Biomedical subjects

William B Mattes

Publications and source records attributed to William B Mattes.

6 recordsLinked to original sources

PubMed2006

Cross-species comparative toxicogenomics as an aid to safety assessment.

Cross-species comparative toxicogenomics has the potential for improving the understanding of the different responses of animal models to toxicants at a molecular level. This understanding could then lead to a more accurate extrapolation of the risk posed by these toxicants to humans. Cross-species comparative studies have been carried out at the genomic sequence level and using microarrays to examine changes in global mRNA profiles. However, these studies face considerable bioinformatic challenges in terms of identifying which genes are truly orthologous across species. The resources to analyse such studies, in the context of such orthologues, beg improvement. Finally, the experimental design of such studies needs to be carefully considered to make their results fully interpretable. These issues are discussed, along with the current state-of-the-art cross-species comparative toxicogenomics in this review.

Animals↗

PubMed2004

Gene expression analysis points to hemostasis in livers of rats cotreated with lipopolysaccharide and ranitidine.

Studies in rats have demonstrated that modest underlying inflammation can precipitate idiosyncratic-like liver injury from the histamine 2-receptor antagonist, ranitidine (RAN). Coadministration to rats of nonhepatotoxic doses of RAN and the inflammagen, bacterial lipopolysaccharide (LPS), results in hepatocellular injury. We tested the hypothesis that hepatic gene expression changes could be distinguished among vehicle-, LPS-, RAN- and LPS/RAN-treated rats before the onset of significant liver injury in the LPS/RAN-treated rats (i.e., 3 h post-treatment). Rats were treated with LPS (44 x 10(6) EU/kg, i.v.) or its vehicle, then two hours later with RAN (30 mg/kg, i.v.) or its vehicle. They were killed 3 h after RAN treatment, and liver samples were taken for evaluation of liver injury and RNA isolation. Hepatic parenchymal cell injury, as estimated by increases in serum alanine aminotransferase (ALT) activity, was not significant at this time. Hierarchal clustering of gene expression data from Affymetrix U34A rat genome array grouped animals according to treatment. Relative to treatment with vehicle alone, treatment with RAN and/or LPS altered hepatic expression of numerous genes, including ones encoding products involved in inflammation, hypoxia, and cell death. Some were enhanced synergistically by LPS/RAN cotreatment. Real-time PCR confirmed robust changes in expression of B-cell translocation gene 2, early growth response-1, and plasminogen-activator inhibitor-1 (PAI-1) in cotreated rats. The increase in PAI-1 mRNA was reflected in an increase in serum PAI-1 protein concentration in LPS/RAN-treated rats. Consistent with the antifibrinolytic activity of PAI-1, significant fibrin deposition occurred only in livers of LPS/RAN-treated rats. The results suggest the possibility that expression of PAI-1 promotes fibrin deposition in liver sinusoids of LPS/RAN-treated rats and are consistent with the development of local ischemia and consequent tissue hypoxia.

Animals↗

PubMed2004

Effects of an E-cadherin-derived peptide on the gene expression of Caco-2 cells.

PURPOSE: The goal of this study was to determine the effects of exposure to an HAV peptide (Ac-SHAVSS-NH2) on the protein and gene expression in Caco-2 cells, a model for the intestinal mucosa. METHODS: Caco-2 cells were incubated with either 100 or 500 microM of the hexapeptide then evaluated over a 48-h time period. RESULTS: Cell detachment from the monolayer was seen only after 48 h of exposure to the peptide, with the greatest effects occurring with a peptide concentration of 500 microM. Total protein expression of E-cadherin showed a decrease of nearly 20% at the 24-h time point for each concentration examined, whereas no significant changes were detected at the other time points studied. Short term exposure to a 500 microM solution of Ac-SHAVSS-NH2 caused few changes in gene expression as determined by Affymetrix GeneChip microarrays; however, longer exposure periods produced numerous changes in the treated cells. The variations in mRNA expression indicate that this HAV peptide has an effect in the E-cadherin signaling pathways. The greatest increases in mRNA expression were found in genes regulating excretion or degradation of the peptide. CONCLUSIONS: This work suggests that this HAV peptide produces effects that reach beyond modulation of adhesion.

Actins↗

PubMed2004

Database development in toxicogenomics: issues and efforts.

