DOCSLIB.ORG

Preliminary Scientific Program*

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Preliminary Scientific Program* ABSTRACTS FROM THE 22ND NORTH AMERICAN ISSX MEETING July 15 - 19, 2018 Montréal, Canada 22nd North American ISSX Meeting July 15 - 19, 2018 Montréal, Canada Contents Sunday, July 15, 2018 Short Course 1: Model Systems and Methods for Assessing Uptake and Efflux of Small Molecules 3 Abstracts: SC1.1 - S1.4 Short Course 2: Enzyme Induction and Regulatory Guidance 4 Abstracts: S2.1 - SC2.4 Short Course 3: In silico Modeling of in vitro Metabolism, Transport, and Toxicity Data 5 Abstracts: SC3.1 - SC3.6 Short Course 4: Immunotoxicology 8 Abstracts: SC4.1 - SC4.4 Keynote Lecture: Immuno Oncology State-of-the-Field and How it Helps Understand the Immune System and Mechanisms for Drug Efficacy and Toxicity 9 Abstract: S1 Monday, July 16, 2018 Plenary Lecture 1: Intracellular Drug Concentrations: Theory, Practice, and Promise 9 Abstract: S2 Parallel Symposium 1: Transporters as Determinants of Target Organ Toxicities 10 Abstracts: S3 - S6 Parallel Symposium 2: Development of Guidelines to Implement Pharmacogenomics-based Clinical Decision 11 Abstracts: S7 - S10 Selected New Investigator Abstract Presentations 43, 46, 47, 95, 97, 107, 114, 129 Abstracts: P5, P12, P13, P110, P114, P135, P150, and P180 Pre-doctoral/Graduate Poster Awards Finalist Poster Presentations 34 Abstracts: A1 - A6 Poster Presentation Session 1 42 Abstracts: P1 - P62 Tuesday, July 17, 2018 Plenary Lecture 2: Novel Synthetic and Computational Approaches to the Discovery of Drugs Targeting 12 Abstract: S11 Parallel Symposium 3: The Impact of Pregnancy on Xenobiotic Disposition 12 Abstracts: S12 - S15 Parallel Symposium 4: Genomic Approaches for Revealing Mechanisms of Cancer Drug Efficacy and Toxicit 14, 110, 111 Abstracts: S16 - S18, P142, and P143 Postdoctoral Poster Awards Finalist Poster Presentations 37 Abstracts: A7 - A12 Poster Presentation Session 2 72 Abstracts: P63 - P117 Wednesday, July 18, 2018 Plenary Lecture 3: Site-specific Deuterium Labeling: A Viable Approach in Drug Discovery and Development 15 Abstract: S19 1 Parallel Symposium 5: Antibody Drug Conjugates (ADCs) Disposition and Modeling 15 Abstracts: S20 - S23 Parallel Symposium 6: Microphysiological Systems/Organs on a Chip 16 Abstracts: S24 - S27 Plenary Session: The Role of the Microbiome in Drug Metabolism and How this Influences Drug Toxicity 18 Abstracts: S28 - S30 Parallel Symposium 7: Revisiting the Regulatory Guidelines (EMA, FDA and PMDA) for Induction Studies and Regulatory DMPK 19 Abstracts: S31 - S35 Parallel Symposium 8: Endogenous Biomarkers for Drug Metabolism and Transporter Activity. Predicting Drug Interactions in Clinical Development and for Application in Precision Medicine 20 Abstracts: S36 - S39 Pre-doctoral/Graduate and Postdoctoral Poster Awards Finalist Poster Presentations 34 Abstracts: A1 - A12 Poster Presentation Session 3 98 Abstracts: P118 - P187 Thursday, July 19, 2018 Plenary Lecture 4: Opportunities and Challenges in the Discovery of Novel Agents for the Treatment of Malaria 21 Abstract: S40 Parallel Symposium 9: Addressing ADME Challenges with High Performance Analytical Capabilities 22 Abstracts: S41 – S44 Parallel Symposium 10: Designed Covalent Inhibitors, ADME Aspects of Design, Characterization and Risk Assessment 23 Abstracts: 45 - S48 Poster Details 25 Finalists for the Pre-doctoral/Graduate Poster Awards Competition (Monday, July 16 - Wednesday, July 18, 2018) 34 Abstracts: A1 - A6 Finalists for the Postdoctoral Poster Awards Competition (Monday, July 16 - Wednesday, July 18, 2018) 37 Abstracts: A7 - A12 Poster Presentations (Monday, July 16 - Wednesday, July 18, 2018) 42 Abstracts: P1 - P187 Author Index 133 Keyword Index 139 Notes Pages 140 2 22nd North American ISSX Meeting Speaker Abstracts SC1.1 - NOVEL IN VITRO