Browsing by Author "Chen, Rui"

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    Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer.
    (J Biol Chem, 2017-01-13) Alexander, Peter B; Chen, Rui; Gong, Chang; Yuan, Lifeng; Jasper, Jeff S; Ding, Yi; Markowitz, Geoffrey J; Yang, Pengyuan; Xu, Xin; McDonnell, Donald P; Song, Erwei; Wang, Xiao-Fan
    Targeted inhibitors of the human epidermal growth factor receptor 2 (HER2), such as trastuzumab and lapatinib, are among the first examples of molecularly targeted cancer therapy and have proven largely effective for the treatment of HER2-positive breast cancers. However, approximately half of those patients either do not respond to these therapies or develop secondary resistance. Although a few signaling pathways have been implicated, a comprehensive understanding of mechanisms underlying HER2 inhibitor drug resistance is still lacking. To address this critical question, we undertook a concerted approach using patient expression data sets, HER2-positive cell lines, and tumor samples biopsied both before and after trastuzumab treatment. Together, these methods revealed that high expression and activation of a specific subset of receptor tyrosine kinases (RTKs) was strongly associated with poor clinical prognosis and the development of resistance. Mechanistically, these RTKs are capable of maintaining downstream signal transduction to promote tumor growth via the suppression of cellular senescence. Consequently, these findings provide the rationale for the design of therapeutic strategies for overcoming drug resistance in breast cancer via combinational inhibition of the limited number of targets from this specific subset of RTKs.
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    Essays on Financial Econometrics
    (2020) Chen, Rui

    This dissertation contains my research results on two topics of nancial econometrics.

    The rst topic is jump regression where the observation selection procedure can be

    viewed as the analogy of dimension reduction for the classical big "P" problem in

    statistics to the big "N" problem in nancial econometrics. The second topic is about

    estimation and testing of time series models for Value-at-Risk (VaR) and Expected

    Shortfall (ES), which is the average return on a risky asset conditional on the return

    being below some quantile of its distribution, namely its VaR.

    The rst chapter, which is joint work with Jia Li, Viktor Todorov and George

    Tauchen, develops an ecient mixed-scale estimator for jump regressions using highfrequency

    asset returns. A novel bootstrap procedure is proposed to make inference

    about our estimator, which has a non-standard asymptotic distribution that cannot

    be made asymptotically pivotal via studentization. The Monte Carlo analysis indicates

    good nite-sample performance of the general specication test and condence

    intervals based on the bootstrap. When the method is applied to a high-frequency

    panel of Dow stock prices together with the market index dened by the S&P 500

    index futures over the period 2007{2014, we observe remarkable temporal stability

    in the way that stocks react to market jumps.

    The second chapter is co-authored with Andrew J. Patton and Johanna F. Ziegel.

    We use recent results from statistical decision theory to overcome the problem of

    \elicitability" for ES by jointly modelling ES and VaR, and propose new time series

    models for these risk measures. Estimation and inference methods are provided for

    the proposed models and conrmed via simulation studies to have good nite-sample

    properties. We apply these models to daily returns on four international equity

    indices, and nd the proposed new ES-VaR models outperform forecasts based on

    iv

    GARCH or rolling window models.

    The third chapter is my single-authored paper which proposes a consistent speci-

    cation test of dynamic joint models for VaR and ES. To overcome the intractability

    problem of the asymptotic distribution of the test statistics under the null hypothesis,

    the subsampling approximation is used to get the asymptotic critical values. A

    Monte Carlo study shows that the proposed test has better empirical size and power

    performance in nite samples than other existing tests.

