Browsing by Author "Zhang, Lin"

Now showing 1 - 7 of 7
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    BID mediates selective killing of APC-deficient cells in intestinal tumor suppression by nonsteroidal antiinflammatory drugs
    (PNAS, 2014-11-18) Leibowitz, Brian; Qiu, Wei; Buchanan, Monica E.; Zou, Fangdong; Vernon, Philip; Moyer, Mary P.; Yin, Xiao-Ming; Schoen, Robert E.; Yu, Jian; Zhang, Lin; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Colorectal tumorigenesis is driven by genetic alterations in the adenomatous polyposis coli (APC) tumor suppressor pathway and effectively inhibited by nonsteroidal antiinflammatory drugs (NSAIDs). However, how NSAIDs prevent colorectal tumorigenesis has remained obscure. We found that the extrinsic apoptotic pathway and the BH3 interacting-domain death agonist (BID) are activated in adenomas from NSAID-treated patients. Loss of BID abolishes NSAID-mediated tumor suppression, survival benefit, and apoptosis in tumor-initiating stem cells in APC(Min/+) mice. BID-mediated cross-talk between the extrinsic and intrinsic apoptotic pathways is responsible for selective killing of neoplastic cells by NSAIDs. We further demonstrate that NSAIDs induce death receptor signaling in both cancer and normal cells, but only activate BID in cells with APC deficiency and ensuing c-Myc activation. Our results suggest that NSAIDs suppress intestinal tumorigenesis through BID-mediated synthetic lethality triggered by death receptor signaling and gatekeeper mutations, and provide a rationale for developing more effective cancer prevention strategies and agents.
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    Continued Beneficial Effects of Burosumab in Adults with X-Linked Hypophosphatemia: Results from a 24-Week Treatment Continuation Period After a 24-Week Double-Blind Placebo-Controlled Period
    (Springer, 2019-09-01) Portale, Anthony A.; Carpenter, Thomas O.; Brandi, Maria Luisa; Briot, Karine; Cheong, Hae II; Cohen-Solal, Martine; Crowley, Rachel; Jan De Beur, Suzanne; Eastell, Richard; Imanishi, Yasuo; Imel, Erik A.; Ing, Steven; Ito, Nobuaki; Javaid, Muhammad; Kamenicky, Peter; Keen, Richard; Kubota, Takuo; Lachmann, Robin; Perwad, Farzana; Pitukcheewanont, Pisit; Ralston, Stuart H.; Takeuchi, Yasuhiro; Tanaka, Hiroyuki; Weber, Thomas J.; Yoo, Han-Wook; Zhang, Lin; Theodore-Oklota, Christina; Mealiffe, Matt; San Martin, Javier; Insogna, Karl; Medicine, School of Medicine
    Burosumab, a fully human monoclonal antibody to FGF23, is the only approved treatment for X-linked hypophosphatemia (XLH), a rare genetic disorder characterized by renal phosphate wasting and substantial cumulative musculoskeletal morbidity. During an initial 24-week randomized, controlled trial, 134 adults with XLH received burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks. After 24 weeks, all subjects received open-label burosumab until week 48. This report describes the efficacy and safety of burosumab during the open-label treatment period. From weeks 24–48, serum phosphorus concentrations remained normal in 83.8% of participants who received burosumab throughout and were normalized in 89.4% who received burosumab after placebo. By week 48, 63.1% of baseline fractures/pseudofractures healed fully with burosumab, compared with 35.2% with burosumab after placebo. In both groups, burosumab was associated with clinically significant and sustained improvement from baseline to week 48 in scores for patient-reported outcomes of stiffness, pain, physical function, and total distance walked in 6 min. Rates of adverse events were similar for burosumab and placebo. There were no fatal adverse events or treatment-related serious adverse events. Nephrocalcinosis scores did not change from baseline by more than one grade at either week 24 or 48. These data demonstrate that in participants with XLH, continued treatment with burosumab is well tolerated and leads to sustained correction of serum phosphorus levels, continued healing of fractures and pseudofractures, and sustained improvement in key musculoskeletal impairments.
