Forty Years of Basic and Translational Heparanase Research.

This review summarizes key developments in the heparanase field obtained 20 years prior to cloning of the HPSE gene and nearly 20 years after its cloning. Of the numerous publications and review articles focusing on heparanase, we have selected those that best reflect the progression in the field as well as those we regard important accomplishments with preference to studies performed by scientists and groups that contributed to this book. Apart from a general 'introduction' and 'concluding remarks', the abstracts of these studies are presented essentially as published along the years. We apologize for not being objective and not being able to include some of the most relevant abstracts and references, due to space limitation. Heparanase research can be divided into two eras. The first, initiated around 1975, dealt with identifying the enzyme, establishing the relevant assay systems and investigating its biological activities and significance in cancer and other pathologies. Studies performed during the first area are briefly introduced in a layman style followed by the relevant abstracts presented chronologically, essentially as appears in PubMed. The second era started in 1999 when the heparanase gene was independently cloned by 4 research groups [1-4]. As expected, cloning of the heparanase gene boosted heparanase research by virtue of the readily available recombinant enzyme, molecular probes, and anti-heparanase antibodies. Studies performed during the second area are briefly introduced followed by selected abstracts of key findings, arranged according to specific topics.

Not only laboratory to clinic: the translational work of William S. C. Copeman in rheumatology.

Since the arrival of Translational Medicine (TM), as both a term and movement in the late 1990s, it has been associated almost exclusively with attempts to accelerate the "translation" of research-laboratory findings to improve efficacy and outcomes in clinical practice (Krueger et al. in Hist Philos Life Sci 41:57, 2019). This framing privileges one source of change in medicine, that from bench-to-bedside. In this article we dig into the history of translation research to identify and discuss three other types of translational work in medicine that can also reshape ideas, practices, institutions, behaviours, or all of these, to produce transformations in clinical effectiveness. These are: (1) making accessible state-of-the-art knowledge and best practice across the medical profession; (2) remodelling and creating institutions to better develop and make available specialist knowledge and practice; and (3) improving public and patient understandings of disease prevention, symptoms and treatments. We do so by examining the work of William S. C. Copeman, a dominant figure in British rheumatology from the 1930 through the late 1960s. Throughout his long career, Copeman blended approaches to "translation" in order to produce transformative change in clinical medicine, making his work an exemplar of our expanded notion of TM.

Lost in Translation? Cortisone and the Treatment of Rheumatoid Arthritis in Britain, 1950-1960. [corrected].

Cortisone, initially known as 'compound E' was the medical sensation of the late 1940s and early 1950s. As early as April 1949, only a week after Philip Hench and colleagues first described the potential of 'compound E' at a Mayo Clinic seminar, the New York Times reported the drug's promise as a 'modern miracle' in the treatment of rheumatoid arthritis (RA). Given its high profile, it is unsurprising that historians of medicine have been attracted to study the innovation of cortisone. It arrived at the end of a decade of 'therapeutic revolutions', kicked off by penicillin transforming the treatment of bacterial infections and ending with hopes of a revolution in the treatment of non-infectious, chronic inflammatory diseases. Despite these studies of cortisone's introduction, few historians have taken the story forward and considered how cortisone was adopted and adapted into clinical practice. This article tells the longer of how the drug and its derivatives were taken from research laboratories and integrated into clinical practice; what has in recent decades become known as translational medicine (TM). In exploring cortisone's first decade in Britain, we focus specifically on its role in the treatment of RA. Our approach is always to consider cortisone's use in the context of other treatments available to clinicians, and at local and national institutional settings. We do not discuss the many other therapeutic uses of cortisone, which ranged for topical applications for skin diseases to the management of cancers, especially childhood leukaemia, nor do we discuss its close analogue ACTH-AdenoCorticoTropic Hormone. We think there are lessons in our study for TM policies today.

Cell death: From initial concepts to pathways to clinical applications - Personal reflections of a clinical researcher.

Cell death research has come a long way from the description of cellular phenomena to identification of pathways to the role of apoptosis in tissue homeostasis in the pathophysiology of diseases and the delineation of targets for therapeutic intervention. In this very personal view of a clinical researcher in the field from the very beginning to recent clinical application, essential elements of cell death research over the past decades are seen from a perspective of development of science and medicine.

