Vincent S. Gallicchio is a professor of biological sciences, public health and microbiology at Clemson University. He is a vice president of the Trace Element Research Centers operating under UNESCO and the immediate past-president of the International Federation of Biomedical Laboratory Science. He has authored more than 200 peer-reviewed scientific articles, book chapters and textbooks. He is the inventor on eleven U.S. and one international patent focused on drug delivery. He has received more than $22 million in research funding. In 2003 he was presented to her majesty Queen Elizabeth of England for his efforts promoting higher education opportunities for British students.
The average daily Li intake of an American 70 kg adult ranges from 650 to 3100 μg. Major dietary sources are vegetables and, in some areas, the drinking water. In Li deficient rats, behavioral abnormalities and a significant negative effect on litter size & litter weight at birth were observed. In Li deficient goats the conception rate was reduced, gravid lithium deficient goats experienced a higher incidence of spontaneous abortions
1I.M.Sechenov First Moscow State Medical University, Russia
2A.I.Evdokimov Moscow State Medical & Dental University, Russia
3EPMA (European Association for Prediction, Prevention and Personalized Medicine), EU
4National Institutes of Health (NIH), USA
5Johns Hopkins University Medical Institutions, USA
Sergey Suchkov MD Ph.D. was born in 1957, a researcher-immunologist, a clinician, graduated from Astrakhan State Medical University, Russia, in 1980. He has been trained at the Institute for Medical Enzymology, The USSR Academy of Medical Sciences, National Center for Immunology (Russia), NIH, Bethesda, USA) and British Society for Immunology to cover 4 British university facilities. Since 2005, he has been working as faculty professor of I.M. Sechenov first Moscow State Medical University and of A.I.Evdokimov Moscow State Medical & Dental University. From 2007, he is the First vice-president and dean of the School of PPPM Politics and Management at the University of World Politics and Law. In 1991-1995, he was a scientific secretary-in-chief of the editorial board of the international journal “Biomedical Science” (Russian Academy of Sciences and Royal Society of Chemistry, UK) and the international publishing bureau at the presidium of the Russian Academy of Sciences. In 1995-2005, he was a director of the Russian-American program in immunology of the eye diseases. He is a member of EPMA (European Association of Predictive, Preventive and Personalized Medicine,Brussels-Bonn), a member of the NY Academy of Sciences, a member of the editorial board for open journal of immunology and others. He is known as an author of the concept of post-infectious clinical and immunological syndrome, co-author of a concept of abzymes and their impact into the pathogenesis of auto immunity conditions, and as one of the pioneers in promoting the concept of PPPM into a practical branch of health services
A new systems approach to disease to pay its crucial attention on the trend would result in a new branch in the healthcare services, namely, predictive, preventive and personalized medicine (PPPM). Meanwhile, all chronic disorders develop gradually over a period of time to take years for a process to reach a level where it could be diagnosed definitively and treatment initiated properly and in time before changes are irreversible! And to achieve the implementation of PPPM concept, it is necessary to create a fundamentally new strategy based upon the subclinical recognition of biomarkers and biopredictors of hidden abnormalities long before the disease clinically manifests itself. PPPM is thus a medical model being tailored to the individual and dictates a construction of PPPM algorithms to diagnose, to predict, and to prevent in time whilst following a concept of biomarkers impact into the daily practice! The key benefits of PPPM include new abilities: (i) to detect disease at a subclinical stage, when it is easier and less expensive to treat effectively; (ii) to stratify patients into groups that enable the selection of optimal preventive treatment; (iii) to reduce adverse drug effects by more effective early assessment of individual drug responses; (iv) to improve the selection of new molecular targets for drug discovery; (v) to shift the emphasis from illness to wellness. The first discriminatory step illustrating the PPPM-oriented survey is estimating of the correlation strength between genetic polymorphism and risks of the disease, and subsequent construction of the groups at risks. Those goals can be solved by using of BioChip methodology (each disease has specific biomarkers and thus the individual fingerprints). As a result, a patient becomes a data carrier, i.e., he/she knows about possible risks of a disease, and the physician can reasonably select of preventive protocol, proceeding from the assays made. Individuals, selected at the first stage, undergo the second phase of the survey, which uses a panel of phenotypic biomarkers and biopredictors. It would be extremely useful to integrate data harvesting from different databanks for applications such as prediction and personalization of further treatment. So PPPM whilst utilizing a highly promising concept of biomarkers and biopredictors, would offer great and real challenge for the future, and next generations will speak about the XXI century as a time, when healthcare services became predictive and preventive, and its outcomes – secured and guaranteed!
