Multivariate analysis is a mainstay of statistical tools in the analysis of biomedical data. It concerns with associating data matrices of n rows by p columns, with rows representing samples (or patients) and columns attributes of samples, to some response variables, e.g., patients outcome. Classically, the sample size n is much larger than p, the number of variables. The properties of statistical models have been mostly discussed under the assumption of fixed p and infinite n. The advance of biological sciences and technologies has revolutionized the process of investigations of cancer. The biomedical data collection has become more automatic and more extensive. We are in the era of p as a large fraction of n, and even much larger than n. Take proteomics as an example. Although proteomic techniques have been researched and developed for many decades to identify proteins or peptides uniquely associated with a given disease state, until recently this has been mostly a laborious process, carried out one protein at a time. The advent of high throughput proteome-wide technologies such as liquid chromatography-tandem mass spectroscopy make it possible to generate proteomic signatures that facilitate rapid development of new strategies for proteomics-based detection of disease. This poses new challenges and calls for scalable solutions to the analysis of such high dimensional data. In this volume, we will present the systematic and analytical approaches and strategies from both biostatistics and bioinformatics to the analysis of correlated and high-dimensional data.

This volume gives a general summary of the current understanding of lymphatic metastasis and the possibilities of more specific detection of lymph node metastasis. It describes in detail the procedure of sentinel lymph node detection in urogenital tumors, neck and thyroid tumors, malignant melanoma, gastric and colorectal cancer and tumors of the breast. The potential and limitations of this new method are discussed. This book provides comprehensive insight into a both clinically and scientifically important new field which is bringing about a marked improvement in the treatment of malignant tumors.

The application of molecular techniques to gastroenterology continues to yield important advances in the development of drugs to treat gastrointestinal disorders. Important new drugs have emerged through the collaborative and complementary efforts of basic scientists, clinicians, and clinical researchers in academia and the pharmaceutical industry. The challenge has been exciting, with a few surprises along the way. Consider peptic ulcer disease as an example. The discovery of H receptors and the availability of potent and 2 selective H-receptor antagonists signaled the beginning of a new era 2 in the treatment of gastric hypersecretory states and peptic ulcers. Introduction of proton pump inhibitors offered another therapeutic option. Though H-receptor antagonists and proton pump inhibitors 2 are important and useful drugs, the discovery of the link between H. pylori infection and peptic ulcer disease has led to even more effective pharmacotherapeutic regimens. Our intent in Drug Development: Molecular Targets for GI Diseases is to bring together hands-on experts to review promising areas of gastrointestinal pharmacology. The contemporary topics covered, from a mechanistic viewpoint, are relevant to gastrointestinal inflammation and motility disorders. Authoritative opinions are offered on both future research directions and potential applications for new therapies.

This volume will consider one of ICH's major categories, Safety i.e. topics relating to in vitro and in vivo pre-clinical studies (Carcinogenicity Testing, Genotoxicity Testing, etc.). Since the start of the ICH process, many guidelines have been written, but even after ICH6 no explanations have been given during a formal Congress about the background of the ICH Guidance documents. Even more important than what has been written, might have been those thoughts of the experts that are not included in the Guidance documents. Why has the guideline been written as it is written, and why have some aspects been deleted. These and other related questions are the contents of this book, written by experts who were involved in the ICH process. Furthermore, the chapters will contain discussions on the "lessons learnt" and "future developments".

This new edition of Animal Models in Cardiovascular Research describes historical and recent advances in our understanding of the cardiovascular system from studies conducted in a variety of animal models. Since the last edition we have witnessed an explosion in the use of both congenic and transgenic animals. The use of specific knock-in and knock-out transgenic models has resulted in an avalanche of genetic, molecular and protein-based information that, potentially, could result in an amazing new array of treatment and management options. However, the results of these studies also introduce a sometime bewildering array of redundant, overlapping and competing molecular pathways involved in both physiological and pathological responses.