25 Years of Dysphagia Rehabilitation: What Have We Done, What are We Doing, and Where are We Going?

As deglutologists, we strive to use the best evidence available in the treatment of swallowing disorders. Evidence-based medicine is a bottom-up approach that thoughtfully combines the best external evidence with individual clinical expertise and the patients' choice reflective of their clinical state and preferences for their specific care plan. Evidence-based medicine is not restricted to randomized clinical trials and meta-analyses; rather, evidence-based medicine includes our ability to discriminate the best external evidence with which to answer clinical questions and then skillfully and appropriately being able to apply this evidence in the care and treatment of our patients (Sackett et al. in BMJ 312:71-72, 1996). Translation of efficient and effective dysphagia rehabilitative clinical practice implies the need to use treatment that has proven therapeutic value, yields measurable physiologic results and most importantly allows appreciable qualitative outcomes for the patient.

Hyperuricaemia, Xanthine Oxidoreductase and Ribosome-Inactivating Proteins from Plants: The Contributions of Fiorenzo Stirpe to Frontline Research.

The enzymes called ribosome-inactivating proteins (RIPs) that are able to depurinate  nucleic acids and arrest vital cellular functions, including protein synthesis, are still a frontline  research field, mostly because of their promising medical applications. The contributions of Stirpe  to the development of these studies has been one of the most relevant. After a short biographical  introduction, an overview is offered of the main results obtained by his investigations during last  55 years on his main research lines: hyperuricaemia, xanthine oxidoreductase and RIPs.

The George W. Comstock Center for Public Health Research and Prevention: A Century of Collaboration, Innovation, and Translation.

The Johns Hopkins Bloomberg School of Public Health has been engaged in public health research and practice in Washington County, Maryland, nearly since its inception a century ago. In 2005, the center housing this work was renamed the George W. Comstock Center for Public Health Research and Prevention to honor its pioneering leader. Principles that guided innovation and translation well in the past included: research synergies and opportunities for translation realized through longstanding connection with the community; integration of training with public health research; lifelong learning, mentorship, and teamwork; and efficiency through economies of scale. These principles are useful to consider as we face the challenges of improving the health of the population over the next 100 years.

Diego and Giorgina Vergani: The two hearts of translational autoimmunity.

Since the publication of the first textbook on autoimmune diseases in 1963, the knowledge in the field has exponentially grown into numerous tracks of research, particularly at benchside. Systemic and organ-specific autoimmune diseases, as in the case of the liver, have witnessed notable advances in terms of epidemiology, genetics, effector and regulatory mechanisms, and ultimately treatment. While the available tools for communication have provided accelerating progress rates, we recognize that key opinion leaders continue to provide significant contributions to the field. The present issue is dedicated to celebrate Giorgina Mieli-Vergani and Diego Vergani as two of the finest examples of excellence in autoimmune liver diseases and the broader field of autoimmunity. Diego and Giorgina are extremely well-liked Colleagues who fully represent the translational efforts between laboratory research and clinically relevant questions in the practice of pediatric liver diseases and autoimmune hepatitis.

Livestock in biomedical research: history, current status and future prospective.

Livestock models have contributed significantly to biomedical and surgical advances. Their contribution is particularly prominent in the areas of physiology and assisted reproductive technologies, including understanding developmental processes and disorders, from ancient to modern times. Over the past 25 years, biomedical research that traditionally embraced a diverse species approach shifted to a small number of model species (e.g. mice and rats). The initial reasons for focusing the main efforts on the mouse were the availability of murine embryonic stem cells (ESCs) and genome sequence data. This powerful combination allowed for precise manipulation of the mouse genome (knockouts, knockins, transcriptional switches etc.) leading to ground-breaking discoveries on gene functions and regulation, and their role in health and disease. Despite the enormous contribution to biomedical research, mouse models have some major limitations. Their substantial differences compared with humans in body and organ size, lifespan and inbreeding result in pronounced metabolic, physiological and behavioural differences. Comparative studies of strategically chosen domestic species can complement mouse research and yield more rigorous findings. Because genome sequence and gene manipulation tools are now available for farm animals (cattle, pigs, sheep and goats), a larger number of livestock genetically engineered (GE) models will be accessible for biomedical research. This paper discusses the use of cattle, goats, sheep and pigs in biomedical research, provides an overview of transgenic technology in farm animals and highlights some of the beneficial characteristics of large animal models of human disease compared with the mouse. In addition, status and origin of current regulation of GE biomedical models is also reviewed.

Thomas Willis, a pioneer in translational research in anatomy (on the 350th anniversary of Cerebri anatome).

