Day 3 :
- Immunology and Infectious Diseases and Advances in Translational Medicine
Location: Las Vegas, USA
University of Puerto Rico USA
Title: Pathways to accelerate translation to implementation: filling the gap in knowledge and skills
Time : 09:05-09:30
Dr. Estela S. Estape is actively involved in training, education and career development initiatives addressing clinical and translational research to eliminate health disparities. She is PI and Director of an R25 NIMHD grant and S21 Hispanics in Research Capability (HiREC) 15m NIMHD Endowment Program. Dr. Estape is also the leader of the NIMHD U54 Puerto Rico Clinical & Translational (PRCTRC) Professional Development Core .Through grant funding for the enhancement of research capacity and infrastructure, she has been team leader to foster strategic change, career development, and interdisciplinary work to facilitate cooperation in a challenging research, academic and workplace environment.
Translational research was incorporated with clinical research into a new discipline to accelerate the transfer of discoveries and innovation into health care. Some of the main goals of this initiative are well known: to improve health, decrease health cost and eliminate health disparities. This clinical and translational research trend has increased the awareness for the need of a workforce with the competencies and skills required to make this transfer of knowledge to happen in the real scenarios. Here it is where two innovative translational research modalities can be integrated into the health research workforce training, education, career and professional development to accelerate translation to implementation. This pathway includes the integration of two emergent research strategies: community based participatory research (CBPR) followed by or together with comparative effectiveness research (CER)to achieve patient –centered outcomes. A diversity of community members should be included in the planning, implementation and discussion of the research findings, such as patients or family members, health care providers, health administrators. This diversity, together with multiple health disciplines in the research team, is expected to facilitate the transfer of the recommendations drawn from the results, in a more effective and efficient process into the real health care scenarios. Once transferred, this new knowledge can be compared with existing health care promotion and prevention strategies, early diagnosis tools and biomarkers , non-invasive treatments or rehabilitation services to determine the best alternatives .
University of Utah USA
Title: Biofeedback-coupled digital health technologies for the treatment of chronic diseases, and opportunities for drug-device translational research
Time : 09:30-09:55
Grzegorz Bulaj is an Associate Professor of Medicinal Chemistry in the College of Pharmacy at the University of Utah. He co-founded the University spinoff company, NeuroAdjuvants, specialized in preclinical development of anticonvulsant neuropeptides that cross the blood-brain barrier. As a Director of Peptide Chemistry in Cognetix, Inc., he was involved in drug discovery, preclinical and clinical development projects. He received his PhD degree in Biochemistry from the University of Wroclaw, Poland. His research is focused on innovative drug-device combination therapies which integrate drug-based targeting of a disease and medical device-based behavioral targeting of comorbidities, medication non-adherence, and disease self-management.
Mobile medical applications and digital health technologies have been merging with health care and medicine practice. The US Food and Drug Administration has already approved or cleared over 75 mobile medical apps, including the mobile therapy for diabetes, and a motion capture game system for patients with stroke or traumatic brain injury. The development of mobile medical apps and video game therapies for chronic diseases creates opportunities to combine medical device software with drug-based therapies. Neurofeedback- and biofeedback-enhanced game therapies for autism spectrum disorders illustrate how such innovative non-pharmacological modalities can maximize digital health technologies by concurrent monitoring of heart rate variability, blood pressure, skin conductance or EEG. Translational research on biofeedback-coupled delivery and streaming of clinically-beneficial digital content (including music, games and apps) will lead to optimized treatments for specific diseases including depression, anxiety, schizophrenia, pain, epilepsy, cancer or neurodegenerative disorders. In this presentation, the author will describe the unique interface between drugs and medical device software, including benefits for developing combination therapies and products comprising specific drugs and medical device software. The author will discuss innovative drug-device therapy strategies for epilepsy, neuropathic pain and other chronic disorders, including preclinical studies which employ enriched environment. This presentation also illustrates why integration of drug-based therapies (including generic drugs, or those under preclinical or clinical development) with copyrighted content of medical device software may offer the patent-independent intellectual property protection of a combination treatment which can last for over 70 years. In conclusion, disruptive technologies such as mobile and digital health are advancing at faster pace, as compared to that of traditional drug development process. Electronic and digital technologies provide new R&D opportunities to innovate pharmacotherapies while establishing long-lasting intellectual property of new drug-digital therapies.
