DOCSLIB.ORG

Systems Biology Approaches to Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Modeling Biological Systems and Analyzing Large-Scale Data Sets ilya shmulevich TCGA Data Types TCGA Research Network Heterogeneous data Clinical variables contributing to tumor aggressiveness Less More Aggressive Aggressive Distant M0=No M1=Yes Metastasis Tumor Stage Early (I-II) Late(III-IV) Fraction Lymph Nodes 0 100 % Positive by H & E Lymphatic No Yes Invasion Present Vascular No Yes Invasion Present Histological Mucinous Non- Type mucinous Vesteinn Thorsson Nature, 487,330- 337, 2012. FBXW7 Vesteinn Thorsson Nature, 487,330- Vesteinn Thorsson 337, 2012. Nature, 487,330- Vesteinn Thorsson, Dick 337, 2012. Kreisberg Web-based Apps http://explorer.cancerregulome.org The Regulome Explorer is an interactive web application that allows the user to explore multivariate relationships in data explorer.cancerregulome.org Richard Kreisberg, Jake Lin, Timo Erkkila, Sheila Reynolds explorer.cancerregulome.org RF-ACE, a multivariate statistical inference method based on ensembles of decision trees, which seeks to uncover significant associations between features in the input data matrix. Timo Erkkilä, Sheila Reynolds, Kari Torkkola RF-ACE has high predictive power and is resistant to over- fitting. http://code.google.com/p/rf-ace/ Computational challenges: • mixed data types: continuous, RF-ACE features: discrete, and categorical • handles mixed variable types • tens of thousands of features • does not require imputation of x tens or hundreds of samples missing values • non-linear, noisy, and • random subsampling rather than multivariate relationships combinatorial search • correlated features • statistical testing removes redundant • missing data features • -value for each candidate predictor • fast, portable implementation in C++ Timo Erkkilä Google I/O keynote presentation 600,000 cores June 27, 2012 A multilevel pan-cancer view: from genes to hallmarks Theo Knijnenburg Mutational investment Billions of Associations! explorer.cancerregulome.org Motivating questions • Repurposing – Which existing cancer drugs may be therapeutic in which other cancers? – Which inhibitors with no current cancer indications may be therapeutic in certain cancers? • Opportunity – TCGA primary tumor data may serve as the basis for guided investigation of these open questions Guiding principle • The direct protein target for most inhibitors is not the sensitizing aberrated protein itself – e.g., AKT1 inhibitors are most effective against cell lines with PTEN mutations Song et al. (2012) Proof of concept: Associations between drug targets (e.g., AKT1) and sensitizing aberrations (e.g., PTEN) also evident in TCGA PTEN mutations in UCEC AKT1 protein expression related to PTEN mutation in UCEC PTEN mutation status Proof of concept: Associations between drug targets (e.g., AKT1) and sensitizing aberrations (e.g., PTEN) also evident in TCGA Association drug target : sensitizing aberration pairs Approach • Create large heterogeneous graph of associations from TCGA data, literature, databases, … – [Billions of edges, Terabytes of data] • Query on Cray YarcData uRiKA graph analytics appliance – No locality of reference, graphs hard to partition – [Minutes rather than hours per query] Synthetic lethal protein targets Candidate compounds ATR CHEK1 Genomic Aberration PAK3 TP53 mutation PLK1 • Identify aberrated gene → target → drug … SGK2 … relationships for drugs with and without WEE1 known efficacy in cancer Integrating multiple data sources into a (big) graph Genomic aberrations Therapeutic targets Candidate inhibitors RNAi Graph Data Model: Resource Description Framework (RDF) 1 0.2515 <http://www.systemsbiology.net/nmd#combocount> <http://www.systemsbiology.net/nmd#nmd> _:blankGeneNMD <http://www.systemsbiology.net/nmd#term2> <http://www.systemsbiology.net/nmd#term1> http://www.systemsbiolo http://www.systemsbiolo gy.net/brca2> gy.net/tp53> <http://www.systemsbiology.net/feature#label> <http://www.systemsbiology.net/nmd#term1> _:blankDrugGeneNMD <http://www.systemsbiology.net/tp5 <http://www.systemsbiology.net/feature#source 3y_n_somatic> > <http://www.systemsbiology.net/nmd#nmd> <http://www.systemsbiology.net/nmd#term2> <http://www.systemsbiology.net/feature#source> <http://www.systemsbiology.net/association#feature1> http://www.systemsbiolo 1.1628 gnab gy.net/biotin> _:blankPairwise <http://www.w3.org/1999/02/22-rdf-syntax-ns#type> <http://www.systemsbiology.net/association#datas et> <http://www.systemsbiology.net/association#feature2> http://www.systemsbiolo gy.net/Drug> <http://www.systemsbiology.net/g brca_05nov ata3gexp> <http://www.systemsbiology.net/association#correlation> <http://www.systemsbiology.net/feature#source> -0.511 gexp Example SPARQL Query Literature Literature Seed Gene TCGA Associated Small Cancer List Genes Molecules Type cancer.gov