Principles of Translational Science in Medicine: From Bench to Bedside, 3rd Edition
- Length: 494 pages
- Edition: 3
- Language: English
- Publisher: Academic Press
- Publication Date: 2021-08-05
- ISBN-10: 0128204931
- ISBN-13: 9780128204931
- Sales Rank: #4357240 (See Top 100 Books)
Principles of Translational Science in Medicine: From Bench to Bedside, Third Edition, provides an update on major achievements in the translation of research into medically relevant results and therapeutics. The book presents a thorough discussion of biomarkers, early human trials, and networking models, and includes institutional and industrial support systems. It also covers algorithms that have influenced all major areas of biomedical research in recent years, resulting in an increasing number of new chemical/biological entities (NCEs or NBEs) as shown in FDA statistics.
New chapters include: Translation in Oncology, Biologicals, and Orphan Drugs. The book is ideal for use as a guide for biomedical scientists to establish a systematic approach to translational medicine and is written by worldwide experts in their respective fields.
Title-page_2021_Principles-of-Translational-Science-in-Medicine Principles of Translational Science in Medicine Copyright_2021_Principles-of-Translational-Science-in-Medicine Copyright Contents_2021_Principles-of-Translational-Science-in-Medicine Contents List-of-contributors_2021_Principles-of-Translational-Science-in-Medicine List of contributors Chapter-1---Introduction-and-defi_2021_Principles-of-Translational-Science-i 1 Introduction and definitions What is translational medicine? Primary translation versus secondary translation The history of translational medicine, obstacles, and remits References Chapter-2---Problems--challenges--and-ini_2021_Principles-of-Translational-S 2 Problems, challenges, and initiatives in translation Attrition What translational medicine can and cannot do The present status of translational medicine (initiatives and deficiencies) New pathways to discovery Research teams of the future Reengineering the clinical research enterprise Translational science in medicine: the current challenge References Chapter-3----Omics--translation--a-challen_2021_Principles-of-Translational- 3 “Omics” translation: a challenge for laboratory medicine Introduction “Omics”: what does it mean? Proteomics as a paradigm of problems in translational medicine Development of biomarkers: from discovery to clinical application Discovery Identification/characterization Validation Standardization/harmonization Clinical association and clinical benefit Translating omics into clinical practice Continuum of translation research and omics Conclusions References Chapter-4---The-power-of-genomics--metabolomics--_2021_Principles-of-Transla 4 The power of genomics, metabolomics, and other omics for target identification and validation Introduction Genomics Genomic tools Sequencing Sequencing by ligation Sequencing by synthesis Arrays Oligonucleotide microarrays cDNA microarrays Quantitative reverse transcription polymerase chain reaction and low-density arrays Applications of genomics in molecular medicine Molecular diagnostics Pharmacogenomics Metabolomics Metabolomics or metabonomics? Metabolite profiling Metabolite fingerprinting Metabolic footprinting Analytical techniques in metabolomics/metabonomics Nuclear magnetic resonance Mass spectrometry Omics and biomarkers Metabolomics and metabonomics in clinical use Conclusion References Chapter-5---Potency-analysis-of-cellular-ther_2021_Principles-of-Translation 5 Potency analysis of cellular therapies: the role of molecular assays Introduction Potency testing Complexities associated with potency testing of cellular therapies Factors affecting the potency of cellular therapies Measuring potency of cellular therapies Gene expression arrays for potency testing Potential applications of gene expression profiling for potency testing Predicting the confluence of human embryonic kidney 293 cells Cell differentiation status analysis of embryonic stem cells Potency testing of hematopoietic stem cells Potency testing of dendritic cells Cultured CD4+ cells Bone marrow stromal cell CAR T cells MicroRNAs as potency assays Conclusions References Chapter-6---Translational-pharmacogenetics--pha_2021_Principles-of-Translati 6 Translational pharmacogenetics: pharmacogenetically driven clinical decision making Introduction Pharmacogenetics as a tool for improving individual drug therapy Types of drug therapies that might profit from pharmacogenetic diagnostics The status of translational pharmacogenetics in various drug therapy fields Depression Cardiovascular disease Beta blockers Vitamin K antagonists Statins and proton pump inhibitors Pain treatment Malignant diseases Tamoxifen Thiopurines 5-Fluorouracil Irinotecan Translational pharmacogenetics and the need for clinical studies to support pharmacogenetically driven prescribing References Chapter-7---Tissue-biobank_2021_Principles-of-Translational-Science-in-Medic 7 Tissue biobanks Introduction The concept of biobanking Population-oriented biobanks Disease-oriented biobanks Virtual biobanks Biobanking for research Biobanking for clinical use Types of biospecimens Tissue Body fluids Cellular models Nucleic acids: DNA and RNA Protein and other subcellular components Quality assurance of biospecimens Biobanking in