not been used to develop the model (ie, bronchoscopy patients in whom cancer was not detected, and patients with metastatic lung cancer [MLC]). RESULTS: Eighty-seven of 178 patients had lung cancer (PLC, 67 patients; MLC, 15 patients; undetermined, 5 patients). A predictive model employing nine VOCs identified PLC with a sensitivity of 89.6% (60 of 67 patients) and a specificity of 82.9% (34 of 41 patients). On cross-validation, the sensitivity was 85.1% (57 of 67 patients) and the specificity was 80.5% (33 of 41 patients). The stratification of patients by tobacco smoking status, histologic type of cancer, and TNM stage of cancer revealed no marked effects. In the two additional tests, the model predicted MLC with a sensitivity of 66.7% (10 of 15 patients), and it classified the cancer-negative bronchoscopy patients with a specificity of 37.4% (34 of 91 patients). CONCLUSIONS: Compared to healthy volunteers, patients with PLC had abnormal breath test findings that were consistent with the accelerated catabolism of alkanes and monomethylated alkanes. A predictive model employing nine of these VOCs exhibited sufficient sensitivity and specificity to be considered as a screen for lung cancer in a high-risk population such as adult smokers

Chromium(VI) [Cr(VI)] is a ubiquitous environmental and industrial contaminant. Cr(VI) exposure is strongly associated with a higher incidence of human lung cancer, but the mechanism of Cr(VI) carcinogenicity remains unclear. Cigarette smoking has been known as the prominent cause of lung cancer, and polycyclic aromatic hydrocarbons (PAHs), the major carcinogens in cigarette smoke, have been suggested as being responsible for the initiation and development of lung cancer. It has been reported that lung cancer from workers exposed to Cr(VI) has a high percentage of G to T transversion mutations in the non-transcribed strand of the p53 gene, a hallmark of PAH-induced mutation. Cr(VI) is a weak mutagen although it can induce a high percentage of G to T transversion mutations. These results raise the possibility that Cr(VI) may enhance PAH binding at the p53 gene in lung tissue. To test this possibility, we have determined the effect of Cr(VI) exposure on benzo[a]pyrene diol epoxides (BPDE)-DNA binding at total genomic DNA level and at the p53 gene in normal human lung fibroblast cells. We found that in lung cells Cr(VI) pre-exposure does not affect the BPDE-DNA binding at the total genomic DNA level or at exons 5, 6 and 9 of the p53 gene; however, it greatly enhances BPDE-DNA binding at exons 7 and 8 of the p53 gene, especially at mutational hotspots of lung cancer: codons 248, 273 and 282 of the p53 gene. No enhancement of BPDE-DNA binding in the p53 was observed when naked genomic DNA isolated from Cr(VI)-exposed cells was modified with BPDE in vitro. These results suggest that Cr(VI) exposure may enhance chromatin structure-dependent carcinogen-DNA binding. This effect may contribute to the synergism of Cr(VI) and BPDE on mutagenesis and cell transformation, and may also contribute to the higher incidence of lung cancer in Cr(VI)-exposed populations

Tuberculosis is the seventh leading cause of morbidity and mortality in the world, with eight million cases per year. Animal and human studies demonstrate an enrichment of CD4 cells at sites of disease, with a more favorable clinical course when there is a Th1 response with the presence of gamma interferon (IFN-gamma). We previously treated patients who had multidrug-resistant tuberculosis with recombinant IFN-gamma (rIFN-gamma) in aerosol form and were able to convert smear-positive cases to smear negative with 12 treatments over 1 month. We hypothesized that rIFN-gamma would induce signal transducer and activator of transcription (STAT) and interferon regulatory factor (IRF) binding activity in alveolar macrophages (AM). AM treated in vitro showed clear upregulation of STAT-1 and IRF-1 by rIFN-gamma. STAT-1 was not activated and IRF-1 was only weakly induced after 1 day of infection by Mycobacterium tuberculosis TN913. In bronchoalveolar lavage (BAL) cells obtained from 10 of 10 tuberculosis patients 10 +/- 2 days post-antituberculosis treatment, there was no detectable STAT-1 or IRF-1 DNA-binding activity. After 4 weeks of treatment with rIFN-gamma aerosol in addition to the antituberculosis drugs, 10 of 10 patients had increased STAT-1, IRF-1, and/or IRF-9 DNA-binding activity in BAL cells from lung segments shown radiographically to be involved and in those shown to be uninvolved. Symptoms and chest radiographs improved, and amounts of macrophage inflammatory cytokines and human immunodeficiency virus type 1 (HIV-1) viral loads (in five of five HIV-1-coinfected patients) declined in the second BAL specimens. rIFN-gamma aerosol induces signal transduction and gene expression in BAL cells and should be evaluated for efficacy in a randomized, controlled clinical trial