LeRoy, E. C., Moore, J. H., Hu, C., Martínez, M. E., Lance, P., Duggan, D., & Thompson, P. A. (2011). Genes in the insulin and insulin-like growth factor pathway and odds of metachronous colorectal neoplasia. Human genetics, 129(5), 503-12.
Insulin and insulin-like growth factor (IGF) genes are implicated in colorectal carcinogenesis. Gene-by-gene interactions that influence the insulin/IGF pathways were hypothesized as modifiers of colorectal neoplasia risk. We built a classification tree to detect interactions in 18 IGF and insulin pathway-related genes and metachronous colorectal neoplasia among 1,439 subjects pooled from two chemoprevention trials. The probability of colorectal neoplasia was greatest (71.8%) among carriers of any A allele for rs7166348 (IGF1R) and AA genotype for rs1823023 (PIK3R1). In contrast, carriers of any A at rs7166348 (IGF1R), any G for the PIK3R1 variant, and AA for rs10426094 (INSR) had the lowest probability (14.3%). Logistic regression modeling showed that any A at rs7166348 (IGF1R) with the AA genotype at rs1823023 (PIK3R1) conferred the highest odds of colorectal neoplasia (OR 3.7; 95% CI 2.2-6.5), compared with carriage of GG at rs7166348 (IGF1R). Conversely, any A at rs7166348 (IGFR1), any G allele at rs1823023 (PIK3R1), and the AA genotype at rs10426094 (INSR) conferred the lowest odds (OR 0.22; 95% CI 0.07-0.66). Stratifying the analysis by parent study and intervention arm showed highly consistent trends in direction and magnitude of associations, with preliminary evidence of genotype effects on measured IGF-1 levels in a subgroup of subjects. These results were compared to those from multifactor dimensionality reduction, which identified different single nucleotide polymorphisms in the same genes (INSR and IGF1R) as effect modifiers for colorectal neoplasia. These results support a role for genetic interactions in the insulin/IGF pathway genes in colorectal neoplasia risk.
Hu, C., Harber, P., & Su, J. (2016). Predicting future protection of respirator users: Statistical approaches and practical implications. Journal of occupational and environmental hygiene, 13(5), 393-400.
The purpose of this article is to describe a statistical approach for predicting a respirator user's fit factor in the future based upon results from initial tests. A statistical prediction model was developed based upon joint distribution of multiple fit factor measurements over time obtained from linear mixed effect models. The model accounts for within-subject correlation as well as short-term (within one day) and longer-term variability. As an example of applying this approach, model parameters were estimated from a research study in which volunteers were trained by three different modalities to use one of two types of respirators. They underwent two quantitative fit tests at the initial session and two on the same day approximately six months later. The fitted models demonstrated correlation and gave the estimated distribution of future fit test results conditional on past results for an individual worker. This approach can be applied to establishing a criterion value for passing an initial fit test to provide reasonable likelihood that a worker will be adequately protected in the future; and to optimizing the repeat fit factor test intervals individually for each user for cost-effective testing.
Dickinson, S. E., Olson, E. R., Zhang, J., Cooper, S. J., Melton, T., Criswell, P. J., Casanova, A., Dong, Z., Hu, C., Saboda, K., Jacobs, E. T., Alberts, D. S., & Bowden, G. T. (2011). p38 MAP kinase plays a functional role in UVB-induced mouse skin carcinogenesis. Molecular carcinogenesis, 50(6), 469-78.
UVB irradiation of epidermal keratinocytes results in the activation of the p38 mitogen-activated protein kinase (MAPK) pathway and subsequently activator protein-1 (AP-1) transcription factor activation and cyclooxygenase-2 (COX-2) expression. AP-1 and COX-2 have been shown to play functional roles in UVB-induced mouse skin carcinogenesis. In this study, the experimental approach was to express a dominant negative p38α MAPK (p38DN) in the epidermis of SKH-1 hairless mice and assess UVB-induced AP-1 activation, COX-2 expression, and the skin carcinogenesis response in these mice compared to wild-type littermates. We observed a significant inhibition of UVB-induced AP-1 activation and COX-2 expression in p38DN transgenic mice, leading to a significant reduction of UVB-induced tumor number and growth compared to wild-type littermates in a chronic UVB skin carcinogenesis model. A potential mechanism for this reduction in tumor number and growth rate is an inhibition of chronic epidermal proliferation, observed as reduced Ki-67 staining in p38DN mice compared to wild-type. Although we detected no difference in chronic apoptotic rates between transgenic and nontransgenic mice, analysis of acutely irradiated mice demonstrated that expression of the p38DN transgene significantly inhibited UVB-induced apoptosis of keratinocytes. These results counter the concerns that inhibition of p38 MAPK in a chronic situation could compromise the ability of the skin to eliminate potentially tumorigenic cells. Our data indicate that p38 MAPK is a good target for pharmacological intervention for UV-induced skin cancer in patients with sun damaged skin, and suggest that inhibition of p38 signaling reduces skin carcinogenesis by inhibiting COX-2 expression and proliferation of UVB-irradiated cells.
Mirochnick, M., Best, B. M., Stek, A. M., Capparelli, E. V., Hu, C., Burchett, S. K., Rossi, S. S., Hawkins, E., Basar, M., Smith, E., Read, J. S., & , I. 1. (2011). Atazanavir pharmacokinetics with and without tenofovir during pregnancy. Journal of acquired immune deficiency syndromes (1999), 56(5), 412-9.
Few data are available describing atazanavir exposure during pregnancy, especially when used in combination with tenofovir, whose coadministration with atazanavir results in decreased atazanavir exposure.
Spaite, D. W., Bobrow, B. J., Gaither, J. B., & Hu, C. (2017). In reply. Annals of emergency medicine, 70(2), 263-264.
