The ubiquitin system has two major functions in eukaryotic cells: it r- ulates protein degradation, which is essential for normal cellular fu- tion and for the removal of potentially harmful, damaged, or misfolded proteins, and it controls protein activity by regulating protein-protein interactions and subcellullar localization. The ubiquitin system is thus involved in processes as diverse as cell cycle progression, signal tra- duction, gene transcription, and DNA repair. Not surprisingly, defects in the ubiquitin system have been linked with numerous diseases such as cancer, in?ammation, central nervous system disorders, and metabolic dysfunction. Ubiquitin is a highly conserved 76-amino acid protein which is transferred to its target protein in an ATP-dependent manner. This post-translational modi?cation takes place in a hierarchical, three-step fashion involving an E1 ubiquitin-activating enzyme, an E2 ubiquit- conjugating enzyme, and an E3 ubiquitin ligase. Substrate speci?city is predominantly controlled by members of a large family of E3 - zymes, which form complexes with the proteins that will be modi?ed. This ultimately leads to the covalent attachment of the C-terminus of ubiquitin to usually an?-amino group of a lysine residue in the targeted protein. Additional ubiquitin transfer to lysine-48 of ubiquitin itself will form a polyubiquitin chain, which usually targets the conjugate for degradation by the proteasome. By contrast, mono- or polyubiquityla- VI Preface tion involving lysine-63 is normally involved in the control of protein activity. Ubiquitylation can be reverted by deubiquitylating enzymes, of which approximately 95 exist in mammals.

This volume provides in-depth descriptions and discussion of clinical trial designs based on novel data analysis of high-quality trials for 11 different neurological conditions in order to ultimately improve the quality of care in neurology. Some of the conditions discussed in this book are stroke, traumatic brain injury, Alzheimer's disease, epilepsy, and tumors of the central nervous system. In Neuromethods series style, chapters include the kind of detail and key advice from the specialists needed to get successful results in your research center and clinical investigation. Thorough and comprehensive, Clinical Trials in Neurology is a valuable guide for individuals in the research, education, and clinical practice fields, specifically in the fields of medicine, physical therapy, occupational therapy, nursing, and public health. This volume is also an important resource for clinicians aiming to improve their understanding in methodology of clinical trials.

This handbook provides an in-depth review of information across the developmental spectrum of gene and cell therapy products. From introductory information to state-of-the-art technologies and concepts, the book provides insights into upstream processes such as vector design and construction, purification, formulation and fill/finish as well as delivery options. Planning steps for compliance with current good manufacturing practice (CGMP) to readiness for chemistry, manufacturing, and controls (CMC) are also discussed.This book wraps up with examples of successes and pitfalls addressed by experts who have navigated the multiple challenges that are part of any innovative endeavor. Features Intended as a one-stop resource for availability of state-of-the-art information related to cell and gene therapy products for researchers, scientists, management and other academic and research institutions. Provides the most up to date information on the development of gene therapy, from the technology involved to gene correction and genome editing. Discusses siRNA, mRNA, and plasmid manufacturing. Describes the importance of supplier-sponsor synergies on the path to commercialization. Diverse audience with a large number of individuals in the core technologies and supportive practices.

Hundreds of eponyms are used within the field of immunology-Petri dish, Crohn's disease, Bence Jones protein, Kupffer cells, Freund's adjuvant, Ouchterlony immunodiffusion, to name just a few-but most of us don't know much about the individuals who gave their names to these terms. Where were they born and educated, what other accomplishments are they credited with, why has history chosen to remember them, or not? This book presents the first comprehensive collection of immunologic eponyms, and through them tells the story of this fascinating field, from its earliest beginnings to present day. Organized by surname and meticulously cross-referenced and indexed, this book offers historical anecdotes and little-known facts which scientists, clinicians, students, and general readers will find captivating and memorable. A one-of-a-kind introduction to immunology that serves as both a history lesson and current reference on the diseases, treatments, and individuals who have been crucial to this field.

Key Features: 1. Describes the development of the randomized, controlled trial as the gold standard of proof. 2. Unravels the meaning of "randomized," "double-blind" and "p-values" in a simplified manner for students and clinicians. 3. Contains timeless information on how medical evidence can be understood.

