{"product_id":"drug-metabolism-handbook-9781119851011","title":"Drug Metabolism Handbook","description":"\u003cb\u003eBook Synopsis\u003c\/b\u003e\u003cbr\u003eA comprehensive explanation of drug metabolism concepts and applications in drug development and cancer treatment In the newly revised second edition of Drug Metabolism Handbook: Concepts and Applications in Cancer Research, a distinguished team of researchers delivers an incisive and robust exploration of the drug metabolism system and a well-illustrated and detailed explanation of the latest tools and techniques used in the research, pharmacology, and medicine. The book discusses the creation of new molecular entities, drug development, troubleshooting, and other highly relevant concepts, guiding readers through new applications in pharmaceutical research, development, and assessment. The latest edition offers updated content on metabolism basics and the application of a variety of new techniques to cancer treatment, including mass spectrometry, imaging, metabolomics, and immunotherapy. It also offers in-depth case studies highlighting the role of metabolism in drug development. Read\u003cbr\u003e\u003cbr\u003e\u003cb\u003eTable of Contents\u003c\/b\u003e\u003cbr\u003e\u003cp\u003e\u003cb\u003eVolume 1\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003ePreface xiii\u003c\/p\u003e \u003cp\u003eList of contributors xv\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart I. Introduction 1\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1. Historical Perspective 3\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eRoberta S. King\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e1.1 Controversies Spanning Past, Present, and Future 3\u003c\/p\u003e \u003cp\u003e1.2 1800s: Discovery of Major Drug Metabolism Pathways (Conti and Bickel, 1977) 5\u003c\/p\u003e \u003cp\u003e1.3 1900–1950s: Confirmation of Major Pathways and Mechanistic Studies 8\u003c\/p\u003e \u003cp\u003e1.4 1950s–1980: Modern Drug Metabolism Emerges, with Enzymatic Basis 9\u003c\/p\u003e \u003cp\u003e1.5 1980–2005: Field Driven by Improved Technologies 10\u003c\/p\u003e \u003cp\u003e1.6 2005+: High Technology 10\u003c\/p\u003e \u003cp\u003eReferences 10\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2. Factors Affecting Metabolism 13\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eRoberta S. King\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003eReferences 16\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3. Biotransformations in Drug Metabolism 17\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eRoberta S. King\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e3.1 Drug Metabolism in Drug Development and Drug Therapy 17\u003c\/p\u003e \u003cp\u003e3.2 Prediction of Metabolite and Enzyme Responsible 20\u003c\/p\u003e \u003cp\u003e3.3 Functional Group Biotransformations: Phase I, Phase II, and Catalysis 21\u003c\/p\u003e \u003cp\u003e3.4 Oxidations and Cytochrome P450 23\u003c\/p\u003e \u003cp\u003e3.5 Enzymology and Modifiers of Cytochrome P450s 34\u003c\/p\u003e \u003cp\u003eReferences 39\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4. A Comprehensive Picture of Biotransformation in Drug Discovery 41\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eJoe R. Cannon, Prakash Vachaspati, and Yang Yuan\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e4.1 Introduction 41\u003c\/p\u003e \u003cp\u003e4.2 Rate of Metabolism 43\u003c\/p\u003e \u003cp\u003e4.3 Metabolism of Small Molecules 46\u003c\/p\u003e \u003cp\u003e4.4 Analytical Technologies in Drug Metabolism 65\u003c\/p\u003e \u003cp\u003e4.5 Biotransformation for Novel Modalities – Peptides and Protein Degraders 79\u003c\/p\u003e \u003cp\u003e4.6 Conclusion 93\u003c\/p\u003e \u003cp\u003eReferences 93\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5. In Vivo Drug Metabolite Kinetics 103\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eZheng Yang\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e5.1 Introduction 103\u003c\/p\u003e \u003cp\u003e5.2 \u003ci\u003eIn Vivo \u003c\/i\u003eDrug Metabolite Kinetic Concepts and Principles 105\u003c\/p\u003e \u003cp\u003e5.3 Effect of Inhibition and Induction on Metabolite Kinetics 122\u003c\/p\u003e \u003cp\u003e5.4 Determination of Formation and Elimination Clearance of\u003c\/p\u003e \u003cp\u003eMetabolite 127\u003c\/p\u003e \u003cp\u003e5.5 Incorporation of Pharmacologically Active Metabolite(s) in\u003c\/p\u003e \u003cp\u003ePharmacokinetic\/Pharmacodynamic Modeling 130\u003c\/p\u003e \u003cp\u003e5.6 Summary 135\u003c\/p\u003e \u003cp\u003eAbbreviations 135\u003c\/p\u003e \u003cp\u003eReferences 137\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6. LC-MS\/MS-Based Proteomics Methods for Quantifying Drug-Metabolizing Enzymes and Transporters 143\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eLogan S. Smith, Sun Min Jung, Jiapeng Li, and Hao-Jie Zhu\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e6.1 Introduction 143\u003c\/p\u003e \u003cp\u003e6.2 Mass Spectrometry Versus Alternative Protein Quantification Methods 144\u003c\/p\u003e \u003cp\u003e6.3 Mass Spectrometry Data Acquisition Methods for Proteomics Analysis 145\u003c\/p\u003e \u003cp\u003e6.4 Targeted Approaches 146\u003c\/p\u003e \u003cp\u003e6.5 Untargeted Proteomics Approaches 147\u003c\/p\u003e \u003cp\u003e6.6 Relative Quantification Versus Absolute Quantification 150\u003c\/p\u003e \u003cp\u003e6.7 Label-Based Proteomics 152\u003c\/p\u003e \u003cp\u003e6.8 Label-Free Proteomics 155\u003c\/p\u003e \u003cp\u003e6.9 DMET Protein Quantification Using LC-MS\/MS-Based Proteomics 158\u003c\/p\u003e \u003cp\u003e6.10 Potential Application of DMET Expression Studies 160\u003c\/p\u003e \u003cp\u003e6.11 Considerations of DMET Protein Quantification Utilizing LC-MS\/MS Methods 163\u003c\/p\u003e \u003cp\u003e6.12 Conclusion 164\u003c\/p\u003e \u003cp\u003eReferences 164\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart II. Technologies for in vitro and in vivo studies 177\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7. Mass Spectrometry 179\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eThomas R. Sharp\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e7.1 Introduction 179\u003c\/p\u003e \u003cp\u003e7.2 A Brief History 180\u003c\/p\u003e \u003cp\u003e7.3 The Mass Spectrometry Literature 182\u003c\/p\u003e \u003cp\u003e7.4 Mass Spectrometry Instrumentation 183\u003c\/p\u003e \u003cp\u003e7.5 Interpretation:What Does it Mean 211\u003c\/p\u003e \u003cp\u003e7.6 Conclusions 254\u003c\/p\u003e \u003cp\u003eReferences 255\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8. Accelerating Metabolite Identification Mass Spectrometry Technology Drives Metabolite Identification Studies Forward 267\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eAla F. Nassar\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e8.1 Introduction 267\u003c\/p\u003e \u003cp\u003e8.2 Criteria for LC-MS Methods 269\u003c\/p\u003e \u003cp\u003e8.3 Matrices Effect 269\u003c\/p\u003e \u003cp\u003e8.4 Tool of Choice for Metabolite Characterization 270\u003c\/p\u003e \u003cp\u003e8.5 Strategies for Identifying Unknown Metabolites 274\u003c\/p\u003e \u003cp\u003e8.6 Online HD-LC-MS 275\u003c\/p\u003e \u003cp\u003e8.7 “All-in-One” Radioactivity Detector, Stop Flow, and Dynamic\u003c\/p\u003e \u003cp\u003eFlow for Metabolite Identification 282\u003c\/p\u003e \u003cp\u003e8.8 Metabolic Activation Studies by Mass Spectrometry 287\u003c\/p\u003e \u003cp\u003e8.9 