the era of precision medicine Ethical issues References Chapter-8---Animal-models--value-and-tr_2021_Principles-of-Translational-Sci 8 Animal models: value and translational potency What is the value of animal models? Pathophysiological concepts What is a good animal model for translational research? Modeling comorbidities Modeling care of patients What is the translational value of animal models? Remedies for failed translation: improving preclinical research Improving models Improve rigor of preclinical studies Summary References Chapter-9---Biomarkers-in-the-context-of-he_2021_Principles-of-Translational 9 Biomarkers in the context of health authorities and consortia Introduction From biomarkers to diagnostic tests to improve patient care In vitro diagnostic tests In vitro diagnostic tests and US regulations In vitro diagnostic tests and Europe regulations Companion diagnostics Lab tests (CLIA test or lab-developed test) Drug development tools The critical path initiative New regulatory pathways for qualification of biomarkers and drug development tools Examples Collaborations for biomarkers and drug development tools Public-private partnerships (cooperative R&D agreements) Consortia The Critical Path Institute’s Predictive Safety Testing Consortium The innovative medicines initiative in Europe The PhRMA Biomarkers Consortium References Chapter-10---Human-studies-as-a-source-o_2021_Principles-of-Translational-Sc 10 Human studies as a source of target information Using old drugs for new purposes: baclofen Serendipity: sildenafil Reverse pharmacology References Chapter-11---Target-profiling-in-terms-of-tran_2021_Principles-of-Translatio 11 Target profiling in terms of translatability and early translation planning Essential dimensions of early translational assessment A translatability scoring instrument: risk balancing of portfolios and project improvement Case studies: applying the translatability scoring instrument to real-life experiences References Chapter-12---Biomarkers_2021_Principles-of-Translational-Science-in-Medicine 12 Biomarkers Defining biomarkers as very important contributors to translational science Classes of biomarkers Development of biomarkers Predictivity classification of biomarkers and scores Case studies References Chapter-13---Genetics--molecular-biomarkers--and-ar_2021_Principles-of-Trans 13 Genetics, molecular biomarkers, and artificial intelligence to improve diagnostic and prognostic efficacy Introduction Source of errors in clinical proteomics studies Source of errors in next-generation sequencing Bioinformatics and computational tools for clinical proteomic studies Bioinformatics and computational tools for next-generation sequencing Artificial intelligence, machine learning, and deep learning techniques to improve the clinical utility of clinical proteom... Machine learning: supervised and unsupervised learning Techniques to avoid overfitting issues Examples of the applications of genetics and molecular markers for diagnostic or prognostic purposes Ovarian cancer Genetic studies Prostate cancer Genetics studies Pancreatic cancer Machine learning-derived biomarkers Genetics studies Conclusions References Chapter-14---Cardiovascular-translational-biomarkers--t_2021_Principles-of-T 14 Cardiovascular translational biomarkers: translational aspects of hypertension, atherosclerosis, and heart failure in dr... What is new? Hypertension Introduction Animal models of hypertension Biomarkers of hypertension Blood-borne biomarkers Renin-angiotensin-aldosterone system and sympathetic-adrenergic system activity Endothelial dysfunction Markers of vascular resistance Markers of inflammation Markers of coagulation MicroRNAs and genetic variants Digital biomarkers of hypertension Atherosclerosis Introduction Animal models of atherosclerosis Biomarkers for atherosclerosis Imaging (digital) biomarkers in atherosclerosis conditions Continuously measured digital biomarkers in atherosclerosis conditions Heart failure Introduction Animal models in heart failure Valvular lesions Dilated cardiomyopathies Genetically driven heart failure models Ischemic heart failure models Traditional biomarkers of heart failure Soluble markers for cardiac remodeling and fibrosis Soluble markers for myocardial stretch Markers of inflammation Digital biomarkers of heart failure Cardiovascular biomarkers: Quo Vadis? Case study: atrial fibrillation Conclusion References Chapter-15---Biomarkers-in-onc_2021_Principles-of-Translational-Science-in-M 15 Biomarkers in oncology Circulating biomarkers Pharmacodynamic markers: target inhibition Focus on lung cancer The PD-1/PD-L1 axis Conclusion References Chapter-16---Translational-medicine-in-psychi_2021_Principles-of-Translation 16 Translational medicine in psychiatry: challenges and imaging biomarkers Biological treatment of psychiatric disorders Specific challenges of translation in psychiatry Unknown pathophysiology Stigma and the second translation New biomarkers for translation in psychiatry Imaging biomarkers in schizophrenia Structural brain biomarkers Functional imaging markers in schizophrenia Auditory and language processing Motor functioning Working memory Selective attention Imaging of genetic susceptibility factors Characterization of antipsychotic drug effects Multiomics and transdiagnostic biomarker discovery Conclusions and future directions References