MODELS TO STUDY TRANSPORTERS Yurong Lai Gilead Sciences Drug transporters are involved in the uptake or efflux of drugs across barriers such as the intestine, liver, kidney and brain, and play a key role in drug ADME/Tox. Disruption of drug transporter functions leads to changes in the pharmacokinetics and, as a result, possibly to impact efficacy and toxicity profiles. Hence, regulatory agencies such as US FDA or European Medicines Agency (EMEA) provide guidelines to characterize transporter drug interactions. In vitro transporter assays are usually carried out with either intact cells or cell fractions over expressing transporter proteins. Although an increasing number of experimental methods and models are developed to study drug-transporter interactions and the tools appear to be useful to address transporter-related questions, it still remains challenge to translate results from in vitro transporter models to the human situation. The method selected is based on the physicochemical features of a drug, as well as the specific question one would like to address. The short course presentation will introduce the in vitro tools that are commonly used for transporter characterization, and describe the pros and cons of the tools for characterizing transporter interactions. SC1.2 - ANIMAL MODELS FOR DRUG TRANSPORTERS Daniel Bow AbbVie In addition to the use of in vitro tools to study drug transport, animal models can also be used to facilitate our understanding of the role uptake and efflux drug transporters play in compound disposition and elimination. These models can be used at various stages in drug discovery and development. The application, timing, and translation of data generated from multiple models will be discussed. Models that will be covered include transporter knockout animals, humanized transporter models, and the use of chemical inhibition studies. Daniel Bow is an employee of AbbVie. The design, study conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. SC1.3 - PET IMAGING TO UNDERSTAND HEPATOBILIARY TRANSPORTERS Yuichi Sugiyama Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Research Cluster for Innovation, RIKEN The changes in pharmacokinetics due to genetic polymorphisms and drug-drug interactions involving transporters can often have an adverse effect on the therapeutic safety and efficacy of many drugs. For drugs, the target molecule of which is inside the cells, the efflux transporter is the determinant for their pharmacological effect or adverse reactions even though it had negligible impact in the plasma concentrations. Because of difficulty in quantitative evaluation of the subsequent efflux process (both basolateral and apical side), the transporters playing key roles in the efflux process remains unclear in humans. Development of probe substrates applicable to the PET imaging will elucidate the quantitative relationship between the transport activities and drug response. Labeled PET probes are being developed for specific transporters. Here in this presentation, I will show you our recent progress in the use of the analysis of plasma clearance of drugs and PET imaging to evaluate the transporter function in vivo including PET probes for hepatic uptake transporters (OATP1B1, OATP1B3) and biliary excretion transporters (MRP2, BCRP)) both in experimental animals and in human. Acknowledgments I would like to thank Drs. Y.Watanabe, K.Maeda and H.Kusuhara for their great contribution to these PET studies. References: 1. Takashima T et al., PET imaging-based evaluation of hepatobiliary transport in humans with (15R)-11C-TIC-Me.J Nucl Med, 53: 741-8 (2012) 2. Takashima T et al., Evaluation of Breast Cancer Resistance Protein Function in Hepatobiliary and Renal Excretion Using PET with 11C-SC-62807.Nucl Me Jd, 54: 267-76 (2013) 3. Kaneko K et al. A clinical quantitative evaluation of hepatobiliary transport of [11C]Dehydropravastatin in humans using positron emission tomography. Drug Metab Disposit in press Drug Metab Dispos. 