"Heart Failure: From Research to Clinical Practice" contains chapters that describe the current views on the biological mechanisms, clinical assessment, diagnosis and evidence-based treatments of the condition. Topics in this volume range from basic research at cell and molecular level to patient care in everyday clinical practice and provide essential background information and analyses of recent advances for a deeper understanding of the issues involved. With contributions from international experts in their specified fields and are suitable for both beginners and more advanced readers. This volume includes not only the essential information for clinical practice but also the latest information from the contemporary guidelines and the recommendations from leading societies. It also covers ongoing research and puts forward new hypotheses that can be tested in future research. This comprehensive volume will provide a valuable resource for both research students and expert clinicians.

Real-world evidence (RWE) has been at the forefront of pharmaceutical innovations. It plays an important role in transforming drug development from a process aimed at meeting regulatory expectations to an operating model that leverages data from disparate sources to aid business, regulatory, and healthcare decision making. Despite its many benefits, there is no single book systematically covering the latest development in the field. Written specifically for pharmaceutical practitioners, Real-World Evidence in Drug Development and Evaluation, presents a wide range of RWE applications throughout the lifecycle of drug product development. With contributions from experienced researchers in the pharmaceutical industry, the book discusses at length RWE opportunities, challenges, and solutions. Features Provides the first book and a single source of information on RWE in drug development Covers a broad array of topics on outcomes- and value-based RWE assessments Demonstrates proper Bayesian application and causal inference for real-world data (RWD) Presents real-world use cases to illustrate the use of advanced analytics and statistical methods to generate insights Offers a balanced discussion of practical RWE issues at hand and technical solutions suitable for practitioners with limited data science expertise

This book, which is the third volume of Biomedical translational research, focuses on the fundamental role of biomedical research in developing new medicinal products. It emphasizes the importance of understanding biological and pathophysiological mechanisms underlying the disease to discover and develop new biological agents. The book uniquely explores the genomic computational integrative approach for drug repositioning. Further, it discusses the health benefits of nutraceuticals and their application in human diseases. Further, the book comprehensively reviews different computational approaches that employ GWAS data to guide drug repositioning. Finally, it summarizes the major challenges in drug development and the strategies for the rational design of the next generation more effective but less toxic therapeutic agents.

This volume describes the identification of emerging organic pollutants, mainly from industrial sources, their associated toxicological threats, and the latest green methods and biotechnological solutions to abate harmful impacts on people and the environment. The chapters present reviews on current applied toxicology research, occupational health hazards and green remedial solutions for pollution control in terrestrial and aquatic environments, with the aim of raising public awareness of these issues and providing chemists, toxicologists and environmental scientists with the knowledge to combat organic pollutants through sustainable means. Readers will learn about the multi-dimensional applications of materials and processes which harvest energy out of environmental remediation technologies, as well as the roles of biotechnology and nanotechnology in addressing high pollutant load. Specific attention is paid to technologies that draw energy through wastewater remediation, as this covers the primary means by which organic pollutants are introduced into the environment from industry and other sources. The book will be of use to pollution control boards, industry regulators, and students and researchers in the fields of biotechnology, biomedical science, hydrology and water chemistry.

With new statistical and scientific issues arising in adaptive clinical trial design, including the U.S. FDA's recent draft guidance, a new edition of one of the first books on the topic is needed. Adaptive Design Methods in Clinical Trials, Second Edition reflects recent developments and regulatory positions on the use of adaptive designs in clinical trials. It unifies the vast and continuously growing literature and research activities on regulatory requirements, scientific and practical issues, and statistical methodology. New to the Second EditionAlong with revisions throughout the text, this edition significantly updates the chapters on protocol amendment and clinical trial simulation to incorporate the latest changes. It also includes five entirely new chapters on two-stage adaptive design, biomarker adaptive trials, target clinical trials, sample size and power estimation, and regulatory perspectives. Following in the tradition of its acclaimed predecessor, this second edition continues to offer an up-to-date resource for clinical scientists and researchers in academia, regulatory agencies, and the pharmaceutical industry. Written in an intuitive style at a basic mathematical and statistical level, the book maintains its practical approach with an emphasis on concepts via numerous examples and illustrations.

This book will focus on DNA and histone methylation in epigenetics and describe how it is involved in the molecular mechanisms responsible for the development of cancer. Chapters will summarize the current knowledge of the molecular basis of DNA and histone methylation and explain how it is involved in cancer, describe the features of DNA and histone methylation associated with particular types of cancer, diagnostic/therapeutic applications, and future directions of DNA and histone methylation as cancer targets.

