Biomedical subjects

Alan Ho

Publications and source records attributed to Alan Ho.

5 recordsLinked to original sources

PubMed2006

PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity.

The objective was to determine PON1 status as a predictor for organophosphorus insecticide sensitivity in a cohort of Latina mothers and newborns from the Salinas Valley, California, an area with high levels of organophosphorus insecticide use. PON1 status was established for 130 pregnant Latina women and their newborns using a high-throughput two substrate activity/analysis method which plots rates of diazoxon (DZO) hydrolysis against rates of paraoxon (PO) hydrolysis. Arylesterase activity (AREase) was determined using phenylacetate as a substrate, allowing comparison of PON1 levels across PON1192 genotypes in mothers and children. Phenylacetate hydrolysis is not affected by the Q192R polymorphism. Among newborns, levels of PON1 (AREase) varied by 26-fold (4.3-110.7 U/ml) and among mothers by 14-fold (19.8-281.4 U/ml). On average, children's PON1 levels were four-fold lower than the mothers' PON1 levels (P<0.001). Average PON1 levels in newborns were comparable with reported hPON1 levels in transgenic mice expressing human PON1Q192 or PON1R192, allowing for prediction of relative sensitivity to chlorpyrifos oxon (CPO) and DZO. The predicted range of variability in sensitivity of mothers and children in the same Latino cohort was 65-fold for DZO and 131 to 164-fold for CPO. Overall, these findings indicate that many of the newborns and some of the mothers in this cohort would be more susceptible to the adverse effects of specific organophosphorus pesticide exposure due to their PON1 status. Of particular concern are exposures of pregnant mothers and newborns with low PON1 status.

Agriculture↗

PubMed2006

Regulation of late G1/S phase transition and APC Cdh1 by reactive oxygen species.

Proliferating cells have a higher metabolic rate than quiescent cells. To investigate the role of metabolism in cell cycle progression, we examined cell size, mitochondrial mass, and reactive oxygen species (ROS) levels in highly synchronized cell populations progressing from early G1 to S phase. We found that ROS steadily increased, compared to cell size and mitochondrial mass, through the cell cycle. Since ROS has been shown to influence cell proliferation and transformation, we hypothesized that ROS could contribute to cell cycle progression. Antioxidant treatment of cells induced a late-G1-phase cell cycle arrest characterized by continued cellular growth, active cyclin D-Cdk4/6 and active cyclin E-Cdk2 kinases, and inactive hyperphosphorylated pRb. However, antioxidant-treated cells failed to accumulate cyclin A protein, a requisite step for initiation of DNA synthesis. Further examination revealed that cyclin A continued to be ubiquitinated by the anaphase promoting complex (APC) and to be degraded by the proteasome. This antioxidant arrest could be rescued by overexpression of Emi1, an APC inhibitor. These observations reveal an intrinsic late-G1-phase checkpoint, after transition across the growth factor-dependent G1 restriction point, that links increased steady-state levels of endogenous ROS and cell cycle progression through continued activity of APC in association with Cdh1.

Anaphase-Promoting Complex-Cyclosome↗

PubMed2005

Molecular epidemiology biomarkers--sample collection and processing considerations.

Biomarker studies require processing and storage of numerous biological samples with the goals of obtaining a large amount of information and minimizing future research costs. An efficient study design includes provisions for processing of the original samples, such as cryopreservation, DNA isolation, and preparation of specimens for exposure assessment. Use of standard, two-dimensional and nanobarcodes and customized electronic databases assure efficient management of large sample collections and tracking results of data analyses. Standard operating procedures and quality control plans help to protect sample quality and to assure validity of the biomarker data. Specific state, federal and international regulations are in place regarding research with human samples, governing areas including custody, safety of handling, and transport of human samples. Appropriate informed consent must be obtained from the study subjects prior to sample collection and confidentiality of results maintained. Finally, examples of three biorepositories of different scale (European Cancer Study, National Cancer Institute and School of Public Health Biorepository, University of California, Berkeley) are used to illustrate challenges faced by investigators and the ways to overcome them. New software and biorepository technologies are being developed by many companies that will help to bring biological banking to a new level required by molecular epidemiology of the 21st century.

Automation↗

PubMed2003

Activation of p53 by oxidative stress involves platelet-derived growth factor-beta receptor-mediated ataxia telangiectasia mutated (ATM) kinase activation.

Phosphorylation of the p53 tumor suppressor protein is a critical event in the up-regulation and activation of p53 during cellular stress. In this study, we characterized the signaling pathway linking oxidative stress to p53 through the platelet-derived growth factor beta (PDGF beta) receptor and the ataxia telangiectasia mutated (ATM) kinase. In response to H2O2, we observed phosphorylation of p53 specifically at serine 15, but not serine 9, 20, or 392. Phosphorylation of Ser-15 was correlated with enhanced induction and functional activation of p53 manifest as transcription of the p53 target p21CIP/WAF. We found that H2O2 induced phosphorylation of the PDGF beta receptor and increased ATM kinase activity, two events integral to p53 activation as either AG1433 (a PDGF beta receptor inhibitor) or caffeine (an ATM kinase inhibitor) inhibited Ser-15 phosphorylation. Similarly, p53 activation by H2O2 was inhibited by kinase-inactive forms of the PDGF beta receptor or ATM. Inhibition of ATM kinase had no effect on H2O2-induced PDGF beta receptor tyrosine phosphorylation, whereas PDGF beta receptor suppression with RNA interference impaired H2O2-induced ATM activation, indicating that ATM lies downstream to the PDGF beta receptor in this signaling cascade. Functionally, inhibition of the PDGF beta receptor abrogated the inhibition of cell proliferation, and promotion of apoptosis due to H2O2 treatment. Thus, these data link PDGF beta receptor transactivation to H2O2-induced p53 phosphorylation and suggest a functional role for growth factor receptors in modulation of p53 function.

3T3 Cells↗

PubMed2002

Regulation of G(1) cell-cycle progression by oncogenes and tumor suppressor genes.

Progression of resting quiescent G(0) cells into early G(1) and transition across the restriction point are highly regulated processes. Mutation of proto-oncogenes and tumor suppressor genes regulating these transitions are targeted during oncogenesis. Recent work has underscored the importance of the G(0) to early G(1) transition and metabolism to neoplastic cells.

Animals↗