DOCSLIB.ORG

Discovery of Novel Molecular and Biochemical Predictors of Response and Outcome in Diffuse Large B-Cell Lymphoma Last, Kim William

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Discovery of Novel Molecular and Biochemical Predictors of Response and Outcome in Diffuse Large B-Cell Lymphoma Last, Kim William Discovery of novel molecular and biochemical predictors of response and outcome in diffuse large B-cell lymphoma Last, Kim William The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author For additional information about this publication click this link. https://qmro.qmul.ac.uk/jspui/handle/123456789/563 Information about this research object was correct at the time of download; we occasionally make corrections to records, please therefore check the published record when citing. For more information contact [email protected] Discovery of Novel Molecular and Biochemical Predictors of Response and Outcome in Diffuse Large B-cell Lymphoma Kim William Last A thesis submitted for the degree of Doctor of Philosophy At the University of London Cancer Research UK Centre of Medical Oncology St Bartholomew’s Hospital Queen Mary University of London, London UK 2008 1 Abstract ABSTRACT Discovery of Novel Molecular and Biochemical Predictors of Response and Outcome in Diffuse Large B-cell Lymphoma Diffuse large B-cell lymphoma (DLBCL) is the commonest form of non-Hodgkin lymphoma and responds to treatment with a 5-year overall survival (OS) of 40-50%. Predicting outcome using the best available method, the International Prognostic Index (IPI), is inaccurate and unsatisfactory. This thesis describes research undertaken to discover, explore and validate new molecular and biochemical predictors of response and long-term outcome with the aims of improving on the inaccurate IPI and of suggesting novel therapeutic approaches. Two strategies were adopted: a rational and an empirical approach. The rational strategy used gene expression profiling to identify transcriptional signatures that correlated with outcome to treatment and from which a model of 13-genes accurately predict long-term OS. Two components of the 13-gene model, PKC and PDE4B, were studied using inhibitors in lymphoma cell-lines and primary cell cultures. PKC inhibition using SC-236 proved to be cytostatic and cytotoxic in the cell-lines examined and to a lesser extent in primary tumours. PDE4 inhibition using piclamilast and rolipram had no effect either alone or in combination with chemotherapy. The empirical approach investigated the trace element selenium in presentation serum and found that it was a biochemical predictor of response and outcome to treatment. In an attempt to provide evidence of a causal relationship as an explanation for the associations between presentation serum selenium, response and outcome, two selenium compounds, methylseleninic acid (MSA) and selenodiglutathione (SDG) were studied in vitro in the same lymphoma cell-lines and primary cell cultures. Both MSA and SDG exhibited cytostatic and cytotoxic activity and caspase-8 and caspase-9 driven apoptosis. For SDG reactive oxygen species generation was important for its activity in three of the four cell-lines. In conclusion, molecular and biochemical predictors of response and survival were discovered in DLBCL that led to viable targets for drug intervention being validated in vitro. 2 Declaration I Dr Kim William Last hereby declare that this document is the work of my own hand. 3 Dedication I dedicate this thesis to my wife, Marie-Christine and my son, Raphael and to my late mum, without who’s unfailing love and support the completion of this work would have been impossible. I give heartfelt thanks to my brother and my ‘Aunty’ Ann for steadfast encouragement and belief in my abilities. 