approved drugs Database Example Result: PTEN associations in UCEC Genomic aberrations Candidate targets Candidate inhibitors Acepromazine Acitretin Adapalene Adenine Adenosine monophosphate Adenosine triphosphate Adinazolam Alfuzosin Alitretinoin Allylestrenol Alpha-Linolenic Acid Alprazolam Alteplase Aminocaproic Acid Amiodarone Amitriptyline Amoxapine Amsacrine Anistreplase Aprotinin Arcitumomab Aripiprazole Astemizole Atomoxetine Atorvastatin Bepridil Biotin Bromazepam Bromocriptine Bupropion Caffeine Capromab Carglumic acid ASRGL1 Carmustine Carvedilol Chlordiazepoxide Chlorotrianisene Chlorpheniramine Chlorpromazine ESR1 Cinolazepam Cisapride Clobazam Clomifene Clomipramine Clonazepam GLYATL2 Clorazepate Clotiazepam Clozapine Cocaine Conjugated Estrogens Cysteamine PLIN3 Danazol Dantrolene Dapiprazole Debrisoquin Desipramine Desogestrel HADH Desvenlafaxine Dexmethylphenidate Dextroamphetamine Diazepam Dicumarol Dienestrol NT5E Diethylpropion Diethylstilbestrol Dipyridamole Dofetilide Doxazosin Doxepin PIK3R3 Drospirenone Droxidopa Duloxetine Dutasteride Dydrogesterone Ephedra GABRE Ephedrine Epinephrine Ergotamine Escitalopram Estazolam Estradiol PGR Estramustine Estriol Estrone Estropipate Ethinyl Estradiol Ethynodiol Diacetate FBP1 Etonogestrel Felodipine Finasteride Fludiazepam Fluoxymesterone Flurazepam SMPD3 Fluticasone Propionate Fluvastatin Fulvestrant Gabapentin Galsulfase Ginkgo biloba GRIN1 Glutathione Glycine Guanadrel Sulfate Guanethidine Halazepam Halofantrine PIK3R1 Hydroxocobalamin Ibutilide Idursulfase Imipramine Isoproterenol Isradipine RARG Ketazolam Labetalol L-Alanine L-Arginine L-Asparagine L-Aspartic Acid AADAT L-Carnitine L-Citrulline L-Cysteine Levonordefrin Levonorgestrel L-Glutamic Acid CACNA2D2 L-Histidine Lindane Lisdexamfetamine L-Methionine Lorazepam L-Ornithine SST Lovastatin L-Proline L-Serine Maprotiline Mazindol Medroxyprogesterone SRD5A1 Megestrol Melatonin Menadione Meperidine Mestranol Methamphetamine B4GALT1 Methotrimeprazine Methoxamine Methylphenidate Mianserin Miconazole Midazolam ADRA1B Midodrine Mifepristone Milnacipran Modafinil N-Acetyl-D-glucosamine NADH KCNJ12 Naloxone Nefazodone Nicardipine Nitrazepam Nitrendipine Norelgestromin RYR1 Norepinephrine Norethindrone Norgestimate Nortriptyline Olanzapine Olopatadine SLC6A14 Orphenadrine Oxazepam Paliperidone Paroxetine Pentostatin Pentoxifylline RETSAT Pergolide Phendimetrazine Phenmetrazine Phentermine Phenylephrine Phosphatidylserine FAAH Pimozide Pravastatin Prazepam Prazosin Progesterone Promazine SRR Propafenone Propericiazine Propiomazine Protriptyline Pseudoephedrine Pyridoxine NQO1 Quazepam Quetiapine Quinestrol Quinidine Raloxifene Reboxetine CEACAM1 Reteplase Risperidone Rosuvastatin S-Adenosylmethionine Sertindole Sibutramine KCNK6 Simvastatin Sotalol Streptokinase Suramin Tamoxifen Tamsulosin ACADS Tazarotene Temazepam Tenecteplase Terazosin Terfenadine Tetracycline CRAT Thiopental Thioproperazine Thioridazine Toremifene PTEN Tramadol Tranexamic Acid ELOVL4 Tretinoin Triazolam Trilostane Trimipramine Urokinase Venlafaxine FOLH1 Verapamil Vitamin A Xylometazoline Ziprasidone ALDH1A3 Zonisamide SORD ASS1 NADSYN1 PRNP NDUFA11 KCNH2 CPS1 SLC22A5 HMGCR ALDH18A1 PARS2 GLS B4GALT4 ACACB SLC38A3 GSR OAZ3 TCN1 SLC1A1 SMPD4 BHMT2 HSD17B4 GRIK5 GLDC PPIB PIPOX ADA SCN3B S100A1 PLG SLC1A4 CBS GLRB ACVR1B SLC6A2 Example Result: PTEN associations in UCEC Genomic aberrations Candidate targets Candidate inhibitors PTEN PIK3R1/PIK3CA Wortmannin PTEN mutation status PDB id 3hhm Repurposing existing cancer drugs in other cancers Genomic aberrations Candidate targets Candidate inhibitors Existing cancer indication Target Cancer Drug A New cancer indication Example Result • TP53 is frequently mutated in most tumor types • ABCG2, also known as Breast Cancer Resistance Protein (BCRP), is associated with TP53 mutation in TCGA breast cancer data • Nelfinavir, an HIV protease inhibitor, also binds ABCG2 and many other proteins • High-throughput cell line screening of breast cancer cells recently identified Nelfinavir as a selective inhibitor. “It can be brought to HER2-breast cancer treatment trials with the same dosage regimen as that used among HIV patients. “ [Shim et al. JNCI 2012] Understanding behavior of massive multicellular systems: BioCellion Source: http://www.sjrcd.org/soilhealth/soilagg.html Source: http://www.theregister.co.uk source: EMBO Rep. 2004 May; 5(5): 470–476. Ductal Carcinoma model: Nicholas Flann, Utah State Univ. Source: http://www.webmd.com Acknowledgments Brady Bernard, Ryan Bressler, Andrea Eakin, Timo Erkkilä, Lisa Iype, Seunghwa Kang, Theo Knijnenburg, Roger Kramer, Richard Kreisberg, Kalle Leinonen, Jake Lin, Yuexin Liu, Michael Miller, Sheila Reynolds, Hector Rovira, Vesteinn Thorsson, Da Yang, Wei Zhang .
Recommended publications
  • Supplement Ii to the Japanese Pharmacopoeia Fifteenth Edition

