Day 1 :
University of Louisville, USA
Keynote: PLG scaff olds engineered with an immunomodulatory molecule as an effective means of establishing localized tolerance to pancreatic islet grafts
Time : 09:30-10:10
Haval Shirwan is Dr. Michael and Joan Hamilton Endowed Chair in Autoimmune Disease, Professor of Microbiology and Immunology, Director of Molecular Immunomodulation Program at the Institute for Cellular Therapeutics. He conducted his Graduate studies at the University of California in Santa Barbara, CA and Postdoctoral studies at California Institute of Technology in Pasadena, CA. He joined the University of Louisville in 1998 after holding academic appointments at various academic institutions in the United States. His research focuses on the modulation of the immune system for the treatment of immune-based diseases with a particular focus on type 1 diabetes, transplantation and cancer immunoprevention and immunotherapy. He is an inventor on over a dozen of worldwide patents, founder and CEO/CSO of FasCure Therapeutics, LLC, widely published, organized and lectured at numerous national/international conferences, served on study sections for various federal and non-profit funding agencies and is on the Editorial Board of a number of scientific journals. He is a member of several national and international societies and recipient of various awards.
Transplantation of allogeneic pancreatic islets is an effective means of treating type1 diabetes (T1D). However, widespread application of this approach is hampered by the need for chronic immunosuppression to control rejection. Immunosuppressive agents used in the clinic have various adverse effects that compromise the life quality of graft recipients. The development of immunomodulatory approaches that induce tolerance without the need for chronic immunosuppression is an immediate medical need. In this study, we engineered PLG scaffolds with SA-FasL as an immunomodulatory molecule and demonstrated that allogenic islets loaded on the engineered scaffolds when transplanted into epididymal fat pad of allogeneic recipients under a short course of rapamycin (15 daily doses only) achieved indefinite survival. Importantly, the grafted islets normalized blood glucose levels, demonstrating function. Thus, PLG scaffolds engineered with SA-FasL represent a novel immunomodulatory concept for the induction of tolerance to islet allografts with significant translational potential.
Albany Medical College of Pharmacy, USA
Keynote: A cell surface receptor for thyroid hormone analogues on integrin αvβ3 in tumor cells regulates expression of cancer cell genes relevant to the cell cycle apoptosis chemoresistance and angiogenesis
Time : 10:10-10:50
Paul J Davis obtained the MD degree at Harvard Medical School and had his internal medicine clinical and endocrine research training, respectively, at Albert Einstein College of Medicine (NY) and the NIH. He has served in a number of senior administrative positions in academic institutions and in national societies. His research is focused on the molecular mechanisms of thyroid hormone actions. He has co-authored 275 research publications and 40 textbook chapters; he has co-edited four textbooks. He and colleague SA Mousa described the cell surface receptor for thyroid hormone on integrin αvβ3. They also co-founded NanoPharmaceuticals LLC (Rensselaer, NY
Integrin αVβ3 is a structural protein of the plasma membrane that is generously expressed by cancer cells and dividing endothelial cells; until recently, important functions of the integrin have been seen to relate to cell-cell and cell-extracellular matrix protein interactions. The extracellular domain of αvβ3 is now appreciated to contain a small molecule receptor for thyroid hormone, primarily, L-thyroxine (T4). From this cell surface hormone receptor, the expression of a large panel of cancer-relevant genes is differentially regulated by thyroid hormone analogues. These genes include multiple cell division regulating cyclins and HRAS and KRAS genes linked to uncontrolled cell division; KRAS is also related to cancer stem cell (CSC) maintenance and to tumor recurrence. Transcription of these genes is downregulated by P-bi-TAT, consisting of a thyroid hormone analogue, tetraiodothyroacetic acid (tetrac), chemically coupled to polyethylene glycol (PEG). IDH2 is involved in tumor cell mitochondrial metabolism; P-bi-TAT decreases IDH2 transcription, thus promoting apoptosis by the intrinsic (mitochondrial) pathway. Expression of ERBB2 is important to tumor cell invasiveness and metastasis and is downregulated by P-bi-TAT. The ERBB family of proteins is also important to tumor cell chemoresistance. αvβ3 regulates via the thyroid hormone receptor the transcription of ABCB1, whose gene product— the P-glycoprotein of the plasma membrane—exports a number of chemotherapeutic agents from tumor cells as a component of chemoresistance. Expression of pro-angiogenic VEGFA, bFGF and PDGF genes is also decreased by P-bi-TAT action at αvβ3, as is the EGFR gene whose transcription is important to angiogenesis and tumor cell proliferation. Matrix metalloproteinase (MMP) gene expression is critical to cell migration/metastasis and to angiogenesis; P-bi-TAT induces a signal at the integrin to reduce MMP production. The EGFR protein is a tyrosine kinase and thus P-bi-TAT, by downregulating expression of EGFR, functions as a tumor cell-relevant tyrosine kinase inhibitor (TKI). Another TKI gene affected by P-bi-TAT is KIT. This complex set of actions of P-bi-TAT on gene expression implies that T4 may act on tumor cell αvβ3 to support, rather than inhibit, the expression of these genes whose products are linked to tumor cell survival. We have. shown that T4 via αvβ3 does stimulate expression of VEGFA and bFGF, of MMPs, ABCB1 in tumor cells. Transduction of thyroid hormone and hormone analogue signals downstream of αvβ3 is a function of MAPK/ ERK1/2 and PI3K, the genes and enzyme activities of which are regulated by thyroid hormone. These observations indicate that the importance of αvβ3 to cancer cell function and survival also includes the actions of thyroid hormone analogues on the integrin.