National Cancer Institute, USA
Mukesh Verma is a Program Director and Chief in the Methods and Technologies Branch (MTB), Epidemiology and Genetics Research Program (EGRP) of the Division of Cancer Control and Population Sciences (DCCPS) at the National Cancer Institute (NCI), National Institutes of Health (NIH). Before coming to the DCCPS, he was a Program Director in the Division of Cancer Prevention (DCP), NCI, providing direction in the areas of biomarkers, early detection, risk assessment and prevention of cancer, and cancers associated with infectious agents. He holds a M.Sc. from Pantnagar University and a Ph.D. from Banaras Hindu University. He did postdoctoral research at George Washington University and was a faculty member at Georgetown University. He has published 136 research articles and reviews and edited three books in cancer epigenetics and epidemiology field.
Cancer is a genetic and epigenetic disease. Biomarkers identified recently have helped in cancer detection, diagnosis, prognosis, and follow up of survival. Cancer is one of the leading causes of death in the United States, and more than 1.5 million new cases and more than 0.5 million deaths were reported during 2010 in the United States alone. Following completion of the sequencing of the human genome, substantial progress has been made in characterizing the human epigenome, proteome, and metabolome; a better understanding of pharmacogenomics has been developed, and the potential for customizing health care for the individual has grown tremendously. Recently, personalized medicine has mainly involved the systematic use of genetic or other information about an individual patient to select or optimize that patients preventative and therapeutic care. Molecular profiling in healthy and cancer patient samples may allow for a greater degree of personalized medicine than is currently available. Information about a patients proteinaceous, genetic, and metabolic profile could be used to tailor medical care to that individuals needs. A key attribute of this medical model is the development of companion diagnostics, whereby molecular assays that measure levels of proteins, genes, or specific mutations are used to provide a specific therapy for an individuals condition by stratifying disease status, selecting the proper medication, and tailoring dosages to that patients specific needs. Additionally, such methods can be used to assess a patients risk factors for a number of conditions and to tailor individual preventative treatments. Recent advances, challenges, and future perspectives of personalized medicine in cancer are discussed.
Coffee Break 10:45-11:05 @ Atrium
University of Genova, Italy
Claudio Nicolini was born in Udine, Italy. He received his doctoral degree in physics from the University of Padua, in 1967. After serving as adjunct professor at the University of Bari, he moved for 17 years to the United States, of which he became citizen since 1974, and was originally at Brown University, MIT, and BNL. He then moved to Temple University School of Medicine, Philadelphia, where after a period of intensive training and research in pathology he became associate professor of pathology and then professor and chairman of the Biophysics in 1976. In 1985, he was called as eminent scientist to the chair of Biophysics of the University of Genova, in Italy until 2012 where he was successively became the director of Biophysics Institute, DISTBIMO and CIRSDNNOB. From 1993 until now is life president of the Fondazione ELBA Nicolini and of the Nanoworld Institute. On 2008 has been elected as a foreign member of the Russian academy of sciences and on 2010 received Honoris Causa and became professor of Biophysics and Nanobiotechnology at Moscow State University. He was chief editor of Cell Biophysics (USA), Science and Technology advisor to Italian Prime Minister Craxi, member of the National Science and Technology Council upon Parliament election, scientific director industrial consortium CIREF, founder Technobiochip, president of Polo National Bioelectronics, president Scientific Technological Park of Elba Island. He received several awards and prizes and has authored more than 480 publications in international scientific journals (SCI), 35 patents (WPI), 28 books and series editor in Bioelectronics (Plenum) and Nanobiotechnology (Pan Stanford). His main scientific activities concerned cancer research, biophysics and nanotechnology, pioneering world-wide chromatin structure-function, bioelectronics and nanobiotechnology.
Nucleic Acid Programmable Protein Arrays utilize a complex mammalian cell free expression system to produce proteins in situ. In alternative to fluorescent-labelled approaches a new label free method, emerging from the combined utilization of three independent and complementary nanotechnological approaches, appears capable to analyze protein function and protein-protein interaction in studies promising for Personalized Medicine. Quartz Micro Circuit nanogravimetry, based on frequency and dissipation factor, mass spectrometry and anodic porous alumina overcome indeed the limits of correlated fluorescence detection plagued by the background still present after extensive washes. This has been further optimized by an homogeneous and well defined bacterial cell free expression system capable to realize the ambitious objective to quantify the regulatory protein networks in humans. Implications for a new frontiers in Personalized Medicine of the above Label Free protein array technologies using different test genes proteins are reported along with recent conductometric monitoring of drug-gene and drug-protein interactions is of fundamental importance in the field of personalized medicine
Track 1 Current Focus of Personalized Medicine
Track 2:Clinical aspects of Predictive, Preventive, Personalized Medicine
Track 3: Genomics Evolution
Track 4: Molecular Diagnostics
Track 5: Molecular Biomarkers
National Cancer Institute, USA
Clemson University, USA
Boston childrens hospital, USA
Catherine Brownstein is a geneticist and toxicologist with eleven years experience in human genetics and three years in applying patient-reported outcomes to the study of disease. She has been project manager of the Research Sequencing Program at Boston Children’s Hospital since 2011.
