Programmed death 1 (PD-1) is an immune checkpoint molecule that negatively regulates T-cell immune function through the interaction with its ligand PD-L1. Blockage of this interaction unleashes the immune system to fight cancer. Immunotherapy using PD-1 blockade has led to a paradigm shift in the field of cancer drug discovery, owing to its durable effect against a wide variety of cancers with limited adverse effects. A brief history and development of PD-1 blockade, from the initial discovery of PD-1 to the recent clinical output of this therapy will be first summarized. Despite its tremendous clinical success rate over other cancer treatments, PD-1 blockade has its own pitfall; a significant fraction of patients remains unresponsive to this therapy. The key to improve the PD-1 blockade therapy is the development of combination therapies. Since this approach has garnered worldwide interest, here, I will overview the recent trends in the development of PD-1 blockade-based combination therapies and the ongoing clinical trials. These include combinations with checkpoint inhibitors, radiation therapy, chemotherapy, and several other existing cancer treatments. Energy metabolism has emerged as one of the important regulatory mechanisms for the function and differentiation of T cells. I will discuss here the recent results regarding the augmentation of PD-1 blockade efficacy by augmenting mitochondrial energy metabolism of T cell.

In April 2015, AMED was started to fast-track medical R&D and to improve a quality of life for people. Among a diversity of different medical researches, AMED has chosen a field of rare and undiagnosed diseases to tackle with a number of obstacles including rigid and inflexible funding systems and "Balkanization" of mindsets among academia and researchers. We launched "Initiative for Rare and Undiagnosed Diseases (IRUD)" as the first leading project. It aims to spread a concept of sharing clinical data, and "microattribution" that should be recognized by all project leaders. AMED has also joined in International Rare Disease Consortium (IRDiRC) to share many experiences in rare disease researches which were accumulated over 40 years in Japan. Solving Balkanization among different sectors which participate in medical R&D gives a clue to fast-track implementation of outcomes among all other fields of medical researches. AMED has started up a new project for supporting development of "Medical Arts" which includes developing new medical technology including genome editing and gene therapies, and software for medical support that might contribute to improving medical safety and cost performance. I would present an overview of our missions and vision for medical innovations, and introduce our novel projects including IRUD and medical ICT networks.

Although 46 drug approvals by the FDA in 2017 was the highest in 20 years, drug development remains a highly inefficient process with a declining rate of return on investment. Public pressure and the decline in spending power by the NIH have fostered in the US engagement of academia in translational science. This requires investment in human capital pertinent to understanding the mechanisms of drug action and the factors contributing to variability in drug response. Additional challenges are the development of organizational and physical infrastructure to support the deep phenotyping characteristic of human phenomic science and its integration with data derived at scale from electronic health records and linked biobanks. Novel approaches to collaboration with industry, addressing issues of conflict of interest and patent coverage can facilitate access to expertise in medicinal chemistry and kinetic modelling.

The concept of Open Innovation as articulated by its originator, Henry Chesborough, relies on the premise that today (as opposed to a few decades ago) the innovation process relies on knowledge that is created by many disparate groups or individuals who are not located in the same geographical place nor have predetermined disciplinary or sector descriptors. In many modern innovation ecosystems it is now necessary to bring many skill sets together that act at different stages in any particular innovation process in order to accelerate the implementation of innovations in society. This end-to-end integration of ideas, people and processes is nowhere more clearly needed that in the healthcare innovation space.

The Innovative Medicines Initiative (IMI) was launched in 2008 with the goal of significantly improving the efficiency and effectiveness of the drug development process in Europe, to make drug R&D processes in Europe more innovative and efficient, to enhance Europe's competitiveness and to address key societal challenges of health, demographic change and wellbeing. It represents a true model of open innovation in action. IMI is now in its second phase of development and IMI2 expands the scope of IMI to cover the entire medical research and innovation value chain going from bottlenecks in industry to bottlenecks in industry and society, involving all relevant partners: pharmaceutical; other health-related industries; patients; academia; SMEs; regulators; HTA bodies; in open innovation networks.

IMI projects have developed new taxonomies in diseases such as schizophrenia and respiratory diseases, identified and curated new models in chronic pain and autism, used digital advances to develop relevant databases, and published relevant standards, which are used by industry, and guidelines which impact the regulatory framework. The over 2000 publications resulting from IMI projects have a high citation indices (20% higher than EU average) and therefore demonstrate the excellence of the science we support.

Japan is facing an ultra-aging society ahead of other countries, where maintenance and improvement of health is one of the biggest concerns of the people. And the pharmaceutical industry is asked to contribute greatly to the extension of healthy expectancy. Also, the pharmaceutical industry is expected as a driver for Japan's economic growth in "Growth Strategy 2017" and "Healthcare Policy" since this industry is higher value-added and knowledge-intensive industry.

Since the declaration of completion of human genome decoding in 2003, progress of science and technology in life sciences, including the appearance of next generation sequencers, establishment of new technologies in genome engineering, expectation for personalized medicine, has brought dramatic changes to drug discovery research. In addition, the factors such as the decreasing the number of drug targets and the spiraling R&D costs have made it more difficult to create new drugs.

To create continuously innovative drugs in this challenging business climate as above, it is necessary to understand pathogen more deeply from the initial stages of drug discovery research and to apply cutting-edge technology to entire research process actively. These are reasons why companies that join Japan Pharmaceutical Manufacturers Association (JPMA) are enhancing collaboration with external partners by shifting away from in-house research model to open innovation, including the introduction of seeds from academia and ventures.

In order to achieve the expected goals through open innovation, it goes without saying that the way how to collaborate is important as well as selecting partners. In response to new trend of recent drug discovery research, Japan Agency for Medical Research and Development (hereinafter referred to as AMED) was established in 2015 as a control tower to allocate research funds strategically. Since then, the opportunities for industry to get contact and discuss with academia have been expanding gradually through the activity of AMED. However, it shall need more time to cross the barriers and reach the mutual understanding in terms with the research interest and approach with each other.

In my presentation, by introducing our recent examples of open innovation, I would like to refer to expectations toward academia research, and the role which academia and industry should play respectively from the viewpoint of industry.

Induced pluripotent stem cells (iPSCs) can proliferate almost indefinitely and differentiate into multiple lineages, giving them wide medical application. As a result, they are being used for new cell-based therapies, disease models and drug development around the world.

In 2014, the world's first clinical study using iPSCs began for the treatment of age-related macular degeneration. iPSCs can be used for regenerative medicine to restore organ function. To push these efforts, we are proceeding with an iPSC stock project in which clinical-grade iPSC clones are being established from “super” donors with homologous HLA haplotypes. Homologous HLA haplotypes are associated with decreased immune response and therefore less risk of transplant rejection. The iPSC stock is being designed with the intention of providing quality-assured cells for medical treatments around the world. In 2015, we started distributing an iPSC stock clone to organizations in Japan.

Other applications of iPSCs include drug screening, toxicity studies and the elucidation of disease mechanisms using disease-specific iPSCs from patients with intractable diseases. iPSCs established from patients contain a complete set of the genes that resulted in the disease and thus represent a new disease model that complements or in some cases replaces animal models.

Finally, accumulating evidence is demonstrating the benefits of iPSCs in drug repositioning. Indeed, Bosutinib, a drug for leukemia was revealed to be efficacious for the treatment of amyotrophic lateral sclerosis (ALS) using a disease model established from patient-derived iPSC. In Addition, we reported a new drug screening system using iPSCs derived from fibrodysplasia ossificans progressiva (FOP) patients, revealing one drug candidate, Rapamycin. Based on these findings, we have received approval from the Japanese government to initiate a clinical trial to treat FOP patients. This clinical trial is the world's first for a drug that is based on results from an iPS cell-based model.

Over the past decade iPSCs research made a great progress. However, there are still various hurdles to be overcome, iPSC-based science is certainly moving forward for delivering innovative therapeutic options to the patients with intractable diseases.

Diverse cells underlie basic drives and actions essential for animal survival, including behaviors such as those related to thirst, hunger, and sleep. Cell-type-specific activity signals that underlie these animal behaviors have been elucidated, interestingly, using proteins essential for plant behaviors¹. These channelrhodopsin proteins are light-gated ion channels that enable motile algae to seek light conditions suitable for photosynthesis¹; we have been able to discover principles of function by solving the key high-resolution channelrhodopsin crystal structures and by structure-guided redesign for altered ion selectivity, kinetics, and spectral properties^1,2. These discoveries not only revealed basic principles governing operation of light-gated ion channels for plant survival-drive behavior, but also enabled the creation of new proteins for illuminating (via optogenetics)³ fundamental animal survival-drive behavior via application to circuit function. Here we will present our structures and structure-guided tool redesign outcomes, and our application of these tools to uncover basic hypothalamic mechanisms underlying thirst^4,5, feeding^6,7, sleep⁸, and other fundamental drives⁹, via identification of internal cellular-resolution brain states that dynamically control the elements of drive-motivated behavior. And we will present in detail a new general method for identifying the cellular manifestation of internal states by integrating brain-wide single-cell activity imaging and control with hydrogel-tissue chemistry¹⁰ for high-content cellular-resolution molecular phenotyping¹¹. Together, these experiments have established an approach for unbiased discovery of cellular elements underlying behavior, and have revealed an evolutionarily-conserved set of diverse cellular systems that collectively govern survival drive-related internal states.