    Supplement Ii to the Japanese Pharmacopoeia Fifteenth Edition

    SUPPLEMENT II TO THE JAPANESE PHARMACOPOEIA FIFTEENTH EDITION Official From October 1, 2009 English Version THE MINISTRY OF HEALTH, LABOUR AND WELFARE Notice: This English Version of the Japanese Pharmacopoeia is published for the conven- ience of users unfamiliar with the Japanese language. When and if any discrepancy arises between the Japanese original and its English translation, the former is authentic. The Ministry of Health, Labour and Welfare Ministerial Notification No. 425 Pursuant to Paragraph 1, Article 41 of the Pharmaceutical Affairs Law (Law No. 145, 1960), we hereby revise a part of the Japanese Pharmacopoeia (Ministerial Notification No. 285, 2006) as follows*, and the revised Japanese Pharmacopoeia shall come into ef- fect on October 1, 2009. However, in the case of drugs which are listed in the Japanese Pharmacopoeia (hereinafter referred to as “previous Pharmacopoeia”) [limited to those listed in the Japanese Pharmacopoeia whose standards are changed in accordance with this notification (hereinafter referred to as “new Pharmacopoeia”)] and drugs which have been approved as of October 1, 2009 as prescribed under Paragraph 1, Article 14 of the same law [including drugs the Minister of Health, Labour and Welfare specifies (the Ministry of Health and Welfare Ministerial Notification No. 104, 1994) as those ex- empted from marketing approval pursuant to Paragraph 1, Article 14 of the Pharmaceu- tical Affairs Law (hereinafter referred to as “drugs exempted from approval”)], the Name and Standards established in the previous Pharmacopoeia (limited to part of the Name and Standards for the drugs concerned) may be accepted to conform to the Name and Standards established in the new Pharmacopoeia before and on March 31, 2011.
  • (19) United States (12) Patent Application Publication (10) Pub