Her research career includes training in genetics, medical genetics, epidemiology, and environmental health. She has also completed MPH at the Yale School of Epidemiology and Public Health and worked as a toxicologist at the Massachusetts Department of Public Health. Before coming to BCH and HMS, she spent four years creating online patient communities for individuals with chronic or terminal diseases.
The overall goal of clinical and research pharmacogenomics (PGx) at Boston Children´s Hospital (BCH)is to ultimately improve medication safety through precision genetic medicine.
The Clinical Pharmacogenomics Service (CPS) was created to facilitate the incorporation of pharmacogenomic (PGx) information into the medication management cycle. The service provides consultations for the clinicians at BCH who request assistance with the interpretation and application of relevant PGx data for patient care. Complete with an oversight committee composed of clinical experts who ensure the safe and rational movement of drug/gene pairs and return the results to the electronic medical record, the CPS is also responsible for the creation, maintenance and monitoring of related decision support rules in the EMR.
This has highlighted potential problem areas in the clinical application of PGx, such as overcalling secondary to the inability to resolve diplotypes, and the ability to convey uncertainty in a meaningful way to patients when dealing with difficult to interpret regions. Careful metrics are maintained, such as clinical decision support statistics, outcomes, and adverse drug reaction (ADR) avoidance. Early statistics related to cost-savings from ADR avoidance have been generated. In the coming months, the CPS aims to evolve into a billable service with clinic hours.
Research in pharmacogenomics at BCH is also thriving. Educational sessions have been developed in response to needs identified. BCH is also retrospectively studying the relationship between genotype and reported ADRs. One exciting project is enrolling patients from participating clinics (epilepsy, inflammatory bowel disease, renal transplant) and genotyping them on a broad PGx platform, returning results to providers and a selected subset of results to the EMR. This project also assess the patient´s response to medication and outcome in the context of their genotype and phenotype. Finally, groundbreaking research out of two Harvard laboratories has created a novel all-optical electrophysiology platform to rapidly screen drugs for functional effects in human neurons and cardiomyocytes.
BCH considers clinical and research pharmacogenomics essential to offering world-class patient care using state-of-the-art drug/gene knowledge.
Yale University of school medicine, USA
David Cheng completed a PhD in Biomedical Physics from UCLA and a dual residency in Internal Medicine and Nuclear Medicine at Montefiore Medical Center, the hospital for the Albert Einstein College of Medicine in Bronx, NY. He has served as the Chief of Nuclear Medicine for more than 10 years at Yale-New Haven Hospital. He has joined Sidra Medical and Research Center in July 2014 as the Chief of Nuclear Medicine and Molecular Imaging to develop his own research
With continued advancement in personalized therapies in medicine, there is a need for improvements in diagnostic imaging. This talk will give a brief update in equipments (such as PET/MRI) and in biomarkers currently under investigation and being used in clinical practice.
University of Veterinary Medicine, Germany
Julia Matena has completed her studies of veterinary medicine at the age of 25 from University of Veterinary Medicine, Foundation, Hanover. Now she is PhD student at Small Animal Clinic, University of Veterinary Medicine, Foundation, Hanover. She participates in research training group biomedical engineering, sfb 599.
Skeletal critical size defects can occur due to tumor resections, infections or trauma. Autologous bone grafts are still the gold standard for the reconstruction of skeletal defects, having an excellent combination of osteoconduction, osteoinduction and osteogenesis properties. However, the use of autologous bone grafts has certain limitations, since their use requires surgical procedure for harvest, the amount and size is limited and is associated with donor site morbidities. Because every skeletal defect has a unique form, any implant that is created to fill the defect has to be patient specific. Rapid manufacturing methods are a favorable possibility to overcome this problem. In our study we combined the principles of rapid manufacturing with a degradable implant material having good mechanical properties. Recently the production of magnesium structure using Selective Laser Melting (SLM) could be established. This material has the potential to create a patient specific, absorbable implant that meets physiological requirements. Especially in critical size defects an early and fast vascularization of implants is of great importance. Porous scaffolds enable vessel in growth and thus support bone ingrowth. Using SLM technique interconnected pores of the implant can be produced. To control the degradation of absorbable magnesium implants we examined different polymer coatings.
Primary osteoblasts and mesenchymal stem cells, as cell with vital importance for vascularization and bone growth, were seeded on these different coatings and analyzed by means of proliferation and viability assays. To support angiogenesis pro-angiogenic factors were incorporated into the polymers and examined. We used live cell imaging to follow osteoblasts and mesenchymal stem cells seeded on the SLM produced magnesium constructs coated with polymers for seven days to show cell morphology and migration. Osteoblasts showed a flattened cell shape even one week after seeding. Next steps are in vivo tests to examine osseointegration and angiogenesis.
