Biomedical subjects

David A Weaver

Publications and source records attributed to David A Weaver.

4 recordsLinked to original sources

PubMed2005

Gene expression profiling of the left ventricles in a rat model of intrinsic aerobic running capacity.

Our previous work found DA rats superior for intrinsic aerobic running capacity (ARC) and several cardiac function indexes compared with Copenhagen (COP) rats, and identified ARC quantitative trait loci (QTLs) on rat chromosomes 16 (RNO16) and 3 (RNO3). The purpose of this study was to use these inbred rat strains as a genetic substrate for differential cardiac gene expression to identify candidate genes for the observed ARC QTLs. RNA expression was examined globally in left ventricles of 15-wk-old DA, F1(COP x DA), and COP rats using microarrays to identify candidate genes for ARC QTLs. We identified 199 differentially expressed probe sets and determined their chromosomal locations. Six differentially expressed genes and expressed sequence tags (ESTs) mapped near ARC QTL regions, including PDZ and LIM domain 3 (Pdlim3). Differential expression of these genes/ESTs was confirmed by quantitative RT-PCR. The Ingenuity Pathways program identified 13 biological networks containing 50 (of the 199) differentially expressed probe sets and 85 additional genes. Four of these eighty-five genes mapped near ARC QTL-containing regions, including insulin receptor substrate 2 (Irs2) and acyl-CoA synthetase long-chain family member 1 (Acsl1). Most (148/199) differentially expressed probe sets showed left ventricular expression patterns consistent with the alleles exerting additive effects, i.e., F1(COP x DA) rat RNA expression was intermediate between DA and COP rats. This study identified several potential ARC QTL candidate genes and molecular networks, one of them related to energy expenditure involving Pik3r1 mRNA expression that may, in part, explain the observed strain differences in ARC and cardiac performance.

Animals↗

PubMed2005

ABCC5, ERCC2, XPA and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines.

BACKGROUND: Although 40-50% of non-small cell lung cancer (NSCLC) tumors respond to cisplatin chemotherapy, there currently is no way to prospectively identify potential responders. The purpose of this study was to determine whether transcript abundance (TA) levels of twelve selected DNA repair or multi-drug resistance genes (LIG1, ERCC2, ERCC3, DDIT3, ABCC1, ABCC4, ABCC5, ABCC10, GTF2H2, XPA, XPC and XRCC1) were associated with cisplatin chemoresistance and could therefore contribute to the development of a predictive marker. Standardized RT (StaRT)-PCR, was employed to assess these genes in a set of NSCLC cell lines with a previously published range of sensitivity to cisplatin. Data were obtained in the form of target gene molecules relative to 106 beta-actin (ACTB) molecules. To cancel the effect of ACTB variation among the different cell lines individual gene expression values were incorporated into ratios of one gene to another. Each two-gene ratio was compared as a single variable to chemoresistance for each of eight NSCLC cell lines using multiple regression. In an effort to validate these results, six additional lines then were evaluated. RESULTS: Following validation, single variable models best correlated with chemoresistance (p < 0.001), were ERCC2/XPC, ABCC5/GTF2H2, ERCC2/GTF2H2, XPA/XPC and XRCC1/XPC. All single variable models were examined hierarchically to achieve two variable models. The two variable model with the highest correlation was (ABCC5/GTF2H2, ERCC2/GTF2H2) with an R2 value of 0.96 (p < 0.001). CONCLUSION: These results provide markers suitable for assessment of small fine needle aspirate biopsies in an effort to prospectively identify cisplatin resistant tumors.

Carcinoma, Non-Small-Cell Lung↗

PubMed2005

Social security: a program and policy history.