    (19) United States (12) Patent Application Publication (10) Pub

    US 20130289061A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0289061 A1 Bhide et al. (43) Pub. Date: Oct. 31, 2013 (54) METHODS AND COMPOSITIONS TO Publication Classi?cation PREVENT ADDICTION (51) Int. Cl. (71) Applicant: The General Hospital Corporation, A61K 31/485 (2006-01) Boston’ MA (Us) A61K 31/4458 (2006.01) (52) U.S. Cl. (72) Inventors: Pradeep G. Bhide; Peabody, MA (US); CPC """"" " A61K31/485 (201301); ‘4161223011? Jmm‘“ Zhu’ Ansm’ MA. (Us); USPC ......... .. 514/282; 514/317; 514/654; 514/618; Thomas J. Spencer; Carhsle; MA (US); 514/279 Joseph Biederman; Brookline; MA (Us) (57) ABSTRACT Disclosed herein is a method of reducing or preventing the development of aversion to a CNS stimulant in a subject (21) App1_ NO_; 13/924,815 comprising; administering a therapeutic amount of the neu rological stimulant and administering an antagonist of the kappa opioid receptor; to thereby reduce or prevent the devel - . opment of aversion to the CNS stimulant in the subject. Also (22) Flled' Jun‘ 24’ 2013 disclosed is a method of reducing or preventing the develop ment of addiction to a CNS stimulant in a subj ect; comprising; _ _ administering the CNS stimulant and administering a mu Related U‘s‘ Apphcatlon Data opioid receptor antagonist to thereby reduce or prevent the (63) Continuation of application NO 13/389,959, ?led on development of addiction to the CNS stimulant in the subject. Apt 27’ 2012’ ?led as application NO_ PCT/US2010/ Also disclosed are pharmaceutical compositions comprising 045486 on Aug' 13 2010' a central nervous system stimulant and an opioid receptor ’ antagonist.
  • (12) United States Patent (10) Patent No.: US 6,319,953 B1 Carlson Et Al

    (12) United States Patent (10) Patent No.: US 6,319,953 B1 Carlson Et Al

    US006319953B1 (12) United States Patent (10) Patent No.: US 6,319,953 B1 Carlson et al. (45) Date of Patent: *Nov. 20, 2001 (54) TREATMENT OF DEPRESSION AND WO 95/08549 3/1995 (W0). ANXIETY WITH FLUOXETINE AND AN WO 95/18124 7/1995 (W0). NK-1 RECEPTOR ANTAGONIST W0 96/05181 2/1996 (W0). W0 96/18643 6/1996 (W0). (75) Inventors: Emma Joanne Carlson, Puckeridge; W0 96/19233 6/1996 (W0). Nadia Melanie Rupniak, Bishops W0 96/24353 8/1996 (W0). W0 98/15277 4/1998 (W0). Stortford, both of (GB) OTHER PUBLICATIONS (73) Assignee: Merck Sharp & Dohme Ltd., Hoddesdon (GB) Aguiar, M., et al., Physiology& Behavior, 1996, 60(4) 1183—1186. ( * ) Notice: Subject to any disclaimer, the term of this Barden, N., et al., J. Neurochem., 1983, 41, 834—840. patent is extended or adjusted under 35 BristoW, L., et al., Eur J. Pharmacol., 1994, 253, 245—252. U.S.C. 154(b) by 0 days. Brodin, E., et al., Neuropharmacology, 1987, 26(6) 581—590. This patent is subject to a terminal dis Brodin, E., et al., Neuropeptides, 1994, 26, 253—260. claimer. Culman, J., et al., J. Physiol. Pharmacol., 1995, 73, 885—891. Cutler, et al., J. Psychopharmacol, 1994, 8, A22, 87. (21) Appl. N0.: 09/457,241 Elliott, P. J., Exp. Brain Res. UK, 1988, 73, 354—356. (22) Filed: Dec. 8, 1999 F—D—C Reports—Prescription Pharmaceuticals and Bio technology, Dec. 8, 1997, 59(49), 10. Related US. Application Data File, S. E., Pharm. Biochem. Behavior, 1997, 58, 3, 747—752. (60) Division of application No.
  • A Drug Repositioning Approach Identifies Tricyclic Antidepressants As Inhibitors of Small Cell Lung Cancer and Other Neuroendocrine Tumors

