Rebooting the collagen gel: Artificial hydrogels for the study of epithelial mesenchymal transformation.

The collagen gel has been used to study epithelial-mesenchymal transformation (EMT) for over 30 years. With advances in the field of materials sciences, new options are available to design optically clear, three-dimensional nature-inspired matrix mimetics to study EMT. Here, we review the history of the collagen gel assay, discuss its current use and how newer artificial matrices can be built to simulate in vivo extracellular environments and investigate important current questions in the EMT field. We suggest that further collaborations between materials scientists and biologists will be critical to move the field of EMT forward. Developmental Dynamics 247:332-339, 2018. © 2017 Wiley Periodicals, Inc.

Regulatory Forum Opinion Piece: Carcinogen Risk Assessment: The Move from Screens to Science.

Throughout the last 50 years, the paradigm for carcinogenicity assessment has depended on lifetime bioassays in rodents. Since 1997, the International Conference on Harmonisation (ICH) S1B has permitted the use of a 2-year rodent bioassay (usually in the rat) and an alternative, genetically modified mouse model to support cancer risk assessment of pharmaceuticals. Since its introduction, it has become apparent that many of the stated advantages of the 6-month Tg mouse bioassay have, in actual fact, not been realized, and the concern exists that an albeit imperfect, 2-year mouse bioassay has been replaced by a similarly imperfect 6-month equivalent. This essay argues strongly that model systems, using cancer as the end point, should be discontinued, and that the recent initiatives, from the Organization for Economic Cooperation and Development and Institute of Peace and Conflict Studies, on "mode of action," "adverse outcome pathways," and "human relevance framework" should be embraced as being risk assessments based upon the available science. The recent suggested revisions to the ICH S1 guidelines, utilizing carcinogenicity assessment documents, go some way to developing a science-based risk assessment that does not depend almost entirely on a single, imperfect, cancer-based end point in nonrelevant animal species.

Historical perspective on the use of animal bioassays to predict carcinogenicity: evolution in design and recognition of utility.

The animal testing protocols used today to evaluate the carcinogenicity of chemicals are very different from those used in the earlier part of the 20th century. To explore how cancer bioassays have changed over time, we surveyed the literature discussing test design and interpretation from the 1930s to the present. We also analyzed compendia of bioassays published by the US Public Health Service (US PHS) from 1938 to 1978, and evaluated the data to understand the evolution of testing methodology (e.g., animals used, test duration) and the types of chemicals being studied. The cancer bioassay evolved in several stages. At the beginning of the 20th century, animal bioassays were primarily used to re-create known human diseases, whereas in the 1940s to 1960s, animal bioassays were largely used to evaluate the safety of chemicals in foods, drugs, and cosmetics. Beginning in the late 1960s and 1970s, chemicals primarily associated with occupational or environmental exposures were also evaluated. Testing strategies now emphasize a suite of tests including multiple in vitro tests and both short-term and long-term animal tests. The objectives of testing are broader, too, with test goals encompassing information regarding mode of action and other parameters aimed at evaluating potential species differences (e.g., in toxicokinetics) and their relevance for evaluating human risks. It is important to consider this evolution when evaluating the testing methodology and scientific conclusions in earlier eras. As toxicology continues to develop, testing methods will continue to change in concert with increased knowledge and understanding.

Bioanalysis Rising Star Award 2020: announcing our finalists.

Over the past 10 years, Bioanalysis and Bioanalysis Zone have been proud to host the Bioanalysis Rising Star Award (formerly the New Investigator Award), to recognize and showcase the most promising early-career scientists in our community. The time has now come for you to select your winner for the Bioanalysis Rising Star Award 2020. We are delighted to present our judges' selection of finalists (in alphabetical order): Ashley Ross, University of Cincinnati (OH, USA) Chris Williams, QPS (Groningen, The Netherlands) Danielle Moncrieffe, King's College London (UK) Omar Barnaby, Amgen (CA, USA) Sooraj Baijnath, University of KwaZulu-Natal (South Africa) Sumit Kar, Celerion (NE, USA).

Biochemical Detection of cGMP From Past to Present: An Overview.

Cyclic guanosine monophosphate (cGMP), generated via the guanylate cyclase (GC)-catalyzed conversion from GTP, is unequivocally recognized as crucial second messenger, intimately involved in the regulation of a broad range of physiological processes such as long term potentiation, blood pressure regulation, or platelet aggregation (for review: Hobbs 2000). Since its first identification in rat urine by Ashman and co-workers (1963), various approaches have been conceived and established to quantify cGMP in biological samples, or to detect cGMP as the reaction product of enzymatic assays, allowing the determination of kinetic parameters. These approaches have evolved from laborious handling of small numbers of samples with average sensitivity to highly developed biochemical detection assays allowing the processing of very large numbers of samples. The present article focuses upon the history of biochemical cGMP detection from the pioneering work of the early years to the actual state-of-the-art approaches for the detection of this important biological messenger.