The purpose and subject of this book is to provide a comprehensive overview of all types of phantoms used in medical imaging, therapy, nuclear medicine and health physics. For ionizing radiation, dosimetry with respect to issues of material composition, shape, and motion/position effects are all highlighted. For medical imaging, each type of technology will need specific materials and designs, and the physics and indications will be explored for each type. Health physics phantoms are concerned with some of the same issues such as material heterogeneity, but also unique issues such as organ-specific radiation dose from sources distributed in other organs. Readers will be able to use this book to select the appropriate phantom from a vendor at a clinic, to learn from as a student, to choose materials for custom phantom design, to design dynamic features, and as a reference for a variety of applications. Some of the information enclosed is found in other sources, divided especially along the three categories of imaging, therapy, and health physics. To our knowledge, even though professionally, many medical physicists need to bridge the three catagories described above.

* Innovative clinical trial design * Regulatory approval * Real world evidence

The feld of regenerative medicine is in its infancy state. Enthusiasm for the potential of organ regeneration lies with the potential pluripotency of stem cells to differentiate into various tissue types. This volume of Methods in Molecular Biology will focus on the use of stem cells for myocardial repair and regeneration. The emphasis of this issue will be to provide basic scientists, translational investigators, and cardiologists a means to evaluate the effcacy and safety of stem cells in a standardized fashion for myocardial regeneration. Many different cell types have been considered for myocardial repair. Adult card- myocytes are unable to survive even when transplanted into normal myocardium. The use of fetal or neonatal cardiomyocytes is not a feasible source of cells due to ethical concerns and donor availability. Therefore, the use of pluripotent stem cells has become the focus of a cell source for myocardial repair and regeneration. A variety of stem cell types have been suggested to participate in myocardial repair. This has led the investigators to search for the "optimal cell type for myocardial repair". Reliable isolation of the cell source with the ability to expand the cell population is a prerequisite. In the frst section of this book, methods for isolation of commonly used stem cells being investigated for myocardial regeneration are presented. Once a stem cell source has been selected, the stem cell needs to be tested in an app- priate animal model before being translated into clinical practice.

Congenital malformations are worldwide occurrences striking in every condition of society. These severe physical abnormalities which are present at birth and affecting every part of the body happen more often than usually realized, once in every 33 births. The most common, after heart defects, are those of the neural tube (the brain and spinal cord) which happen in as many as one in every 350 births. They have been noted as curiousities in man and beast throughout recorded history and received great attention in our time by various fields of study, for example, their faulty prenatal development by embryologists, familial patterns by geneticists, causation by environmentalists and variability by population scientists.

Attention turned much in recent years to the relation of these malformations to deficiency of a particular dietary ingredient, folic acid, a subject this book analyzes in depth. The greatest conundrum of all, which this latest matter like so much else hinges on, is the amazing fact of the tremendous, almost universal decrease in the frequency of these anomalies since early in the 20th century. The puzzle is 'What can this downward trend possibly mean?' and at bottom 'Whether it is part of a long-term cyclical pattern'. This fascinating biological phenomenon is explored in the book together with various other topics.

A unique point of this book is its low threshold, textually simple and at the same time full of self-assessment opportunities. Other unique points are the succinctness of the chapters with 3 to 6 pages, the presence of entire-commands-texts of the statistical methodologies reviewed and the fact that dull scientific texts imposing an unnecessary burden on busy and jaded professionals have been left out. For readers requesting more background, theoretical and mathematical information a note section with references is in each chapter. The first edition in 2010 was the first publication of a complete overview of SPSS methodologies for medical and health statistics. Well over 100,000 copies of various chapters were sold within the first year of publication. Reasons for a rewrite were four. First, many important comments from readers urged for a rewrite. Second, SPSS has produced many updates and upgrades, with relevant novel and improved methodologies. Third, the authors felt that the chapter texts needed some improvements for better readability: chapters have now been classified according the outcome data helpful for choosing your analysis rapidly, a schematic overview of data, and explanatory graphs have been added. Fourth, current data are increasingly complex and many important methods for analysis were missing in the first edition. For that latter purpose some more advanced methods seemed unavoidable, like hierarchical loglinear methods, gamma and Tweedie regressions and random intercept analyses. In order for the contents of the book to remain covered by the title, the authors renamed the book: SPSS for Starters and 2nd Levelers. Special care was, nonetheless, taken to keep things as simple as possible, simple menu commands are given. The arithmetic is still of a no-more-than high-school level. Step-by-step analyses of different statistical methodologies are given with the help of 60 SPSS data files available through the internet. Because of the lack of time of this busy group of people, the authors have given every effort to produce a text as succinct as possible.