    A Drug Repositioning Approach Identifies Tricyclic Antidepressants As Inhibitors of Small Cell Lung Cancer and Other Neuroendocrine Tumors

    Published OnlineFirst September 26, 2013; DOI: 10.1158/2159-8290.CD-13-0183 RESEARCH ARTICLE A Drug Repositioning Approach Identifi es Tricyclic Antidepressants as Inhibitors of Small Cell Lung Cancer and Other Neuroendocrine Tumors Nadine S. Jahchan 1 , 2 , Joel T. Dudley 1 , Pawel K. Mazur 1 , 2 , Natasha Flores 1 , 2 , Dian Yang 1 , 2 , Alec Palmerton 1 , 2 , Anne-Flore Zmoos 1 , 2 , Dedeepya Vaka 1 , 2 , Kim Q.T. Tran 1 , 2 , Margaret Zhou 1 , 2 , Karolina Krasinska 3 , Jonathan W. Riess 4 , Joel W. Neal 5 , Purvesh Khatri 1 , 2 , Kwon S. Park 1 , 2 , Atul J. Butte 1 , 2 , and Julien Sage 1 , 2 Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst September 26, 2013; DOI: 10.1158/2159-8290.CD-13-0183 ABSTRACT Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug repositioning bioinformat- ics approach querying a large compendium of gene expression profi les to identify candidate U.S. Food and Drug Administration (FDA)–approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endog- enous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein–coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma.
  • CAS Number Index

    CAS Number Index

    2334 CAS Number Index CAS # Page Name CAS # Page Name CAS # Page Name 50-00-0 905 Formaldehyde 56-81-5 967 Glycerol 61-90-5 1135 Leucine 50-02-2 596 Dexamethasone 56-85-9 963 Glutamine 62-44-2 1640 Phenacetin 50-06-6 1654 Phenobarbital 57-00-1 514 Creatine 62-46-4 1166 α-Lipoic acid 50-11-3 1288 Metharbital 57-22-7 2229 Vincristine 62-53-3 131 Aniline 50-12-4 1245 Mephenytoin 57-24-9 1950 Strychnine 62-73-7 626 Dichlorvos 50-23-7 1017 Hydrocortisone 57-27-2 1428 Morphine 63-05-8 127 Androstenedione 50-24-8 1739 Prednisolone 57-41-0 1672 Phenytoin 63-25-2 335 Carbaryl 50-29-3 569 DDT 57-42-1 1239 Meperidine 63-75-2 142 Arecoline 50-33-9 1666 Phenylbutazone 57-43-2 108 Amobarbital 64-04-0 1648 Phenethylamine 50-34-0 1770 Propantheline bromide 57-44-3 191 Barbital 64-13-1 1308 p-Methoxyamphetamine 50-35-1 2054 Thalidomide 57-47-6 1683 Physostigmine 64-17-5 784 Ethanol 50-36-2 497 Cocaine 57-53-4 1249 Meprobamate 64-18-6 909 Formic acid 50-37-3 1197 Lysergic acid diethylamide 57-55-6 1782 Propylene glycol 64-77-7 2104 Tolbutamide 50-44-2 1253 6-Mercaptopurine 57-66-9 1751 Probenecid 64-86-8 506 Colchicine 50-47-5 589 Desipramine 57-74-9 398 Chlordane 65-23-6 1802 Pyridoxine 50-48-6 103 Amitriptyline 57-92-1 1947 Streptomycin 65-29-2 931 Gallamine 50-49-7 1053 Imipramine 57-94-3 2179 Tubocurarine chloride 65-45-2 1888 Salicylamide 50-52-2 2071 Thioridazine 57-96-5 1966 Sulfinpyrazone 65-49-6 98 p-Aminosalicylic acid 50-53-3 426 Chlorpromazine 58-00-4 138 Apomorphine 66-76-2 632 Dicumarol 50-55-5 1841 Reserpine 58-05-9 1136 Leucovorin 66-79-5
  • Transdermal Drug Delivery Device Including An