Prostaglandins, bioassay and inflammation.

The formation of the British Pharmacological Society coincided almost exactly with a series of ground-breaking studies that ushered in an entirely new field of research--that of lipid mediator pharmacology. For many years following their chemical characterisation, lipids were considered only to be of dietary or structural importance. From the 1930s, all this changed--slowly at first and then more dramatically in the 1970s and 1980s with the emergence of the prostaglandins (PGs), the first intercellular mediators to be clearly derived from lipids, in a dynamic on-demand system. The PGs exhibit a wide range of biological activities that are still being evaluated and their properties underlie the action of one of the world's all-time favourite medicines, aspirin, as well as its more modern congeners. This paper traces the development of the PG field, with particular emphasis on the skillfull utilisation of the twin techniques of bioassay and analytical chemistry by U.K. and Swedish scientists, and the intellectual interplay between them that led to the award of a joint Nobel Prize to the principal researchers in the PG field, half a century after the first discovery of these astonishingly versatile mediators.

Vascular prostaglandin synthesis: the early days.

Prostacyclin (PGI2) and thromboxane (TxA2) labile cyclooxygenase (COX) products via PGH2 were identified in biological fluids by the ingenious application of the principle of parallel pharmacological assays developed by John Vane. Either organ perfusates or circulating blood superfuse bioassay tissues arranged in a cascade. Tissues were selected based on specificity of responses to targeted eicosanoids. Additionally, PGI2 inhibited platelet aggregation, a finding that led to discovery of its critical anti-thrombotic activity at the blood-endothelial interface. The biological activities of PGI2 and TxA2 were the fingerprints for tracking their isolation and ultimate chemical identification. These studies were responsible for opening the modern era of vascular biology that has facilitated the development of a rational approach to the treatment of diabetic and hypertensive complications involving the arterial circulation.

Trophoblastic reminiscences.

Development of the radioimmunoassay in the 1950s and early '60s largely eliminated early problems with human chorionic gonadotropin and permitted the U.K. to offer a national service for gestational trophoblastic disease (GTD) patients. In 1973 a voluntary registration scheme for patients with hydatidiform mole (HM) opened at 3 U.K. locations. The Charing Cross Centre has followed > 35,000 women with HM, and 2,500 have undergone treatment for various forms of GTD. All treated patients are followed indefinitely and the data computerized. Disasters have occurred in 1 country from misinterpretation of erroneous hCG assays. In terms of experience and data collection, the advantages of a specialized service are overwhelming. This society's main thrust should be to ensure that women with GTD in all countries benefit from specialized management.

Contribution of Harold M. Swartz to In Vivo EPR and EPR Dosimetry.

In 2015, we are celebrating half a century of research in the application of Electron Paramagnetic Resonance (EPR) as a biodosimetry tool to evaluate the dose received by irradiated people. During the EPR Biodose 2015 meeting, a special session was organized to acknowledge the pioneering contribution of Harold M. (Hal) Swartz in the field. The article summarizes his main contribution in physiology and medicine. Four emerging themes have been pursued continuously along his career since its beginning: (1) radiation biology; (2) oxygen and oxidation; (3) measuring physiology in vivo; and (4) application of these measurements in clinical medicine. The common feature among all these different subjects has been the use of magnetic resonance techniques, especially EPR. In this article, you will find an impressionist portrait of Hal Swartz with the description of the 'making of' this pioneer, a time-line perspective on his career with the creation of three National Institutes of Health-funded EPR centers, a topic-oriented perspective on his career with a description of his major contributions to Science, his role as a mentor and his influence on his academic children, his active role as founder of scientific societies and organizer of scientific meetings, and the well-deserved international recognition received so far.

G protein-coupled receptors: an overview of signaling mechanisms and screening assays.

