Browsing by Author "Zhang, W."

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    HINCUTs in cancer: hypoxia-induced noncoding ultraconserved transcripts
    (Nature Publishing Group, 2013-12) Ferdin, J.; Nishida, N.; Wu, X.; Nicoloso, M. S.; Shah, M. Y.; Devlin, C.; Ling, H.; Shimizu, M.; Kumar, K.; Cortez, M. A.; Ferracin, M.; Bi, Y.; Yang, D.; Czerniak, B.; Zhang, W.; Schmittgen, T. D.; Voorhoeve, M. P.; Reginato, M. J.; Negrini, M.; Davuluri, R. V.; Kunej, T.; Ivan, M.; Calin, G. A.; Department of Medicine, IU School of Medicine
    Recent data have linked hypoxia, a classic feature of the tumor microenvironment, to the function of specific microRNAs (miRNAs) however, whether hypoxia affects other types of noncoding transcripts is currently unknown. Starting from a genome-wide expression profiling, we demonstrate for the first time a functional link between oxygen deprivation and the modulation of long noncoding transcripts from ultraconserved regions, termed transcribed-ultraconserved regions (T-UCRs). Interestingly, several hypoxia-upregulated T-UCRs, henceforth named ‘hypoxia-induced noncoding ultraconserved transcripts' (HINCUTs), are also overexpressed in clinical samples from colon cancer patients. We show that these T-UCRs are predominantly nuclear and that the hypoxia-inducible factor (HIF) is at least partly responsible for the induction of several members of this group. One specific HINCUT, uc.475 (or HINCUT-1) is part of a retained intron of the host protein-coding gene, O-linked N-acetylglucosamine transferase, which is overexpressed in epithelial cancer types. Consistent with the hypothesis that T-UCRs have important function in tumor formation, HINCUT-1 supports cell proliferation specifically under hypoxic conditions and may be critical for optimal O-GlcNAcylation of proteins when oxygen tension is limiting. Our data gives a first glimpse of a novel functional hypoxic network comprising protein-coding transcripts and noncoding RNAs (ncRNAs) from the T-UCRs category.
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    Nonlinear Population Pharmacokinetics of Sirolimus in Patients With Advanced Cancer
    (Wiley, 2012-12-05) Wu, K.; Cohen, E. E. W.; House, L. K.; Ramírez, J.; Zhang, W.; Ratain, M. J.; Bies, R. R.; Medicine, School of Medicine
    Sirolimus, the prototypical inhibitor of the mammalian target of rapamycin, has substantial antitumor activity. In this study, sirolimus showed nonlinear pharmacokinetic characteristics over a wide dose range (from 1 to 60 mg/week). The objective of this study was to develop a population pharmacokinetic (PopPK) model to describe the nonlinearity of sirolimus. Whole blood concentration data, obtained from four phase I clinical trials, were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach. The influence of potential covariates was evaluated. Model robustness was assessed using nonparametric bootstrap and visual predictive check approaches. The data were well described by a two-compartment model incorporating a saturable Michaelis-Menten kinetic absorption process. A covariate analysis identified hematocrit as influencing the oral clearance of sirolimus. The visual predictive check indicated that the final pharmacokinetic model adequately predicted observed concentrations. The pharmacokinetics of sirolimus, based on whole blood concentrations, appears to be nonlinear due to saturable absorption.