    Transdermal Drug Delivery Device Including An

    (19) TZZ_ZZ¥¥_T (11) EP 1 807 033 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61F 13/02 (2006.01) A61L 15/16 (2006.01) 20.07.2016 Bulletin 2016/29 (86) International application number: (21) Application number: 05815555.7 PCT/US2005/035806 (22) Date of filing: 07.10.2005 (87) International publication number: WO 2006/044206 (27.04.2006 Gazette 2006/17) (54) TRANSDERMAL DRUG DELIVERY DEVICE INCLUDING AN OCCLUSIVE BACKING VORRICHTUNG ZUR TRANSDERMALEN VERABREICHUNG VON ARZNEIMITTELN EINSCHLIESSLICH EINER VERSTOPFUNGSSICHERUNG DISPOSITIF D’ADMINISTRATION TRANSDERMIQUE DE MEDICAMENTS AVEC COUCHE SUPPORT OCCLUSIVE (84) Designated Contracting States: • MANTELLE, Juan AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Miami, FL 33186 (US) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • NGUYEN, Viet SK TR Miami, FL 33176 (US) (30) Priority: 08.10.2004 US 616861 P (74) Representative: Awapatent AB P.O. Box 5117 (43) Date of publication of application: 200 71 Malmö (SE) 18.07.2007 Bulletin 2007/29 (56) References cited: (73) Proprietor: NOVEN PHARMACEUTICALS, INC. WO-A-02/36103 WO-A-97/23205 Miami, FL 33186 (US) WO-A-2005/046600 WO-A-2006/028863 US-A- 4 994 278 US-A- 4 994 278 (72) Inventors: US-A- 5 246 705 US-A- 5 474 783 • KANIOS, David US-A- 5 474 783 US-A1- 2001 051 180 Miami, FL 33196 (US) US-A1- 2002 128 345 US-A1- 2006 034 905 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations.
  • Eg Phd, Mphil, Dclinpsychol

    Eg Phd, Mphil, Dclinpsychol

    This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: • This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. • A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. • This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. • The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. • When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Equine laminitis pain and modulatory mechanisms at a potential analgesic target, the TRPM8 ion channel Ignacio Viñuela-Fernández Thesis presented for the degree of Doctor of Philosophy The College of Medicine and Veterinary Medicine The University of Edinburgh 2011 DECLARATION I hereby declare that the composition of this thesis and the work presented are my own, with the exception of the ATF-3 and NPY immunohistochemistry which was carried out by Emma Jones. The contribution of others is also appropriately credited. Some of the data included in this thesis have been published and are included in the Appendix. Ignacio Viñuela-Fernández i ACKNOWLEDGEMENTS This work was supported by a Scholarship from the Royal (Dick) Veterinary School at Edinburgh University. I would like to thank Professor Sue Fleetwood- Walker and Dr Rory Mitchell for their supervision, support and guidance throughout my PhD.
  • Comparison of Electropharmacological Effects of Bepridil and Sotalol in Halothane-Anesthetized Dogs

    Comparison of Electropharmacological Effects of Bepridil and Sotalol in Halothane-Anesthetized Dogs

    Circ J 2008; 72: 1003–1011 Comparison of Electropharmacological Effects of Bepridil and Sotalol in Halothane-Anesthetized Dogs Tomomichi Ishizaka, DVM*,**; Akira Takahara, PhD*; Hiroshi Iwasaki, MD*; Yoshitaka Mitsumori, MD*; Hiroaki Kise, MD*; Yuji Nakamura, MS*; Atsushi Sugiyama, MD*,** Background Bepridil is known to have a multiple ion channel-blocking property in the heart, which has been applied for the treatment of atrial fibrillation and drug-refractory ventricular tachyarrhythmias. In this study, the electro-pharmacological effects of bepridil were compared with those of dl-sotalol, a representative class III anti- arrhythmic drug, using the halothane-anesthetized canine model. Methods and Results Cardiovascular and electrophysiological variables were measured under the halothane anesthesia. Intravenous administration of bepridil (0.3mg/kg, n=4) delayed the intraventricular conduction and prolonged the ventricular effective refractory period, whereas dl-sotalol (0.3mg/kg, iv, n=4) inhibited atrioven- tricular conduction and prolonged the atrial and ventricular effective refractory period. The additional adminis- tration of 10 times the higher dose of bepridil or dl-sotalol (ie, 3mg/kg, iv, n=4 for each group) decreased blood pressure, suppressed ventricular contraction and sinus automaticity, and prolonged the atrial and ventricular effective refractory period and monophasic action potential duration, in addition to the effects of the low dose. Conclusions The electropharmacological effects of bepridil and dl-sotalol were similar,
  • Evaluation and Management of Chronic Hepatitis C Virus Infection