4 Acknowledgements ACKNOWLEDGEMENTS The work described in this thesis was carried out whilst I was a clinical research fellow at the Cancer Research UK Medical Oncology Unit at St Bartholomew’s Hospital. I am indebted to numerous of my scientific, medical and nursing colleagues for their support and encouragement throughout my time within the Unit and to the patients that donated material for research. In particular I wish to thank Dr Jude Fitzgibbon and Dr Simon Joel for scientific supervision, Dr’s Margaret Shipp and Todd Golub and their teams at the Dana Farber Cancer Centre and the Whitehead Institute for the opportunity to participate in their micro-array project and Professor T Andrew Lister and Professor Ama Rohatiner for supervision of the translational and clinical aspects of the research undertaken. I will always be grateful to CR-UK for their generous funding of the clinical research fellowship I held and the charity’s enlightened and enabling ethos towards my time in research. Of the many others who have helped me I would like to mention Dr Lindsey Goff, Ms Suzanne Jordan, Dr Andrew Norton, Dr Abigail Lee for assistance with immunohistochemistry; Dr Silvana Debarnardi, Dr Spouros Sgouros for assistance with gene expression profiling; Dr Wai Liu, Dr Sandra Strauss, Dr Theresa Davis, Ms Lenushka Maharaj, Ms Jackie Perrie and Mr Patrick Grimshaw for assistance with cell culture and FACS analysis; Dr Sandra Strauss with assistance with western blotting and Ms Jackie Perrie for assistance with annexin V and propidium iodide staining and FACS analysis and for performing the reactive oxygen species experiments; Mr Keith Adams, Ms Fauzia Khan and Mr Dave Wilkinson for assistance with patient material identification, reagent and equipment requirements; Mr Andrew Wilson and Dr Victoria Cornelius for clinical data collation and statistical analysis, Mr Linden and Mrs Ann Emery for proofreading and Mrs Margaret Cresswell and Ms Susan Chandler for tracking me down to ensure the thesis was submitted. 5 Individual Contributions INDIVIDUAL CONTRIBUTIONS Archived sample identification and retrieval: Kim Last Cell cycle FACS analysis: Kim Last Clinical data extraction and analysis: Kim Last and Andy Wilson Ethics approval: Jude Fitzgibbon, Simon Joel and Andrew Lister Histopathology review: Andrew Norton John Amess and Jon C. Aster In vitro proliferation, cell count and viability experiments: Kim Last Microarray project leadership Margaret A. Shipp & Todd R. Golub Microarray sample preparation: Michelle Gaasenbeek Microarray data analysis (US): Ken N. Ross, Pablo Tamayo, Michael Angelo, Michael Reich, Tane S. Ray, Jill Mesirov Microarray data analysis (UK): Spouros Sgouros N-acetyl cysteine in vitro experiments: Lenushka Maharaj Novel drug identification for in vitro studies: Kim Last and Jude Fitzgibbon Primary cell culture in vitro experiments: Kim Last and Lenushka Maharaj Propidium iodide and annexin V FACS analysis: Jackie Perrie Reactive Oxygen Species Measurement: Jackie Perrie Serum selenium measurement: Trevor Delves, Christine Sieniawska Statistics for serum selenium associations: Victoria Cornelius Western blotting: Sandra Strauss 6 Contents TABLE OF CONTENTS ACKNOWLEDGEMENTS 5 INDIVIDUAL CONTRIBUTIONS 6 TABLE OF CONTENTS 7 LIST OF TABLES 11 LIST OF FIGURES 12 LIST OF APPENDIX TABLES 16 ABBREVIATIONS 19 THESIS AIMS 26 CHAPTER 1: INTRODUCTION 27 1.1 PATHOGENESIS OF LYMPHOMA AND CANCER 27 1.1.1 The Process of Carcinogenesis 27 1.1.2 Impaired Apoptosis in NHL and Cancer 29 1.1.3 Impairment of the Intrinsic Apoptotic Pathway: Alterations in The Bcl-2 Family of Proteins 31 1.1.4 Impairment of the Extrinsic Apoptotic Pathway: Fas and TRAIL Death Receptor Signalling in NHL 32 1.1.5 Cell Cycle Deregulation in Cancer and Lymphoma 35 1.1.6 Resistance to Cell Cycle Arrest 36 1.2 DIFFUSE LARGE B-CELL LYMPHOMA 39 1.2.1 Pathology 39 1.2.2 Clinical Presentation and Natural History 42 1.2.3 Treatment 43 1.2.4 Epidemiology of DLBCL and NHL 51 1.2.5 Clinical Aetiolology of DLBCL 51 