This volume takes an in-depth look at the potential pharmacological applications of 11 important antidiabetic plants, examining their antihyperglycemic, hypoglycemic, and anti-lipidemic properties along with current genome editing research perspectives. Plant natural products, or phytoconstituents, are promising candidates for antidiabetic pharmacological actions. The phytoconstituents, such as i' avonoids, terpenoids, saponins, carotenoids, alkaloids and glycosides, play vital roles in the current and future potent antidiabetic drug development programs Each chapter reviews a particular plant with antidiabetic properties, explaining the therapeutic aspects, its active antidiabetic compounds, and relevant genome editing technology. The specific plants discussed include Azadirachta indica (commonly known as neem, nimtree or Indian lilac), Gymnema sylvestre (commonly called gymnema, Australian cowplant, and Periploca of the woods), Syzygium cumini (commonly known as Malabar plum, Java plum, black plum, jamun or jambolana), Ceylon cinnamon (or true cinnamon, as opposed to cassia cinnamon), insulin plant (or Costus pictus), Trigonella foenum-graecum (better known as fenugreek), Mulberry, Nigella sativa L. (black caraway, also known as black cumin, nigella, kalojeera, kalonji or kalanji), Aegle marmelos (L.) (commonly known as bael (or bili or bhel), also Bengal quince, golden apple, Japanese bitter orange, stone apple or wood apple), Ficus benghalensis (the banyan, banyan fig and Indian banyan), and of course, garlic (Allium sativum). Antidiabetic Plants for Drug Discovery: Pharmacology, Secondary Metabolite Profiling, and Ingredients with Insulin Mimetic Activity will serve as a valuable source of information for students, drug researchers, medical practitioners, diabetic patients, and many others in the effort to gain understand of how these plant drug molecules can help fight diabetes.

The book presents the latest developments in clinical medicine, particularly involved with pulmonary care and diseases. Emphasis is placed on the role of childhood obesity, often a result of the ill effects of an unhealthy diet and nutritional deficits, in shaping propensity for inflammatory pathologies, allergies, immune deficiency and respiratory and cardiovascular sequelae in adult life. Oxidative damage, caused by not full well understood cellular biochemistry, when unchecked by antioxidative rescue mechanisms, takes toll on a respiratory health. The book underscores the need to consider the complexity of mutual interactions of pathophysiological processes, which calls for tailoring the management strategies depending on the subgroups which patients belong to, be it obesity, children or elderly. The chapters also tackle biological diseases with genetic underpinnings. The application of genetics to identify the molecular alterations or mutations will serve well both diagnostics and targeted optimization of treatment; the poignant exemplar being the histological subtypes of lung cancer. The book provides a source of current facts and trends in clinical research and practice.

This book discusses recent advances in the field of translational stroke research. The editors have designed the book to provide new insight into the importance of regeneration and repair mechanisms for stroke victims. The editors have brought together a talented group of international stroke researchers and clinicians to contribute to this volume, which is written for students, researchers and physicians in biotechnology, neurosciences, neurology, neuroradiology and neurosurgery. Throughout the world, stroke is still a leading cause of mortality and morbidity; there are 152,000 strokes in the United Kingdom, 62,000 in Canada, and approximately 15 million people worldwide. Large communities of stroke survivors are eagerly awaiting scientific advances in translational stroke research related to regeneration and recovery of function that would offer new therapeutics for rehabilitation and regeneration utilizing novel stem cell and molecular-based approaches. This volume will allow the reader to undersnd the future of stroke treatment from its inception in the laboratory through to clinical trial design. The reader will learn about the recent advances made in these areas related to basic and applied stroke research and their translational potential. Dr. Paul A. Lapchak is Professor of Neurology and Director of Translational Research in the Departments of Neurology & Neurosurgery at Cedars-Sinai Medical Center in Los Angeles CA, USA. Dr. Lapchak is an internationally recognized expert conducting translational drug development research for ischemic and hemorrhagic stroke. Dr. John H. Zhang is Professor of Anesthesiology, Neurosurgery, Neurology, and Physiology, and Director, Center for Neuroscience Research at Loma Linda University School of Medicine, Loma Linda, CA, USA. Dr. Zhang is an internationally recognized expert working on drug development for hemorrhagic stroke.

This book discusses normal sex-related differences in lung structure and function and the role these differences play in lung disease. New research on the effects of sex hormone signaling on specific cell types of the lung has begun to reveal how these hormones may drive or prevent lung disease. Expertly written chapters examine the effects of sex hormones on normal pulmonary structure and function, hormone signaling in lung health, and specific diseases such as chronic obstructive pulmonary disease, asthma, pulmonary hypertension, and lung cancer. Gender, Sex Hormones, and Respiratory Disease: A Comprehensive Guide focuses on our current understanding and the gaps in research, with suggestions for future directions and implications for therapy. This book is a useful reference for pulmonologists and researchers and will prompt further inquiry aimed at improving overall lung health.