    Evaluation and Management of Chronic Hepatitis C Virus Infection

    EVALUATION AND MANAGEMENT OF CHRONIC HEPATITIS C VIRUS (HCV) INFECTION Federal Bureau of Prisons Clinical Guidance MAY 2017 Federal Bureau of Prisons (BOP) Clinical Guidance is made available to the public for informational purposes only. The BOP does not warrant this guidance for any other purpose, and assumes no responsibility for any injury or damage resulting from the reliance thereof. Proper medical practice necessitates that all cases are evaluated on an individual basis and that treatment decisions are patient- specific. Consult the BOP Health Management Resources Web page to determine the date of the most recent update to this document: http://www.bop.gov/resources/health_care_mngmt.jsp. Federal Bureau of Prisons Evaluation and Management of Chronic HCV Infection Clinical Guidance May 2017 WHAT’S NEW IN BOP GUIDANCE REGARDING HCV INFECTION? The major changes included in this May 2017 update to the BOP guidance on chronic HCV infection are based primarily on the April 2017 changes to the American Association for the Study of Liver Diseases (AASLD) guidelines, as follows: • The term resistance-associated substitutions (RASs) is now being used instead of resistance- associated variants (RAVs). • Anti-HBs and anti-HBc, in addition to HBsAg, are recommended for baseline testing of hepatitis B status (see LABORATORY TESTS under BASELINE EVALUATION). • Ledipasvir/sofosbuvir once daily for eight weeks is now an AASLD-recommended regimen for treatment in a subgroup of HCV-infected persons who have genotype 1a or 1b, have an HCV viral load <6 million IU/ml, and are treatment-naïve—but who are not black, are not HIV-coinfected, and do not have cirrhosis.
  • A Small Molecular Activator of Cardiac Hypertrophy Uncovered in a Chemical Screen for Modifiers of the Calcineurin Signaling Pathway

    A Small Molecular Activator of Cardiac Hypertrophy Uncovered in a Chemical Screen for Modifiers of the Calcineurin Signaling Pathway

    A small molecular activator of cardiac hypertrophy uncovered in a chemical screen for modifiers of the calcineurin signaling pathway Erik Bush*†, Jens Fielitz‡, Lawrence Melvin*, Michael Martinez-Arnold‡, Timothy A. McKinsey*, Ryan Plichta*, and Eric N. Olson†‡ *Myogen, Incorporated, Westminster, CO 80021; and ‡Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148 Contributed by Eric N. Olson, January 5, 2004 The calcium, calmodulin-dependent phosphatase calcineurin, regu- ative roles for these proteins in the control of calcineurin activity. lates growth and gene expression of striated muscles. The activity of Overexpression of MCIP1 (also called Down syndrome critical calcineurin is modulated by a family of cofactors, referred to as region 1), for example, suppresses calcineurin signaling (12). In modulatory calcineurin-interacting proteins (MCIPs). In the heart, the contrast, MCIP1 also seems to potentiate calcineurin signaling, MCIP1 gene is activated by calcineurin and has been proposed to as demonstrated by the diminution of calcineurin activity in the fulfill a negative feedback loop that restrains potentially pathological hearts of MCIP1 knockout mice (13). Intriguingly, the MCIP1 calcineurin signaling, which would otherwise lead to abnormal car- gene is a target of NFAT and is up-regulated in response to diac growth. In a high-throughput screen for small molecules capable calcineurin signaling (15), which has been proposed to create a of regulating MCIP1 expression in muscle cells, we identified a unique negative feedback loop that dampens calcineurin activity, which 4-aminopyridine derivative exhibiting an embedded partial structural would otherwise lead to abnormal cardiac growth. motif of serotonin (5-hydroxytryptamine, 5-HT).
  • Comparison of In-Cell Immunoassay and Automated Electrophysiology for Assessment of Herg Trafficking Liability for New Drugs