The year 2014 marked the 350th anniversary of the publication in London of Cerebri anatome, a ground-breaking work of neuroscience heavily influenced by the political and cultural context of Baroque Europe and mid-17th century England. This article aims to review the work of the English physician and anatomist Thomas Willis, specifically with regard to the contents of his Cerebri anatome. Willis's academic and professional career was influenced by the turbulent period of the English Civil War during which he studied medicine. Willis went from chemistry to dissection arguably because of his need to justify the body-brain-soul relationship. As a result, he became a fellow of a select club of eminent experimentalists, and afterward was a Fellow of the Royal Society. Later on, he went to London, leaving the academic life to dedicate himself fully to the profession of medicine. As a physician, Willis did not base his practice on aphorisms but on a 'bench to bedside' approach to medicine, while studying neuroanatomy--covering embryology, comparative anatomy and pathological anatomy--as a basis for the comprehension of neurological pathology. He developed innovative anatomical methods for the preservation and dissection of the brain, injection of coloured substances and illustration of his findings. In Cerebri anatome, Willis recognized the cerebral cortex as the substrate of cognition. He also claimed that the painful stimuli came from the meninges, but not from the brain itself. He explained for the first time the pathological and functional meaning of the brain's circular arterial anastomosis, which is named after him. He also specified some features of the cranial origin of the sympathetic nerves and coined the term 'neurologie'. Cerebri anatome marked the transition between the mediaeval and modern notions of brain function, and thus it is considered a cornerstone of clinical and comparative anatomy of the nervous system. The new contributions and methods employed by Willis justify his place as a father of neurology and a pioneer of translational research.

Historical lessons in translational medicine: cyclooxygenase inhibition and P2Y12 antagonism.

The development of drugs that inhibit platelets has been driven by a combination of clinical insights, fundamental science, and sheer luck. The process has evolved as the days of stumbling on therapeutic gems, such as aspirin, have long passed and have been replaced by an arduous process in which a drug is designed to target a specific protein implicated in a well-characterized pathophysiological process, or so we would like to believe. The development of antiplatelet therapy illustrates the importance of understanding the mechanisms of disease and the pharmacology of the compounds we develop, coupled with careful clinical experimentation and observation and, yes, still, a fair bit of luck.

Pharmaco-EEG Studies in Animals: A History-Based Introduction to Contemporary Translational Applications.

Current research on the effects of pharmacological agents on human neurophysiology finds its roots in animal research, which is also reflected in contemporary animal pharmaco-electroencephalography (p-EEG) applications. The contributions, present value and translational appreciation of animal p-EEG-based applications are strongly interlinked with progress in recording and neuroscience analysis methodology. After the pioneering years in the late 19th and early 20th century, animal p-EEG research flourished in the pharmaceutical industry in the early 1980s. However, around the turn of the millennium the emergence of structurally and functionally revealing imaging techniques and the increasing application of molecular biology caused a temporary reduction in the use of EEG as a window into the brain for the prediction of drug efficacy. Today, animal p-EEG is applied again for its biomarker potential - extensive databases of p-EEG and polysomnography studies in rats and mice hold EEG signatures of a broad collection of psychoactive reference and test compounds. A multitude of functional EEG measures has been investigated, ranging from simple spectral power and sleep-wake parameters to advanced neuronal connectivity and plasticity parameters. Compared to clinical p-EEG studies, where the level of vigilance can be well controlled, changes in sleep-waking behaviour are generally a prominent confounding variable in animal p-EEG studies and need to be dealt with. Contributions of rodent pharmaco-sleep EEG research are outlined to illustrate the value and limitations of such preclinical p-EEG data for pharmacodynamic and chronopharmacological drug profiling. Contemporary applications of p-EEG and pharmaco-sleep EEG recordings in animals provide a common and relatively inexpensive window into the functional brain early in the preclinical and clinical development of psychoactive drugs in comparison to other brain imaging techniques. They provide information on the impact of drugs on arousal and sleep architecture, assessing their neuropharmacological characteristics in vivo, including central exposure and information on kinetics. In view of the clear disadvantages as well as advantages of animal p-EEG as compared to clinical p-EEG, general statements about the usefulness of EEG as a biomarker to demonstrate the translatability of p-EEG effects should be made with caution, however, because they depend on the particular EEG or sleep parameter that is being studied. The contribution of animal p-EEG studies to the translational characterisation of centrally active drugs can be furthered by adherence to guidelines for methodological standardisation, which are presently under construction by the International Pharmaco-EEG Society (IPEG).

Platelet receptors and patient responses: The contributions of Professor Stan Heptinstall to platelet research.