Strategies to Screen for Reactive Metabolites 288\u003c\/p\u003e \u003cp\u003e8.10 Summary 289\u003c\/p\u003e \u003cp\u003eAbbreviations and Glossary 290\u003c\/p\u003e \u003cp\u003eReferences 299\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9. Role of Structural Modifications of Drug Candidates to Enhance Metabolic Stability 303\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eAla F. Nassar\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e9.1 Background 303\u003c\/p\u003e \u003cp\u003e9.2 Introduction 304\u003c\/p\u003e \u003cp\u003e9.3 Significance of Metabolite Characterization and Structure Modification 305\u003c\/p\u003e \u003cp\u003e9.4 Enhance Metabolic Stability 305\u003c\/p\u003e \u003cp\u003e9.5 Metabolic Stability and Intrinsic Metabolic Clearance 306\u003c\/p\u003e \u003cp\u003e9.6 Advantages of Enhancing Metabolic Stability 307\u003c\/p\u003e \u003cp\u003e9.7 Strategies to Enhance Metabolic Stability 307\u003c\/p\u003e \u003cp\u003e9.8 Analytical Tools 317\u003c\/p\u003e \u003cp\u003e9.9 Case Studies 318\u003c\/p\u003e \u003cp\u003e9.10 Conclusions 320\u003c\/p\u003e \u003cp\u003eReferences 320\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10. Drug Design Strategies: Role of Structural Modifications of Drug Candidates to Improve PK Parameters of New Drugs 323\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eAla F. Nassar\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e10.1 Active Metabolites 323\u003c\/p\u003e \u003cp\u003e10.2 Oral Absorption and Intravenous Dose 333\u003c\/p\u003e \u003cp\u003e10.3 PK Analysis 333\u003c\/p\u003e \u003cp\u003e10.4 Case Studies 334\u003c\/p\u003e \u003cp\u003e10.5 Prodrugs to IncreaseWater Solubility 338\u003c\/p\u003e \u003cp\u003e10.6 Conclusion 339\u003c\/p\u003e \u003cp\u003eReferences 340\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11. Chemical Structural Alert and Reactive Metabolite Concept as Applied in Medicinal Chemistry to Minimize the Toxicity of Drug Candidates 345\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eAla F. Nassar\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e11.1 Importance of Reactive Intermediates in Drug Discovery and Development 345\u003c\/p\u003e \u003cp\u003e11.2 Idiosyncratic Drug Toxicity and Molecular Mechanisms 349\u003c\/p\u003e \u003cp\u003e11.3 Key Tools and Strategies to Improve Drug Safety 352\u003c\/p\u003e \u003cp\u003e11.4 Peroxidases 357\u003c\/p\u003e \u003cp\u003e11.5 Acyl Glucuronidation and \u003ci\u003eS\u003c\/i\u003e-Acyl-CoA Thioesters 358\u003c\/p\u003e \u003cp\u003e11.6 Covalent Binding 359\u003c\/p\u003e \u003cp\u003e11.7 Mechanistic Studies 360\u003c\/p\u003e \u003cp\u003e11.8 Preclinical Development 363\u003c\/p\u003e \u003cp\u003e11.9 Clinical Development: Strategy 364\u003c\/p\u003e \u003cp\u003e11.10 Case Studies 364\u003c\/p\u003e \u003cp\u003e11.11 Conclusion and Future Possibilities 366\u003c\/p\u003e \u003cp\u003eReferences 367\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12. Studies of Reactive Metabolites using Genotoxicity Arrays and Enzyme\/DNA Biocolloids – 2021 373\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eJames F. Rusling and Eli G. Hvastkovs\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e12.1 Introduction 373\u003c\/p\u003e \u003cp\u003e12.2 On Demand Metabolic Reactions 374\u003c\/p\u003e \u003cp\u003e12.3 Arrays with Electrochemical Detection 376\u003c\/p\u003e \u003cp\u003e12.4 Electrochemiluminescent Arrays 379\u003c\/p\u003e \u003cp\u003e12.5 ECL Arrays can Measure Both DNA Oxidation and Nucleobase Adduction 388\u003c\/p\u003e \u003cp\u003e12.6 Detecting Site-Specific Damage to TUMOR SUPPRESSORGenes 392\u003c\/p\u003e \u003cp\u003e12.7 Emerging Technologies and Methods 394\u003c\/p\u003e \u003cp\u003e12.8 