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Biomedical subjects

Jerome S Brody

Publications and source records attributed to Jerome S Brody.

11 recordsLinked to original sources
PubMed2006

State of the art. Chronic obstructive pulmonary disease, inflammation, and lung cancer.

Both lung cancer and chronic obstructive pulmonary disease (COPD) are associated with cigarette smoking, which, by generating reactive oxidant species, induces a chronic inflammatory state in the lung. Activation, particularly of nuclear factor-kappaB, occurs in both cancer and COPD, and expression of a number of genes is altered in both diseases. In lung cancer, DNA damage, lack of DNA repair, and genomic instability predominate, whereas matrix degradation, lack of repair, and an intense immune response predominate in COPD. The reasons for the different responses to a common inflammatory response induced by smoking remain to be determined, but likely lie in genetic polymorphisms in genes that regulate genome integrity in cancer and that regulate the immune response to tissue destruction in COPD.

DNA, Neoplasm↗
PubMed2005

SIEGE: Smoking Induced Epithelial Gene Expression Database.

The SIEGE (Smoking Induced Epithelial Gene Expression) database is a clinical resource for compiling and analyzing gene expression data from epithelial cells of the human intra-thoracic airway. This database supports a translational research study whose goal is to profile the changes in airway gene expression that are induced by cigarette smoke. RNA is isolated from airway epithelium obtained at bronchoscopy from current-, former- and never-smoker subjects, and hybridized to Affymetrix HG-U133A Genechips, which measure the level of expression of approximately 22,500 human transcripts. The microarray data generated along with relevant patient information is uploaded to SIEGE by study administrators using the database's web interface, found at http://pulm.bumc.bu.edu/siegeDB. PERL-coded scripts integrated with SIEGE perform various quality control functions including the processing, filtering and formatting of stored data. The R statistical package is used to import database expression values and execute a number of statistical analyses including t-tests, correlation coefficients and hierarchical clustering. Values from all statistical analyses can be queried through CGI-based tools and web forms found on the 'Search' section of the database website. Query results are embedded with graphical capabilities as well as with links to other databases containing valuable gene resources, including Entrez Gene, GO, Biocarta, GeneCards, dbSNP and the NCBI Map Viewer.

Databases, Genetic↗
PubMed2004

Gene expression profiling of human lung tissue from smokers with severe emphysema.

The mechanism by which inhaled smoke causes the anatomic lesions and physiologic impairment of chronic obstructive pulmonary disease remains unknown. We used high-density microarrays to measure gene expression in severely emphysematous lung tissue removed from smokers at lung volume reduction surgery (LVRS) and normal or mildly emphysematous lung tissue from smokers undergoing resection of pulmonary nodules. Class prediction algorithms identified 102 genes that accurately distinguished severe emphysema from non-/mildly emphysematous lung tissue. We also defined a number of genes whose expression levels correlated strongly with lung diffusion capacity for carbon monoxide and/or forced expiratory volume at 1 s. Genes related to oxidative stress, extracellular matrix synthesis, and inflammation were increased in severe emphysema, whereas expression of endothelium-related genes was decreased. To identify candidate genes that might be causally involved in the pathogenesis of emphysema, we linked gene expression profiles to chromosomal regions previously associated with chronic obstructive pulmonary disease in genome-wide linkage analyses. Unsupervised hierarchical clustering of the LVRS samples revealed distinct molecular subclasses of severe emphysema, with body mass index as the only clinical variable that differed between the groups. Class prediction models established a set of genes that predicted functional outcome at 6 mo after LVRS. Our findings suggest that the gene expression profiles from human emphysematous lung tissue may provide insight into pathogenesis, uncover novel molecular subclasses of disease, predict response to LVRS, and identify targets for therapeutic intervention.

Aged↗
PubMed2004

Effects of cigarette smoke on the human airway epithelial cell transcriptome.

Cigarette smoke is the major cause of lung cancer, the leading cause of cancer death, and of chronic obstructive pulmonary disease, the fourth leading cause of death in the United States. Using high-density gene expression arrays, we describe genes that are normally expressed in a subset of human airway epithelial cells obtained at bronchoscopy (the airway transcriptome), define how cigarette smoking alters the transcriptome, and detail the effects of variables, such as cumulative exposure, age, sex, and race, on cigarette smoke-induced changes in gene expression. We also determine which changes in gene expression are and are not reversible when smoking is discontinued. The persistent altered expression of a subset of genes in former smokers may explain the risk these individuals have for developing lung cancer long after they have discontinued smoking. The use of gene expression profiling to explore the normal biology of a specific subset of cells within a complex organ across a broad spectrum of healthy individuals and to define the reversible and irreversible genetic effects of cigarette smoke on human airway epithelial cells has not been previously reported.