This third edition is designed to provide a better basis for understanding and using animal models in the current climate of background knowledge and information. It is significantly different than the previous two editions. Chapter 1 is updated from the previous editions addressing general principles of animal selection. It also provides expanded tables of normal physiological values for easy reference. Chapter 2 covers preoperative care, pre-anesthesia, chemical restraint, and includes a significantly expanded section on pain recognition and analgesia particularly in rodents. Chapter 3 provides a summary of normal cardiovascular parameters obtained from intact, awake animals. The data have been rearranged in outline rather than the previous tabular form hopefully resulting in easier reference.

Chapter 4 addresses the techniques, problems and pitfalls of measuring cardiac function in animals. There is an emphasis on the proper use of these measurements to develop new treatment and management strategies as well as using them to study mechanisms of disease. Chapter 5 emphasizes the techniques, problems and pitfalls involved in the measurement of arterial function and ventricular/arterial coupling dynamics. Again the emphasis is on the use of these parameters to develop new treatment and management strategies and for studying the mechanisms of disease. Chapter 6 is a all new chapter dealing specifically with the problems and pitfalls inherent in using isolated heart preparations. The need for this chapter became apparent because so much information was published using obviously non-physiologic preparations. The use of both pumping and non-pumping preparations are described along with techniques necessary for using hearts from larger species where oxygen carrying capacity of the perfusate is critical. The importance of hypoxia and anoxia in the interpretation of results is discussed.

Chapter 7 focuses on the cardiovascular effects of the post-operative analgesic drugs commonly used today and how to avoid potential problems resulting from these effects when reporting experimental data. These data are also presented in outline form rather than the tabular format used in the two previous editions. Chapter 8 addresses the use of naturally occurring animal models of valvular and infectious cardiovascular disease. The information presented has been updated and expanded from the second edition. Chapter 9 examines iatrogenic models of ischemic heart disease.

Chapter 10 is new. It provides a review of iatrogenic, transgenic and naturally occurring animal models of cardiomyopathy and heart failure. Chapter 11 includes new, updated and revised information reviewing iatrogenic and transgenic models of hypertension. Chapter 12 contains new, and updated information on iatrogenic and transgenic models of atherosclerotic disease.

Chapter 13 is completely new material dealing with animal models for the study of neurohumeral and central nervous system control of the cardiovascular system. Chapter 14 is also new. It provides examples of cardiovascular studies involving the use of specific transgenic models not normally associated with the cardiovascular system, such as estrogen receptor knockouts, to study cardiovascular function.

Stable isotope techniques offer advantages in safety, sensitivity, specificity, and economy for many types of pharmaceutical investigations when compared to conventional techniques. Nevertheless, pharmaceutical researchers are slow to embrace stable isotope techniques.

This book assembles in one place comprehensive reviews of the many applications of stable isotopes and the background material necessary to understand the application. This approach is a deliberate attempt to encourage the usage of stable isotopes in pharmaceutical research. A bonus to the reader is the high standard of contributions from a very talented and diverse group of investigators.

Antibiotics are truly miracle drugs. As a class, they are one of the only ones that actually cure disease as opposed to most drugs that only help relieve symptoms or control disease. Since bacteria that cause serious disease in humans are becoming more and more resistant to the antibiotics we have today, and because they will ultimately become resistant to any antibiotic that we use for treatment or for anything else, we need a steady supply of new antibiotics active against any resistant bacteria that arise. However, the antibiotics marketplace is no longer attractive for large pharmaceutical companies, the costs of development are skyrocketing because of ever more stringent requirements by the regulatory agencies, and finding new antibiotics active against resistant strains is getting harder and harder. These forces are all combining to deny us these miracle drugs when we need them the most. I provide a number of possible paths to shelter from this perfect storm.

Metabolic Bone Disease, Third Edition is the new, expanded edition of the classic text, featuring the latest advancements and research information in this fast-moving field. The Third Edition includes the most up-to-date information on molecular mechanisms, basic biology, pathophysiology, and diagnosis and management strategies of metabolic bone disease.
Key Features
* Edited by "fathers of the field"
* An expanded version of a classic AP text
* Complete coverage of a fast-growing field