University of Heidelberg Germany
Time : 09:55-10:20
Martin Wehling, MD, is full Professor of Clinical Pharmacology at the University of Heidelberg. He is also board certified internist (cardiologist) and has longstanding experiences in basic science (cell physiology, steroid pharmacology, nongenomic steroid actions), clinical trials (translating basic science into human studies) and clinical medicine (invasive cardiology, endocrinology). In 2004, he was appointed by AstraZeneca as Director of discovery (=translational) medicine. Returning to academia in 2007, he promotes translational medicine by aligning academic and private activities. Main tools are connecting distant players in the translational process, assembling, developing and profiling of biomarkers and developing smart translational plans to promote promising projects.
Despite tremendous efforts and investments, despite the cloning of the entire human genome, innovations at the patient level are becoming rare events. Failures to predict human efficacy/safety of new drugs from early discovery and development work are being blamed to cause early or late attrition of too many drug projects. The pressure of increasing R&D costs and low output in terms of critically novel drugs forced the Federal Drug Administration (FDA) to reconsider its own actions and those of major players in biomedical research in terms of time lines, costs, design and, ultimately, success. The ‘critical path initiative’ of 2004 represents a milestone in this context. It reflects a concerted action initiated by a regulatory authority criticized for its ‘retarding’ activities claimed to result in the low output syndrome described above. Though certainly not the first public initiative to address translational medicine issues as major concern, it was one of the most influential and respected ones. American universities addressed the challenge as well and established centers for translational medicine, e.g. at Duke or Pennsylvania University. The CTSA recipients (68 in 2014) are joining this club. The NIH founded the NCATS (National Center for Advancing Translational Science) which now has a budget of close to billion USD. In Europe, The European Organization for the Treatment of Cancer (EORTC) which is committed to making translational research a part of all cancer clinical trials, and the National Translational Cancer Research Network announced by the British government to facilitate and enhance translational research in the United Kingdom are working on this route. In general, research funding programs such as the 7th Framework Program or Horizon 2020 of the European Union use the phrase ‘translational’ activities in almost half of their topics, but institutionalization is rare on this continent. Almost all major drug companies have addressed the issue of translational medicine in one way or the other. The institutional structures range from independent departments of translational or discovery medicine to entirely ‘embedded” dependent structures which are part of the drug discovery/development teams without central facilities. In general, US biomedical players have invested the most (NIH has announced to spend a total of up to 10 billion USD) and are at the forefront of translational institutionalization, with Europe lagging behind at very different distances as far as the individual countries are concerned. Commercialization of academic inventions has traditionally been much more efficient in the US than the EU, and translational medicine has a lot to do with expertise accrued during commercialization processes. Latter processes can only be lucrative if translational steps have been added to a biomedical invention, and facilitating such early developmental investments has been ‘on the list” of successful universities (e.g. UCSF, Harvard), but also smaller companies for many years. Yet, translational medicine as a complex science is still in its infancy, and needs careful development both as a generic science, and in concrete projects. One dimension and particular challenge of this novel science is certainly the assessment of the translational potential of an innovative project, thereby rating the risk of investment and creating a base for portfolio considerations. In a structured approach following pre-specified algorithms, the translatability potential of a given drug, device or diagnostic test project may be assessed by analysis of multiple variables. Biomarkers, disease models, test tube results, genetic and ‘omics’ data and other dimensions will be integrated into a translatability scoring system to achieve two goals: - quantitatively position the likelihood of translational success of a given project in the environment of competing projects to support stop/go decisions - develop a strategy for successful translation by the identification of weaknesses and the generation of a program for amelioration (e.g. biomarker development) This approach is envisioned to help biomedical and drug companies, funding agencies, regulatory authorities, venture capital and academia to - detect promising projects with high potential for exploitation in the value chain - rate funding applications in regard to their translational potential and prioritize them - thus, find a reasonable balance of more and less risky projects in a portfolio - define and implement a strategy for the development of translational aspects in given projects By this reproducible process which even (but not only) produces numerical denominators, decision makers in biomedical or venture capital companies, funding agencies could add value to sometimes gut-feeling and expert opinion driven evaluation processes, and connect investment decisions to the evidence-based analysis of the translational soundness of a project. Academia might consider to partially re-shape research strategies if the route to out-licensing success and generation of revenues would be easier to travel in the light of this service.