Chapter-17---Methodological-st_2021_Principles-of-Translational-Science-in-M 17 Methodological studies Conventional phase I trial methodology Aims Design Patient entry criteria Performance status Cancer type Laboratory investigations within appropriate limits as entry criteria Special drug administration or procedures Patient consent Calculation of the starting dose Dose escalation Number of patients required for dose administration Stopping rules Measuring endpoints Toxicity Pharmacodynamic endpoints Mechanism-oriented trial design Proof-of-mechanism Proof-of-principle Proof-of-concept Can we make go-or-no-go decisions at the end of phase I? Phase II trials Personalized medicine The contribution of modern imaging to early-phase trials Anatomical and molecular imaging evaluation Metabolic measurements using positron emission tomography ligands Choice of imaging modality Radiomics Quantification imaging methods The role of imaging in phase I trials Challenges for novel imaging methodologies and clinical trials Conclusion Open access clinical trials References Chapter-18---The-pharmaceutical-research-and-develo_2021_Principles-of-Trans 18 The pharmaceutical research and development productivity crisis: can exploratory clinical studies be of any help? Traditional drug development Definition of exploratory clinical studies Decision making: regulatory perspective versus company internal perspective in phase I and phase IIa The problem at hand: attrition versus opportunity focus From phase thinking to question-based development Does the biologically active compound or active metabolites get to the site of action? Does the compound cause its intended pharmacological/functional effect(s)? Does the compound have beneficial effects on the disease or its pathophysiology? What is the therapeutic window of the new drug? How do the sources of variability in drug response in the target population affect the development of the product? High risk and variable costs: how to address the risk-cost combination in development? Real options in translational development Exploratory studies: the scorn perspective Exploratory studies: the value perspective Summary: challenges and outlook References Chapter-19---Adaptive-trial-de_2021_Principles-of-Translational-Science-in-M 19 Adaptive trial design References Chapter-20---Combining-regulatory-and-e_2021_Principles-of-Translational-Sci 20 Combining regulatory and exploratory trials References Chapter-21---Accelerating-proof-of-concept-_2021_Principles-of-Translational 21 Accelerating proof of concept by smart early clinical trials References Chapter-22---Pharmaceutical-toxi_2021_Principles-of-Translational-Science-in 22 Pharmaceutical toxicology Introduction Discovery toxicology Target Chemistry Patient Regulatory toxicology Historical context Good laboratory practice The goals of regulatory toxicology Dose-response relationships Translational considerations and context Animal models and future perspectives Alternative approaches in regulatory toxicology: the exploratory investigational new drug approach Biomarkers Preclinical safety from a translational perspective References Chapter-23---Translational-safety-_2021_Principles-of-Translational-Science- 23 Translational safety medicine Introduction State of affairs of translational safety medicine Constraints to effective translational safety medicine The broken safety value chain The conceptual approach to safety The nature of safety work Organizational structure Practicing translational safety medicine Organizational setup The safety management team Safety governance Conflict resolution Safety strategy Recording safety information and strategy Safety strategy document Constant 360-degree vigilance Preparing for the unexpected Practical aspects Test substance Dose Exposure Effect In summary Translational safety future Creating a digital memory Changes in sampling Pharmacokinetics sampling Safety and efficacy biomarker monitoring Monitoring disease state Improved monitoring of known safety biomarkers Detecting previously nonquantifiable tolerability Identifying the right population Embracing data Understanding tolerability Summary: looking to the future References Chapter-24---Cancer-vaccines--translat_2021_Principles-of-Translational-Scie 24 Cancer vaccines: translational strategies Introduction Historic perspective of immune system involvement in the biology of cancer Spontaneous regression Abscopal response Microbes: the first cancer vaccine platform in the history of modern medicine Discovery of cytokines and the first usage in cancer treatment Discovery of white blood cell subtypes and translation from bench to bed Nucleic acid–based cancer vaccines Synthetic peptides as a cancer vaccine Medical advances with monoclonal antibodies in clinical fields Virus-based cancer vaccine platforms Neoepitope vaccines Combination strategies Cancer vaccines with broader goals Vaccines targeting the tumor microenvironment Vaccines with preventive or adjuvant purposes Challenges and future directions Conclusion References Chapter-25---Translational-aspects-of-biologicals-_2021_Principles-of-Transl 25 Translational aspects of biologicals: monoclonal antibodies and antibody-drug conjugates as examples Overview of monoclonal antibodies for cancer therapy Structure and functions of antibodies Generation of monoclonal antibodies for cancer therapy