Shanghai University of Traditional Chinese Medicine, China
Tao Wu is a research assistant with certain working capability in scientific research independently, especially in Chinese traditional medicine for the prevention and treatment of chronic liver disease, and application of metabonomics in clinical metabolic disease. He has 6 years of experience in his research field, he is a research assistant in Center of Chinese Medicine Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
Introduction: In Western medicine, non-alcoholic fatty liver disease (NAFLD) is diagnosed by imaging, histology and biochemical parameters. Traditional Chinese Medicine (TCM) uses unique diagnostic techniques to classify NAFLD into subtypes based on different TCM symptoms (syndrome classification). Sterol regulatory element-binding protein (SREBP), also known as SREBP cleavage-activating protein or SCAP is encoded by the SCAP gene SCAP genes have important functions in defining genetic susceptibility to NAFLD. This study investigated whether the polymorphisms of SREBF-1, SREBF-2, and SCAP genes were associated with the TCM syndromes of NAFLD.
Materials and methods: Fourteen tag single nucleotide polymorphisms (SNPs) of SREBF-1, SREBF-2, and SCAP were chosen for our study We genotyped and analyzed 100 healthy control subjects and 211 NAFLD subjects who were classified by TCM into two groups, namely, deficiency syndrome group and excess syndrome group.
Results: The results showed that rs12636851 SNP of SCAP exhibited a significant genotype and allelic variation between the deficiency syndrome and healthy control subjects, as well as between the deficiency and excess syndrome subjects In the deficiency syndrome group, the subjects who had the CC or TC genotype of SCAP rs12636851 had a threefold elevated risk for NAFLD compared with the TT genotype (adjusted OR, 3107; 95% CI, 1023, 9433, P = 0.045; adjusted OR, 2970; 95% CI, 1121, 7864, P = 0.028).
Discussion: We speculate that the SCAP rs12636851 SNP in the deficiency syndrome subjects affects the cholesterol-sensing function of SCAP, increasing cholesterol and fatty acid synthesis in liver Therefore, this SNP may help in the understanding of the genetic basis of NAFLD patients with deficiency syndrome and in the development of personalized medical care.
San Diego Medical Center, USA
Alice E Zemljic-Harpf obtained her medical degree at the University of Graz, Austria, in 1997. She completed her postdoctoral training at the Cedars-Sinai Medical Center, Los Angels, and at the University of California, Los Angeles. In 2003 she moved to the University of California, San Diego. She currently holds a faculty level position in the Department of Anesthesiology, and Cardiac and Neuro Protection Laboratories, at the University of California, San Diego. Her research investigates molecular pathways leading to heart failure, with the ultimate goal to design novel approaches for the prevention and treatment of cardiac dysfunction.
Cardiovascular disease is the number one killer in the United States. Statins reduce low-density lipoprotein cholesterol (LDL-C) and decrease cardiovascular events. About 43 million Americans currently take statins, and the 2013 cardiovascular disease prevention guidelines will increase statin drug prescriptions for approximately 13 million more Americans. The FDA warns that statins may induce skeletal muscle side effects, cognitive changes and increase fasting glucose levels. Observational studies show that the incidence of skeletal muscle side effects has been underestimated in randomized trials and may affect up to 20% of patients taking statins. Some individuals are more susceptible to statin myopathy because of female gender, advanced age, drug-drug interactions or underlying genetic polymorphisms. Currently five lipophilic and two hydrophilic statins are on the market. Statin effects on cardiac muscle are currently unknown. Healthy mice received either the lipophilic atorvastatin or the hydrophilic pravastatin daily for seven months and were compared to vehicle treated animals. Atorvastatin and pravastatin reduced LDL-C compared to vehicle. Long-term atorvastatin treatment altered the ultrastructure of cardiac muscle in healthy mice, but pravastatin did not. Only atorvastatin administration increased the mortality of mice prone to heart failure, and repressed mitochondrial genes by genome-wide expression profiling. In cultured cardiac myocytes atorvastatin treatment down-regulated survival pathways, decreased RhoA activation, and induced apoptosis. Personalized medicine in CVD prevention should; 1) focus on lifestyle changes, 2) add investigation and documentation for possible statin-induced adverse effects, and 3) determine a treatment regimen that does not impair the patients quality of life during healthy aging.
Lunch Break 13:10-14:10 @ Atrium
Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, China
Jing-Bin Huang, Medicine Doctor, now is an Associate Professor of Surgery, director of Department of Cardiothoracic surgery, The Affiliated Ruikang Hospital of Guangxi Traditional Chinese Medical College, member of Chinese Medical Doctor Association and China Association for cardio-thoracic surgery. He got his bachelor of medicine, master of medicine in surgery at Sun Yat-Sen University, Medicine Doctor's degree (M.D.) at Peking Union Medical College and Tsinghua University, China. Currently his researches focus on the basic and clinical studies of cardiothoracic surgery, especially on pulmonary arterial hypertension associated with congenital heart disease. His 13 papers have been published in journals indexed by SCI, and he is the author of 3 books published by NOVA, USA, and 1 book published by InTech, Europe.