46 719-728 (2018) 3 22nd North American ISSX Meeting Speaker Abstracts SC1.4 - PROBE DRUGS FOR CLINICAL TRANSPORTER DDI EVALUATION Maciej J. Zamek-Gliszczynski, GlaxoSmithKline This presentation will highlight the state-of-the-art in transporter clinical probes based on upcoming 2018 ITC whitepapers (Clin Pharmacol Ther 104, November 2018). Special emphasis will be placed on emerging transporters of clinical relevance and transporters with recent advances in their clinical evaluation approaches. For example, OCT1 was shown recently to be the rate-determining step in the clearance of several drugs in humans (e.g., sumatriptan, ondansetron, tropisetron, fenoterol, etc.), and thereby a mechanism of pharmacogenetic variability and DDIs. OCT1 modulation impacts metformin response, but not pharmacokinetics, and therefore OCT1 inhibition is a driver for the conduct of a metformin DDI study, but metformin is not a preferred clinical OCT1 probe drug. Similarly, P-gp inhibition can trigger a digoxin safety study, but digoxin is neither a specific nor sensitive P-gp probe. Dabigatran etexilate has been proposed as a specific intestinal P-gp probe, and is particularly sensitive when administered as a microdose. Clinical investigation of BCRP DDIs has been controversial in part due to a lack of consensus on clinical probes and inhibitors, which has now been reached. Oral sulfasalazine (immediate release) is the best available clinical probe for intestinal BCRP, oral rosuvastatin for both intestinal and hepatic BCRP, and intravenous rosuvastatin for hepatic BCRP. Ultimately, selection of clinical probes depends on co-medication relevance and the specific questions being addressed (e.g. direct characterization
Load more

Recommended publications
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Regulation of Xenobiotic and Bile Acid Metabolism by the Anti-Aging Intervention Calorie Restriction in Mice
    REGULATION OF XENOBIOTIC AND BILE ACID METABOLISM BY THE ANTI-AGING INTERVENTION CALORIE RESTRICTION IN MICE By Zidong Fu Submitted to the Graduate Degree Program in Pharmacology, Toxicology, and Therapeutics and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Dissertation Committee ________________________________ Chairperson: Curtis Klaassen, Ph.D. ________________________________ Udayan Apte, Ph.D. ________________________________ Wen-Xing Ding, Ph.D. ________________________________ Thomas Pazdernik, Ph.D. ________________________________ Hao Zhu, Ph.D. Date Defended: 04-11-2013 The Dissertation Committee for Zidong Fu certifies that this is the approved version of the following dissertation: REGULATION OF XENOBIOTIC AND BILE ACID METABOLISM BY THE ANTI-AGING INTERVENTION CALORIE RESTRICTION IN MICE ________________________________ Chairperson: Curtis Klaassen, Ph.D. Date approved: 04-11-2013 ii ABSTRACT Calorie restriction (CR), defined as reduced calorie intake without causing malnutrition, is the best-known intervention to increase life span and slow aging-related diseases in various species. However, current knowledge on the exact mechanisms of aging and how CR exerts its anti-aging effects is still inadequate. The detoxification theory of aging proposes that the up-regulation of xenobiotic processing genes (XPGs) involved in phase-I and phase-II xenobiotic metabolism as well as transport, which renders a wide spectrum of detoxification, is a longevity mechanism. Interestingly, bile acids (BAs), the metabolites of cholesterol, have recently been connected with longevity. Thus, this dissertation aimed to determine the regulation of xenobiotic and BA metabolism by the well-known anti-aging intervention CR. First, the mRNA expression of XPGs in liver during aging was investigated.