Mechanisms of action of antibodies for cancer therapy Fab-mediated mechanisms of antibodies for cancer therapy Fc-mediated mechanisms of antibodies for cancer therapy Engaging the adaptive immune response Engaging antitumor immune responses via checkpoint blockade Harnessing IgE-mediated immune surveillance against cancer cells Antibody-drug conjugates Mechanism of action of antibody-drug conjugates Antibody-drug conjugates in preclinical development and clinical use Trastuzumab emtansine Examples of target antigens for antibody-drug conjugates in preclinical and clinical development Epidermal growth factor receptor as a potential antigen for antibody-drug conjugate therapy Folate receptor alpha as a potential antigen for antibody and antibody-drug conjugate therapy Choice of antibody Importance of the antibody Fc region Choice of linker Choice of cytotoxic payload Challenges in antibody-drug conjugate design, evaluation and translation Conclusion Acknowledgments References Chapter-26---Orphan-drugs--why-is-transl_2021_Principles-of-Translational-Sc 26 Orphan drugs: why is translation so successful? Introduction Special characteristics of translational processes for orphan drugs References Chapter-27---Translational-science-b_2021_Principles-of-Translational-Scienc 27 Translational science biostatistics Statistical problems in translational science Statistical models and statistical inference Design and interpretation of an experiment Multiplicity Biomarkers Biological modeling Example 1: pharmacodynamics Example 2: pharmacokinetics Statistical models References Chapter-28---Computational-biology-and-model-b_2021_Principles-of-Translatio 28 Computational biology and model-based approaches in translational medicine Introduction: Model building in sciences Compartmental modeling of pharmacokinetics: A conceptual framework for translational applications in clinical pharmacology Physiologically based modeling: prediction of pharmacokinetics in children Blood coagulation modeling: Prediction of pharmacodynamic drug interactions Model-informed drug development and discovery (MID3) References Chapter-29---Intellectual-property-and-innov_2021_Principles-of-Translationa 29 Intellectual property and innovation in translational medicine Introduction Context General description of translational medicine Intellectual property and translational medicine Basic functioning of patents4 Importance of the patent system Open science Definition and principles Benefits of open science Renewed interest in open science Open innovation Definition and objectives Benefits of open innovation Public-private partnership models Definition and objectives Benefits of public-private partnership models Trends in translational intellectual property Patents and research tools Patents on genetic tests and personalized therapies Genetic tests Personalized therapies Patents on risk prediction models Patents on new and repositioned drugs 3D bioprinters Secrecy Discussion A perspective on the future of genetic patents Patentability of gene sequences Patenting of gene sequences and promotion of innovation Patenting of gene sequences and access to healthcare Trade secrecy as an option alternative to patents Toward balanced innovation environment Conclusion Acknowledgments References Chapter-30---Translational-research-in-the-fa_2021_Principles-of-Translation 30 Translational research in the fastest-growing population: older adults Introduction Why study aging? Lifespan versus healthspan Translational aging research Using a geroscience approach Biology of aging: hallmarks, pillars, and health Damage accumulation over time Failure of endogenous repair mechanisms Higher-order consequences of damage From biological mechanisms to clinical aging phenotypes Animal models in translational aging research Human approaches to translational aging research Testing treatments to extend healthspan and lifespan Clinical trials in geroscience Outcomes for clinical trials testing geroscience-inspired interventions Limitations for both animal and human models Examples of experimental therapies in aging research Caloric restriction and intermittent fasting Experimental therapies targeting cellular senescence Dasatinib + quercetin Fisetin BCL and MDM2 pathway inhibitors Senolytic drug trials Translational aging resources Animals and animal tissues Cohorts and populations Tools and toolboxes Conclusion References Chapter-31---Translational-medicine--the-c_2021_Principles-of-Translational- 31 Translational medicine: the changing role of big pharma Introduction History: how did we get here? Biotech: the big disruptor Expansion of the biotech sector Academia and integrated discovery nexuses Pharma meets academia: models of external innovation Precompetitive consortia Attitudes, ethics, and standards Coronavirus and the road ahead References Chapter-32---Translational-science-in-medicine--puttin_2021_Principles-of-Tr 32 Translational science in medicine: putting the pieces together-biomarkers, early human trials, networking, and translata... References Chapter-33---Learning-by-exper_2021_Principles-of-Translational-Science-in-M 33 Learning by experience Example of a smart, successful translational process Example of a failed translational process References Index_2021_Principles-of-Translational-Science-in-Medicine Index
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