Many of the federal and state programs that provide income security to U.S. families have their roots in the Social Security Act (the Act) of 1935. This Act provided for unemployment insurance, old-age insurance, and means-tested welfare programs. The Great Depression was clearly a catalyst for the Social Security Act of 1935, and some of its provisions--notably the means-tested programs--were intended to offer immediate relief to families. However, the old-age insurance program-the precursor to today's Old-Age, Survivors, and Disability Insurance, or Social Security, program-was not designed specifically to deal with the economic crisis of that era. Indeed, monthly benefit payments, under the original Act, were not scheduled to begin until 1942. In addition, from the beginning, the Social Security program has embodied social insurance principles that were widely discussed even before the onset of the Great Depression. The first four decades of the Social Security program were, in general, ones of expansion. In fact, the program was expanded even before it became truly operational. In 1939, amendments added child, spouse, and survivor benefits to the retirement benefits authorized by the 1935 Act. Those amendments also allowed for monthly benefits to begin in 1940. Although the program was not changed substantially during the war years and the initial postwar period, the 1950s were a transformational decade in the program's history: benefit amounts were increased substantially, coverage under the program became close to universal, and a new disability insurance benefit was offered. The 1960s witnessed additional growth in Social Security, but the most important development in social insurance occurred in health insurance, with the creation of the Medicare program in 1965. Legislative actions in the 1970s had profound effects on the Social Security program and, indeed, set the stage for many of today's reform debates. Large benefit increases, a new benefit formula that was erroneously generous, and other changes in the early 1970s created a situation in which annual program costs, as a share of gross domestic product, increased during a 12-year period from about 3 percent to 5 percent. In 1977, amendments to the Act corrected the flawed benefit formula and made other changes in the financing of the system to shore up the program. Thus, the 1970s represent a watershed in the program's history-program growth gave way to increasing concerns about the program's finances. Those concerns were reflected in the amendments to the Act in 1983, which were the last major changes to the program. These amendments, based largely on recommendations from a commission chaired by Alan Greenspan, adjusted benefits and taxes to address pressing near-term financing problems faced by the system. Although the Greenspan Commission focused to a large extent on short-range issues, the resulting reforms have generated large surpluses in the program and the buildup of a substantial trust fund. However, the looming retirement of the baby boomers and several other demographic factors will, according to projections, result in the exhaustion of the trust fund by 2042.

Adult↗

PubMed2002

Transcript profiling of enzymes involved in detoxification of xenobiotics and reactive oxygen in human normal and simian virus 40 T antigen-immortalized oral keratinocytes.

The metabolic detoxification capacity may critically regulate the susceptibility of human tissues to cancer development. We used standardized and quantitative, reverse transcription-polymerase chain reaction (StaRT-PCR) and microarray chip techniques to analyze transcript levels of multiple detoxification enzymes in cultured normal human oral keratinocytes (NOK) and the Siman virus 40 T antigen-immortalized oral keratinocyte line SVpgC2a, viewing the latter as a model of a benign tumor state. With good agreement between the 2 methodologies, NOK and SVpgC2a were found to express transcripts for cytochrome P450 enzymes (CYPs), factors related to CYP induction and enzymes involved in conjugation reactions or detoxification of reactive oxygen. The cell types expressed similar levels of CYP 2B6/7, CYP 2E1, P450 oxidoreductase, the aryl hydrocarbon receptor nuclear translocator, sulfotransferase 1A1, sulfotransferase 1A3, epoxide hydrolase, glutathione S-transferase M3, glutathione S-transferase pi and catalase, superoxide dismutase 1, glutathione peroxidase 1 and glutathione peroxidase 3. In contrast, SVpgC2a exhibited comparatively higher levels of CYP1A1, 1B1, aryl hydrocarbon receptor, glutathione S-transferase M1, 2, 4, 5, glutathione S-transferase theta 1 and superoxide dismutase 2 and comparatively lower levels of UDP glycosyltransferase 2 and microsomal glutathione S-transferase 1. Some transcripts, e.g., CYP 2A6/7, were not detected by either standard, non quantitative RT-PCR or the above methods, whereas others were barely quantifiable by StaRT-PCR, i.e., were present at 1-10 molecules/10(6) molecules of actin. Overall, the expression analysis demonstrated presence of mRNA for multiple enzymes involved in foreign compound metabolism and detoxification pathways, including several enzymes not previously reported for oral epithelium. Generally, the comparison of NOK from 2 individuals indicated relatively similar transcript levels of these enzymes. In contrast, differences between NOK and SVpgC2a, e.g., for CYP1B1, may reflect alteration caused by immortalization and aid identification of early stage tumor markers in oral epithelium.

Antigens, Polyomavirus Transforming↗