Conclusions and Future Outlook 398\u003c\/p\u003e \u003cp\u003eAcknowledgments 399\u003c\/p\u003e \u003cp\u003eBiographies 399\u003c\/p\u003e \u003cp\u003eReferences 399\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart III. Drug interactions 407\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e13. Enzyme Inhibition 409\u003cbr\u003e \u003c\/b\u003e\u003ci\u003ePaul F. Hollenberg\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e13.1 Introduction 409\u003c\/p\u003e \u003cp\u003e13.2 Mechanisms of Enzyme Inhibition 411\u003c\/p\u003e \u003cp\u003e13.3 Competitive Inhibition 412\u003c\/p\u003e \u003cp\u003e13.4 Noncompetitive Inhibition 413\u003c\/p\u003e \u003cp\u003e13.5 Uncompetitive Inhibition 414\u003c\/p\u003e \u003cp\u003e13.6 Product Inhibition 414\u003c\/p\u003e \u003cp\u003e13.7 Transition-State Analogs 415\u003c\/p\u003e \u003cp\u003e13.8 Slow, Tight-Binding Inhibitors 415\u003c\/p\u003e \u003cp\u003e13.9 Mechanism-Based Inactivators 415\u003c\/p\u003e \u003cp\u003e13.10 Inhibitors that are Metabolized to Reactive Products that Covalently Attach to the Enzyme 418\u003c\/p\u003e \u003cp\u003e13.11 Substrate Inhibition 419\u003c\/p\u003e \u003cp\u003e13.12 Partial Inhibition 419\u003c\/p\u003e \u003cp\u003e13.13 Inhibition of Cytochrome P450 Enzymes 420\u003c\/p\u003e \u003cp\u003e13.14 Reversible Inhibitors 421\u003c\/p\u003e \u003cp\u003e13.15 Quasi-Irreversible Inhibitors 421\u003c\/p\u003e \u003cp\u003e13.16 Mechanism-Based Inactivators 422\u003c\/p\u003e \u003cp\u003eReferences 424\u003c\/p\u003e \u003cp\u003e\u003cb\u003e14. Xenobiotic Receptor-Mediated Gene Regulation in Drug Metabolism and Disposition 427\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eHongbing Wang and Wen Xie\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e14.1 Introduction 427\u003c\/p\u003e \u003cp\u003e14.2 Pregnane X Receptor 429\u003c\/p\u003e \u003cp\u003e14.3 Constitutive Androstane\/Activated Receptor (CAR) 441\u003c\/p\u003e \u003cp\u003e14.4 Closing Remarks and Perspectives 452\u003c\/p\u003e \u003cp\u003eAcknowledgments 453\u003c\/p\u003e \u003cp\u003eReferences 453\u003c\/p\u003e \u003cp\u003e\u003cb\u003e15. Characterization of Cytochrome P450 Mechanism Based Inhibition 465\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eDan A. Rock and Larry C. Wienkers\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e15.1 Introduction 465\u003c\/p\u003e \u003cp\u003e15.2 Inhibitors that Upon Activation Bind Covalently to the P450 Apoprotein 475\u003c\/p\u003e \u003cp\u003e15.3 Inhibitors that Interact in a Pseudoirreversible Manner with Heme Iron 478\u003c\/p\u003e \u003cp\u003e15.4 Inactivation that Cause Destruction of the Prosthetic Heme Group, Often Times Leading to Heme-Derived Products that Covalently Modify the Apoprotein 480\u003c\/p\u003e \u003cp\u003eReferences 515\u003c\/p\u003e \u003cp\u003e\u003cb\u003e16. An Introduction to Metabolic Reaction-Phenotyping 527\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eCarl Davis\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e16.1 Introduction 527\u003c\/p\u003e \u003cp\u003e16.2 Significant Drug-Metabolizing Enzymes 528\u003c\/p\u003e \u003cp\u003e16.3 Common In VitroMethods to Assess Drug Metabolism 534\u003c\/p\u003e \u003cp\u003e16.4 In Vitroto In VivoExtrapolation of Metabolic Clearance 539\u003c\/p\u003e \u003cp\u003e16.5 Summary 546\u003c\/p\u003e \u003cp\u003eReferences 546\u003c\/p\u003e \u003cp\u003e\u003cb\u003e17. Epigenetic Regulation of Drug-Metabolizing Enzymes in Cancer 553\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eJiaqi Wang, Xiaoli Zheng, and Su Zeng\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e17.1 Introduction 553\u003c\/p\u003e \u003cp\u003e17.2 DNA Methylation of DMEs 554\u003c\/p\u003e \u003cp\u003e17.3 Histone Modification 558\u003c\/p\u003e \u003cp\u003e17.4 Noncoding RNA 559\u003c\/p\u003e \u003cp\u003e17.5 RNA Methylation 561\u003c\/p\u003e \u003cp\u003e17.6 Closing Remarks and Perspectives 563\u003c\/p\u003e \u003cp\u003eAcknowledgments 564\u003c\/p\u003e \u003cp\u003eReferences 564\u003c\/p\u003e \u003cp\u003e\u003cb\u003e18. Epigenetic Regulation of Drug Transporters in Cancer 573\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eYingying Wang, Ying Zhou, Yu Wang, Lushan Yu, and Su Zeng\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e18.1 Introduction 573\u003c\/p\u003e \u003cp\u003e18.2 DNA Methylation 575\u003c\/p\u003e \u003cp\u003e18.3 Histone Modifications 579\u003c\/p\u003e \u003cp\u003e18.4 Noncoding RNAs 581\u003c\/p\u003e \u003cp\u003e18.5 Closing Remarks and Perspectives 591\u003c\/p\u003e \u003cp\u003eAcknowledgments 592\u003c\/p\u003e \u003cp\u003eReferences 592\u003c\/p\u003e \u003cp\u003e\u003cb\u003eVolume 2\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003ePreface xi\u003c\/p\u003e \u003cp\u003eList of contributors xiii\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart IV. Toxicity 605\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e19. The Role of Drug Metabolism in Toxicity 607\u003cbr\u003e \u003ci\u003eUmesh M. Hanumegowda and Carl Davis\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e20. Allergic Reactions to Drugs 677\u003cbr\u003e \u003ci\u003eMark P. Grillo\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e21. Chemical Mechanisms in Toxicology 703\u003cbr\u003e \u003ci\u003eMark P. Grillo\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e22. Role of Bioactivation Reactions in Chemically Induced Nephrotoxicity 745\u003cbr\u003e \u003ci\u003eLawrence H. Lash\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart V. Applications 773\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e23. Mapping the Heterogeneous Distribution of Cancer Drugs by Imaging Mass Spectrometry 775\u003cbr\u003e \u003ci\u003ePurva S. Damale and Shibdas Banerjee\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e24. Systemic Metabolomic Changes Associated with Chemotherapy: Role in Personalized Therapy 811\u003cbr\u003e \u003ci\u003eBhargab Kalita, Ganesh K. Barik, Tanisha Sharma, Khushman Taunk, Praneeta P. Bhavsar, Manas K. Santra, and Srikanth Rapole\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e25. Metabolic Reprogramming in Cancer 841\u003cbr\u003e \u003ci\u003eDebasish Prusty and Soumen Kanti Manna\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e26. Case Study: Metabolism and Reactions of Alkylating Agents in Cancer Therapy 893\u003cbr\u003e \u003ci\u003eAla F. Nassar, Adam V. Wisnewski, and Ivan King\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e27. Rewiring of Drug Metabolism and Its Cross-talk with Metabolic Reprogramming in Cancer 923\u003cbr\u003e \u003ci\u003eSubhabrata Majumder and Soumen Kanti Manna\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e28. Principles of Drug Metabolism and Interactions in Cardio-Oncology 967\u003cbr\u003e\u003ci\u003eSherry-Ann Brown, Craig Beavers, Sailaja Kamaraju, Meera Mohan, Olubadewa \u003c\/i\u003e\u003ci\u003eFatunde, Gift Echefu, Svetlana Zaharova, Brianna Wallace, and Carolyn Oxencis\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003eIndex 993\u003c\/p\u003e","brand":"John Wiley \u0026 Sons Inc","offers":[{"title":"Default Title","offer_id":52090801324375,"sku":"9781119851011","price":234.9,"currency_code":"GBP","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0817\/1739\/5799\/files\/9781119851011.jpg?v=1762273512","url":"https:\/\/bookcurl.com\/products\/drug-metabolism-handbook-9781119851011","provider":"Book Curl","version":"1.0","type":"link"}