1.2.6 Prognostic Factors in DLBCL and other Lymphomas 56 1.3 GENETIC EVENTS IN LYMPHOMA AND DLBCL 67 1.3.1 Genetic Instability: an Integral Part of Tumourigenesis 67 1.3.2 Chromosomal Instability: Gains and Losses 68 1.3.3 Chromosomal Instability: Translocations in the NHLs 70 1.3.4 Epigenetic Changes in Lymphoma 76 1.4 APPLICATION OF EMPIRICAL AND RATIONAL RESEARCH STRATEGIES TO DISCOVER AND VALIDATE NOVEL FACTORS PREDICTIVE OF RESPONSE AND OUTCOME IN DLBCL 77 1.4.1 The Empirical Research Strategy: To Investigate Serum Selenium for Associations with Response and Outcome in DLBCL 79 1.4.2 The Physiological Role of Selenium 79 7 Contents 1.4.3 Dietary Sources of Selenium 81 1.4.4 Normal Daily Intake of Selenium 81 1.4.5 Selenium Deficiency 82 1.4.6 Selenosis: Selenium Toxicity 83 1.4.7 Selenium Metabolites And Chemoprevention 83 1.4.8 Selenium Intake and Cancer Risk 86 1.4.9 The Selenoproteome and Cancer 93 1.4.10 Molecular Mechanisms of Selenium Chemoprevention 94 1.4.11 The Rational Research Strategy: Identification of Gene Expression Signatures Predictive of Outcome in DLBCL 95 1.4.12 An Introduction to Microarray Technology 97 1.4.13 The Different Types of Microarray Platform 98 1.4.14 Expression Profiling in Cancer and DLBCL 100 1.4.15 Exploration and Validation of The Empirical and Rational Research Strategy Results 102 CHAPTER 2. MATERIALS AND METHODS 105 2.1 MICROARRAY AND EXPRESSION VALIDATION MATERIALS AND METHODS 105 2.1.1 Patients and their Samples 105 2.1.2 ‘Target’ preparation for Microarray 107 2.1.3 Data processing and analysis 108 2.1.4 Immunohistochemical Staining 109 2.2 PRESENTATION SERUM SELENIUM MATERIALS AND METHODS 110 2.2.1 Patient Samples, Histology and Clinical Variables Investigated 110 2.2.2 Treatment 112 2.2.3 Selenium Concentration Measurement 112 2.2.4 Statistical Methods 113 2.3 IN VITRO TARGET VALIDATION MATERIALS AND METHODS 117 2.3.1 Established Tumour Cell-lines 117 2.3.2 3-day Cell-line
Load more

Recommended publications
  • Effects of Phosphodiesterase Inhibitors on Human Lung Mast Cell and Basophil Function
    British Journal of Pharmacology (1997) 121, 287 ± 295 1997 Stockton Press All rights reserved 0007 ± 1188/97 $12.00 Eects of phosphodiesterase inhibitors on human lung mast cell and basophil function Marie C. Weston, Nicola Anderson & 1Peter T. Peachell Department of Medicine & Pharmacology, University of Sheeld, Royal Hallamshire Hospital (Floor L), Glossop Road, Sheeld S10 2JF 1 The non-hydrolysable cyclic AMP analogue, dibutyryl (Bu2)-cyclic AMP, inhibited the stimulated release of histamine from both basophils and human lung mast cells (HLMC) in a dose-dependent manner. The concentrations required to inhibit histamine release by 50% (IC50) were 0.8 and 0.7 mM in basophils and HLMC, respectively. The cyclic GMP analogue, Bu2-cyclic GMP, was ineective as an inhibitor of histamine release in basophils and HLMC. 2 The non-selective phosphodiesterase (PDE) inhibitors, theophylline and isobutyl-methylxanthine (IBMX) inhibited the IgE-mediated release of histamine from both human basophils and HLMC in a dose-dependent fashion. IBMX and theophylline were more potent inhibitors in basophils than HLMC. IC50 values for the inhibition of histamine release were, 0.05 and 0.2 mM for IBMX and theophylline, respectively, in basophils and 0.25 and 1.2 mM for IBMX and theophylline in HLMC. 3 The PDE 4 inhibitor, rolipram, attenuated the release of both histamine and the generation of sulphopeptidoleukotrienes (sLT) from activated basophils at sub-micromolar concentrations but was ineective at inhibiting the release of histamine and the generation of both sLT and prostaglandin D2 (PGD2) in HLMC. Additional PDE 4 inhibitors, denbufylline, Ro 20-1724, RP 73401 and nitraquazone, were all found to be eective inhibitors of mediator release in basophils but were ineective in HLMC unless high concentrations (1 mM) were employed.