Pulmonary hypertension (PH), and resulting right ventricular (RV) failure occur in many critical illnesses and may be associated with a worse prognosis. PH and RV failure may be difficult to manage: Principles include maintenance of appropriate RV preload, augmentation of RV function, and reduction of RV afterload by lowering pulmonary vascular resistance. Therefore, a detailed update on the management of PH and RV failure in adult critical care is provided. Clinical studies of intensive care management of pulmonary vascular dysfunction were identified, describing volume therapy, vasopressors, sympathetic inotropes, inodilators, levosimendan, pulmonary vasodilators, and mechanical devices. Advances in diagnosis and management have granted insights into the following pathophysiologic mechanisms of RV dysfunction: Impaired RV contractility, RV pressure overload, and RV volume overload. Emerging imaging modalities, such as cardiac MRI, and new therapeutic agents, such as pulmonary selective vasodilators, have expanded our options for evaluation and management, respectively. An improved understanding of pathophysiology and technologic progress provides us with new pathways in the diagnosis and hemodynamic support of these often critically ill patients.
Emil Alexov has completed his Ph.D in 1991 from Sofia University and postdoctoral studies from City College of New York and Columbia University. Currently he is professor at Department of Physics at Clemson University, SC, USA. He has published more than 110 papers in various journals and serving as an editorial board member of numerous journals
Human genome sequence differs among individuals and differences known as non-synonymous single nucleotide polymorphisms (nsSNPs) can be responsible for many human diseases or cause the natural differences among the individuals by affecting the structure, function, interactions and other properties of expressed proteins. From computational standpoint the mono-genetic diseases resulting from missense mutations which affect the wild type characteristics of a specific protein are of specific interest. Using various cases of disorders, it is demonstrated that almost always the mutations do not directly affect the functional properties of the corresponding protein, but rather indirectly alter its wild type characteristics. In addition, it is indicated that disease-causing mutations do not necessary destabilize protein stability or protein-protein interactions, but can be stabilizing and still be harmful. Overall, a detailed computational analysis combined with an analysis of the corresponding biological function is needed to make reasonable prediction of the disease association of missense mutations. Once the molecular mechanism of disease is revealed, the disease-causing effect can be targeted with small molecule binding.
National Taiwan University, Taiwan
Hsiu-Ni Kung completed her Ph.D. at National Taiwan University in 2008 and was a postdoctoral fellow at Duke University in 2011. She joined as a faculty member in anatomy and cell biology in National Taiwan University since 2011.
Breast cancer heterogeneity occurs as a consequence of the dysregulation of oncogenic and non-genetic factors, including tumor microenvironmental stresses. Although the non-genetic factors are important, it is not clear how to integrate these factors within the genetic framework of cancer as the next step in understanding tumor heterogeneity.
In the first part, series of gene expression signatures were developed to exam the influences of microenvironmental stresses. Through the integrative pathway analysis of microenvironmental stresses and oncogenic events in breast tumors, we identify many known and novel correlations. We further determine two subgroups,which have features consistent with basal and luminal breast tumors including patterns of oncogenic signaling pathways and cellular mechanisms that regulate the hypoxia response,in HER2 breast cancers.
Although significant variations in the metabolic profiles exist among different cells, little is understood in genetic regulations of cell type specific metabolism and nutrient requirements. While cancer cells depend on exogenous glutamine for survival, the mechanisms of glutamine dependence, the response and resistance of glutamine targeting strategies among cancers are largely unknown. In the second part, we find a systematic variation in the glutamine dependence among breast tumor subtypes: basal- but not luminal type breast cells are more glutamine-dependent and may be susceptible to glutamine-targeting therapeutics. The ability of glutamine synthetase to predict patterns of glutamine metabolism and dependency among tumors is also crucial in the rational design and application of glutamine targeted therapies.
Taking two studies together, results demonstrate the potential of genetic and non-genetic factors to investigate the basis of tumor heterogeneity.
Cristina Patassini obtained her second degree in Health Biology in 2011, after a first degree in Medical Biotechnology in 2005, and a Master degree in Molecular Pathology and Biotechnology in 2006. She is the Executive Director of the Genetyx Lab in Marostica (VI). She has published 10 papers in reputed journals and she gave several lectures in National and International Congresses.