The Endoplasmic Reticulum (ER) is an organelle with extraordinary signaling and homeostatic functions. It is the organelle responsible for protein folding, maturation, quality control and trafficking of proteins destined for the plasma membrane or for secretion into the extracellular environment. Failure, overloading or malfunctioning of any of the signaling or quality control mechanisms occurring in the ER may provoke a stress condition known as ER stress . Accumulating evidence indicates that ER stress may dramatically perturb interactions between the cell and its environment, and contribute to the development of human diseases, ranging from metabolic diseases and cancer to neurodegenerative diseases, or impact therapeutic outcome. This book primarily focuses on the pathophysiology of ER stress. It introduces the molecular bases of ER stress, the emerging relevance of the ER-mitochondria cross-talk, the signaling pathways engaged and cellular responses to ER stress, including the adaptive Unfolded Protein Response (UPR), autophagy as well as cell death. Next the book addresses the role of ER stress in physiology and in the etiology of relevant pathological conditions, like carcinogenesis and inflammation, neurodegeneration and metabolic disease. The last chapter describes how ER stress pathways can be targeted for therapeutic benefit. Altogether, this book will provide the reader with an exhaustive view of ER stress biology and the latest insights in the role of ER stress in relevant human diseases."

Hardbound. In this volume, there are five reviews of topical subjects. The availability of drugs for the successful treatment of many diseases results in an increase in the number of people who live to their eighties and nineties at which time Alzheimer's disease is most prevalent. The steady progress which is being made in our understanding of this complex disease and in the development of drugs for its treatment are reviewed in Chapter 1. Chemotherapy of another disease which often resists treatment may have another weapon in its armoury if recent work on modifying a naturally occurring anticancer compound (camptothecin) succeeds in reducing its side-effects; recent efforts in this field (described in Chapter 2) may yield a drug of value in treating cancer of the colon and stomach.Transporting a drug molecule to a specific site of action continues to present a challenge. The use of phosphates and phosphonates to protect the drug from hydrolysis or o

Over the last decade the development of new molecular biology tools, advanced microscopy, live imaging and systems biology approaches have revolutionized our conception of how embryonic development proceeds. One fundamental aspect of development biology is the concept of morphogenesis: understanding how a group of multipotent cells organize and differentiate into a complex organ. In Kidney Development: Methods and Protocols, expert researchers in the field detail different approaches to tackle kidney development. These approaches include culture and live imaging aspects of kidney development, analyzing the 3-dimensional aspects of branching morphogenesis as well as nephrogenesis, manipulation of the gene/protein expression during kidney development as well as in the adult kidney, and how to assess kidney malformation and disease. Written in the highly successful Methods in Molecular Biology (TM) series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and key tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Kidney Development: Methods and Protocols seeks to aid scientists in the further study of the process of morphogenesis which is fundamental important not only for studying developmental biology but also for regenerative medicine.

The year 2010 marks the centennial for the identification of histamine and the first glimpse of its many physiological functions. From these initial findings a rich tapestry of research has uncovered roles for histamine in almost every physiological process with new findings emerging every year. These diverse roles of histamine have made for fertile ground for the discovery of novel therapeutics, and these drugs have been so successful that the term "antihistamine" has entered the common lexicon. This volume is an attempt to give a snapshot in time as to the current understanding of the role of histamine in just one important therapeutic area-inflammation. The first three chapters provide some background context for the rest of the book starting out with a historical perspective by Figueroa and Shankley. Bongers et al provide an overview of the pharmacology of the four histamine receptors and the chapter by Hiroshi Ohtsu describes how histamine is synthesized as well as the insights derived from mice where this synthesis is disrupted. The next several chapters discuss disease areas where histamine is known to be involved. Chapter 4 by Thomas Taylor-Clark outlines the role of histamine in allergic rhinitis, an area were antihistamines are commonly used. This is also true for ocular allergy as discussed by Ohbayashi et al. Both of these chapters highlight aspects of these conditions that are still not well-controlled and suggest the utility of new antihistamines targeting other histamine receptors.

Exercise Genomics encompasses the translation of exercise genomics into preventive medicine by presenting a broad overview of the rapidly expanding research examining the role of genetics and genomics within the areas of exercise performance and health-related physical activity. Leading researchers from a number of the key exercise genomics research groups around the world have been brought together to provide updates and analysis on the key discoveries of the past decade, as well as lend insights and opinion about the future of exercise genomics, especially within the contexts of translational and personalized medicine. Clinicians, researchers and health/fitness professionals will gain up-to-date background on the key findings and critical unanswered questions across several areas of exercise genomics, including performance, body composition, metabolism, and cardiovascular disease risk factors. Importantly, basic information on genomics, research methods, and statistics are presented within the context of exercise science to provide students and professionals with the foundation from which to fully engage with the more detailed chapters covering specific traits.