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    Identification of Hydrolyzable Tannins (Punicalagin, Punicalin and Geraniin) as Novel inhibitors of Hepatitis B Virus Covalently Closed Circular DNA
    (Elsevier, 2016-10) Liu, Chunlan; Cai, Dawei; Zhang, Lin; Tang, Wei; Yan, Ran; Guo, Haitao; Chen, Xulin; Department of Microbiology and Immunology, IU School of Medicine
    The development of new agents to target HBV cccDNA is urgently needed because of the limitations of current available drugs for treatment of hepatitis B. By using a cell-based assay in which the production of HBeAg is in a cccDNA-dependent manner, we screened a compound library derived from Chinese herbal remedies for inhibitors against HBV cccDNA. Three hydrolyzable tannins, specifically punicalagin, punicalin and geraniin, emerged as novel anti-HBV agents. These compounds significantly reduced the production of secreted HBeAg and cccDNA in a dose-dependent manner in our assay, without dramatic alteration of viral DNA replication. Furthermore, punicalagin did not affect precore/core promoter activity, pgRNA transcription, core protein expression, or HBsAg secretion. By employing the cell-based cccDNA accumulation and stability assay, we found that these tannins significantly inhibited the establishment of cccDNA and modestly facilitated the degradation of preexisting cccDNA. Collectively, our results suggest that hydrolyzable tannins inhibit HBV cccDNA production via a dual mechanism through preventing the formation of cccDNA and promoting cccDNA decay, although the latter effect is rather minor. These hydrolyzable tannins may serve as lead compounds for the development of new agents to cure HBV infection.
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    Level and Duration of IgG and Neutralizing Antibodies to SARS-CoV-2 in Children with Symptomatic or Asymptomatic SARS-CoV-2 Infection
    (AAI, 2022-06-01) Khaitan, Alka; Datta, Dibyadyuti; Bond, Caitlin; Goings, Michael; Co, Katrina; Odhiambo, Eliud O.; Miller, Lucy; Zhang, Lin; Beasley, Stephanie; Poorbaugh, Josh; John, Chandy C.; Pediatrics, School of Medicine
    There are conflicting data about level and duration of Abs to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children after symptomatic or asymptomatic infection. In this human population, we enrolled adults and children in a prospective 6-mo study in the following categories: 1) symptomatic, SARS-CoV-2 PCR+ (SP+; children, n = 8; adults, n = 16), 2) symptomatic, PCR−, or untested (children, n = 27), 3) asymptomatic exposed (children, n = 13), and 4) asymptomatic, no known exposure (children, n = 19). Neutralizing Abs (nAbs) and IgG Abs to SARS-CoV-2 Ags and spike protein variants were measured by multiplex serological assay. All SP+ children developed nAb, whereas 81% of SP+ adults developed nAb. Decline in the presence of nAb over 6 mo was not significant in symptomatic children (100 to 87.5%; p = 0.32) in contrast to adults (81.3 to 50.0%; p = 0.03). Among children with nAb (n = 22), nAb titers and change in titers over 6 mo were similar in symptomatic and asymptomatic children. In children and adults, nAb levels postinfection were 10-fold lower than those reported after SARS-CoV-2 mRNA vaccination. Levels of IgG Abs in children to SARS-CoV-2 Ags and spike protein variants were similar to those in adults. IgG levels to primary Ags decreased over time in children and adults, but levels to three spike variants decreased only in children. Children with asymptomatic or symptomatic SARS-CoV-2 infection develop nAbs that remain present longer than in adults but wane in titer over time and broad IgG Abs that also wane in level over time. However, nAb levels were lower postinfection than those reported after immunization.