    [Show full text]
  • Phosphodiesterase (PDE)
    Phosphodiesterase (PDE) Phosphodiesterase (PDE) is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases. The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators ofsignal transduction mediated by these second messenger molecules. www.MedChemExpress.com 1 Phosphodiesterase (PDE) Inhibitors, Activators & Modulators (+)-Medioresinol Di-O-β-D-glucopyranoside (R)-(-)-Rolipram Cat. No.: HY-N8209 ((R)-Rolipram; (-)-Rolipram) Cat. No.: HY-16900A (+)-Medioresinol Di-O-β-D-glucopyranoside is a (R)-(-)-Rolipram is the R-enantiomer of Rolipram. lignan glucoside with strong inhibitory activity Rolipram is a selective inhibitor of of 3', 5'-cyclic monophosphate (cyclic AMP) phosphodiesterases PDE4 with IC50 of 3 nM, 130 nM phosphodiesterase. and 240 nM for PDE4A, PDE4B, and PDE4D, respectively. Purity: >98% Purity: 99.91% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 10 mM × 1 mL, 10 mg, 50 mg (R)-DNMDP (S)-(+)-Rolipram Cat. No.: HY-122751 ((+)-Rolipram; (S)-Rolipram) Cat. No.: HY-B0392 (R)-DNMDP is a potent and selective cancer cell (S)-(+)-Rolipram ((+)-Rolipram) is a cyclic cytotoxic agent. (R)-DNMDP, the R-form of DNMDP, AMP(cAMP)-specific phosphodiesterase (PDE) binds PDE3A directly.
    [Show full text]
  • Rolipram, but Not Siguazodan Or Zaprinast, Inhibits the Excitatory Noncholinergic Neurotransmission in Guinea-Pig Bronchi
    Eur Respir J, 1994, 7, 306–310 Copyright ERS Journals Ltd 1994 DOI: 10.1183/09031936.94.07020306 European Respiratory Journal Printed in UK - all rights reserved ISSN 0903 - 1936 Rolipram, but not siguazodan or zaprinast, inhibits the excitatory noncholinergic neurotransmission in guinea-pig bronchi Y. Qian, V. Girard, C.A.E. Martin, M. Molimard, C. Advenier Rolipram, but not siguazodan or zaprinast, inhibits the excitatory noncholinergic neuro- Faculté de Médecine Paris-Ouest Labora- transmission in guinea-pig bronchi. Y. Qian, V. Girard C.A.E. Martin, M. Molimard, toire de Pharmacologie, Paris, France. C. Advenier. ERS Journals Ltd 1994. ABSTRACT: Theophylline has been reported to inhibit excitatory noncholinergic Correspondence: C. Advenier Faculté de Médecine Paris-Ouest but not cholinergic-neurotransmission in guinea-pig bronchi. As theophylline might Laboratoire de Pharmacologie exert this effect through an inhibition of phosphodiesterases (PDE), and since many 15, Rue de l'Ecole de Médecine types of PDE have now been described, the aim of this study was to investigate the F-75270 Paris Cedex 06 effects of three specific inhibitors of PDE on the electrical field stimulation (EFS) France of the guinea-pig isolated main bronchus in vitro. The drugs used were siguazo- dan, rolipram and zaprinast, which specifically inhibit PDE types, III, IV and V, Keywords: C-fibres respectively. neuropeptides Guinea-pig bronchi were stimulated transmurally with biphasic pulses (16 Hz, 1 phosphodiesterase inhibitors ms, 320 mA for 10 s) in the presence of indomethacin 10-6 M and propranolol 10-6 Received: March 11 1993 M. Two successive contractile responses were observed: a rapid cholinergic con- Accepted after revision August 8 1993 traction, followed by a long-lasting contraction due to a local release of neuropep- tides from C-fibre endings.