¹Deisseroth K & Hegemann P (2017). The form and function of channelrhodopsin. Science 357: eaan5544.

²Kato et al. (2012). Crystal structure of the channelrhodopsin light-gated cation channel. Nature 482: 369-74.

³Deisseroth K (2015). Optogenetics: ten years of microbial opsins in neuroscience. Nature Neuroscience 18: 1213-25.

⁴Allen WE et al. (2017). Thirst-associated preoptic neurons encode an aversive motivational drive. Science 357: 1149-55.

⁵Augustine et al. (2018). Hierarchical neural architecture underlying thirst regulation. Nature, doi: 10.1038/nature25488.

⁶Domingos et al. (2011). Leptin regulates the reward value of nutrient. Nature Neuroscience 14: 1562-8.

⁷Ferenczi et al. (2016). Prefrontal regulation of brainwide circuit dynamics and reward-related behavior. Science 351 (6268): aac9698.

⁸Adamantidis et al. (2007). Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450: 420-4.

⁹Kim et al. (2013). Assembling behavioral states: divergent neural pathways recruit separable anxiety features. Nature 496: 219-23.

¹⁰Gradinaru et al. (2018). Hydrogel-tissue chemistry: principles and applications. Annual Review of Biophysics, in press.

¹¹Lovett-Barron et al. (2017). Ancestral circuits for the coordinated modulation of brain state. Cell 171: 1411-23.

Angiotensin-converting enzyme (ACE) inhibitors are widely used in the treatment of hypertension, heart disease and diabetic nephropathy and reduce mortality. In addition to preventing the degradation of angiotensin (Ang) I to Ang II, ACE inhibitors potentiate the effects of the vasodilator and natriuretic hormone bradykinin. Studies using specific bradykinin receptor antagonists demonstrate that bradykinin contributes to favorable effects of ACE inhibitors on blood pressure and fibrinolytic balance but also to the side effect of angioedema. Neutral endopeptidase inhibitors (now given in combination with angiotensin receptor blockers to treat heart failure) are also likely to potentiate endogenous bradykinin. Dipeptidyl peptidase-4 (DPP4) inhibitors are widely used in the treatment of type 2 diabetes mellitus (T2DM) and prevent the cleavage of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Whereas treatment with exogenous GLP-1 agonists causes weight loss and reduces mortality, treatment with DPP4 inhibitors has no effect on weight or risk of acute coronary events, and may increase the risk of heart failure. In addition to decreasing the degradation of GLP-1 and GIP, DPP4 inhibitors prevent the degradation of a number of potentially vasoactive peptides with a penultimate alanine or proline at the amino terminus including substance P, neuropeptide Y (NPY), polypeptide Y (PYY), and growth hormone releasing hormone (GHRH). Among these, substance P is also cleaved by ACE. DPP4 inhibition attenuates the acute effect of ACE inhibition on blood pressure. During combined DPP4 and ACE inhibition, intra-arterial infusion of substance P increases sympathetic activity in humans. In addition, during ACE inhibition or angiotensin receptor blockade, DPP4 inhibition potentiates the vasoconstrictor response to intra-arterial NPY in both normal controls and patients with T2DM. There is no effect of DPP4 inhibition on vasodilation in response to intra-arterial infusion of brain natriuretic peptide (BNP) in humans. GLP-1 does not cause vasodilation when infused intra-arterially. In summary, the anti-diabetic DPP4 inhibitors affect the degradation of vasoactive peptides as well as the incretin hormones. These effects may account for differential effects on cardiovascular risk compared to GLP-1 agonists.

First administration of a new substance to humans is extremely safe and the rate of serious complications low. These experiments are often performed in healthy subjects who do not otherwise benefit and perhaps because of that any serious mishap gets wide attention. Two famous cases need further examination to see what can be learned from them to improve safe and informative drug development. A number of aspects of early drug reesearch will be covered in this lecture.

The first one of the method paradox. Current development delivers extremely sophisticated interventions that affect human biology fundamentally. Yet, in the more standard drug development plans the methodology of the evaluation of effects is in many cases less sophisticated or is not used in the decision making about further steps. Such methods or biomarkers have to be developed and validated beforehand which impacts the planning of Phase I experiments.

Secondly there is often a mismatch between the methodology and the pharmacological mechanisms of the intervention. To obtain such a match, it is necessary to define a detailed set of questions that can be answered in early research. Just describing these generically in terms of tolerability and safety is insufficient.

When a medicine is developed preclinically, a very large amount of information is generated. Currently this is often done by a multitude of external suppliers, in contrast to the all in-house activities that were common in the 1980's. This has led to a fragmentation of knowledge that is visible in the Investigator's brochure with a collected but unconnected set of data. The investigator administering a drug for the first time to a human being has the task of bringing this collection of animal models, manufacturing information, toxicology and pharmacokinetics in biological systems ranging from cell culture to several animal species, together in a starting dose. This is also true for regulators. The IB-Derisk (www.IB-derisk.org) tool will be demonstrated for this purpose.

The safety of subjects in trials has to be balanced against the importance of developing new drugs and this can only be assured by integration of knowledge by adequately educated specialists.

When I entered into the medical school, I dreamed to be a surgeon with god hands. However, I realized soon that people suffer so many incurable diseases such as cancer, virus infection, genetic disease, etc. Therefore, I changed my mind and decided to be a scientist to develop "magic bullets" to rescue patients who suffer incurable diseases. Since then, I have struggled like Don Quijote to realize the new therapeutics. However, recently I feel that my impossible dream will come true soon. The main objective of my research is to develop novel therapeutic methods manipulating transcriptome with small chemicals to cure genetic diseases. Some congenital genetic defects are caused by the reduced activities of the affected gene products due to deletions or loss-of-function mutations. In other cases, they might be associated with amplified copies of genomic domains that contain pathogenic genes or with mutations that generate abnormal active forms of enzymes. Chemical compounds may then reverse the pathogenic process by agonizing the reduced activities or by antagonizing the aberrant activities of the gene products. This approach is rather conventional as drug compounds target the specific pathogenic proteins. In case of diseases caused by gene amplification, chemical compounds may provide particularly ideal therapeutics; when a gene amplification raised an excessive activity of a pathogenic protein, carefully dose-controlled administration of its inhibitor may restore the enzymatic activity to the normal levels.

Dopaminergic neurons in the substantia nigra project to the striatum. In humans, a selective loss of the nigrostriatal projection is a pathological hallmark of Parkinson disease (PD). The regeneration of this pathway shows great promise as a therapy for PD. Although several factors are known to direct dopaminergic axons into the striatum, it remains unclear how the axons extend in the striatum in order to innervate their targets. To address this issue, we reconstructed the dopaminergic innervation of striatal cells using primary cultured cells derived from rat embryos. When mesencephalic cells containing dopaminergic neurons were adjacently paired-cultured with striatal cells, dopaminergic neurites extended from the mesencephalic cell region to the striatal cell region. The neurites were mainly axons and extended along the striatal neuronal clusters. In addition, this paired-cultivation enabled the quantitative evaluation of dopaminergic neurite outgrowth to the striatal cell region. Integrin family is one of intercellular adhesion molecules forming αβ heterodimers, and to date, 8 β subunits have been reported to assemble with 18 α subunits to form 24 distinct integrins. The extension of dopaminergic neurites was suppressed by the pharmacological inhibition of integrin α5β1. Knockdown of integrin α5 in dopaminergic neurons suppressed the neurite outgrowth to the striatal cell region. In contrast, the knockdown of integrin α5 in non-dopaminergic mesencephalic and striatal cells had no effect. Integrin α5 assembles only with integrin β1. These results indicate that integrin α5β1 expression on dopaminergic neurons is involved in the dopaminergic neurite outgrowth on striatal neurons. Pluripotent stem cells are promising candidates of cell transplantation therapy for PD. Mouse embryonic stem cells were transfected with integrin α5 gene. They were differentiated into dopaminergic neurons, and replated on striatal cultures. Overexpression of integrin α5 in dopaminergic neurons enhanced their neurite outgrowth on striatal cells. This finding suggests that integrin α5 overexpression in dopaminergic neurons promote the innervation of striatal neurons. In summary, we established the evaluation system for dopaminergic innervation of striatal neurons and proposed that integrin α5β1 plays a key role in the innervation.

Extracellular matrix (ECM) is a group of macromolecules contributing to support tissue structure and maintain homeostasis. Accumulating evidence suggest that ECM-degrading enzymes contribute to cause cardiac remodeling through the proteolytic degradation of ECM during cardiac diseases. Although several mechanisms have been proposed, relationships between the ECM degradation and development of cardiac diseases have not been fully clarified. In order to explore them, our group focused on matricryptin, a group of bioactive fragments cleaved from ECM. Type IV collagen, a major component of basement membrane, is ubiquitously expressed around cardiac cells. We showed that canstatin, a cleaved fragment of type IV collagen α2 chain, is abundantly expressed in normal myocardial tissue, while it decreases in the infarcted area of myocardial infarction model rats. Canstatin has been previously investigated as an endogenous anti-angiogenic and anti-tumor factor. However, the roles of canstatin in cardiac cells have not been elucidated. We for the first time showed that canstatin exerts cytoprotective effects against hypoxia-induced cell death in H9c2 cardiomyoblasts. Canstatin also mediates the biologic functions such as proliferation and migration in cardiac fibroblasts from normal rats and in myofibroblasts from myocardial infarction model rats. These findings provide a new insight into the role of canstatin in cardiac remodeling, which can contribute to develop new drugs for cardiac diseases.