    Comparison of In-Cell Immunoassay and Automated Electrophysiology for Assessment of Herg Trafficking Liability for New Drugs

    Comparison of in-cell immunoassay and automated electrophysiology for assessment of hERG trafficking liability for new drugs Yuri Kuryshev, Peter Hawryluk, Caiyun Wu, Abby Sewell, James Kramer, Carlos Obejero-Paz, Luke Armstrong, Arthur M. Brown Charles River, Cleveland, Ohio, USA IWB/PPC 1 h IWB/PPC 24 h 1.8 1.8 hERG-Lite 16 h hERG-Lite 1 h 1 3 1.6 Abstract Results 1.6 4 Summary 1.4 1.4 hERG-Lite® is an antibody-based chemiluminescent assay that identifies compounds that disrupt Voltage clamp population patch: functional assay for 1.2 1.2 trafficking or suppress expression of hERG channel protein. Electrophysiological recording from measuring relative changes in membrane surface hERG 1.0 1.0 hERG-Lite® : in-cell immunoassay for measuring relative single cell using the manual patch-clamp technique is more direct way to quantify hERG expression in 0.8 0.8 0.6 0.6 cell membrane but this method has critical limitations: low throughput and selection bias during choice channelAa levels Ab Vehicle Control Pentamidine changes in hERG channel surface levels 24 hr. 1 hr. 0.4 0.4 Fraction of Control Fraction of Control of cells for patching. Application of the automated population patch clamp technique for the hERG 1hr. 30 M/1 hr. 30 M 30 M 0.2 0.2 VC Pent. VC Pent. expression analysis provides a dramatic increase in throughput and eliminates the cell selection bias. 0.0 0.0 hERG-Lite WB* IWB/PPC We analyzed a panel of drugs (Amiodarone, Amitriptyline, Bepridil, Diphenhydramine, Dofetilide, 0.03 0.1 0.3 1 0.03 0.1 0.3 1 Amiodarone ↓ ↓ N.D.** Fluoxetine, Imipramine, Ouabaine, Pentamidine, Pimozide, Sunitinib and Verapamil) for chronic effects Pimozide, M Pimozide, M Amitriptyline ↓ ↓ ↓ on hERG channel trafficking and expression by the hERG-Lite® method and with IonWorks Barracuda IWB/PPC 1 h IWB/PPC 24 h hERG-Lite 1 h hERG-Lite 16 h (IWB), a population-based automated patch clamp platform.
  • (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau Et Al

    (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau Et Al

    US 20150202317A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau et al. (43) Pub. Date: Jul. 23, 2015 (54) DIPEPTDE-BASED PRODRUG LINKERS Publication Classification FOR ALPHATIC AMNE-CONTAINING DRUGS (51) Int. Cl. A647/48 (2006.01) (71) Applicant: Ascendis Pharma A/S, Hellerup (DK) A638/26 (2006.01) A6M5/9 (2006.01) (72) Inventors: Harald Rau, Heidelberg (DE); Torben A 6LX3/553 (2006.01) Le?mann, Neustadt an der Weinstrasse (52) U.S. Cl. (DE) CPC ......... A61K 47/48338 (2013.01); A61 K3I/553 (2013.01); A61 K38/26 (2013.01); A61 K (21) Appl. No.: 14/674,928 47/48215 (2013.01); A61M 5/19 (2013.01) (22) Filed: Mar. 31, 2015 (57) ABSTRACT The present invention relates to a prodrug or a pharmaceuti Related U.S. Application Data cally acceptable salt thereof, comprising a drug linker conju (63) Continuation of application No. 13/574,092, filed on gate D-L, wherein D being a biologically active moiety con Oct. 15, 2012, filed as application No. PCT/EP2011/ taining an aliphatic amine group is conjugated to one or more 050821 on Jan. 21, 2011. polymeric carriers via dipeptide-containing linkers L. Such carrier-linked prodrugs achieve drug releases with therapeu (30) Foreign Application Priority Data tically useful half-lives. The invention also relates to pharma ceutical compositions comprising said prodrugs and their use Jan. 22, 2010 (EP) ................................ 10 151564.1 as medicaments. US 2015/0202317 A1 Jul. 23, 2015 DIPEPTDE-BASED PRODRUG LINKERS 0007 Alternatively, the drugs may be conjugated to a car FOR ALPHATIC AMNE-CONTAINING rier through permanent covalent bonds.