Browsing by Author "Huang, Tim"

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    A dynamic time order network for time-series gene expression data analysis
    (Springer Nature, 2012) Zhang, Pengyue; Mourad, Raphaël; Xiang, Yang; Huang, Kun; Huang, Tim; Nephew, Kenneth; Liu, Yunlong; Li, Lang; Center for Computational Biology and Bioinformatics, School of Medicine
    Background: Typical analysis of time-series gene expression data such as clustering or graphical models cannot distinguish between early and later drug responsive gene targets in cancer cells. However, these genes would represent good candidate biomarkers. Results: We propose a new model - the dynamic time order network - to distinguish and connect early and later drug responsive gene targets. This network is constructed based on an integrated differential equation. Spline regression is applied for an accurate modeling of the time variation of gene expressions. Then a likelihood ratio test is implemented to infer the time order of any gene expression pair. One application of the model is the discovery of estrogen response biomarkers. For this purpose, we focused on genes whose responses are late when the breast cancer cells are treated with estradiol (E2). Conclusions: Our approach has been validated by successfully finding time order relations between genes of the cell cycle system. More notably, we found late response genes potentially interesting as biomarkers of E2 treatment.
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    Epigenetic Resensitization to Platinum in Ovarian Cancer
    (American Association for Cancer Research, 2012) Matei, Daniela; Fang, Fang; Shen, Changyu; Schilder, Jeanne; Arnold, Alesha; Zeng, Yan; Berry, William A.; Huang, Tim; Nephew, Kenneth P.; Obstetrics and Gynecology, School of Medicine
    Preclinical studies have shown that hypomethylating agents reverse platinum resistance in ovarian cancer. In this phase II clinical trial, based upon the results of our phase I dose defining study, we tested the clinical and biologic activity of low-dose decitabine administered before carboplatin in platinum-resistant ovarian cancer patients. Among 17 patients with heavily pretreated and platinum-resistant ovarian cancer, the regimen induced a 35% objective response rate (RR) and progression-free survival (PFS) of 10.2 months, with nine patients (53%) free of progression at 6 months. Global and gene-specific DNA demethylation was achieved in peripheral blood mononuclear cells and tumors. The number of demethylated genes was greater (P < 0.05) in tumor biopsies from patients with PFS more than 6 versus less than 6 months (311 vs. 244 genes). Pathways enriched at baseline in tumors from patients with PFS more than 6 months included cytokine-cytokine receptor interactions, drug transporters, and mitogen-activated protein kinase, toll-like receptor and Jak-STAT signaling pathways, whereas those enriched in demethylated genes after decitabine treatment included pathways involved in cancer, Wnt signaling, and apoptosis (P < 0.01). Demethylation of MLH1, RASSF1A, HOXA10, and HOXA11 in tumors positively correlated with PFS (P < 0.05). Together, the results of this study suggest that low-dose decitabine altered DNA methylation of genes and cancer pathways, restoring sensitivity to carboplatin in patients with heavily pretreated ovarian cancer and resulting in a high RR and prolonged PFS.
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    NF-κB-HOTAIR axis links DNA damage response, chemoresistance and cellular senescence in ovarian cancer.
    (Nature, 2016-10-13) Özeş, Ali R.; Miller, David F.; Özeş, Osman N.; Fang, Fang; Liu, Yunlong; Matei, Daniela; Huang, Tim; Nephew, Kenneth P.; Department of Cellular and Integrative Physiology, IU School of Medicine
    The transcription factor nuclear factor kappa B (NF-κB) and the long non-coding RNA (lncRNA) HOTAIR (HOX transcript antisense RNA) play diverse functional roles in cancer. In this study, we show that upregulation of HOTAIR induced platinum resistance in ovarian cancer, and increased HOTAIR levels were observed in recurrent platinum-resistant ovarian tumors vs. primary ovarian tumors. To investigate the role of HOTAIR during DNA damage induced by platinum, we monitored double-strand breaks and show that HOTAIR expression results in sustained activation of DNA damage response after platinum treatment. We demonstrate that ectopic expression of HOTAIR induces NF-κB activation during DNA damage response and MMP-9 and IL-6 expression, both key NF-κB target genes. We show that HOTAIR regulates activation of NF-κB by decreasing Iκ-Bα (NF-κB inhibitor) and establish that by inducing prolonged NF-κB activation and expression of NF-κB target genes during DNA damage, HOTAIR plays a critical role in cellular senescence and platinum sensitivity. Our findings suggest that a