    [Show full text]
  • Type of the Paper (Article
    Supplementary Material A Proteomics Study on the Mechanism of Nutmeg-induced Hepatotoxicity Wei Xia 1, †, Zhipeng Cao 1, †, Xiaoyu Zhang 1 and Lina Gao 1,* 1 School of Forensic Medicine, China Medical University, Shenyang 110122, P. R. China; lessen- [email protected] (W.X.); [email protected] (Z.C.); [email protected] (X.Z.) † The authors contributed equally to this work. * Correspondence: [email protected] Figure S1. Table S1. Peptide fraction separation liquid chromatography elution gradient table. Time (min) Flow rate (mL/min) Mobile phase A (%) Mobile phase B (%) 0 1 97 3 10 1 95 5 30 1 80 20 48 1 60 40 50 1 50 50 53 1 30 70 54 1 0 100 1 Table 2. Liquid chromatography elution gradient table. Time (min) Flow rate (nL/min) Mobile phase A (%) Mobile phase B (%) 0 600 94 6 2 600 83 17 82 600 60 40 84 600 50 50 85 600 45 55 90 600 0 100 Table S3. The analysis parameter of Proteome Discoverer 2.2. Item Value Type of Quantification Reporter Quantification (TMT) Enzyme Trypsin Max.Missed Cleavage Sites 2 Precursor Mass Tolerance 10 ppm Fragment Mass Tolerance 0.02 Da Dynamic Modification Oxidation/+15.995 Da (M) and TMT /+229.163 Da (K,Y) N-Terminal Modification Acetyl/+42.011 Da (N-Terminal) and TMT /+229.163 Da (N-Terminal) Static Modification Carbamidomethyl/+57.021 Da (C) 2 Table S4. The DEPs between the low-dose group and the control group. Protein Gene Fold Change P value Trend mRNA H2-K1 0.380 0.010 down Glutamine synthetase 0.426 0.022 down Annexin Anxa6 0.447 0.032 down mRNA H2-D1 0.467 0.002 down Ribokinase Rbks 0.487 0.000
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Hanna Joleen 2018 Thesis.Pdf
    Validation of an In Vitro Mutagenicity Assay Based on Pulmonary Epithelial Cells from the Transgenic MutaMouse: Intra-Laboratory Variability and Metabolic Competence By: Joleen Hanna, B.Sc. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science In Biology Specializing in Chemical and Environmental Toxicology Supervisor: Dr. Paul White (University of Ottawa) Thesis Advisory Committee: Dr. Frances Pick (University of Ottawa) Dr. Iain Lambert (Carleton University) University of Ottawa Ontario, Canada March 2018 © Joleen Hanna, Ottawa, Canada, 2018 Abstract: Genetic toxicity tests used for regulatory screening must be rigorously validated to ensure accuracy, reliability and relevance. Hence, prior to establishment of an internationally- accepted test guideline, a new assay must undergo multi-stage validation. An in vitro transgene mutagenicity assay based on an immortalized cell line derived from MutaMouse lung (i.e., FE1 cells) is currently undergoing formal validation. FE1 cells retain a lacZ transgene in a λgt10 shuttle vector that can be retrieved for scoring of chemically-induced mutations. This work contributes to validation of the in vitro transgene (lacZ) mutagenicity assay in MutaMouse FE1 cells. More specifically, the work includes an intra-laboratory variability study, and a follow-up study to assess the endogenous metabolic capacity of FE1 cells. The former is essential to determine assay reliability, the latter to define the range of chemicals that can be reliably screened without an exogenous metabolic activation mixture (i.e., rat liver S9). The intra- laboratory variability assessment revealed minimal variability; thus, assay reproducibility can be deemed acceptable. Assessment of metabolic capacity involved exposure of FE1 cells to 5 known mutagens, and subsequent assessment of changes in the expression of genes involved in xenobiotic metabolism; induced transgene mutant frequency (±S9) was assessed in parallel.
    [Show full text]
  • FMO3) As a Novel Genetic Determinant of Acetaminophen (APAP) Induced Hepatotoxicity Swetha Rudraiah University of Connecticut - Storrs, [email protected]
    University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 8-4-2014 Characterization of Flavin-containing Monooxygenase-3 (FMO3) as a Novel Genetic Determinant of Acetaminophen (APAP) Induced Hepatotoxicity Swetha Rudraiah University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Rudraiah, Swetha, "Characterization of Flavin-containing Monooxygenase-3 (FMO3) as a Novel Genetic Determinant of Acetaminophen (APAP) Induced Hepatotoxicity" (2014). Doctoral Dissertations. 506. https://opencommons.uconn.edu/dissertations/506 Characterization of Flavin-containing Monooxygenase-3 (FMO3) as a Novel Genetic Determinant of Acetaminophen (APAP) Induced Hepatotoxicity Swetha Rudraiah, Ph.D. University of Connecticut, 2014 Mice pretreated with a mild toxic dose of acetaminophen (APAP) acquire resistance to a second, higher APAP dose. This phenomenon is termed APAP autoprotection and the exact mechanism by which such resistance develops is not clearly known. Given the prevalence of APAP- hepatotoxicity and the human health impact of this potentially hepatotoxic agent, a further understanding of the mechanism(s) involved in such protection are of considerable significance and could lead to new modalities of treatment of acute drug-induced liver injury. The work presented in this thesis investigates FMO3 gene expression during APAP-induced liver injury as well as the functional significance of FMO3 over-expression during APAP- induced liver injury. Furthermore, FMO3 gene regulation during oxidative stress conditions is also examined. Acetaminophen treatment resulted in up-regulation of liver Fmo3 protein in male mice. Female mice express higher liver Fmo3 than males and are highly resistant to APAP hepatotoxicity.