Development of obesity has been associated with inadequate dietary and sedentary habits, as well as a genetic predisposition. Single Nucleotide Polymorphisms (SNPs) in several genes encoding for proteins involved in hypothalamic control of food intake, energy balance and lipid metabolism have been associated with common (non-Mendelian) obesity. A panel of SNPs that allows analyzing 5 genes through real-time PCR was developed. FTO gene codes a protein expressed in the hypothalamus which plays an important role in appetite regulation and food intake. LEPR gene codes the leptin receptor, an adipocyte-specific hormone that regulates the amount of adipose tissue by a direct effect on the hypothalamus. DNMT3B gene codes a protein that modulates the status of DNA methylation, important for the regulation of food intake. Homozygous mutated subjects for the 3 SNPs above mentioned have a 6-8 times increased risk to develop obesity. THRA gene codes thyroid hormone receptor, that regulates energy metabolism, glucose and lipid metabolism, food intake and oxidation of fatty acids. Carriers of mutated variant that consume high amounts of saturated fats have a 3-fold risk of developing obesity. ADRB2 gene codes the beta2-adrenergic receptor, involved in lipolysis and obesity development. Carriers of mutated variant are less able to burn fat stores after exercise. The analysis of these genes allows obtaining useful information for the proper setting of a diet and a customized physical activity.
Max Planck Institute for Heart and Lung Research, Germany
Guillermo Barreto is leader of the LOEWE Research Group Lung Cancer Epigenetic at the MPI for Heart and Lung Research and Faculty Member of the University of Giessen Lung Center (UGLC) and the Excellence Cluster Cardio-Pulmonary System (ECCPS). His research activities are centered on the epigenetic mechanisms that regulate the determination of the respiratory cell fate in the primitive foregut, leading to the formation of the lung bud and later on to the cellular diversity generated in the developing lung, with particular focus on those mechanisms that are recapitulated in several lung diseases.
Several genes that are relevant during embryonic lung development share a similar gene structure with two distinct promoters driving the expression of two different transcripts. Expression of both transcripts from the same gene is complementary and is differentially regulated during embryonic development, with one transcript been expressed during early stages of lung development (embryonic isoform) and the other transcript been expressed at later stages and in adult lung (adult isoform). Interestingly, the embryonic isoforms are enriched in lung tumors of mice as well as of human, making them good candidates for lung cancer diagnosis. In addition, forced expression of the embryonic isoforms in murine adult lung is sufficient to induce hyperplasia with characteristics of lung adenocarcinoma supporting their oncogenic potential. Moreover, we found that the complementary expression of both isoforms from the same gene is mediated by differential promoter usage that is regulated by mechanisms that involve changes in the chromatin structure as specific histone modifications and dynamic DNA methylation. In conclusion, we suggest that an embryonic specific phenotype is acquired during lung cancer progression and this can be used for early diagnosis of lung tumors. In addition, approaches to suppress embryonic specific isoforms can be exploited to develop therapeutic strategies against lung cancer.
Coffee Break 15:50-16:10 @ Atrium
University of Sydney, Australia
Associate Professor Mark Gorrell has a PhD from the Australian National University and conducted postdoctoral studies at the University of Melbourne and Johns Hopkins University School of Medicine. He heads a liver disease pathogenesis, dipeptidyl peptidases and diabetes research group in the Centenary Institute and the University of Sydney Medical School. He has authored 115 papers and patents, primarily on DPP4 and related proteases DPP8, DPP9 and fibroblast activation protein and on liver disease pathogenesis. His team uncovered mechanisms of protein binding and of enzyme activity in DPP4. He is treasurer of the International Proteolysis Society, sits on the Australian Gastroenterological Society research committee and is on four editorial boards.
Humans have more than 400 proteases, many of which have potential uses in medicine. The main advantages of exploiting proteases are that assays are rapid and cheap and a chemical compound can target a specific proteasefar less expensively than an antibody.The most successful example is inhibitors of DPP4 protease activity for type 2 diabetes (T2DM).T2DMfrequently associates with non-alcoholic fatty liver disease (NAFLD), which can progress toinflammation and fibrosis. Fibrosisis reversible but sometimesinstead progresses to liver failure or cancer. We are investigating the potential ofthesister protease of DPP4, fibroblast activation protein (FAP),to become a biomarker and therapeutic target in T2DM and NAFLD as well as cancer.FAP expression byactivated fibroblastic cells is predominantly associated with pathological processes in tumors, arthritis and fibrosis.
We found that in a diet induced obesitymodel, both DPP4 knockout and FAP knockout mice resist liver damage and have improved glucose tolerance and less insulin resistance.We developed a novel specific sensitive quantitative assay for FAP enzyme activity. FAP was dramatically increased in tissue samples from cirrhotic liver and tumors. However, in assays of patients era, FAP levels rose above controls only in patients with severe liver fibrosis, as assessed by biopsy or elastography score. These associations may reflect the shedding of FAP from fibroblastic cells in chronic liver injury and the large mass of the liver. Low serum FAP was strongly associated with normal elastography scores such that adding FAP to the NAFLD Fibrosis Score algorithm correctly predicted normal elastography score in two-thirds of T2DMpatients, thereby correctly diagnosing as non-fibrotic about half of the patients who now receive an uncertain diagnosis and are then shown to be non-fibrotic by elastography.In contrast, serum DPP4, which is probably mainly hepatocyte derived, was lower in the T2DM patients and associated with hepatocyte steatosis rather than with fibrosis.