Exercise Genomics will be of great value to health/fitness professionals and graduate students in kinesiology, public health and sports medicine desiring to learn more about the translation of exercise genomics into preventive medicine.

This book provides in-depth information on the applications of cannabis products as a legitimate medicine in treating a variety of diseases and disorders in domestic animals. Pharmacology and toxicology of cannabinoids and their effects on the endocannabinoid system, which is involved in the regulation of diverse physiological and cognitive processes, are discussed in detail. Furthermore, the book reviews development and testing of cannabis based medical products and introduces the nutritional components of cannabis plants. Cannabis as a therapeutic in veterinary medicine is gaining interest among owners and practitioners. Numerous studies have been completed or are currently underway that analyze the potential of clinical application of cannabinoid and terpenoid molecules. In this book the authors take a comprehensive look at previous studies in animal and human models and discuss translational applications based on these scientific data. This seminal text serves as a go-to resource for veterinary practitioners on cannabinoid therapy. It will also serve as a foundation for clinicians and researchers interested in this emerging field of veterinary medicine.

This book offers a comprehensive but highly readable compilation of papers on the role of dopamine in sleep and sleep disorders. Leading experts in sleep medicine, psychiatry and neuroendocrinology provide a broad perspective on the field, from established theories to the latest research advances. Accordingly, it represents an interdisciplinary, cutting-edge guide for sleep disorder specialists, sleep researchers, psychiatrists, neurologists, pulmonologists, psychologists, and behavioral sleep medicine specialists.

This unique book is the proceedings of The Future of Life and the Future of our Civilization symposium, which was held in May of 2005 in Germany. It is unique since it contains articles of the Future in all aspects of our life. Besides, until now such publications are absent. In this book we can find articles about the spread of life trough out the cosmos and about solar evolution, about origin of life and about cardiology in XXIst century, about structural regularities of encoding in DNA chromosomes, about preservation of biodiversity in marine systems and about defeat of aging, about life-time of technological civilization and about the future of the poor, marginalized populations, about the early cancer diagnositcs of skin, about human clonius and about transition to the next level civilization."

If there is one aspect of current cancer research that represents a major ch- lenge in both novice and experienced researchers, it is the rapid advance in our understanding of the disease. Researchers can be required to switch from analysis of gene expression to kinetics of protein activation, from genetic studies to the analysis of protein funtion. Cancers are highly complex disease systems and researchers aiming to understand the functioning of cancer systems require access to a wide range of laboratory techiques from a broad range of research disciplines. Increasingly, however, published methods are incomplete or refer back to a series of previous publications each containing only a small part of the complete pro- col. The aim of Ovarian Cancer: Methods and Protocols is to provide for ovarian cancer researchers in the first instance, a laboratory handbook that will facilitate research into cancer systems by providing a series of expert protocols, with proven efficacy, across a broad range of technical expertise. Thus, there are sections on tumor genetics and cellular signal transduction, as well as sections on apoptosis and RNA analysis. The value of Ovarian Cancer: Methods and Protocols to the ovarian cancer researcher will, I trust, be considerably enhanced by (1) the provision of a series of overviews relating to the biology, diagnosis, and treatment of this important neoplasm, and (2) the provision of a series of technical overviews introducing each part that provides an expert review of the applications and pitfalls of the various techniques included.

Dr. Gordon Meiklejohn was a world renowned physician, and Chairman of the Department of Medicine at the University of Colorado. He is best known for being a catalyst in researching, diagnosing, and inoculating for the flu virus, and was instrumental in the eradication of Smallpox.Dr. Meiklejohn was the son of Alexander Meiklejohn. He excelled in academics and sports, especially ice hockey, and was twice invited to participate on the U.S. Olympic Hockey teams.