    [Show full text]
  • Consequences of Exchanging Carbohydrates for Proteins in the Cholesterol Metabolism of Mice Fed a High-Fat Diet
    Consequences of Exchanging Carbohydrates for Proteins in the Cholesterol Metabolism of Mice Fed a High-fat Diet Fre´de´ ric Raymond1.¤a, Long Wang2., Mireille Moser1, Sylviane Metairon1¤a, Robert Mansourian1, Marie- Camille Zwahlen1, Martin Kussmann3,4,5, Andreas Fuerholz1, Katherine Mace´ 6, Chieh Jason Chou6*¤b 1 Bioanalytical Science Department, Nestle´ Research Center, Lausanne, Switzerland, 2 Department of Nutrition Science and Dietetics, Syracuse University, Syracuse, New York, United States of America, 3 Proteomics and Metabonomics Core, Nestle´ Institute of Health Sciences, Lausanne, Switzerland, 4 Faculty of Science, Aarhus University, Aarhus, Denmark, 5 Faculty of Life Sciences, Federal Institute of Technology, Lausanne, Switzerland, 6 Nutrition and Health Department, Nestle´ Research Center, Lausanne, Switzerland Abstract Consumption of low-carbohydrate, high-protein, high-fat diets lead to rapid weight loss but the cardioprotective effects of these diets have been questioned. We examined the impact of high-protein and high-fat diets on cholesterol metabolism by comparing the plasma cholesterol and the expression of cholesterol biosynthesis genes in the liver of mice fed a high-fat (HF) diet that has a high (H) or a low (L) protein-to-carbohydrate (P/C) ratio. H-P/C-HF feeding, compared with L-P/C-HF feeding, decreased plasma total cholesterol and increased HDL cholesterol concentrations at 4-wk. Interestingly, the expression of genes involved in hepatic steroid biosynthesis responded to an increased dietary P/C ratio by first down- regulation (2-d) followed by later up-regulation at 4-wk, and the temporal gene expression patterns were connected to the putative activity of SREBF1 and 2.
    [Show full text]
  • Folliculin Regulates Mtorc1/2 and WNT Pathways in Early Human Pluripotency
    ARTICLE https://doi.org/10.1038/s41467-018-08020-0 OPEN Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency J. Mathieu1,2,3, D. Detraux1,2,8, D. Kuppers4, Y. Wang2,5, C. Cavanaugh2,3, S. Sidhu1,2,S.Levy1,2, A.M. Robitaille2,6, A. Ferreccio1,2, T. Bottorff1,2, A. McAlister1,2, L. Somasundaram1,2, F. Artoni1,2, S. Battle2,7, R.D. Hawkins2,7, R.T. Moon2,6, C.B. Ware2,3, P.J. Paddison2,4 & H. Ruohola-Baker 1,2 To reveal how cells exit human pluripotency, we designed a CRISPR-Cas9 screen exploiting 1234567890():,; the metabolic and epigenetic differences between naïve and primed pluripotent cells. We identify the tumor suppressor, Folliculin(FLCN) as a critical gene required for the exit from human pluripotency. Here we show that FLCN Knock-out (KO) hESCs maintain the naïve pluripotent state but cannot exit the state since the critical transcription factor TFE3 remains active in the nucleus. TFE3 targets up-regulated in FLCN KO exit assay are members of Wnt pathway and ESRRB. Treatment of FLCN KO hESC with a Wnt inhibitor, but not ESRRB/FLCN double mutant, rescues the cells, allowing the exit from the naïve state. Using co-immunoprecipitation and mass spectrometry analysis we identify unique FLCN binding partners. The interactions of FLCN with components of the mTOR pathway (mTORC1 and mTORC2) reveal a mechanism of FLCN function during exit from naïve pluripotency. 1 Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. 2 Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