This work may show a new potential clinical application for measuring circulatingFAP as a diagnostic and prognostic tool in managing T2DM patients who are at risk of liver fibrosis. FAP assay might also be used to monitor liver fibrosis patients following therapeutic intervention.The association of FAP with fibrosis supports the concept thattargeting FAP or FAP-expressing cellsmight be a successful therapeutic in combatting diabetes and alleviating chronic liver diseases.
Conclusions:FAP has an important role in glucose and lipid metabolism and in fibrosis. Adding a FAP measurement to the existing clinical NFS algorithm appears to greatly increase the accuracy of this diagnostic.
Synlab genetics s.r.o, Czech Republic
Tereza Jancuskova is a Ph.D. student at the 3rd Medical Faculty of the Charles University in Prague, Czech Republic. Her research is focused on the identification of specific markers for minimal residual disease assessment in acute leukemia patients. She graduated from Charles University, Faculty of Science in 2008, specializing in genetics, molecular biology and virology.
Acute leukemias (AL) comprise a heterogeneous group of hematologic malignancies, and individual patient responses to treatment can be difficult to predict. Monitoring of minimal residual disease (MRD) is thus very important and holds great potential for improving treatment strategies. Common MRD targets include recurrent cytogenetic abnormalities, gene rearrangements and gene mutations. Unfortunately, these well-characterized targets are not available for all AL patients. Identification of new specific molecular markers of leukemic blasts is therefore required.
Our aim was to develop a flexible strategy for mapping of cytogenetically identified unique clone-specific abnormalities down to the single nucleotide level and, based on the sequence, design a specific real-time PCR assay for MRD assessment in AL patients without any previously described MRD marker.
Using a combination of cytogenetic (chromosome banding), molecular cytogenetic (mFISH, mBAND) and molecular biological (next-generation sequencing, long-range PCR, Sanger sequencing) techniques we are able to characterize the DNA sequence flanking unique chromosomal breakpoints. For precise identification of these breakpoints we use fine-needle micro dissection of derivative chromosomes followed by next-generation sequencing of the dissected material. Finally, we design a specific real-time PCR assay for monitoring MRD level during the patients treatment.
Our work clearly shows that walking from chromosomal level to the nucleotide level is feasible and readily applicable for eligible AL patients. The described approach is accurate for standard clinical practice and could be used as a tool for personalized tailor-made medicine.
University of Genova, Italy
Evgeniya Peshkova is presently an Assistant Professor of Biochemistry and Biophysics at the University of Genova Medical School. After taking her Doctoral degree in Chemistry at Moscow State Lomonosov University in 1998, and the PhD in Biophysics at University of Genova in 2003, was Scientific Director of Fondazione ELBA (Electronic Biotechnology Advanced) and Principle Investigator of a big FIRB research grant on Organic Nanotechnology. Later she acquired the scientific responsibility of the laboratory of Nanobiocrystallography at the Nanoworld Institute, University of Genova. In 2007 she worked as a Visiting Scientist at the European Synchrotron Radiation Facility (ESRF) in Grenoble in Macromolecular Crystallography and Soft Condensed Matter, remaining up to now one of the PI of Radiation Damage BAG. She is author of more than 50 international scientific publications (ISI-SCI), 2 patents, several chapters to books and textbooks. Her main scientific interests are structural proteomics, functional nanoproteomics and nanocrystallography
Towards a new generation of Personalized Medicine an innovative self-assembling protein microarray, based on NAPPA and SNAP tag coupled to E. coli cell free expression system, is here introduced along with Matrix Assisted Laser Desorption Ionization Time-of-Flight (MALDI-TOF). This aims indeed to develop in clininical setting a standardized procedure to identify the leading protein-protein interaction in a given pathology towards the enhancement of both diagnosis and therapy. In the process we employ Protein synthesis Using Recombinant Elements (PURE) system which due to its high complexity has required ad hoc bioinformatic tools. The PURE system represents a step towards a totally defined in vitro transcription/translation system, thus avoiding the black box nature of the cell extract. The immediate advantage is the E. coli IVTT that respect to the RRL or human lysate proved an advantage for the MS analysis of the results. The presence of background molecules, in fact, represents the main obstacle to the MS data interpretation. For this latter reason SpADS: An R Script for Mass Spectrometry Data Preprocessing before Data Mining an ad hoc script was implemented. SpADS provides useful preprocessing functions such binning, peak extractions, spectra background subtraction and dataset managing. Moreover, in its final version, it is able to perform peak recognition and amplitude independent subtraction functions were implemented. The MS samples are obtained from SNAP-NAPPA spots printed on gold coated glass slides in higher density, in order to obtain an amount of protein appropriate for MS analysis. The spots of 300 microns were printed in 12 boxes, each box with 100 identical spots. The sample genes immobilized as test cases were p53_Human (Cellular tumor antigen p53); CDK2_Human (Cyclin-dependent kinase), 2;Src_Human-SH2 (the SH2 domain of Proto-oncogene tyrosine-protein kinase), PTPN11 (Human-SH2, the SH2 domain of Tyrosine-protein phosphatase non-receptor type 11). This represents a proof of principles with optimization in progress.