Stress-related information is conveyed to the brain, which recruits neuronal and neuroendocrine systems for adaptation to stressful conditions, thereby inducing physical and behavioral responses to stress (stress responses). These responses are both beneficial and deleterious. Transient and proper stress responses are essential for adaptation to stress, while prolonged or excessive activation of the responses could contribute to the development of physical and psychological disorders such as hypertension, peptic ulcer and depression (stress-related disorders). Therefore, it is necessary to clarify the "central" regulation mechanisms for the stress responses in order to prevent stress-mediated exacerbation of these disorders. We have been examining central regulation mechanisms for the sympatho-adrenomedullary system, one of the components of the primary systems for maintaining or reinstating homeostasis during stress exposure. We have found novel roles of brain cannabinoid CB₁ receptors and hemoglobin-derived neuropeptides, hemopressins, in regulation of the sympatho-adrenomedullary outflow, indicating that these molecules may open new avenues of central therapeutic intervention to stress-related disorders by modulating the sympatho-adrenomedullary outflow. In addition, we have been also examining central regulation mechanisms for micturition, because (1) the sympatho-adrenomedullary system can modulate micturition, and (2) stress exacerbates symptoms of bladder dysfunction including overactive bladder and bladder pain syndrome/interstitial cystitis not only in rodent models but also in human patients. By using bombesin, a stress-related neuropeptide, we have found that brain bombesin induces frequent urination through the serotoninergic nervous system, and interestingly, the bombesin-induced response is independent of the sympatho-adrenomedullary outflow activated by bombesin. These findings indicate that brain bombesin and serotonin receptors could be new therapeutic targets for bladder dysfunction exacerbated by stress exposure. There are several concepts regarding bladder function and central control in the normal and pathological condition, however, the exact brain pathophysiological mechanisms underlying stress-induced effects on the bladder are largely unknown. Therefore, our findings could pioneer a novel neuropharmacological field, "Neuro-Uro-Pharmacology".

In the five years since the initial demonstration of mammalian genome editing using the Cas9 enzyme, the molecular scissors of the microbial adaptive immune CRISPR system, a number of advancements in genome editing technology have been made with astounding speed. Cas9 has been leveraged for a range of genome manipulation tools, including gene activation and repression as well as modulation of chromatin and DNA modifications. Additional DNA-targeting Cas enzymes have been discovered, broadening the possible targeting space within the human genome and offering greater activity in other species. More recently, RNA-targeting Cas enzymes have been discovered, expanding CRISPR-mediated technologies into the realm of the transcriptome modulation. We have characterized a number of these novel enzymes, known as Cas13, and identified orthologs that work in mammalian cells with high activity and specificity. We have shown that Cas13 can be used to knock down endogenous transcripts as well as serve as a programmable RNA-binding platform. Additionally, we engineered a fusion between Cas13 and the adenine deaminase ADAR to achieve RNA Editing for Precise A-to-I Replacement (REPAIR). We showed that REPAIR has the potential to correct single-base pathogenic mutations at the transcriptional level. REPAIR may be a powerful therapeutic for diseases that affect cell types and tissues not amenable to DNA-based gene therapies, such as neurons and other post-mitotic cells. We are continuing to explore microbial diversity to find new enzymes and systems that can be adapted for use as molecular biology tools and novel therapeutics.

In this talk I will summarize findings from my lab which reveal molecular details of drug actions at G protein coupled receptors. I will show how high resolution GPCR structures are revolutionizing molecular and analytical pharmacology. Finally, I will show how we can leverage these structures to accelerate drug discovery.

Numerous research works have implicated accumulations of pathological protein aggregates, including fibrils of amyloid-beta (Abeta), tau and alpha-synuclein, in the etiology of diverse neurodegenerative disorders as exemplified by Alzheimer's disease (AD) and Parkinson's disease (PD). By developing positron emission tomography (PET) imaging agents for Abeta deposits, in-vivo detection of Abeta pathologies characteristic of AD is currently possible in clinical settings, facilitating early diagnosis of this illness. Meanwhile, failures of clinical trials for anti-Abeta treatments in AD cases have implied needs for diagnostic and therapeutic approaches to tau pathologies, which are conceived to be more closely associated with neuronal deteriorations in AD than Abeta lesions. Based on this rationale, we generated radioligands for tau deposits, and provided the first demonstration that tau fibrils can be visualized by PET with these imaging agents in living patients with AD and various non-AD neurological diseases. This technology enabled us to reveal progressive expansion of tau depositions in the continuum from normal aging to advanced AD, offering an objective index of the disease severity. In addition, tau PET maps have clarified topologies of tau pathologies unique to each illness, which serve differentiation among a wide range of neurodegenerative disorders. Moreover, derivatives of the ligands for tau fibrils were found to react with alpha-synuclein assembles, which are neuropathological hallmarks in PD and related diseases. Diagnostic assessments of alph-synuclein deposits in living cases would accordingly be allowed by optimizing chemical structures of these compounds. Besides clinical and nonclinical PET studies, our imaging agents are applicable to in-vivo two-photon laser microscopy of animal brains, as these chemicals are self-fluorescent. Using this methodology, we have demonstrated a time course of the tau and alpha-synuclein fibrillogenesis in the living brain and loss of neurons burdened with these pathological assemblies. Finally, intravital microscopy of animal models with pharmacological interventions has illustrated critical roles played by activated astrocytes in the clearance of protein aggregates and by phagocytic microglia in elimination of fibril-bearing neurons. Hence, the present imaging platforms will contribute to the discoveries and characterization of candidate drugs capable of modifying neurodegenerative pathologies triggered by misfolded tau and alspha-synuclein species.

Cardiovascular diseases has become the most serious health threat and represents the majoy cause of morbidity and mortality in China, as in industrialized nations. Since the past decades, Chinese economic boom has tremendously improved people living standard, but also changed people life style boosting the prevanlence of cardiovascular disease, so called disease of modern civilization. This new trend has attracted the main force of research. Many of the studies conducted by Chinese investigators are orientated to understanding the molecular mechanisms of cardiovascular disease.At the molecular level, the long-standing consensus is that cardiovascular disease is associated with sequence mutation (genetic anomaly) and expression deregulation (epigenetic disorder) of non-protein-coding genes. However, new research data have established the non-coding RNAs (ncRNA, including microRNAs, lncRNAs, etc.) as a central regulators of pathogenesis of cardiac disease and potential new therapeutic targets for cardiovascular disease. Over the years, a large body of studies on ncRNAs in cardiovascular disease has been conducted by investigators from our lab, yielding fruitful research and better understanding of ncRNAs as a new layer of molecular mechanisms for the pathogenesis of cardiac disease. In this review, we will give a brief summary of our current status of research in the field of ncRNAs in various cardiac conditions including cardiac arrhythmia, myocardial ischemia, cardiac hypertrophy and heart failure, and in exploring the potential of ncRNAs as novel diagnostic biomarkers and therapeutic targets.

Greater emphasis on the study of intact cellular networks in their physiological environment has led to rapid advances in intravital imaging in the central nervous system. However, this has only recently been applied to the study of pain. To assess large networks of hundreds of sensory neurons simultaneously, we developed a method to selectively label these neurons with GCaMP6s and to visualise their functional responses in vivo to peripheral stimulation. We show that this technique is able to monitor simultaneously the activity of hundreds of sensory neurons. It is sensitive enough to detect single action potentials in most cells and also provides a proxy for the amount of firing within the physiological range. We have characterised responses of cells to mechanical, thermal and chemical stimulation. The assessment of multiple sensory neurons simultaneously within a physiological setting and at high spatial and temporal resolution provides a novel method to address 'population' based questions not amenable to traditional recording techniques. We have also recently found that we can monitor the activity of some central circuits responding to noxious stimuli. In particular we have studied the responses of neurons of lamina I of the spinal cord that project to supraspinal sites. We know that functionally, these neurones play an essential role in signalling pain related to both chronic inflammatory and neuropathic disorders. Here I will review our recent work studying populations of these cells again using GCaMP as a reporter.

The scale and sensitivity of these optical techniques provide many opportunities to better understand the neuronal circuitry underpinning pain states.

The Pharmaceuticals and Medical Devices Agency (PMDA) is an independent administrative agency which carries out relief services for persons suffering from adverse health effects, product reviews, and safety measures based on Pharmaceuticals and Medical Devices Act. The activities of PMDA are based on the idea of regulatory science. In this presentation, I will introduce PMDA's international activities and its initiative to develop innovative medicines and medical devices. As a result of the resolution of the drug and medical device lag, PMDA is highly appreciated internationally as well, and is expected to contribute further internationally.

The basic tenet of electrolyte balance has been that extracellular bodily fluids readily equilibrate, allowing the kidney to achieve strict constancy in body Na+ content. Led by discrepancies in human Na+ balance studies, we encountered findings causing us to question the assumption that electrolyte concentration in the interstitium does not substantially deviate from plasma.

In the skin, Na+ storage is not only a component of immunological host defense across the species, but also closely coupled with systemic blood pressure regulation by homeostatic immune cells. In humans, skin Na+ storage occurs with essential hypertension and left ventricular hypertrophy, suggesting that skin osmolyte metabolism contributes to cardiovascular risk.