    [Show full text]
  • Supplementary Material
    Table S1 . Genes up-regulated in the CL of stimulated in relation to control animals ( 1.5 fold, P ≤ 0.05). UniGene ID Gene Title Gene Symbol fold change P value Bt.16350.2.A1_s_at guanylate binding protein 5 GBP5 4.42 0.002 Bt.2498.2.A1_a_at fibrinogen gamma chain FGG 3.81 0.002 Bt.440.1.S1_at neurotensin NTS 3.74 0.036 major histocompatibility complex, class I, A /// major Bt.27760.1.S1_at histocompatibility complex, class I, A BoLA /// HLA-A 3.56 0.022 Bt.146.1.S1_at defensin, beta 4A DEFB4A 3.12 0.002 Bt.7165.1.S1_at chemokine (C-X-C motif) ligand 5 CXCL5 3.06 0.031 Bt.15731.1.A1_at V-set and immunoglobulin domain containing 4 VSIG4 3.03 0.047 Bt.22869.1.S2_at fatty acid binding protein 5 (psoriasis-associated) FABP5 3.02 0.006 Bt.4604.1.S1_a_at acyl-CoA synthetase medium-chain family member 1 ACSM1 2.93 0.001 Bt.6406.1.S3_at CCAAT/enhancer binding protein (C/EBP), delta CEBPD 2.92 0.011 Bt.19845.2.A1_at coagulation factor XIII, A1 polypeptide F13A1 2.83 0.005 Bt.209.3.S1_at lysozyme (renal amyloidosis) LYZ 2.77 0.0003 Bt.15908.1.S1_at methyltransferase like 7A METTL7A 2.59 0.007 Bt.28383.1.S1_at granulysin GNLY 2.58 0.034 Bt.20455.1.S1_at Microtubule-associated protein tau MAPT 2.56 0.047 Bt.6556.1.S1_at regakine 1 LOC504773 2.55 0.011 Bt.11259.1.S1_at putative ISG12(a) protein ISG12(A) 2.55 0.037 Bt.28243.1.S1_a_at vanin 1 VNN1 2.54 0.008 Bt.405.1.S1_at follistatin FST 2.52 0.002 Bt.9510.2.A1_a_at T-cell immunoglobulin and mucin domain containing 4 TIMD4 2.47 0.024 Bt.499.1.S1_a_at prolactin receptor PRLR 2.44 0.010 serpin peptidase
    [Show full text]
  • Methods and Compositions for the Treatment of Non-Small Cell Lung Cancer
    (19) TZZ_¥_T (11) EP 1 743 947 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12Q 1/68 (2006.01) C12N 15/12 (2006.01) 11.01.2012 Bulletin 2012/02 G01N 33/50 (2006.01) C12N 15/11 (2006.01) A61P 35/00 (2006.01) A61K 39/00 (2006.01) (21) Application number: 06022167.8 (22) Date of filing: 22.09.2003 (54) Methods and compositions for the treatment of non-small cell lung cancer Verfahren und Zusammensetzungen zur Behandlung von nichtkleinzelligem Lungenkrebs Méthodes et compositions pour le traitement du cancer du poumon "non à petites cellules" (84) Designated Contracting States: (60) Divisional application: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 10010306.8 / 2 264 185 HU IE IT LI LU MC NL PT RO SE SI SK TR 10010307.6 / 2 264 186 10010308.4 / 2 264 187 (30) Priority: 30.09.2002 US 414673 P 10010309.2 / 2 264 190 28.02.2003 US 451374 P 10010310.0 / 2 264 457 28.04.2003 US 466100 P 10010311.8 / 2 278 028 10010312.6 / 2 270 498 (43) Date of publication of application: 10010313.4 / 2 270 499 17.01.2007 Bulletin 2007/03 10010314.2 / 2 270 500 10010315.9 / 2 270 501 10010316.7 / 2 270 502 10010317.5 / 2 270 503 10010318.3 / 2 270 210 10010319.1 / 2 270 211 10010320.9 / 2 270 212 10010321.7 / 2 270 213 10010322.5 / 2 270 214 10010323.3 / 2 270 215 10010324.1 / 2 270 216 10010325.8 / 2 270 217 10010326.6 / 2 270 218 10010327.4 / 2 270 219 10010328.2 / 2 270 220 10010329.0 / 2 270 221 10010330.8 / 2 270 222 10010331.6 / 2 270 223 10010332.4 / 2 270 224 10010333.2 / 2 270 225 (62) Document number(s) of the earlier application(s) in accordance with Art.