    [Show full text]
  • Effects of Various Selective Phosphodiesterase Inhibitors on Relaxation and Cyclic Nucleotide Contents in Porcine Iris Sphincter
    FULL PAPER Pharmacology Effects of Various Selective Phosphodiesterase Inhibitors on Relaxation and Cyclic Nucleotide Contents in Porcine Iris Sphincter Takuya YOGO1), Takeharu KANEDA2), Yoshinori NEZU1), Yasuji HARADA1), Yasushi HARA1), Masahiro TAGAWA1), Norimoto URAKAWA2) and Kazumasa SHIMIZU2) 1)Laboratories of Veterinary Surgery and 2)Veterinary Pharmacology, Nippon Veterinary and Life Science University, 7–1 Kyonan-cho 1– chome, Musashino, Tokyo 180–8602, Japan (Received 26 March 2009/Accepted 1 July 2009) ABSTRACT. The effects of various selective phosphodiesterase (PDE) inhibitors on muscle contractility and cyclic nucleotide contents in porcine iris sphincter were investigated. Forskolin and sodium nitroprusside inhibited carbachol (CCh)-induced contraction in a concen- tration-dependent manner. Various selective PDE inhibitors, vinpocetine (type 1), erythro -9-(2-hydroxy-3-nonyl)adenine (EHNA, type 2), milrinone (type 3), Ro20–1724 (type 4) and zaprinast (type 5), also inhibited CCh-induced contraction in a concentration-dependent manner. The rank order of potency of IC50 was zaprinast > Ro20–1724 > EHNA milrinone > vinpocetine. In the presence of CCh (0.3 M), vinpocetine, milrinone and Ro20–1724 increased cAMP, but not cGMP, contents. In contrast, zaprinast and EHNA both increased cGMP, but not cAMP, contents. This indicates that vinpocetine-, milrinone- and Ro20–1724-induced relaxation is correlated with cAMP, while EHNA- and zaprinast- induced relaxation is correlated with cGMP in porcine iris sphincter. KEY WORDS: cAMP, cGMP, iris sphincter, PDE inhibitor, smooth muscle. J. Vet. Med. Sci. 71(11): 1449–1453, 2009 Cyclic nucleotides are important secondary messengers, chol (CCh)-induced contraction of porcine iris sphincter and are associated with smooth muscle relaxation [7]. induced by selective PDE (type1–5) inhibitors.
    [Show full text]
  • General Pharmacology
    GENERAL PHARMACOLOGY Winners of “Nobel” prize for their contribution to pharmacology Year Name Contribution 1923 Frederick Banting Discovery of insulin John McLeod 1939 Gerhard Domagk Discovery of antibacterial effects of prontosil 1945 Sir Alexander Fleming Discovery of penicillin & its purification Ernst Boris Chain Sir Howard Walter Florey 1952 Selman Abraham Waksman Discovery of streptomycin 1982 Sir John R.Vane Discovery of prostaglandins 1999 Alfred G.Gilman Discovery of G proteins & their role in signal transduction in cells Martin Rodbell 1999 Arvid Carlson Discovery that dopamine is neurotransmitter in the brain whose depletion leads to symptoms of Parkinson’s disease Drug nomenclature: i. Chemical name ii. Non-proprietary name iii. Proprietary (Brand) name Source of drugs: Natural – plant /animal derivatives Synthetic/semisynthetic Plant Part Drug obtained Pilocarpus microphyllus Leaflets Pilocarpine Atropa belladonna Atropine Datura stramonium Physostigma venenosum dried, ripe seed Physostigmine Ephedra vulgaris Ephedrine Digitalis lanata Digoxin Strychnos toxifera Curare group of drugs Chondrodendron tomentosum Cannabis indica (Marijuana) Various parts are used ∆9Tetrahydrocannabinol (THC) Bhang - the dried leaves Ganja - the dried female inflorescence Charas- is the dried resinous extract from the flowering tops & leaves Papaver somniferum, P album Poppy seed pod/ Capsule Natural opiates such as morphine, codeine, thebaine Cinchona bark Quinine Vinca rosea periwinkle plant Vinca alkaloids Podophyllum peltatum the mayapple
    [Show full text]
  • Pharmaceutical Appendix to the Tariff Schedule 2
    Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. ABACAVIR 136470-78-5 ACIDUM LIDADRONICUM 63132-38-7 ABAFUNGIN 129639-79-8 ACIDUM SALCAPROZICUM 183990-46-7 ABAMECTIN 65195-55-3 ACIDUM SALCLOBUZICUM 387825-03-8 ABANOQUIL 90402-40-7 ACIFRAN 72420-38-3 ABAPERIDONUM 183849-43-6 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABATACEPTUM 332348-12-6 ACITEMATE 101197-99-3 ABCIXIMAB 143653-53-6 ACITRETIN 55079-83-9 ABECARNIL 111841-85-1 ACIVICIN 42228-92-2 ABETIMUSUM 167362-48-3 ACLANTATE 39633-62-0 ABIRATERONE 154229-19-3 ACLARUBICIN 57576-44-0 ABITESARTAN 137882-98-5 ACLATONIUM NAPADISILATE 55077-30-0 ABLUKAST 96566-25-5 ACODAZOLE 79152-85-5 ABRINEURINUM 178535-93-8 ACOLBIFENUM 182167-02-8 ABUNIDAZOLE 91017-58-2 ACONIAZIDE 13410-86-1 ACADESINE 2627-69-2 ACOTIAMIDUM 185106-16-5 ACAMPROSATE 77337-76-9