Body water conservation is another biological pattern of salt excretion. This requires energy-intense urea production by liver and skeletal muscle, which couples increased salt consumption with increased food intake, reprioritization of energy metabolism in liver and skeletal muscle, and a hormone profile which predisposes to muscle loss, fat accumulation, insulin resistance, and diabetes mellitus.

Cost-effectiveness analysis has been used for policy decision-making processes in pharmaceuticals in many countries. In Japan, no pharmacoeconomic data have been requested for reimbursement or pricing decision. However, cost-effectiveness analysis is gradually gaining importance, and a trial implementation of the cost-effectiveness evaluation of drugs and medical devices has begun. Discussions on economic evaluation began in May 2012 within a newly established sub-committee of the Chuikyo, referred to as the "Special Committee on Cost- effectiveness." After four years of discussions, this committee determined that during the trial implementation, the results of the cost-effectiveness evaluation would be used for the re-pricing of drugs and medical devices at the end of fiscal year (FY) 2017. Chuikyo selected 13 products (7 drugs and 6 medical devices) as targets for this evaluation. These products were evaluated until the end of FY 2017 based on the following process: manufacturers submit the data of cost- effectiveness analysis; the National Institute of Public Health coordinates the review process; academic groups perform the review of the submitted data, and the expert committee appraise these data. This represents the first step to introducing cost-effectiveness analysis in the Japanese healthcare system. These efforts will contribute to the efficiency and sustainability of the Japanese healthcare system.

Since the publication of the first atomic structure of the Ca2+-pump (SERCA1a) in 2000 (1), more than 10 reaction intermediates that roughly cover the entire reaction cycle have been crystallised, allowing us to describe a fairly detailed scenario of ion pumping. We now know how SERCA1a binds two Ca2+ sequentially, utilising more abundant Mg2+ and K+ for acceleration. Furthermore, by developing a technology for visualising lipid bilayers in the crystals, we now begin to understand how P-type ATPases interact with phospholipids as an integral component of the pumping mechanism (2). In this lecture, I would like to overview our current understanding of the SERCA pumps through their atomic structures.

1. Toyoshima, et al. Nature 405, 647-655 (2000).

2. Norimatsu et al. Nature 545, 193-198 (2017).

Conventional approaches to drug discovery and development have relied on identification of a molecular target, selection and refinement of a drug candidate and ultimately establishing its safety and efficacy in randomized trials. However, detection of such large average effects will be superseded by the need for information relevant to drug response at the individual level. Correspondingly, it has been appreciated that many drugs perturb wider biological networks than their canonical targets and that this may contribute to variability of drug response. The importance of parsing and predicting such variability is exemplified by the case of CAR-T cells in leukemia, where response can vary from apparent “cure” to death from cytokine release syndrome. Aside from cancer, most drugs are used to treat syndromes, such as pain. We have begun to parse sources of variability in the response to nonsteroidal anti-inflammatory drugs (NSAIDs) given the commonality of their use and the risk of serious cardiovascular or gastrointestinal adverse effects in perhaps 1-2% of people exposed. To realize the goal of a more precise medicine we need to parse endophenotypes by integrating diverse consequences of drug induced network perturbation. Ultimately, we can apply deep learning and artificial intelligence to such data to refine the development of algorithms predictive of drug efficacy and safety. These can be tested prospectively in randomized trials to determine their predictive utility using surrogates, such as hypertension for cardiovascular outcomes.

Chronic stress and depression decrease neurotrophic factor expression, dendrite complexity, and synaptic density, contributing to reduced volume of prefrontal cortex (PFC) and hippocampus in depressed patients. Conversely, blocking or reversing the neurotrophic and synaptic deficits caused by stress produces antidepressant responses in rodents. Typical monoaminergic antidepressants have limited efficacy to alter synaptic deficits associated with stress and depression, which could account for the time lag and low response rates of these agents. Recent studies demonstrate that the NMDA receptor antagonist ketamine produces rapid (within hours) antidepressant effects in treatment resistant depressed patients, addressing these limitations. Importantly, ketamine causes rapid, activity dependent release of BDNF, stimulation of mTORC1 signaling, and increased synthesis of synaptic proteins that rapidly reverse the atrophy of PFC neurons caused by chronic stress. Deficits in mTORC1 signaling, as well as BDNF, contribute to the synaptic deficits caused by chronic stress and depression, indicating that mTORC1 activation could be a novel approach for drug development. Despite this progress, the cellular mechanisms underlying the actions of ketamine remain unclear. In particular, whether ketamine acts directly on glutamate pyramidal neurons or indirectly via blockade of GABA neurons has not been determined. Using a viral mediated, cell specific shRNA approach we have found that knockdown of GluN2B on GABA interneurons but not glutamate neurons in the PFC blocks the antidepressant behavioral actions of ketamine. These findings indicate that ketamine blockade of tonic firing GABA interneurons results in a transient burst of glutamate that causes long-lasting changes in synapse number and function that underlie the rapid and sustained antidepressant actions of ketamine. Studies are being conducted to determine if other rapid acting antidepressants, including the ketamine metabolite, (2R, 6R)-hydroxynorketamine and the glycine-like partial agonist Repastinel, act via a similar cellular trigger mechanism and to determine which types of GABA interneurons, somatostatin or parvalbumin, mediate the actions of ketamine. Together these studies further characterize the pathophysiology of stress and depression and the mechanisms by which rapid antidepressants rescue this pathology, and could lead to new targets for the development of rapid and efficacious antidepressants without the side effects of ketamine.

Voltage-gated sodium channels initiate action potentials, and voltage-gated calcium channels initiate neurotransmission and contraction. Recent discovery of their bacterial ancestors, including NavAb, allowed us to determine the structural basis for voltage-dependent activation, inactivation, and selective ion conductance. Structural studies support a sliding-helix mechanism of voltage-dependent activation, in which gating charges in the S4 transmembrane helix move across the membrane through the protein structure, exchange ion-pair partners, and initiate a conformational change to open the pore. Pore-opening is mediated by subtle rotation and bending of the pore-lining S6 helices to open the activation gate at their intracellular ends to an orifice of ～10.5 Å. Slow inactivation involves partial collapse of the pore, in which two S6 segments move toward the central axis. Rapid and selective ion conductance is mediated by an ion selectivity filter that is ～4.6 Å wide and water-filled. Sodium is conducted as a partially hydrated cation. It interacts first with a square array of glutamate sidechains, which displace a variable number of waters and catalyze inward sodium movement with a dunking motion. Sodium then binds to two additional coordination sites formed by backbone carbonyls. Mutation of three negative charges to give the construct CavAb changes ion selectivity 12,000-fold to Ca:Na=400. High-resolution structures reveal the mechanism of ion conduction and selectivity through interactions of hydrated calcium ions with sites in the extracellular vestibule and selectivity filter. High-affinity calcium binding prevents monovalent cation permeation, and alternating occupancy of three calcium-binding sites generates a knock-off effect and mediates rapid and selective conductance. Sodium and calcium channels are drug targets for pain, epilepsy, arrhythmia, hypertension, and angina pectoris. We imaged CavAb with phenylalkylamine and dihydropyridine calcium-antagonist drugs bound to their receptor sites. Verapamil binds in the ion permeation pathway, just on the intracellular side of the selectivity filter. Dihydropyridines bind to an allosteric site on the lipid-facing surface of the pore, creating an asymmetric pore structure with calcium tightly bound in a blocking position. The binding sites for sodium-channel-blocking local anesthetics and antiarrhythmic drugs are now being elucidated at atomic resolution, with important implications for structure-based drug design.

Paul Ehrlich pioneered the use of cytotoxic chemotherapy and pointed to the future of antibodies as 'magic bullets'. These two classes of therapeutic agent are both widely used in oncology, but they have largely developed independently. Naked antibodies have specificity but, as single agents, often have limited antitumour activity, particularly against solid tumours. Because of their favourable safety profile, antibodies can be combined successfully with chemotherapy, which alone suffers from lack of tumour specificity and significant systemic toxicity.

Development of antibody-drug conjugates (ADCs) has the aim of achieving potent and selective target cell killing by taking advantage of the selectivity of a monoclonal antibody combined with the potent cell-killing activity of a small molecule cytotoxic. Although simple in concept, developing clinically effective ADCs has proven to be highly challenging and it is only recently that they are emerging as an important and rapidly growing class of therapeutic agents against both haematological malignancies and solid tumours with potential in other therapeutic areas.

The three components of an ADC - antibody, linker and drug - all need careful optimization. In addition, the choice of target antigen is critical to the activity and tolerability of an ADC. The current status of approved ADCs, and the considerable pipeline of ADCs in clinical and pre-clinical development will be reviewed. The rational design of improved linker and conjugation technologies and novel classes of drug warhead will be discussed. This will include the highly potent DNA minor groove interstrand cross-linking pyrrolobenzodiazepine (PBD) dimer class of warhead which is currently being evaluated in multiple clinical trials. The considerable manufacturing, pharmacological and clinical challenges posed by ADCs will also be discussed.