University of KwaZulu-Natal South Africa
Time : 10:20-10:45
Rajendra Bhimma, MB, ChB, MD, DCH (SA), FCP (Paeds)(SA), MMed (Natal), is Associate Professor of Pediatrics, Principal Specialist, Department of Pediatrics and Child Health, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, South Africa. He has published over 50 articles in peer-reviewed journals. He is a member of the following Societies: American Association for the Advancement of Science, International Pediatric Transplant Association, International Society of Nephrology, South African Medical Association, South African Paediatric Association, South African Transplant Society. Research interest in glomerular diseases, especially HIV associated kidney diseases. He is also a long-standing member of the Biomedical Research Ethics Committee of the University of KwaZulu-Natal and an editorial board member of two international journals.
Nephrotic syndrome (NS) is one of the most frequent glomerular diseases seen in children. Children who go into complete remission following treatment with corticosteroids are classified as having “steroid sensitive” NS. In developed countries over 80% of children with idiopathic NS have steroid sensitive disease although response to steroids is somewhat tempered in developing countries, especially in black children, the majority of whom have steroid resistant disease. The exact pathogenesis of this condition remains elusive. Podocyte injury and proteinuria are the two main issues in the pathogenesis. Recent studies suggest alterations in both innate and adaptive immune responses. There is release of cytokines by T-cells as well as a strong contribution of B-cell immunity. Genetic studies have reported human leucocyte antigen (HLA) class II antigens DR and DQ associations liked to steroid sensitive NS and in small case studies, single gene mutations e.g. PLCE1 although to date no hemozygous mutations in NPHS1 or NPHS2 and WT-1 genes have been reported. Most children with steroid sensitive NS have multiple relapses and a significant percentage also develop steroid dependent NS. These children receive multiples courses of steroids and are at high risk of developing steroid toxicity. Patient with frequent relapses who develop steroid dependency thus require alternative treatment. Steroids sparing agents used include levamisole, cyclophosphamide, mycophenolate mofetil (MMF), calcineurin inhibitors (cyclosporine and tacrolimus), rituximab and vincristine. The steroid-sparing effects of these agents have greatly reduced the adverse effects seen with long-term use of steroids. Despite the wide arsenal of agents available, therapy needs to be individualised to achieve optimal care of each child. More randomised controlled trials are required to evaluate the therapeutic and economic efficacy of this agent, define criteria for selection of patients for use of particular agents and to determine the safety profile of these drugs in children. This presentation reviews the pathogenesis, clinical presentation, diagnosis, complications, management and long term outcome of children with steroid sensitive NS.
University of Toyama Japan
Title: Gemcitabine Chemotherapy Induces Phenotypic Alterations of Tumor Cells That Facilitate Antitumor T cell Responses in a Mouse Model of Oral Cancer
Time : 11:05-11:30
Dr. Tomihara received his Ph.D. degree in 2006 from Sapporo Medical University, working on immune gene therapy by adenovirus vector. He then moved to Cancer Therapy and Research Center (CTRC) at The University of Texas Health Science Center at San Antonio (UTHSCSA) to work with Dr. Shin as a post-doctoral fellow. He obtained an assistant professor position in 2013 in the Department of Oral and Maxillofacial Surgery Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, where he started independent research on cancer immunology.
Gemcitabine (GEM) is a pyrimidine nucleoside analogue that is a new chemotherapeutic agent used for treating various cancers. Because accumulating evidence indicates that GEM may activate host immune responses, its potential as an immune modulator in cancer chemotherapy has generated considerable interest. In the present study, we sought to identify the antitumor immune effects of GEM in a mouse oral cancer model using immunological analyses. GEM induced significant oral cancer-cell apoptosis in vitro, and in vivo GEM administration markedly attenuated established mouse tumor growth. In vivo GEM administration decreased the numbers of both myeloid-derived suppressor cells (MDSCs) and B cells in tumor-bearing mice and enhanced dendritic cell maturation. Moreover, GEM treatment upregulated tumor-cell surface expressions of several immune accessory molecules and adhesion molecules, including CD80, CD86, CD40, ICAM-1, VCAM-1, and P-selectin. Remarkably, these tumor cells augmented T-cell responses. These results suggest that GEM can induce host antitumor immune responses, which would facilitate antitumor effects in the treatment of oral cancer.
Chinese Academy of Sciences China
Time : 11:30-11:55
Xiao Fei has completed her PhD and Postdoctoral studies from Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. Her research interest is to understand the cellular and molecular mechanisms underlying genetic and nutritional regulation of metabolic diseases including obesity, diabetes, and fatty liver. She has published several papers in Diabetes, Diabetologia and Metabolism as first author.