Stan Heptinstall's contributions to platelet research covered organising meetings at the national and European level as well as starting and maintaining the journal "Platelets". The major part of his research addressed problems of inhibition of platelet receptors and the effects of this on patient health. In particular, the effects of P2Y12 inhibitors on patients with acute cardiovascular problems were a major focus. Other studies included the effects of feverfew (Tanacetum parthenium) extracts on platelets, of direct anti-IIb/IIIa receptor (αIIbß3) inhibitors and of prostanoids on platelet function. Recently, methods for assessing the effectiveness of platelet inhibition were investigated.

[Takeki Kudoh's Research on Modern Medical Science and Japanized Confucianism in Colonial Korea (Choson)].

This paper reviews Kudoh Takeki's activity critically during the colonial Korea period, regarding his research on Medical Science and Japanized Confucianism. He managed 'The Seoul Gynecological Hospital'for approximately 35 years in the Choson period as a Japanese resident with Choson status. He published medical knowledge about obstetrics through more than 280 articles, and attempted to improve the hygiene and health of 'Korean Women'. He tried to complete his will toward 'One Unity of Choson and Japan'by terminating the Choson culture 'gene'as an intention. The purpose would enlighten Choson by Japanese blessing. This paper aims to confirm his intention by two aspect of analysis by 'Medical Science'as an occupation and 'Confucianism'and the background of his thought. The content of Kudoh Takeki's research in Choson regarding Medical Science-Confucianism is described as below. First, the purpose and mission of Kudoh Takeki regarding Choson was analyzed. The papers revealed the Kudoh Takeki mentioned only the 'HusbandMurders of Corean Women', which was defined by Kudoh Takeki as 'A Special Crime of Corea'. This paper examined his intensions. Second, writings by Kudoh Takeki were listed to verify the 'medical'field and 'non-medical'field according to the subject. No list of contents was found for his more than 280 articles or essays in magazines/newspapers/ publications, and these papers only described the Kudoh paper "A Special Crime of Corea"and studied the separate book publication by Kudoh THE GYNAECOLOGICAL RESEARCH OF HUSBANDMURDERS OF COREAN WOMEN, A SPECIAL CRIME OF COREA. Third, the genealogy of Confucianism of Kudoh Takeki was analyzed as his background of mental·thought by his hometown and the school he graduated from. The people from Kumamoto and Seiseiko school who were influenced by 'Yi Toegye'of Choson Confucianism were more active than general Japanese. Fourth, the practical activity of Kudoh Takeki in Choson was described. The paper revealed that his brother Tadaske and Shigeo also stayed in Choson to act as an important assistants for the Colonial Choson Government-general. Kudoh was an important man in Japanese society in Choson, acting as a member of 「Group of Same Origin」 and 'Choson Association of great Asia'which was an important organization assisting Colonial Choson Government-general and was a representative position in Seoul district of Bukmichang-jeong(now Bukchang-dong) Fifth, Kudoh Takeki's precise activity to terminate Choson cultural 'gene'and lead to enlightenment was analyzed by an examination of his Medical Science as an occupation and Confucianism as a background of his thought. Even he attempted to enlighten the brutal Choson people in cultural aspects but it was only a tool to assist the colonial policy of Japan by emphasizing 'Kyoikuchokugo(Imperial Rescript on Education)'to implant the Kodo-Seishin(Imperial Spirit). Analyzing the relationship of Kumamoto Practical Party with Yi Toegye, the intention of a deep connection toward 'One Unity of Japan and Choson'by colonial policy was revealed. In conclusion, the paper revealed the Japanese modernization frame to complete 'One Unity of Japan and Choson'and 'Make people to obey the Japan Emperor'by enlightening the dark Choson and merging them with Japan as Kudoh intended.

The translational biology of remyelination: past, present, and future.

Amongst neurological diseases, multiple sclerosis (MS) presents an attractive target for regenerative medicine. This is because the primary pathology, the loss of myelin-forming oligodendrocytes, can be followed by a spontaneous and efficient regenerative process called remyelination. While cell transplantation approaches have been explored as a means of replacing lost oligodendrocytes, more recently therapeutic approaches that target the endogenous regenerative process have been favored. This is in large part due to our increasing understanding of (1) the cell types within the adult brain that are able to generate new oligodendrocytes, (2) the mechanisms and pathways by which this achieved, and (3) an emerging awareness of the reasons why remyelination efficiency eventually fails. Here we review some of these advances and also highlight areas where questions remain to be answered in both the biology and translational potential of this important regenerative process.