    [Show full text]
  • Selective Phosphodiesterase 4 Inhibitors
    Journal of Scientific & Indu strial Research Vol. 62, June 2003, pp 537-553 Selective Phosphodiesterase 4 Inhibitors - Emerging Trends in Astluna Therapy (Antiasthmatics-3) Ranju Gupta*, Oeepika Gandhi and Oharam Paul Jindal University In stitute of Pharmaceuti cal Sciences, Panjab Universit y, Chandigarh 160014 Considerable interest has been generated in th e potential utility of isozyme selective inhibitors of phosph odiesterases in the treatment of asthma and other inflali1matory disorders. Heterogeneity in ti ssue distribution as well as their different fun cti onal roles make these enzymes very attractive targets for medicinal chemi sts. To date at least II different fami lies of POE isozymes are known, among which POE 4 plays a major rol e in mod ul ating the activity of virtu ally all cell s involved in the inflammatory process. In hibitors of thi s enzyme family display impressive antiasthmatic ac ti vity by red ucing th e bronchial smooth mu scle tone and consid erable anti-inflammatory activity. The review details th e various classes of POE 4 inhibitors stru cturall y related to rolipram, nitraquazone and xa nthines, which appear to be very attractive models for synthesis of novel selecti ve POE 4 inhibitors potentially useful for the treatment of asthma and chronic obstructive pulmonary di seases. Rationale for the use of POE4 inhibitors in th e treatment of asthma is also discussed. Key words: Phosphodiesterase 4 inhibitors, Asthma therapy, Antiasthmatics, Isozyme, Rol ipram, Nitraquazonc. Xanthincs. Introduction Phosphodiesterase Superfamily There has been growing interest in recent years At least e leven different fami li es of POE tn the utility of selective phosphodiesterase (POE) isozymes are known based on the ir substrate inhibitors as novel targets for drug d iscovery.
    [Show full text]
  • Nivedita Singh
    Xanthine Based Inhibitors for Therapeutics Targeting Phosphodiesterase 9A A Thesis Submitted in Partial Fulfilment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY BY NIVEDITA SINGH DEPARTMENT OF BIOSCIENCES & BIOENGINEERING INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI GUWAHATI-781039, ASSAM, INDIA NOVEMBER 2016 Xanthine Based Inhibitors for Therapeutics Targeting Phosphodiesterase 9A A Thesis Submitted in Partial Fulfilment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY BY NIVEDITA SINGH DEPARTMENT OF BIOSCIENCES & BIOENGINEERING INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI GUWAHATI-781039, ASSAM, INDIA NOVEMBER 2016 TH-1894_11610615 TH-1894_11610615 INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI DEPARTMENT OF BIOSCIENCE & BIOENGINEERING STATEMENT I do hereby declare that the matter embodied in this thesis entitled: “Xanthine based inhibitors for therapeutics targeting phosphodiesterase 9A”, is the result of investigations carried out by me in the Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati, India, under the guidance of Dr. Sanjukta Patra and co-supervision of Prof. Parameswar Krishnan Iyer. In keeping with the general practice of reporting scientific observations, due acknowledgements have been made wherever the work described is based on the findings of other investigators. November, 2016 Ms. Nivedita Singh Roll No. 11610615 TH-1894_11610615 INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI DEPARTMENT OF BIOSCIENCE & BIOENGINEERING CERTIFICATE It is certified that the work described in this thesis, entitled: “Xanthine based inhibitors for therapeutics targeting phosphodiesterase 9A”, done by Ms Nivedita Singh (Roll No: 11610615), for the award of degree of Doctor of Philosophy is an authentic record of the results obtained from the research work carried out under my supervision in the Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati, India, and this work has not been submitted elsewhere for a degree.