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    Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.
    (Genet Med, 2014-10) Enns, Gregory M; Shashi, Vandana; Bainbridge, Matthew; Gambello, Michael J; Zahir, Farah R; Bast, Thomas; Crimian, Rebecca; Schoch, Kelly; Platt, Julia; Cox, Rachel; Bernstein, Jonathan A; Scavina, Mena; Walter, Rhonda S; Bibb, Audrey; Jones, Melanie; Hegde, Madhuri; Graham, Brett H; Need, Anna C; Oviedo, Angelica; Schaaf, Christian P; Boyle, Sean; Butte, Atul J; Chen, Rui; Chen, Rong; Clark, Michael J; Haraksingh, Rajini; FORGE Canada Consortium; Cowan, Tina M; He, Ping; Langlois, Sylvie; Zoghbi, Huda Y; Snyder, Michael; Gibbs, Richard A; Freeze, Hudson H; Goldstein, David B
    PURPOSE: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1. METHODS: Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data. RESULTS: All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele. CONCLUSION: NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.
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    Synthetic lethality between HER2 and transaldolase in intrinsically resistant HER2-positive breast cancers.
    (Nature communications, 2018-10) Ding, Yi; Gong, Chang; Huang, De; Chen, Rui; Sui, Pinpin; Lin, Kevin H; Liang, Gehao; Yuan, Lifeng; Xiang, Handan; Chen, Junying; Yin, Tao; Alexander, Peter B; Wang, Qian-Fei; Song, Er-Wei; Li, Qi-Jing; Wood, Kris C; Wang, Xiao-Fan
    Intrinsic resistance to anti-HER2 therapy in breast cancer remains an obstacle in the clinic, limiting its efficacy. However, the biological basis for intrinsic resistance is poorly understood. Here we performed a CRISPR/Cas9-mediated loss-of-function genetic profiling and identified TALDO1, which encodes the rate-limiting transaldolase (TA) enzyme in the non-oxidative pentose phosphate pathway, as essential for cellular survival following pharmacological HER2 blockade. Suppression of TA increases cell susceptibility to HER2 inhibition in two intrinsically resistant breast cancer cell lines with HER2 amplification. Mechanistically, TA depletion combined with HER2 inhibition significantly reduces cellular NADPH levels, resulting in excessive ROS production and deficient lipid and nucleotide synthesis. Importantly, higher TA expression correlates with poor response to HER2 inhibition in a breast cancer patient cohort. Together, these results pinpoint TA as a novel metabolic enzyme possessing synthetic lethality with HER2 inhibition that can potentially be exploited as a biomarker or target for combination therapy.
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    UHRF1 is required for basal stem cell proliferation in response to airway injury.
    (Cell Discov, 2017) Xiang, Handan; Yuan, Lifeng; Gao, Xia; Alexander, Peter B; Lopez, Omar; Lau, Calvin; Ding, Yi; Chong, Mengyang; Sun, Tao; Chen, Rui; Liu, Si-Qi; Wu, Haiyang; Wan, Ying; Randell, Scott H; Li, Qi-Jing; Wang, Xiao-Fan
    Cellular senescence is a cell fate characterized by an irreversible cell cycle arrest, but the molecular mechanism underlying this senescence hallmark remains poorly understood. Through an unbiased search for novel senescence regulators in airway basal cells, we discovered that the epigenetic regulator ubiquitin-like with PHD and ring finger domain-containing protein 1 (UHRF1) is critical for regulating cell cycle progression. Upon injury, basal cells in the mouse airway rapidly induce the expression of UHRF1 in order to stimulate stem cell proliferation and tissue repair. Targeted depletion of Uhrf1 specifically in airway basal cells causes a profound defect in cell cycle progression. Consistently, cultured primary human basal cells lacking UHRF1 do not exhibit cell death or differentiation phenotypes but undergo a spontaneous program of senescence. Mechanistically, UHRF1 loss induces G1 cell cycle arrest by abrogating DNA replication factory formation as evidenced by loss of proliferating cell nuclear antigen (PCNA) puncta and an inability to enter the first cell cycle. This proliferation defect is partially mediated by the p15 pathway. Overall, our study provides the first evidence of an indispensable role of UHRF1 in somatic stem cells proliferation during the process of airway regeneration.