The marriage of toxicology and genomics has created not only opportunities but also novel informatics challenges. As with the larger field of gene expression analysis, toxicogenomics faces the problems of probe annotation and data comparison across different array platforms. Toxicogenomics studies are generally built on standard toxicology studies generating biological end point data, and as such, one goal of toxicogenomics is to detect relationships between changes in gene expression and in those biological parameters. These challenges are best addressed through data collection into a well-designed toxicogenomics database. A successful publicly accessible toxicogenomics database will serve as a repository for data sharing and as a resource for analysis, data mining, and discussion. It will offer a vehicle for harmonizing nomenclature and analytical approaches and serve as a reference for regulatory organizations to evaluate toxicogenomics data submitted as part of registrations. Such a database would capture the experimental context of in vivo studies with great fidelity such that the dynamics of the dose response could be probed statistically with confidence. This review presents the collaborative efforts between the European Molecular Biology Laboratory-European Bioinformatics Institute ArrayExpress, the International Life Sciences Institute Health and Environmental Science Institute, and the National Institute of Environmental Health Sciences National Center for Toxigenomics Chemical Effects in Biological Systems knowledge base. The goal of this collaboration is to establish public infrastructure on an international scale and examine other developments aimed at establishing toxicogenomics databases. In this review we discuss several issues common to such databases: the requirement for identifying minimal descriptors to represent the experiment, the demand for standardizing data storage and exchange formats, the challenge of creating standardized nomenclature and ontologies to describe biological data, the technical problems involved in data upload, the necessity of defining parameters that assess and record data quality, and the development of standardized analytical approaches.

Animals↗

PubMed2004

Annotation and cross-indexing of array elements on multiple platforms.

On the surface, transcript profiling using microarrays seems to offer a way of looking at the global response of the cell to perturbation, with a focus on changes in gene expression. The difficulty, however, is that the response of a particular gene is actually measured on the array by an element that is a short, defined nucleic acid sequence. Sequences that map back to the same genetic locus may actually be given different names and descriptions when they are deposited in public sequence databases; when such sequences are used in microarray construction, elements that monitor the same genetic locus may have different names and descriptions. The algorithm described here uses a hierarchical approach to assign a single best annotation to the elements in a given microarray in such a fashion that elements from one microarray platform may be cross-indexed with those of another. The algorithm relies on the nucleic acid accession number for a given array element, and uses that to retrieve annotation from the most recent versions of LocusLink and UniGene. Both database resources are searched, with a priority being given to annotation derived from the curated LocusLink database. In lieu of annotation found in these databases, the default GenBank annotation is used. As a final outcome, a cross-chip identifier is generated that may be used to cross-index array elements. The program is available as a practical extraction and report language (Perl) script that can run under any Perl interpreter.

Algorithms↗

PubMedDate not supplied

Modulation of cell adhesion molecules in various epithelial cell lines after treatment with PP2.

Regulation and expression of E-cadherin and other adhesion molecules were evaluated after exposure to a selective inhibitor of the Src family of tyrosine kinases and inducer of E-cadherin, PP2. E-cadherin is located within the intercellular junction, and it is involved in the management of paracellular permeability of various epithelial barriers in the body. Epithelial cell lines HCT-116, HT29, Caco-2, LS174T, and ARPE-19 were examined for morphological, functional, protein, and mRNA changes following 20 microM PP2 treatment. PP2 treatment caused cell clustering in Caco-2, HT29, and HCT-116 cells. E-cadherin also redistributed to the points of cell contact in Caco-2 cells. These changes suggest increased E-cadherin-dependent cell adhesion. Studies evaluating transepithelial electrical resistance, an established measurement of paracellular permeability, displayed increases in resistance for the Caco-2 cells following PP2 treatment, which correlates with our microscopy data. In addition, E-cadherin protein levels increased for all cells except HCT-116. ARPE-19 cells did not express E-cadherin at the protein or mRNA level. Expression of adhesion molecules varied for the cell lines, and only Claudin 3 mRNA expression was significantly increased in the three intestinal cell lines treated with PP2. Overall, our data suggest that E-cadherin is positively regulated by inhibition of Src tyrosine kinases at the functional and protein expression levels within these epithelial cell lines.

Adenocarcinoma↗