We have previously shown that serum insulin levels decrease three-fold whereas blood glucose levels remain normal in mice fed leucine-deficient diet, suggesting increased insulin sensitivity. The goal of the present study is to investigate this possibility and elucidate underlying mechanisms. Here it was shown that leucine deprivation improves hepatic insulin sensitivity by activating General Control Nonderepressible (GCN)2 and decreasing mammalian Target of Rapamycin (mTOR)/ ribosomal protein S6 kinase 1 (S6K1) signaling. Activation of AMP-activated protein kinase (AMPK) also contributes to this phenomenon. In addition, it was also shown that leucine deprivation improves insulin sensitivity under insulin-resistant conditions. This study describes mechanisms underlying increased hepatic insulin sensitivity under leucine deprivation and demonstrates a novel function for GCN2 in the regulation of insulin sensitivity. Besides, it was found that valine or isoleucine deprivation for 7 days produces similar effects as leucine on insulin sensitivity regulated in a similar manner. Different from leucine, valine or isoleucine deprivation for 7 days significantly decreases fed blood glucose levels, possibly by decreasing expression of a key gluconeogenesis gene glucose-6-phosphatase. It was also found that insulin sensitivity is rapidly improved in mice following maintenance on a diet deficient for any individual BCAAs for 1 day. Results showed that the effect of leucine deprivation represents a general effect of BCAAs on regulation of insulin sensitivity, but not glucose levels, suggesting that each individual BCAA has unique feature in metabolic regulation. These observations also provide a rationale for short-term dietary deprivation or restriction of BCAAs for the treatment of insulin resistance and associated metabolic diseases.
University of Medical Sciences-Urmia Iran
Title: Effect of oral herbal oil supplement (Cannabis Sativa L, Oenothera Biennis L) and advised Hot-nature diet on clinical signs and symptoms and inflammatory factors in patients with multiple sclerosis
Time : 11:55-12:20
Soheila Rezapour-Firouzi is pursuing PhD from Department of Immunology, Microbiology and Genetics; Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran. In 2013, she published her papers on "Effect of Oral Herbal Oil Supplement (Cannabis sativa L, Oenothera biennis L) and Advised Diet with Hot-Nature on Clinical Signs and Symptoms and Inflammatory Factors in Multiple Sclerosis Patients". This supplement oil was named MS-NUT; it means nutrition for MS patients. Her research is going to be published with the name of the peace, justice and freedom for all around the world, presents for the treatment of suffers of Multiple Sclerosis.
Background: Multiple sclerosis (MS), ensuring demyelization, resulting in physical disability, is the most chronic and inflammatory disorder. Because of limited efficacy and adverse side effects of the current treatments, identifying novel therapeutic and protective agents is important. For many years, it has suspected that the risk of developing MS might be associated with increased dietary intake of saturated fatty acids and consumption of cold natured foods. This study aimed to assess the potential therapeutic and protective effects of hemp seed and evening primrose oils as well as hot-nature dietary intervention on mild MS patients. Methods and materials: In this double blind, randomized trial, 100 RRMS patients (expanded disability status scale<6) allocated into three groups: “Group A” who received co-supplemented oils with advising hot nature diet, “Group B” who received olive oil as placebo, “Group C” who received co-supplemented oils. Mizadj, Clinically EDSS, relapse rate and functional score as well as immunological factors (plasma cytokines of IL-4, IFN-γ and IL-17), biochemical parameters (GGT, AST, ALT, red blood cells PUFA and erythrocyte membrane fatty acids composition, D-6-desaturase (FADS2), Secretory PLA2 (sPLA2) assessed at baseline and after 6 months. Results: Mean follow-up was 180±2.9 SD days (N=65, 23 Male and 42 Female aged 34.25±8.07 years with disease duration 6.80±4.33 years). There was no significant difference in studies parameters at baseline. After 6 months, significant improvements in Mizadj, EDSS score and relapse rate found in the groups A and C while the group B only showed a border significant decrease in relapse rate. Immunological and biochemical parameters showed improvement in the groups A and C whereas there was worsening condition for the group B after the intervention, and immunological parameters correlated with the EDSS score in-group A. After 6 months, the erythrocyte cell membrane with regard to specific fatty acids, showed improvement in the group A and C whereas there was worsening condition for the group B after the intervention. Conclusion: This study suggests that co-supplemented herbal oils with hot nature diet can have beneficial effects in reversing the signs and improve clinical outcome in RRMS patients which were confirmed by immunological and biochemical findings. This intervention causes an increase PUFAs in MS patients and improvement in the erythrocyte membrane fatty acids composition and it could be an indication of restored plasma stores, and a reflection of disease severity reduction.