Prescribing is a complex and challenging task requiring diagnostic skills, knowledge of medicines, communication skills, an understanding of the principles of clinical pharmacology, and an appreciation of risk and uncertainty. The demands on new prescribers have increased because of several important trends including more licensed medicines available, more indications for drug therapy, greater complexity of treatment regimens leading to ‘polypharmacy', and more elderly and vulnerable patients. The systems that prescribers work in are often complex and contribute to suboptimal performance. Medication errors and avoidable adverse reactions are common causes of harm to patients and many involve recently qualified doctors. There have been concerns expressed in various countries that the current approach to the training of junior prescribers may not be sufficient to meet the complex demands of the modern hospital environment. With these challenges in mind it is important that we have reliable assessments that enable us to demonstrate that our training programmes are effective and that all new medical graduates are competent to prescribe. This plenary lecture will (i) explore the evidence that prescribing training may be sub-optimal and that better training improves performance, (ii) identify some of the key challenges in delivering high quality assessment of prescribing, (iii) propose some general principles that should guide the assessment of prescribing, (iv) describe the development and implementation of the UK Prescribing Safety Assessment since 2014, (v) describe other approaches to assessing prescribing, (vi) explore whether a common international assessment of prescribing can be delivered, and (vii) propose how prescribing assessments might be utilised to explore the competence of other prescribing groups.

1. Maxwell SRJ, Coleman JJ, Bollington L, Taylor C, Webb DJ. Prescribing Safety Assessment 2016: Delivery of a national prescribing assessment to 7,343 UK final-year medical students. Br J Clin Pharmacol. 2017 Apr 27. doi: 10.1111/bcp.13319.

2. Maxwell S, Cameron IT, Webb DJ. Prescribing Safety Assessment. Lancet. 2015; 385: 579-581.

Glaucoma is the second leading cause of blindness in the world next to cataract, and will be the first in future. Intraocular pressure (IOP) is the most important physiological mechanism to maintain the visual function of the retina and the optic nerve for the visual cortex. Both low and high IOP affect the structure of the retina and optic nerve head leading to the obstruction of the axon and blood flow. The pathogenesis of glaucoma is a progressive optic nerve atrophy at the optic disc by high and unstable IOP. Thus, IOP reduction is the only and most effective therapy for glaucoma, and many IOP-lowering drugs are currently available. Nevertheless, the physiological mechanism of IOP regulation and the pathogenesis of IOP increase in glaucoma have not been fully understood.

So far, we have investigated the biological function of lipid mediators in ocular diseases, especially in glaucoma. First, prostaglandins and prostanoid receptors were found to be quite important for IOP regulation. FP receptor is indispensable to reduce IOP by the current prostaglandin-related drugs, but EP3 is also additive function with FP to lower IOP. In addition, it was found that EP2 and EP4 agonists reduced IOP in the different mechanism of action from FP. Now, FP/EP3 dual agonist and EP2 agonist has been developed as new targets for glaucoma treatment. Next, we have recently found lysophosphatidic acid (LPA) and its producing enzyme, autotaxin (ATX), have an important role in IOP regulation. In clinical samples of glaucoma, LPA and ATX significantly increased dependent of the level of IOP, glaucoma subtypes categorized by the causes of pre-existing ocular diseases, and the failure rate of filtration surgery aiming for IOP reduction. Especially, in point of the regulation of extracellular matrix in the aqueous outflow pathway and wound scarring of the related tissue, it is possible that LPA and ATX had an important pathological role. LPA-ATX pathway will be a new biomarker to identify the pathogenesis of glaucoma, and a new therapeutic target for glaucoma.

Within the African landscape of pre-clinical pharmacological research, the toxicity and therapeutic potential of herbal medicines are for the most part investigated using laboratory animals, employed as translational models of the human physiology or condition. In most cases the research involves reverse pharmacology of crude preparations already used in traditional treatment regimens, or the screening for new active ingredients. In many instances there are ‘me too' outcomes and in too few instances are focussed drug development with novel clinical applications realised. Barriers not only include financial constraints, but also involve a lack of sustainable support systems and driving forces, as well as inadequate research paradigms and ethics.

Research ethics have proven itself globally to play a key role for the purpose of promoting the quality of science. This is no different in Africa, with its own unique context, value systems, research questions and needs. Ethics review and approval processes independently consider and oversee scientific quality and impact, sound methods and experimental design, justification as measured by risk-benefit (or harms-benefit) analyses, human protection, animal wellbeing and environmental integrity, responsibility and competence, monitoring, legal compliance, record keeping, and even standardisation of procedures and harmonisation of norms. On the one hand research ethics reflect on societal values and attitudes as contextualised in experimental science, outlining the norms for responsible conduct. On the other hand, as ethics link to the core of our being, hopes and aspirations, reflecting on purpose and responsibility, it also becomes a driving force for excellence.

In South Africa and Egypt, animal research ethics is supported by legislation, regulation, academia and comprehensive management and support systems. As from presentations at the SAALAS conference held in South Africa in November 2017, there is now a growing continental realisation at universities and other research institutions of the importance and role of research ethics, actively getting systems in place, including in Algeria, Kenya, Nigeria and Tunisia. In particular there is a drive toward greater harmonisation across the African continent.

The current presentation will reflect on the key and empowering roles of research ethics to promote cutting-edge pre-clinical research on the African continent.

Pharmacometrics represents a firmly established discipline and provides an essential component to model-informed drug discovery, development, and utilization. Grounded in basic principles of pharmacokinetics (PK) and pharmacodynamics (PD), modeling approaches can be readily extended to diverse data types, including dichotomous, ordered categorical, time-to-event, and continuous outcomes. Traditional PK/PD models of drug action utilize compartmental structures to integrate the time-course of drug exposure, pharmacological properties (capacity, sensitivity, and transduction of drug-target interactions), and (patho-) physiological turnover processes. Such semi-mechanistic models contain a minimal number of identifiable parameters to describe temporal profiles of macro-scale therapeutic and adverse drug effects. Coupled with nonlinear mixed effects modeling of relatively large clinical trials, a covariate analysis can be used to identify patient specific characteristics (e.g., genetic polymorphisms) that explain the inter-individual variability in model parameters and outcomes. This approach can be limited by specific study designs and is rarely sufficient for recapitulating multiple, complex genotype-phenotype relationships; however, a major opportunity for pharmacometrics is the extension of pharmacostatistical principles to systems pharmacology models. Significant insights have been realized from the recognition that both drugs and disease processes give rise to complex and dynamic clinical phenotypes by altering natural interconnected biochemical networks and support the emergence of systems pharmacology models of drug action. Multi-scale models that combine physiological PK/PD principles and signaling networks can serve as a platform for integrating genomic/proteomic factors that regulate drug effects and clinical outcomes. Models derived from combining genomic and proteomic databases with systems models and a statistical framework could be used to test confidence in early drug targets, project inter-individual variability and patient subpopulations likely to respond to new drugs or drug combinations, and to ultimately achieve precision medicine.

In 2011 we reported that 153 drug, vaccines and in vivo diagnostics which received FDA approval prior to September 1, 2009 had been discovered in whole or in part in research carried out at U.S. public sector research institutions (PSRI's). A parallel study found that non-U.S. PSRI's also contributed to the discovery of 15 of these drugs and in addition discovered a further 19 FDA-approved drugs.

In the current study, we update the earlier study to include drugs which received FDA approval up to December 31, 2016. Our methodology included a significant new source of information, the Sunshine Act, which requires the disclosure of all payments by medical providers to U.S. physicians and teaching hospitals. This allowed the identification of additional drugs discovered by physicians at PSRI's, some of whom owned the underlying intellectual property in their own names, and also revealed several drugs discovered by physicians in private practice.

We have now identified 252 FDA-approved drugs that were discovered in whole or in part by U.S. PSRI's, and an additional 79 discovered by non-U.S. PSRI's, for a total of 331 drugs discovered at PSRI's worldwide.

We examine in detail two cases of the discovery of new classes of oncology drugs: checkpoint inhibitors, specifically ipilimumab, nivilumab and pembrolizumab; and androgen receptor inhibitors, specifically enzalutamide and apalutamide.

The checkpoint inhibitor case illustrates the challenges in translating radical new treatment modalities from academic lab to patient bedside. Ipilimumab went through the hands of nine companies and was first developed in four combination products over 16 years before receiving FDA approval as a single agent in 2010.

The enzalutamide / apalutamide case illustrates the massive private investment needed to successfully develop drugs whose discovery was publicly funded. Scientists at UCLA received grants totaling $1.3 million, which resulted in the discovery of enzalutamide, apalutamide and a breast cancer drug whose development was discontinued after Phase 2, an average public investment of $433,000 per drug discovered. The cost to develop just enzalutamide worldwide cost around $1.8 billion, some four thousand times more than the cost to discover it.

The recent Global Burden of Disease Study demonstrates how mental disorders such as dementia and depression are a leading source of medical disability in the world. However, in the past decade few compounds have shown truly new mechanisms of action, even fewer represent breakthroughs in efficacy. Genome-wide association studies in neuroscience have yielded little clear-cut drug-target association and have been plagued by a lack of replicability. This situation derives from the heterogeneity of mental disorders and the lack of biomarkers for stratification by their distinct subtypes.

Neuroimaging technologies have the potential to identify the dysfunctional brain circuits and objective neurobiological markers reflecting the underlying pathophysiological process in mental disorders, and can ultimately facilitate the development of personalized treatments. In this lecture, current research findings of structural and functional neuroimaging studies on depressive disorders including our recent fMRI research results will be introduced. In our recent resting fMRI study on the functional connectivity (FC) in patients with depressive disorders, it is suggested that the FC between left dorsolateral prefrontal cortex and posterior cingulate cortex may be a possible biomarker and a target of neuro-feedback treatment for melancholic type of depression.