University of Bradford, UK
Keynote: DNA damage protec on by querce n in isolated primary sertoli cells exposed to the food mutagen 2-amino-3-methylimidazo [4,5-f]quinolone(IQ) in vitro
Time : 11:10-11:50
Diana Anderson (H index 62) holds the established chair in Biomedical sciences at the University of Bradford. She obtained her first degree in the University of Wales and second degrees in the Faculty of Medicine, University of Manchester. She has 450+ peer-reviewed papers, 9 books, has successfully supervised 32 PhDs, is an Editorial Board Member of 10 international journals. She is Editor-in-Chief of a book series on Toxicology for the Royal Society of Chemistry. She gives plenary and key note addresses at various international meetings. She is a consultant for many international organizations including WHO, EU, NATO, TWAS, UNIDO, OECD.
Heterocyclic amines (HCAs) are mutagenic and carcinogenic chemicals generated by heating or processing of cooked foods. The main precursors of HCA formation are creatine/ creatinine found in muscle foods. Creatine supplementation has been associated with a number of adverse events, including cancer. In rodents, a study has suggested an increased risk of testicular germ cell cancer. The most common HCAs found in foods are the thermic HCAs, which include 2-amino-3-methyl-imidazo [4,5- 3f] quinoline (IQ). Antioxidants are very important in order to protect the cells against oxidative damage. The present study explored the mechanism of cytotoxic and genotoxic effects of IQ in a primary culture of Sertoli cells also known as “mother/nurse cells” in vitro. These cells play an essential role in nurturing and providing structural support for cells of spermatogenesis during their proliferation and development. DNA damage was evaluated using the Comet assay. The mRNA expression of p53 and bcl-2 genes and their proteins involved in apoptosis was also investigated. The antioxidant status of treated Sertoli cells was determined by measuring superoxide dismutase (SOD-1), catalase (CAT) and glutathione peroxidase (GPX-1) using quantitative polymerase chain reaction (qPCR). Furthermore, the effect of quercetin and its combination with IQ were examined. Results of the present study clearly showed that IQ-induced DNA damage as evident by increases in the Comet assay parameters. The activation of p53, repression of bcl-2 and reduction of the endogenous antioxidant enzymes were also involved in these mechanistic pathways. This may lead to reduced numbers of Sertoli cells by promoting early male germ cell differentiation. While the exogenous antioxidant quercetin significantly reduced the primary Sertoli cells in vitro.
Harvard Medical School, USA
Keynote: Therapeutic target identification by genetically engineered human neural stem cells in a spinal cord glioblastoma model
Time : 11:50-12:30
Recovery Research and Director, Laboratory of SCI, Stem Cell Biology and Neurofacilitation Research, Departments of PM&R and Neurosurgery, Harvard Medical School/Spaulding Rehabilitation Hospital Network and Brigham and Women’s Hospital. He investigates functional multipotency of stem cells and recovery neurobiology through multimodal approaches that integrate stem cell biology, neural and glial biology, chemical and genetic engineering, molecular pharmacology and neural oncology. Work of his team has received the prestigious Apple award of the American Spinal Injury Association (2011), the ERF New investigator award from the foundation of PM&R (2004) and the Mayfield award and Larson Research award of the CNS/AANS Joint Section on Disorders of the Spine and Peripheral Nerves (2012, 2015 & 2016). Prof. Teng reviews for >50 academic and clinical journals and holds study section membership of the NIH, VA, DoD, European Union academic organizations, research and education institutions and scientific and academic foundations. He was elected President (2013-2014) of the American Society for Neural Therapy and Repair.
We recently established a rodent model of intramedullary cervical spinal cord glioblastoma (ISCG). The system for the first time emulated both somatomotosensory disorders and autonomic dysfunctions of this deadly disease. Using genetically engineered human neural stem cells (hNSCs) that were capable to track and migrate towards the cancer cells we have determined a subpopulation of ISCG cells that are crucial for the tumor survival and could be targeted by therapeutic hNSCs that exerted a localized oncolytic effect. Importantly, the data also illuminated host spinal cord cellular and network components that should be preserved to maximize residual neural function in order to benefit extension of survival. Overall, our findings demonstrated a stem cellbased multimodal approach to developing targeted glioblastoma treatment. Such a strategy can be further optimized for its comprehensive efficacy via a simultaneous application of targeted neuroprotection treatment to sustain neurological function.