The existence of cellular receptors, a group of specialized biomolecules to which endogenous and exogenous compounds bind and exert an effect, is one of the most exciting aspects of cell biology. Among the different receptor types recognized today, G-protein-coupled receptors (GPCRs) constitute, undoubtedly, one of the most important classes, in part due to their versatility, but particularly, due to their central role in a multitude of physiological states. The unveiling of GPCR function and mode of action is a challenging task that prevails until our days, as the full potential of these receptors is far from being established. Such an undertaking calls for a joint effort of multidisciplinary teams that must combine state-of-the-art technologies with in-depth knowledge of cell biology to probe such specialized molecules. This review provides a concise coverage of the scientific progress that has been made in GPCR research to provide researchers with an updated overview of the field. A brief outline of the historical breakthroughs is followed by a discussion of GPCR signaling mechanisms and by a description of the role played by assay technologies.

The discovery, isolation and identification of aldosterone: reflections on emerging regulation and function.

This paper has a focus on the early history of aldosterone. The Taits take us on a chronological trawl through the history in which they had a first hand role and made a major contribution-their bioassay was in many ways the key. The gifted Swiss chemists made a critical contribution to the scale and isolation of larger amounts. This was international collaboration at its best. Developing technologies were utilised as crucial cutting edge applications in the advancing front, technology transfer before the word was invented. Measurement of aldosterone and angiotensin were crucial advances to the understanding of the regulation of the hormone. In the period 1960-2003, some 30,000 papers mentioned aldosterone as a keyword, even so advances on a larger scale were slow. I have indicated some of my own work with the Howard Florey team using the adrenal autotransplant in the conscious sheep. Recently, the understanding of the role of induced proteins, the flow on from the RALES trial and the development of eplerenone has revitalised the aldosterone field.

Carcinogenicity and mutagenicity testing, then and now.

Cancer is a dread disease worldwide. Mortality of individuals suffering from cancer is high, despite the current improved methods of precocious detection, surgery and therapy. Prevention of cancer is the recognized goal of many activities in cancer research. This aim was recognized early to involve the bioassay of environmental chemicals or mixtures. The first such study involved application of coal tar to the ear of rabbits, and later on to the skin of mice. Subsequently, laboratory rats were introduced, and hamsters were utilized as a substitute for the unwieldy tests in rabbits. Investigators also became concerned with the mechanisms of carcinogenesis, and more definitive approaches to carcinogen bioassay in laboratory animals, as possible indicators of cancer risk in humans. These tests were expensive and lengthy, and did not serve the important purpose of accurately measuring risk of cancer to humans. Once it was realized that DNA and the genetic apparatus might be a key target, rapid bioassays in bacterial and mammalian cell systems were introduced successfully. Thus, batteries of tests are now available to detect effectively human cancer risks, and provide novel approaches to determine the underlying mechanisms, as a sound basis for cancer prevention.

Radiation hormesis: its historical foundations as a biological hypothesis.

This paper represents the first systematic effort to describe the historical foundations of radiation hormesis. Spanning the years from 1898 to the early 1940's the paper constructs and assesses the early history of such research and evaluates how advances in related scientific fields affected the course of hormetic related research. The present effort was designed to not only address this gap in current knowledge, but to offer a toxicological basis for how the concept of hormetic dose-response relationships may affect the nature of the bioassay and its role in the risk assessment process.

Interview with Irving W Wainer.

Irving W Wainer, Senior Investigator in the Intramural Research Program at the National Institute on Aging/NIH received his PhD degree in chemistry from Cornell University and did postdoctoral doctoral studies in molecular biology (University of Oregon) and clinical pharmacology (Thomas Jefferson Medical School). He worked for the US FDA and held positions at St Jude's Children's Research Hospital, at McGill University as Professor in the Department of Oncology, and as a Professor of Pharmacology at Georgetown University. Wainer has published over 350 scientific papers, 10 books, 25 book chapters and holds 11 patents. His awards include: 'A.J.P. Martin Medal' presented by the Chromatographic Society; Doctor HonorisCausa awarded by the Medical University of Gdansk (Gdansk, Poland, 2006), Doctor HonorisCausa awarded by the Department of Medicine, University of Liege (Liege, Belgium, 2012), and the 2013 Eastern Analytical Symposium Award for Outstanding Contributions to the Fields of Analytical Chemistry. Wainer's research includes the development of new therapeutic agents for the treatment of congestive heart failure, cancer, pain and depression, many of which are in the later stages of drug development. His laboratory has also continued the development of cellular membrane affinity chromatography technology, and recent work includes the development of columns containing immobilized forms of the breast cancer resistance protein found in cellular and nuclear membranes and mitochondrial membrane columns. Wainer's laboratory has also continued its study of the effect of disease progression and aging on drug metabolism in critically ill and terminal patients. Interview was conducted by Lisa Parks, Assistant Commissioning Editor of Bioanalysis.