To refine our understanding of the underlying pathophysiology and provide more reliable markers to guide treatment, instead of seeking for a single clinical or biological measure, a multi-scale, systems biology approach using analysis by artificial intelligence (AI) technology such as machine learning combined with human genetic, molecular and imaging studies is needed. Our recent multi-dimensional analysis can predict poor treatment responders of escitalopram, one of SSRI antidepressants, by co-clustering method of psychological examination, possible blood biomarkers and the FC of resting fMRI which demonstrated the high score of child abuse trauma scale and the high FC between angular gyrus and default mode network.

Finally, the precompetitive public-private partnerships (PPPs) that share data between academic and industry scientists for the development of psychotropic drugs were proposed by the International College of Neuropsychopharmacology (CINP) and followed by the Japanese Society of Neuropsychopharmacology (JSNP). The activity of the JSNP PPPs taskforce team will be also introduced in this lecture.

In India, the cost of consumption of medicine is estimated to be 60% i.e approx. 1.3% of GDP on health care. Therefore, it is essential to ensure the safe use of medicine which matches the needs. Several studies have reported misconception and misuse of drugs at prescriber, dispenser and consumer level which needs to be addressed. Continuous reporting on patient safety and irrational use of drugs should be done in a structured manner. In India reporting of adverse drug reactions (ADRs) was scattered before the introduction of Pharmacovigilance Programme of India (PvPI) in 2010 by the Ministry of Health & Family Welfare (MoH& FW), Government of India (GOI).

The pharmacovigilance reporting system includes collect, collate and analyze Adverse Drug Reactions (ADRs), through National Coordination Centre (NCC) established at different hospitals, research centres, under Indian Pharmacopoeia Commission (IPC). NCC-PvPI also started working in collaboration with the global ADR monitoring centre (WHO-UMC), Sweden contributing to the global ADRs database.

The data examined by NCC-PvPI will be recommended to the Central Drugs Standard Control Organization (CDSCO), regulator for interventions for developing the awareness program on risk communication.

Since last seven years, one hundred and seventy-nine ADR monitoring centres (AMCs) are established and the authorities are making it mandatory to establish AMCs in all public and private sectors. The Indian Individual Case Safety Reports (ICSRs) are being documented from 2006. The growth of ICSRs reporting has increased from 11633 to 149,000 in 2015 which comprises 3% of WHO global database. Since Pharmacovigilance is an important area of reporting we have combined the investigations which are restricted to consumption profile of medicines. The pilot studies for antihypertensive, hypoglycaemic and cholesterol-lowering medicines have demonstrated nontherapeutic compliance, muscle related ADRs along with vitamin D deficiency.

In addition, reporting of ADRs from specialized centres viz., National Tuberculosis Programme (RNTCP), National Aids Control Organization (ART), Immunization (AEFI) is also linked to ADR reporting under NCC-PvPI. In the recent past, a load of lifestyle disorder led to use of herbal/drug-food/herbals/traditional preparations caused by nonvalidated claims. Therefore, the Nutravigilance Centre has been established under NCC-PvPI at ICMR-National Institute of Nutrition, Hyderabad.

Traditional Chinese medicine (TCM) have been long and widely used in prevention and treatment of diseases in China for thousands of years, which made a great contribution to health care of Chinese people. Prescriptions or formula are the main form of TCM and the compatibility and composition of them are made up following the theory of TCM among which the theory of compatibility is the essential part. The classical preparations of TCM, including decoction, pill, powder, ointment and pellet, etc., are prepared with traditional methods. Clinical application and modern pharmacological study both demonstrated that TCM prescription possesses unique effects in comparison with chemical drugs. However, the pharmacological study of TCM prescription is very difficult due to multiple herbs which contain complicated chemical components in the prescription. So, the key point for the pharmacological study of TCM prescription is to elucidate its integrative effects and the mechanism of action. The study in our laboratory on Liuwei Dihuang decoction (LW), a classic TCM prescription used for about 1000 years in China, is an example in elucidation of the pharmacological characteristics and mechanism of action of TCM prescription. For decades, researches were conducted with different ways and methods including holistic approaches in various experimental model animals and in vitro experiments in tissue, organ and cell models, and a lot of new technics and methods such as “omics” technologies were employed. The above system studies provided an overview of the effective mechanism of LW from the angle of neuroendocrine immunomodulation network. In addition, the bioactive components of LW and their unique combinational effects on learning and memory and immune function were also investigated. Although great advances have been achieved of TCM prescription, such as LW, to elucidate the mechanism of action of TCM are still a great challenge due to the complexity of the prescription. We believe that the pharmacological study on TCM would keep progressing and getting deeper with the rapid development of science and technology and their continuous application in this field.

The RANKL/RANK system was first identified as a key regulator for osteoclast development and bone metabolism. This pathway also controls many other physiological processes, such as immunity, breast progenitor expansion and formation of a lactating mammary gland in pregnancy. Notably, some recent studies have revealed that RANKL/RANK are a critical missing link for sex hormone- and BRCA1 mutation-driven mammary cancer, providing a unique opportunity to target RANKL/RANK as a future strategy to prevent the most common cancer in women - breast cancer.

The Drug Discovery Unit (DDU) was set up at the University of Dundee in 2006. It is a fully integrated drug discovery unit, combining hit discovery, medicinal and computational chemistry, drug metabolism and pharmacokinetics. The key aims of the unit are to tackle unmet medical need. We have two main therapeutic focuses: neglected tropical diseases such as malaria, tuberculosis and kinetoplastid infections; and novel drug targets emerging from the academic sector. In this presentation, I will summarise the capabilities of the DDU and outline some of the work that we have carried out on drug discovery for neglected diseases.

The iPSC technology was established a decade ago, and enormous progress in stem cell medicine has since been made. Human iPSC-derived cells has been used for multiple purposes including disease modeling and cellular transplantation. New drugs originating from iPSC screens are in the pipeline. Furthermore, the combination of iPSC technology with recent developments including CRISPR technology makes iPSC-based platforms even more robust in each area of their application. In this lecture, I talk about human pluripotent stem cells in neurological disease modeling and drug discovery.

G protein-coupled receptors (GPCRs) constitute the largest class of drug targets, but are associated with high attrition in translating preclinical discoveries into the clinic. In part, this may reflect a failure to appreciate and capture novel paradigms associated with drug action at GPCRs. Indeed, it is now well established that GPCRs possess spatially distinct allosteric sites that can be found at extracellular, transmembrane-spanning or intracellular domains. Moreover, GPCRs are highly dynamic proteins that adopt multiple active states, which can be differentially stabilized by different ligand classes to yield biased agonism resulting in recruitment of a subset of possible signaling pathways while sparing or blocking others. Targeting GPCR allosteric sites has the potential to lead to novel modes of GPCR subtype selectivity, signal-pathway-selective (biased) modulation and, importantly, a saturability to the allosteric effect that can be exploited to fine-tune drug responsiveness in a positive or negative direction. However, many of these theoretical advantages of allosteric drugs have yet to be optimally explored in the context of disease, and translating these concepts into clinical programs represents a significant next step for the field. For instance, allosteric modulators can have different effects on orthosteric ligand affinity relative to signaling efficacy, as well as directly activating the receptor themselves, and it is likely that such differences in mode of action will affect the successful targeting of different disease states with allosteric drugs. Excitingly, structural biology studies are starting to identify the molecular mechanisms that underlie the pharmacological effects of allosteric modulators and are facilitating structure-based allosteric drug discovery at this important receptor family. Finally, chemical biology approaches are generating novel tools for interrogating GPCR structure and manipulating GPCR functionality, including bitopic ligands that concomitantly bridge orthosteric and allosteric sites. Although not often appreciated, it should be noted that many of these properties are likely common to all receptor superfamilies.

The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to cause ulceration and bleeding throughout the gastrointestinal (GI) tract is well established. The development of selective cyclooxygenase (COX)-2 inhibitors has not had the beneficial impact that was claimed. Moreover, drugs developed to reduce NSAID-gastropathy, such as proton pump inhibitors and histamine H-2 receptor antagonists, have beneficial effects in the upper GI tract, but markedly worsen NSAID-induced damage in the lower GI tract. The mechanisms underlying the latter detrimental effects are become well understood, and progress is being made in developing NSAIDs that are safer in the lower intestine.

One of the approaches to solving the NSAID-gastroenteropathy problem is to covalently link NSAIDs to a hydrogen sulfide (H2S)-releasing moiety. H2S is a naturally occurring gaseous mediator that contributes significantly to maintenance of GI mucosal integrity. Suppression of endogenous H2S production renders the GI mucosa more susceptible to injury, while administration of H2S donors has significant beneficial effects: improved ulcer healing and resolution of inflammation. H2S-NSAIDs, such as ATB-346 (an H2S-releasing derivative of naproxen) have been shown to exert potent anti-inflammatory effects without producing significant GI damage and bleeding. ATB-346 has now progressed to Phase 2 clinical trials. One trial has been completed that demonstrated markedly increased anti-inflammatory/analgesic potency as compared to naproxen. A second Phase 2 trial is in progress which is examining the relative GI safety of ATB-346 versus naproxen (endoscopic detection of GI damage and bleeding). Results of that trial will be available at the time of this presentation.