    [Show full text]
  • Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DIX to the HTSUS—Continued
    20558 Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DEPARMENT OF THE TREASURY Services, U.S. Customs Service, 1301 TABLE 1.ÐPHARMACEUTICAL APPEN- Constitution Avenue NW, Washington, DIX TO THE HTSUSÐContinued Customs Service D.C. 20229 at (202) 927±1060. CAS No. Pharmaceutical [T.D. 95±33] Dated: April 14, 1995. 52±78±8 ..................... NORETHANDROLONE. A. W. Tennant, 52±86±8 ..................... HALOPERIDOL. Pharmaceutical Tables 1 and 3 of the Director, Office of Laboratories and Scientific 52±88±0 ..................... ATROPINE METHONITRATE. HTSUS 52±90±4 ..................... CYSTEINE. Services. 53±03±2 ..................... PREDNISONE. 53±06±5 ..................... CORTISONE. AGENCY: Customs Service, Department TABLE 1.ÐPHARMACEUTICAL 53±10±1 ..................... HYDROXYDIONE SODIUM SUCCI- of the Treasury. NATE. APPENDIX TO THE HTSUS 53±16±7 ..................... ESTRONE. ACTION: Listing of the products found in 53±18±9 ..................... BIETASERPINE. Table 1 and Table 3 of the CAS No. Pharmaceutical 53±19±0 ..................... MITOTANE. 53±31±6 ..................... MEDIBAZINE. Pharmaceutical Appendix to the N/A ............................. ACTAGARDIN. 53±33±8 ..................... PARAMETHASONE. Harmonized Tariff Schedule of the N/A ............................. ARDACIN. 53±34±9 ..................... FLUPREDNISOLONE. N/A ............................. BICIROMAB. 53±39±4 ..................... OXANDROLONE. United States of America in Chemical N/A ............................. CELUCLORAL. 53±43±0
    [Show full text]
  • Modulation of Th1/Th2 Cytokine Production by Selective And
    Pharmacological Reports Copyright © 2012 2012, 64, 179184 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences ModulationofTh1/Th2cytokineproduction byselectiveandnonselectivephosphodiesterase inhibitorsadministeredtomice MariannaSzczypka1,SebastianPloch2,Bo¿enaObmiñska-Mrukowicz1 1 2 DepartmentofBiochemistry,PharmacologyandToxicology, ITLab,FacultyofVeterinaryMedicine,Wroc³aw UniversityofEnvironmentalandLifeSciences,Norwida31, PL50-375Wroc³aw, Poland Correspondence: MariannaSzczypka,e-mail:[email protected] Abstract: Phosphodiesterase (PDE) inhibitors can modulate the functions of immune cells, including T lymphocytes, due to increased intracel- lular levels of cyclic nucleotides. The drugs (aminophylline, milrinone and sildenafil) were administered once or five times at 24 h intervalsatthefollowingdoses:20mg/kg, im,1mg/kg, im and1mg/kg, po,respectively. Th1 and Th2 cytokine levels (IL-2, IFN-g, IL-4, IL-5, TNF) were determined 12, 24 or 72 h after the last administration of the drugs. A commercial BDTM Cytometric Bead Array Mouse Th1/Th2 Cytokine Kit (CBA) was used to determine the levels of Th1/Th2 cy- tokinesintheserum. Neither of the PDE inhibitors under investigation administered once changed IFN-g, TNF and IL-4 production. A single dose of aminophyl- line decreased the production of IL-2 (after 12 h). A single dose of milrinone did not affect Th1/Th2 cytokine secretion. Sildenafil administered once decreased the production of IL-2 (after 72 h). Atemporary enhancement in the level of IL-5 was observed 12 h after a sin- gle dose of sildenafil. No changes in Th1 and Th2 cytokine production were observed after five doses of PDE inhibitors under investigation. These results indicate that nonstimulated lymphocytes Th1 and Th2 exhibited a slight sensitivity to aminophylline and sildenafil.
    [Show full text]
  • Phosphodiesterases As Therapeutic Targets for Respiratory Diseases
    University of Groningen Phosphodiesterases as therapeutic targets for respiratory diseases Zuo, Haoxiao; Cattani-Cavalieri, Isabella; Musheshe, Nshunge; Nikolaev, Viacheslav O; Schmidt, Martina Published in: Pharmacology & Therapeutics DOI: 10.1016/j.pharmthera.2019.02.002 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2019 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Zuo, H., Cattani-Cavalieri, I., Musheshe, N., Nikolaev, V. O., & Schmidt, M. (2019). Phosphodiesterases as therapeutic targets for respiratory diseases. Pharmacology & Therapeutics, 197, 225-242. https://doi.org/10.1016/j.pharmthera.2019.02.002 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 27-09-2021 Pharmacology & Therapeutics 197 (2019) 225–242 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Phosphodiesterases as therapeutic targets for respiratory diseases Haoxiao Zuo a,c,⁎, Isabella Cattani-Cavalieri a,b,d,NshungeMusheshea, Viacheslav O.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]