This book, written by one of the leaders in the field of the neurosciences, will give an explanation of the symptoms and eventual untimely suicide of one of literatures greatest authors; Virginia Woolf. The sources used are letters and statements from Woolf herself, the literature she wrote and comments, letters and any other documentation that referred to her mental state and her medical status. The author will use current insight into depression, the mental consequences of child abuse and drug interactions/effects to illustrate this case study. The book should appeal to researchers in the neurosciences, psychology and psychiatry as well as to a broader audience, mainly individuals who are interested in the (external and internal) forces that drove Woolf to write her material.

This book provides the most up-to-date review of the simian virus 40 (SV40) minichromosome as a model for the mammalian chromosome in studies of DNA replication. It focuses on disruption of DNA replication by anticancer drugs and DNA-damaging agents. There is a strong emphasis on the unique advantages of SV40 as an experimental system for the analysis of these classes of anticancer drug mechanisms. The new high-resolution gel electrophoresis methods for the analysis of SV40 DNA replication are covered in detail to aid readers in designing and interpreting similar experiments.
Key Features
* Presents unique advantages of SV40 as an experimental system for the study of classes of anticancer drugs
* Details new high-resolution gel electrophoresis methods for the analysis of SV40 DNA replication
* Provides details to help the reader design and interpret similar experiments

This book, an international collaborative effort in the area of molecular respiratory research, showcases a broad range of multidisciplinary approaches to unravel and analyze the underlying mechanisms of a spectrum of respiratory ailments. It discusses immunological and genetic respiratory disorders, cancer, respiratory allergies and cough, sleep disordered breathing and many others. Exciting new results and up-to-date critical overviews of widely debated topics pertaining to respiratory disorders are presented. The contributions provide evidence for the growing interest of the international community of researchers in the field of respiration. The book incorporates modern molecular approaches to diagnostic and treatment solutions, underscoring the need for rational, evidence-based treatment methods. Combining cutting edge basic and clinical research with expert knowledge and experience this book is essential reading for medical students, research scientists and practicing specialists in pulmonology, immunology and allergology.

This book is unique in covering a wide range of design and analysis issues in genetic studies of rare variants, taking advantage of collaboration of the editors with many experts in the field through large-scale international consortia including the UK10K Project, GO-T2D and T2D-GENES. Chapters provide details of state-of-the-art methodology for rare variant detection and calling, imputation and analysis in samples of unrelated individuals and families. The book also covers analytical issues associated with the study of rare variants, such as the impact of fine-scale population structure, and with combining information on rare variants across studies in a meta-analysis framework. Genetic association studies have in the last few years substantially enhanced our understanding of factors underlying traits of high medical importance, such as body mass index, lipid levels, blood pressure and many others. There is growing empirical evidence that low-frequency and rare variants play an important role in complex human phenotypes. This book covers multiple aspects of study design, analysis and interpretation for complex trait studies focusing on rare sequence variation. In many areas of genomic research, including complex trait association studies, technology is in danger of outstripping our capacity to analyse and interpret the vast amounts of data generated. The field of statistical genetics in the whole-genome sequencing era is still in its infancy, but powerful methods to analyse the aggregation of low-frequency and rare variants are now starting to emerge. The chapter Functional Annotation of Rare Genetic Variants is available open access under a Creative Commons Attribution 4.0 International License via link.springer.com.

This book describes important developments and emerging trends in experimental and clinical cancer gene therapy. It reflects the tremendous advances made over recent years with respect to immunogenes, suicide genes and gene correction therapies, as well as in gene suppression and miRNA therapies. Many of the described strategies focus on the generation of more efficient and specific means of attack at known and novel cellular targets associated with tumor development and progression. The book also details parallel improvements in vector design, vector delivery, and therapeutic efficacy. It offers readers a stimulating, broad overview of advances in the field, linking experimental strategies to their clinical applications.

Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors.

This unique reference work offers a diverse and interesting view of the remarkable history of treating disease and understanding human health. More than 500 entries, written in an A-Z format, cover the amazing changes that have taken place in the world of health and medicine. While other volumes may overwhelm readers with extraneous information, "Milestones in Health and Medicine" offers relevant and succinct entries. Each entry includes a definition of the topic, its history, and its current place in medicine today. This book also includes a preface, illustrations, helpful cross-references, sources for additional reading, and a list of entries by subject.