Pharmacokinetics (PK) has been the heart and soul of the discipline of clinical pharmacology. One of the reasons is because PK parameters provide key information necessary to design dosing schedules. Although the clinical relevance of PK information is evident, basic understanding of PK principles among clinicians remains poor, which highlights an important education role clinical pharmacologists need to play. The lack of the general understanding compromises appropriate clinical application of PK data to clinical practice particularly in special populations including infants and children. Difficulties in conducting conventional PK studies in children further intensify their therapeutic orphan status, causing rampant off-label/off-evidence uses of drug. Although the value of population PK allowing opportunistic sampling schedules to circumvent the conventional tight- scheduled sampling-intensive PK methods is widely recognized and advocated for infants and children, consistent efforts need to be made, so that PK information becomes available in a timely manner for this vulnerable population. The pediatric population is characterized by its remarkable transformation from a cluster of cells in the embryonic stage to a mature adult. The developmental trajectory is the hallmark of infants and children, which also poses challenges in PK data acquisition and interpretation. In the neonatal period, drug clearance per body weight (BW) or body surface area (BSA) is generally lower than in the older age groups. Over the following infantile period, drug clearance/BW consistently increases with variable rates among individuals and drugs in question. Specifically, drug-metabolizing enzymes such as CYP3A show relatively developed-expression patterns in the neonatal period, but CYP1A2 takes one year or more to reach an adult level of expression and function per BW or BSA. Due to increased water compartments per BW in the neonatal period, volume of distribution per BW of hydrophilic drugs is larger in this age group than in older age groups. Although the average pictures of these developmental profiles of PK can be described clearly, variations among drugs and individuals along the developmental trajectory are poorly understood. Application of physiologically-based PK modeling may be a first step to deepen our understanding of PK developmental profiles and its variations in the paediatric population.

In addition to reviewing the use PET imaging of translocator protein 18 kDa (TSPO) as a biomarker of neuroinflammation, Dr. Innis will provide novel results on TSPO imaging in Alzheimer's disease. His laboratory found that this marker of neuroinflammation is increased in patients with AD compared to subjects with mild cognitive impairment (MCI, a precursor syndrome) and to control subjects (Kreisl et al., 2013). Furthermore―and unlike amyloid―the amount of inflammation, indirectly measured as TSPO binding, was correlated with the severity of cognitive impairment. The results of this between-group comparison have recently been confirmed in a larger group of subjects and, more importantly, have been extended with repeated PET scans in patients over a two- to three-year follow-up period (Kreisl et al., 2016). Dr. Innis's laboratory found that TSPO binding increases with progression of AD but not in healthy aging. Furthermore, the increased TSPO binding was significantly correlated with the increase of cognitive impairment during the follow-up period. Overall, these results in AD suggest that neuroinflammation is a biomarker of disease severity (based on the cross-sectional study) as well as a biomarker of disease progression (based on the longitudinal study). Finally, Dr. Innis will review the development of radioligands for cyclooxygenase-1 (COX-1) and for COX-2, two well-known targets of anti-inflammatory medications. These radioligands have shown promising results in monkeys, including models of neuroinflammation, and are planned to be studied in humans in the coming year.

Intestinal bacteria are known to have marked effect on development of the immune system and the synthesis of vitamins, however relatively little is known about the effect of intestinal bacteria on the expression of hepatic drug-processing genes in the host. This study characterizes the expression of drug-processing genes in liver and intestine of germ-free (GF) mice using RNA-seq. In the livers of GF mice, the mRNA of the aryl hydrocarbon receptor target gene Cyp1a2 was increased 51%, and the mRNA of the peroxisome proliferator-activated receptor alpha target gene Cyp4a14 was increased 201%. Conversely, the mRNA of the constitutive androstane receptor (CAR) target gene Cyp2b10 was decreased 57%, and the mRNA of the pregnant X receptor target gene Cyp3a11 was decreased 87% in GF mice. Although other non-Cyp phase-1 enzymes in the livers of GF mice were only moderately affected, there was a marked down-regulation in the phase-2 enzymes glutathione S-transferases p1 and p2, as well as a marked up-regulation in the major bile acid transporters Na-taurocholate cotransporting polypeptide and organic anion-transporting polypeptide 1b2, and the cholesterol transporter ATP-binding cassette transporter Abcg5/Abcg8. Lack of intestinal bacteria leads to similar alterations of some of these drug-processing genes in the intestine, especially the lower expression of Cyp3a11, but not all genes are similarly altered in the liver and intestine. In conclusion, intestinal bacteria regulate the expression of a large number of drug-processing genes, which suggests that intestinal bacteria are responsible for some individual differences in drug responses.

Regulatory T (Treg) cells, which specifically express the transcription factor Foxp3, are actively engaged in the maintenance of immunological self-tolerance and homeostasis, for example, preventing autoimmune disease and allergy. They can also be exploited to induce transplantation tolerance by expanding them in an antigen-specific fashion or to evoke effective tumor immunity by reducing them or attenuating their suppressive activity. Treg cells can therefore be a key target for clinical immune suppression or enhancement.

The majority of Foxp3+ Treg cells develop in the thymus as a functionally distinct and mature T-cell subpopulation, while some conventional T cells in the periphery can differentiate into Foxp3+ Treg cells under certain conditions, for example, by in vitro antigenic stimulation in the presence of TGF-beta. Ectopic expression of Foxp3 is also able to confer suppressive activity on conventional T cells. We have recently made attempts to pharmacologically control Treg-specific transcriptional and epigenetic changes and thereby control Treg cell development and function. We found that certain tyrosine kinase inhibitors that blocked T-cell receptor-proximal signaling in T cells were able to specifically deplete mature Treg cells, thereby enhancing tumor immunity in humans. On the other hand, inhibitors of a serine threonine kinase involved in a T-cell signaling pathway evoked Foxp3 expression in conventional T cells and converted them to functionally competent Treg-like cells, which effectively suppressed autoimmune disease and allergy in animal models.

This lecture discusses how the development and function of Treg cells can be controlled by transcriptional and epigenetic interventions and how Treg cells be pharmacologically targeted to control a variety of physiological and pathological immune responses.

Glucocorticoid therapy had been widely used for treatment of systemic autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and vasculitis. Glucocorticoids certainly improved survival of the patients, but also increased risk of complications related to their hormonal effects, such as infection, impaired glucose tolerance, atherosclerosis, osteoporosis, and tissue fragility. In addition, several conditions refractory to glucocorticoids have become clear, and include joint destruction in patients with RA and fibrotic conditions in patients with systemic sclerosis (SSc). To overcome these limitations, cytotoxic immunosuppressants were used in combination with glucocorticoids, resulting in improved outcomes and reduction of glucocorticoid-related side effects due to sparing glucocorticoid dosage. However, long-term safety profiles of cytotoxic immunosuppressants, especially cyclophosphamide, were unfavorable because of increased risk of malignancies. Since a number of ex vivo and in vivo basic researches have identified potential therapeutic targets, development of molecular targeted therapies has attracted much attention in the field of systemic autoimmune diseases. There are two main technology platforms for drug development: small molecules and biologics. Small, chemically manufactured molecules are the classic active substances, while biologics are therapeutic proteins made using genetic engineering technology. Small molecules are usually selected from screening of a library based on a specific inhibitory or activating effect on certain pathways, but some off-target effects are unavoidable. By contrast, biologics (monoclonal antibodies or soluble receptors) are highly specific and exert only on-target effects, although biologics require intravenous or subcutaneous administration, and has ability to generate a significant immune response (immunogenicity). Current molecular targets of biologics include cytokines, including TNF, IL-1, IL-6, IL-17, IL-12/23, and cell surface molecules, whereas small molecules mainly target intracellular signaling pathways, such as JAK. These molecular targeted drugs are truly effective for many intractable conditions, and contribute to minimizing use of glucocorticoids and cytotoxic immunosuppressants significantly. However, a “knockout” or “transgenic” condition induced by molecular targeted drugs sometimes results in emergence of novel pathologic conditions. In clinical practice, proper use of biologics and small molecules based on understanding of their advantages and disadvantages is critical for treating systemic autoimmune diseases.

Adiponectin (Ad) is an antidiabetic adipokine, which binds to adiponectin receptors (AdipoRs), AdiopR1 and AdipoR2, leading to activation of AMPK and PPAR pathways, respectively ^{1) 2)}. Downregulation of adiponectin and AdipoRs in obesity has been proposed and shown to be causally implicated in obesity-linked diseases such as type2 diabetes, steatosis, atherosclerosis and shortened lifespan ³⁾⁴⁾. A small-molecule AdipoR agonist (AdipoRon) was shown to ameliorate diabetes and increase exercise endurance, and at the same time prolong shortened lifespan in obesity ³⁾. AdipoRs were predicted to contain seven-transmembrane (7TM) domains, with the N-terminus inside and the C-terminus outside the cell, whose orientation is opposite to GPCRs ¹⁾.