In recent years, inorganic polymers have attracted much attention in nano-biomedicine, in particular in the area of regenerative medicine and drug delivery. This growing interest in inorganic polymers has been further accelerated by the development of new synthetic and analytical methods in the field of nanotechnology and nanochemistry. Examples for biomedical inorganic polymers that had been proven to exhibit biomedical effects and/or have been applied in preclinical or clinical trials are polysilicate / silica glass (such as naturally formed "biosilica" and synthetic "bioglass") and inorganic polyphosphate. Some members of the mentioned biomedical inorganic polymers have already been applied e.g. as "bioglass" for bone repair and bone tissue engineering, or they are used in food processing and in dental care (inorganic polyphosphates). However, there are a number of further biological and medicinal properties of these polymers, which have been elucidated in the last few years but not yet been applied for treatment of humans. In addition to polysilicates and polyphosphate, there are a series of other inorganic polymers including polyarsenate and polyvanadate, whose biological / biomedical properties have been only marginally studied so far. Moreover, the combined application of inorganic polymers and organic polymeric molecules (formation of organic-inorganic hybrid materials) provides a variety of new materials with novel property combinations and diverse applications in nanomedicine. The planned book summarizes the present state of knowledge on a large group of inorganic polymers that had hitherto been mainly considered with regard to their chemistry but not comprehensively reviewed with respect to their potential biomedical applications.

This book aims to comprehensively review the current cell-based strategies under investigation to achieve the regeneration of human hair follicles. The unique capacity of the human hair follicle to self-renew explains why this complex "mini-organ" has always attracted so much interest as a model for researchers to study stem cell biology and regenerative medicine. The hair follicle is considered a main reservoir of cutaneous stem cells, containing several pools of epithelial, melanocyte, and mesenchymal stem cells involved in hair follicle self-regeneration and pigmentation. In addition, while some of the different follicular cell types contribute to hair shaft growth, others participate in very important interfollicular functions such as dermal remodeling, re-epithelialization after wounding, and cutaneous stem cell homeostasis. The idea of human hair follicle regeneration either "de novo" or by activating dormant miniaturized follicles is not new, yet still continues to arouse enormous interest in the pursuit of a definitive cure for baldness. In contrast to hair follicle regeneration in mice, the attempts made with human follicles have been disappointing in terms of efficiency. However, recent advances in stem cell biology-as well as the appearance of new technologies like 3D printing-have revived expectations in this field of research. This book is divided into four sections. The first part includes an overview of the strategies used in hair follicle regeneration and a historical summary of the most important achievements to date. Parts two and three comprise the main body of the book, with detailed descriptions of the cells and tissue structures involved in hair follicle regeneration, followed by an elaboration of the different therapeutic strategies, engineering techniques, and a clinician's perspective of stem cell-based therapies in hair loss treatments. Finally, the fourth part reviews the important contribution of the hair follicle in healing cutaneous wounds through the regeneration and remodeling of the dermis and epidermis after injury, as well as wound induced hair follicle neogenesis that occurs when the skin is injured.

Unique and timely volume as mRNA is a hot area of research making great strides. Covers the full-scale production systems that are needed to develop vaccines as well as elements of data needed to secure the IND approvals. Introduces a commercial-scale manufacturing process using novel techniques like the PCR, in addition to the traditional plasmid DNA. First book that offers commercial technology for developing and large-scale supply of mRNA products. Renowned author and entrepreneur in the field of drug discovery and production.

This volume provides a comprehensive collection of classical and cutting edge protocols and techniques to examine the normal development and physiological functions of the gastrointestinal system and to model the most common digestive diseases. The chapters focus on diverse research topics including ex vivo systems to study gastrointestinal development and functions, in vivo imaging of the gastrointestinal tract, isolation and characterization of intestinal immune cells, and animal models of gastrointestinal inflammation and cancer. The Gastrointestinal Physiology and Diseases: Methods and Protocols book targets wide audience of physiologists, cell and developmental biologists, immunologists, and physician-scientists working in the field of gastroenterology and beyond. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Highly practical and clearly written, Gastrointestinal Physiology and Diseases: Methods and Protocols will serve both seasoned researchers as well as newcomers to the field and will provide a unique resource and expert guidance to modern laboratory techniques developed for examining normal functions and diseases of the gastrointestinal tract.