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    Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers
    (National Academy of Sciences, 2018-10-02) Feng, Shan; Cheng, Xi; Zhang, Lin; Lu, Xuemin; Chaudhary, Seema; Teng, Ruifang; Frederickson, Christian; Champion, Matthew M.; Zhao, Ren; Cheng, Liang; Gong, Yiyi; Deng, Haiteng; Lu, Xin; Pathology and Laboratory Medicine, School of Medicine
    Potent immunosuppressive mechanisms within the tumor microenvironment contribute to the resistance of aggressive human cancers to immune checkpoint blockade (ICB) therapy. One of the main mechanisms for myeloid-derived suppressor cells (MDSCs) to induce T cell tolerance is through secretion of reactive nitrogen species (RNS), which nitrates tyrosine residues in proteins involved in T cell function. However, so far very few nitrated proteins have been identified. Here, using a transgenic mouse model of prostate cancer and a syngeneic cell line model of lung cancer, we applied a nitroproteomic approach based on chemical derivation of 3-nitrotyrosine and identified that lymphocyte-specific protein tyrosine kinase (LCK), an initiating tyrosine kinase in the T cell receptor signaling cascade, is nitrated at Tyr394 by MDSCs. LCK nitration inhibits T cell activation, leading to reduced interleukin 2 (IL2) production and proliferation. In human T cells with defective endogenous LCK, wild type, but not nitrated LCK, rescues IL2 production. In the mouse model of castration-resistant prostate cancer (CRPC) by prostate-specific deletion of Pten, p53, and Smad4, CRPC is resistant to an ICB therapy composed of antiprogrammed cell death 1 (PD1) and anticytotoxic-T lymphocyte-associated protein 4 (CTLA4) antibodies. However, we showed that ICB elicits strong anti-CRPC efficacy when combined with an RNS neutralizing agent. Together, these data identify a previously unknown mechanism of T cell inactivation by MDSC-induced protein nitration and illuminate a clinical path hypothesis for combining ICB with RNS-reducing agents in the treatment of CRPC.
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    Preclinical Demonstration of Lentiviral Vector-mediated Correction of Immunological and Metabolic Abnormalities in Models of Adenosine Deaminase Deficiency
    (Nature Publishing Group, 2014-03) Carbonaro, Denise A.; Zhang, Lin; Jin, Xiangyang; Montiel-Equihua, Claudia; Geiger, Sabine; Carmo, Marlene; Cooper, Aaron; Fairbanks, Lynette; Kaufman, Michael L.; Sebire, Neil J.; Hollis, Roger P.; Blundell, Michael P.; Senadheera, Shantha; Fu, Pei-Yu; Sahaghian, Arineh; Chan, Rebecca Y.; Wang, Xiaoyan; Cornetta, Kenneth; Thrasher, Adrian J.; Kohn, Donald B.; Gaspar, H. Bobby; Department of Medical & Molecular Genetics, IU School of Medicine
    Gene transfer into autologous hematopoietic stem cells by γ-retroviral vectors (gRV) is an effective treatment for adenosine deaminase (ADA)–deficient severe combined immunodeficiency (SCID). However, current gRV have significant potential for insertional mutagenesis as reported in clinical trials for other primary immunodeficiencies. To improve the efficacy and safety of ADA-SCID gene therapy (GT), we generated a self-inactivating lentiviral vector (LV) with a codon-optimized human cADA gene under the control of the short form elongation factor-1α promoter (LV EFS ADA). In ADA−/− mice, LV EFS ADA displayed high-efficiency gene transfer and sufficient ADA expression to rescue ADA−/− mice from their lethal phenotype with good thymic and peripheral T- and B-cell reconstitution. Human ADA-deficient CD34+ cells transduced with 1–5 × 107 TU/ml had 1–3 vector copies/cell and expressed 1–2x of normal endogenous levels of ADA, as assayed in vitro and by transplantation into immune-deficient mice. Importantly, in vitro immortalization assays demonstrated that LV EFS ADA had significantly less transformation potential compared to gRV vectors, and vector integration-site analysis by nrLAM-PCR of transduced human cells grown in immune-deficient mice showed no evidence of clonal skewing. These data demonstrated that the LV EFS ADA vector can effectively transfer the human ADA cDNA and promote immune and metabolic recovery, while reducing the potential for vector-mediated insertional mutagenesis.
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    A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis
    (Wiley, 2018-08) Insogna, Karl L.; Briot, Karine; Imel, Erik A.; Kamenický, Peter; Ruppe, Mary D.; Portale, Anthony A.; Weber, Thomas; Pitukcheewanont, Pisit; Cheong, Hae Il; Jan de Beur, Suzanne; Imanishi, Yasuo; Ito, Nobuaki; Lachmann, Robin H.; Tanaka, Hiroyuki; Perwad, Farzana; Zhang, Lin; Chen, Chao-Yin; Theodore-Oklota, Christina; Mealiffe, Matt; San Martin, Javier; Carpenter, Thomas O.; Pediatrics, School of Medicine
    In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n = 68) or placebo (n = 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean ± standard error [SE] difference, -8.1 ± 3.24; p = 0.012). Reductions in WOMAC physical function subscale (-4.9 ± 2.48; p = 0.048) and Brief Pain Inventory worst pain (-0.5 ± 0.28; p = 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.