    [Show full text]
  • Supplemental Figures 04 12 2017
    Jung et al. 1 SUPPLEMENTAL FIGURES 2 3 Supplemental Figure 1. Clinical relevance of natural product methyltransferases (NPMTs) in brain disorders. (A) 4 Table summarizing characteristics of 11 NPMTs using data derived from the TCGA GBM and Rembrandt datasets for 5 relative expression levels and survival. In addition, published studies of the 11 NPMTs are summarized. (B) The 1 Jung et al. 6 expression levels of 10 NPMTs in glioblastoma versus non‐tumor brain are displayed in a heatmap, ranked by 7 significance and expression levels. *, p<0.05; **, p<0.01; ***, p<0.001. 8 2 Jung et al. 9 10 Supplemental Figure 2. Anatomical distribution of methyltransferase and metabolic signatures within 11 glioblastomas. The Ivy GAP dataset was downloaded and interrogated by histological structure for NNMT, NAMPT, 12 DNMT mRNA expression and selected gene expression signatures. The results are displayed on a heatmap. The 13 sample size of each histological region as indicated on the figure. 14 3 Jung et al. 15 16 Supplemental Figure 3. Altered expression of nicotinamide and nicotinate metabolism‐related enzymes in 17 glioblastoma. (A) Heatmap (fold change of expression) of whole 25 enzymes in the KEGG nicotinate and 18 nicotinamide metabolism gene set were analyzed in indicated glioblastoma expression datasets with Oncomine. 4 Jung et al. 19 Color bar intensity indicates percentile of fold change in glioblastoma relative to normal brain. (B) Nicotinamide and 20 nicotinate and methionine salvage pathways are displayed with the relative expression levels in glioblastoma 21 specimens in the TCGA GBM dataset indicated. 22 5 Jung et al. 23 24 Supplementary Figure 4.
    [Show full text]
  • Comparative Gene Expression Analysis to Identify Common Factors in Multiple Cancers
    COMPARATIVE GENE EXPRESSION ANALYSIS TO IDENTIFY COMMON FACTORS IN MULTIPLE CANCERS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Leszek A. Rybaczyk, B.A. ***** The Ohio State University 2008 Dissertation Committee: Professor Kun Huang, Adviser Professor Jeffery Kuret Approved by Professor Randy Nelson Professor Daniel Janies ------------------------------------------- Adviser Integrated Biomedical Science Graduate Program ABSTRACT Most current cancer research is focused on tissue-specific genetic mutations. Familial inheritance (e.g., APC in colon cancer), genetic mutation (e.g., p53), and overexpression of growth receptors (e.g., Her2-neu in breast cancer) can potentially lead to aberrant replication of a cell. Studies of these changes provide tremendous information about tissue-specific effects but are less informative about common changes that occur in multiple tissues. The similarity in the behavior of cancers from different organ systems and species suggests that a pervasive mechanism drives carcinogenesis, regardless of the specific tissue or species. In order to detect this mechanism, I applied three tiers of analysis at different levels: hypothesis testing on individual pathways to identify significant expression changes within each dataset, intersection of results between different datasets to find common themes across experiments, and Pearson correlations between individual genes to identify correlated genes within each dataset. By comparing a variety of cancers from different tissues and species, I was able to separate tissue and species specific effects from cancer specific effects. I found that downregulation of Monoamine Oxidase A is an indicator of this pervasive mechanism and can potentially be used to detect pathways and functions related to the initiation, promotion, and progression of cancer.
    [Show full text]