　We successfully determined crystal structures of human AdipoR1/R2 and found that overall structures of AdipoRs are indeed distinct from those of GPCRs ⁵⁾. As for ligand binding functions of AdipoRs, mutational analyses of conserved residues between AdipoR1/R2 shown by crystal structures revealed that Ad may broadly interact with extracellular surface of AdipoRs, in a different manner from previously anticipated. As for catalytic functions of AdipoRs such as specific intracellular signal transduction pathways, the seven-transmembrane domain of both AdipoR1 and AdipoR2 was shown to have a cavity with a zinc-binding site which coordinates water molecules, which contains extra electron densities ⁵⁾ (unpublished results). It was thus suggested that these electron densities may represent potential substrates for AdipoR hydrolytic activity or their products. Determination of AdipoRon based on 3D structure of AdipoRon-AdipoR complex would provide us with an important clue for development of optimized AdipoR agonist.

References

1) Nature 423: 762-769, 2003, 2) Nature (Article) 464: 1313-1319, 2010, 3) Nature (Article) 503: 493-499, 2013, 4) Cell Metabolism 17: 185-196, 2013, 5) Nature (Article) 520: 312-316, 2015

Glycerophospholipids (phospholipids) are a major constituent of biological membrane, pulmonary surfactant lipids or precursors of bioactive lipid mediators. More than 1,000 different species in terms of fatty acid distribution, polar head groups, and linkage between glycerol backbone and fatty acyl moiety (1). Mechanism how these diversity is made, and biological output of the individual or mixed fatty acyl species remain to be fully elucidated. By molecular cloning of acyltransferases in the last decade by our group and others, we propose a new model how the diversity is made. Palmitic acid (16:0), oleic acid (18:1) and arachidonic acid (20:4) are accumulated by Lands' cycle (remodeling pathway, lysoPC to PC), while surprisingly, linoleic acid (18:2) and docosahexaenoic acid (22:6) are enriched by Kennedy pathway (Lyso-PA to PA) (2). To confirm the proposed model, we have established mice and cell lines which genetically lack one or two enzymes responsible for these reactions. We confirmed that DPPC (16:0/16:0) is produced by a Lands'enzyme, LPCAT1, which is critical for surfactant formation and pulmonary functions (2). Similarly, we found that LPCAT3, another Lands'enzyme is pivotal for formation of arachidonate-rich membrane that is related to lipoprotein formation, independent of eicosanoid synthesis (3). DHA is incorporated into phospholipid membrane in testis and retina, and loss of DHA-membrane is associated with male infertility and retinal dysfunctions (4, 5). While the molecular mechanism underlying the roles and mouse phenotypes are unclear, phospholipids with different fatty acyl species play unique and essential roles in health and disease over the just barrier functions. Supported by MEXT, AMED, and Takeda Science Foundation. The laboratory at the U-Tokyo funded by Shimadzu, Co., Ltd, and NCGM laboratory is partly supported by ONO Pharmaceutical.

Ref.

1. Shimizu, T. (2009) Ann. Rev. Pharmacol. Toxicol. 49, 123-150.

2. Harayama, T. et al. (2014) Cell Metabolism 20, 295-305

3. Hashidate-Yoshida, T. Harayama, T. et al. (2015) eLife 06328

4. Shindou, H. et al. (2017) J. Biol. Chem. 292, 12054-12064

5. Iizuka-Hishikawa, Y. et al. (2017) J. Biol. Chem. 292, 12065-12076

Most eukaryotic secretory or membrane proteins reach the plasma membrane through the conventional endoplasmic reticulum (ER)-Golgi pathway. However, evidence suggests that many cytoplasmic, nuclear, and signal-peptide-containing proteins also can reach the cell surface via a Golgi-bypassing route. These pathways are collectively referred to as unconventional protein secretion (UPS). A number of transmembrane proteins including CFTR, CD45, voltage-gated potassium channel Kv4, the yeast protein Ist2, the Drosophila melanogaster alpha-integrins, Mpl, and pendrin are known to reach the cell surface via UPS under specific conditions. Understanding the UPS pathways is important not only to elucidate the mechanisms of intracellular trafficking pathways, but also has important ramifications for human health because many proteins undergo UPS are associated with human diseases. For example, our group recently found that the selective activation of the UPS pathway would be a potential therapeutic strategy for the treatment of diseases arising from the transport defects of misfolded proteins, such as cystic fibrosis and Pendred syndrome. In this talk, I will introduce the molecular machineries involved in the UPS of transmembrane proteins, particularly those related to human diseases, and discuss the potential for new therapeutic strategies for the treatment of UPS-associated diseases.

The central theme of this lecture is that oxidative stress and nitrosative stress bear differential clinical impact, and that therapeutic intervention is only achievable against pathophysiological, but not pathological conditions. Using as the illustrative example is baroreflex dysregulation, which by itself is not a disease per se, although it impacts daily existence of the general populace and in its most severe form is causally related to fatality. Under physiological conditions, the baroreflex provides a rapid negative feedback mechanism that normalizes fluctuations in blood pressure and heart rate induced by environmental insults. Under pathophysiological conditions such as neurogenic hypertension, the baroreflex is rendered dysfunctional because of oxidative stress in its brain stem neural substrates. More importantly, this process is reversible and antioxidant treatment is attainable. When baroreflex is defunct under pathological conditions, nitrosative stress in key nuclei of the baroreflex circuit becomes the primary culprit, which leads to brain dead and other forms of fatality. Intriguingly, this process is irreversible, with diminished therapeutic feasibility. Previous and ongoing work from our group has unveiled an intricate interplay of a multitude of signaling molecules at the level of transcription, translation and post-translational modification in its brain stem neural substrates dictates the phenotypical expression of normal, dysfunctional or defunct baroreflex; and reversible or irreversible disruption of the functional connectivity between key nuclei of the baroreflex circuit determines its pathophysiological or pathological status. Representative examples from our clinical and laboratory work will be used to illustrate these views, including some obtained from recent studies using magnetic resonance imaging/diffusion tensor imaging as an investigative tool in mouse disease models. We conclude that the transition from oxidative stress to nitrosative stress bears crucial clinical impacts on baroreflex dysregulation, and interruption of the associated transition from pathophysiology to pathology should be regarded as a pivotal therapeutic target.

(Supported by the Ministry of Science and Technology and Chang Gung Medical Foundation, Taiwan.)

Deposition of amyloid β peptides (Aβ) as senile plaques and tau as neurofibrillary changes is the hallmark neuropathological lesions of Alzheimer's disease (AD); these fibrous protein deposits are implicated in AD pathogenesis and regarded as the prime target for the disease-modifying therapies (DMT). Aβ is produced by sequential proteolytic cleavages by β- and γ-secretases. γ-Secretase, harboring presenilins (PS) as the catalytic center, forms the C terminus of Aβ that determines its propensity to aggregate: missense mutations in PS genes cause familial AD by altering the preferred γ-secretase cleavage sites to increase production of pathogenic Aβ42 species. Protease inhibitors to suppress Aβ production or anti-Aβ antibodies to promote Aβ clearance were tested in recent clinical trials for DMTs at the dementia stage of AD, which altogether failed to meet the clinical endpoints, underscoring the needs for early intervention and biomarkers. To establish imaging and fluid biomarkers that surrogate the AD pathology, longitudinal observational clinical studies including AD Neuroimaging Initiative (ADNI) and Japanese ADNI have contributed greatly towards the goal of very early treatment hopefully at the mild cognitive impairment (MCI) and preclinical AD stages, by delineating the early natural course of AD. It is being demonstrated that the clinical and biomarker profiles of MCI due to AD, i.e., prodromal stage of AD, in J-ADNI were remarkably similar to those in North American ADNI, supporting the harmonization of global clinical trials in Western and Asian countries. Furthermore, secondary prevention trials in preclinical AD, i.e., anti-Aβ therapies in asymptomatic, amyloid positive elderly individuals, e.g., the A4 study, are successfully being initiated worldwide, paving the way toward the very early treatment of AD.

There are two basic forms of Alzheimer's disease (AD). The common (>95%) form is sporadic, and is caused by the failure to clear the Aβ peptide (mean age at onset 80 years). The rare (<5%) autosomal dominant familial form is caused by the over-production of Aβ₄₂ (mean age at onset 45 years). In both forms, the kinetics of Aβ accumulation are similar, taking about 30 years to accumulate a total of approximately 7mg of Aβ. Thus we estimate that sporadic AD starts about the age of 50 years and the autosomal dominant form starts about 15 years of age. The advent of validated biomarkers (PET/CSF Aβ and tau) now provides us with unprecedented opportunities for preclinical diagnosis, enabling the development of primary and secondary prevention strategies. Predictive algorithms utilizing age, biomarkers, polygenic and vascular risk scores are now being developed from longitudinal cohort studies to estimate times of onset and rates of cognitive decline.

Most Aβ in the brain (>93%) exists in the urea/detergent/formic acid extractable fractions. A disease-modifying strategy needs to keep the total brain Aβ burden close to normal levels (<2 mg) to prevent or delay onset. Such a strategy may encompass lowering production, stabilizing or neutralizing the toxic Aβ species, and promoting Aβ clearance from the brain. We calculate that a 20% improvement in clearance of Aβ may be sufficient to delay onset by five years, if a therapy commences at the Aβ-PET cut-off of 1.4 SUVR, 20 years before onset. Proportionally, a 40% treatment effect would be required if started 10 years before onset, and an 80% effect would be required five years before onset. These objectives should be achievable using combinations of passive immunotherapies, stabilizers of non-toxic Aβ species, and BACE inhibitors.

The ultimate goal is primary prevention using therapeutic strategies or interventions which keep Aβ levels below the 1.4 SUVR threshold. Clinical trials aimed at this objective are now being planned.