Bronchi↗
PubMed2003

The heparan sulfate proteoglycan GPC3 is a potential lung tumor suppressor.

Recently, we used gene expression profiling of lung adenocarcinoma and paired normal tissue from smokers and nonsmokers to identify genes and molecular pathways associated with cigarette smoking and lung carcinogenesis. The gene encoding Glypican 3, a glycosylphosphatidylinositol-linked heparan sulfate proteoglycan, was decreased in lung adenocarcinoma. Within nonmalignant lung, GPC3 expression was decreased in smokers compared with nonsmokers; indicating that expression is associated with cigarette smoking. Microarray results were confirmed using an independent cohort of tumors and nonmalignant lung tissues. Immunohistochemical studies localized Glypican 3 protein expression to the apical surface of lung bronchiolar epithelial cells, potential cells of origin for adenocarcinoma. Northern blot analysis demonstrated expression was absent in all tested non-small cell lung carcinoma lines. Pharmacologic treatment of lung cell lines indicated that GPC3 expression was epigenetically silenced by promoter hypermethylation. Human lung carcinoma tumor cells ectopically expressing GPC3 demonstrated increased apoptosis response when exposed to etoposide and growth inhibition when implanted in nude mice. These findings suggest that GPC3 is a candidate lung tumor suppressor gene whose expression may be regulated by exposure to cigarette smoke and functions to modulate cellular response to exogenous damage.

Adenocarcinoma↗
PubMed2003

Gene expression in lung adenocarcinomas of smokers and nonsmokers.

Adenocarcinoma (AC) has become the most frequent type of lung cancer in men and women, and is the major form of lung cancer in nonsmokers. Our goal in this paper was to determine if AC in smokers and nonsmokers represents the same genetic disease. We compared gene expression profiles in resected samples of nonmalignant lung tissue and tumor tissue in six never-smokers with AC and in six smokers with AC, who were matched for clinical staging and histologic criteria of cell differentiation. Results were analyzed using a variety of bioinformatic tools. Four times as many genes changed expression in the transition from noninvolved lung to tumor in nonsmokers as in smokers, suggesting that AC in nonsmokers evolves locally, whereas AC in smokers evolves in a field of genetically altered tissue. There were some similarities in gene expression in smokers and nonsmokers, but many differences, suggesting different pathways of cell transformation and tumor formation. Gene expression in the noninvolved lungs of smokers differed from that of nonsmokers, and multidimensional scaling showed that noninvolved lungs of smokers groups with tumors rather than noninvolved lungs of nonsmokers. In addition, expression of a number of genes correlated with smoking intensity. Our findings, although limited by small sample size, suggest that additional studies comparing noninvolved to tumor tissue may identify pathogenetic mechanisms and therapeutic targets that differ in AC of smokers and nonsmokers.

Adenocarcinoma↗
PubMed2003

Patterns of allelic loss differ in lung adenocarcinomas of smokers and nonsmokers.

Cigarette smoking is the most important cause of lung cancer, however approximately 10% of patients with lung cancer have no history of smoking. While the molecular pathogenesis of smoking associated lung carcinogenesis is becoming well characterized, the pathogenesis of lung cancer in nonsmokers is not. We designed a study to examine the pathogenesis of adenocarcinoma in nonsmokers by determining if loss of heterozygosity (LOH) in tumors of nonsmokers differs from those of smokers. We evaluated six cases of primary adenocarcinoma in never smokers and six selected cases in smokers, matched by clinical and histological criteria. LOH in tumor DNA relative to nonmalignant lung DNA was determined at 52 microsatellites located on ten chromosomal loci. The extent of allelic loss in smokers, as measured by fractional allelic loss (FAL), was compared with nonsmokers. LOH was more frequent in the tumors of nonsmokers than of smokers with mean FAL of 46% in nonsmokers and 28% in smokers (P<0.05). Increased LOH in nonsmokers was most pronounced at chromosomes: 3p, 8p, 9p, 10p, and 18q. Since this study compared allelic loss between lung and tumor-bearing lung, less frequent LOH in smokers' tumors can be interpreted to suggest LOH was already present in the nonmalignant lung of smokers and fewer additional instances of allelic loss were present in the tumors of smokers. Our results suggest that the early steps of lung carcinogenesis differ in nonsmokers compared with smokers. In addition, the chromosomal sites of LOH may identify genes important for lung carcinogenesis in nonsmokers.

Adenocarcinoma↗