King Saud University, Saudi Arabia
Background: Autistic spectrum disorders (ASD) are characterized by three core behavioral domains: social deficits, impaired
language and communication, and repetitive behaviors. Glutamate excitotoxicity has been found in various preclinical models
of Autism Spectrum Disorders (ASD). On the other hand, inefficient detoxification system leads to oxidative stress, gut
dysbiosis, and immune dysfunction has been also accepted as etiological mechanism of autism. In a trial to understand the
relationship between glutamate excitotoxicity and impaired detoxification mechanisms, selected parameters representing both
pathways will be measured in autistic patients compared to age and sex matching control participants.
Methods: 20 male autistic children aged 3-15 years and 20 age and gender matching healthy children as control group
were included in this study. Levels of reduced glutathione (GSH), glutathione status (GSH/GSSG), glutathione reductase
(GR), glutathione- s-transferase (GST), thioredoxin (Trx), thioredoxin reductase (TrxR) and peroxidoxins (Prxs I and III),
glutamate, glutamine, glutamate/glutamine ratio glutamate dehydrogenase (GDH) in plasma and mercury in red blood cells
were determined in both groups.
Results: Glutamate excitotoxicity was ascertained in autistic patients. While glutamate was significantly elevated, glutamine
was remarkably lower, resulting in a much lower glutamate/glutamine ratio in autistic patients compared to control. Reduced
glutathione, GSH/GSSG and activity levels of GST were significantly lower, GR shows non-significant differences, while, Trx,
TrxR and both Prx I and III recorded a remarkably higher values in autistics compared to control subjects.
Conclusion: Multiple regression analysis show an association between glutamate excitotoxicity and GSH/GSSG, thioredoxin1,
peroxidoxin1, thioredoxin reductase as oxidative stress related parameters. As the consensus among physicians who treat
autism with a biomedical approach is that those on the spectrum are burdened with oxidative stress and excitotoxicity thus the
glutamate system could be an excellent target for therapeutics.
Ain Shams University, Egypt
Abeer Ahmed Kadry El-Zoheiry is a Ass. Professor of physical medicine, rheumatology and rehabilitation, Ain shams university hospitals. She did her M.D. degree in physical medicine, rheumatology and rehabilitation, in Nov 2007 in Ain shams university. She has Unrestricted license to practice medicine in Egypt 138689, active member of the Egyptian society of Rheumatology and Rehabilitation, Egyptian society of joint disorders and arthritis, American Association of Neuromuscular & Electrodiagnostic medicine( AANEM).
Many different factors contribute to the onset and progression of OA. The bone morphogenetic proteins (BMPs), that are subsets of the (TGF- B) superfamily, stimulate production of extracellular matrix components by chondrocytes and have the ability to counteract catabolic cytokines like interleukin 1 (IL-1).
Aim of the work:
The aim of this study was to investigate the role of plasma BMP-2 in primary knee osteoarthritis and its relation to disease severity.
The study included 30 patients with primary knee O.A and ten apparently healthy matched individuals as a control group. Plasma levels of BMP-2, radiological severity of the disease, pain intensity as well as, assessment of functional status using the Western Ontario and Mc Master University Osteoarthritis Index (WOMAC) were done.
Plasma levels of BMP-2 were significantly higher in patients than in control group.
Patients with palpable osteophytes have the highest BMP-2 levels.
A strong positive correlation was found between plasma levels of BMP-2 and each of: radiological severity, disease duration and WOMAC score.
In conclusion :BMP-2 levels correlate with radiographic severity of O.A. which make such biomarker measurement may not only act as a substitute marker for the disease, but also has the potential to contribute to the fundamental processes underlying the pathogenesis of O.A.
Thomas Jefferson University, USA
Emmanuel C. Besa completed his M.D. from the University of the Philippines, College of Medicine, finished his postdoctoral studies from the University of Pennsylvania at Presbyterian Medical Center in Hematology and Oncology. He joined the faculty of the Medical College of Pennsylvania and promoted to full professor in 1994 with tenure in 1995. He moved to Thomas Jefferson University as Professor of Medicine and Medical Oncology, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation program. He was in the Educational Committee of the American Society of Hematology and awarded the MDS Center of Excellence by the MDS Foundation. He recently retired from his academic position in June 30, 2013 but continues to conduct CME lectures and is the Hematology Editor of Medscape Emedicine.
Themyelodysplastic syndrome (MDS) evolves into acute myelogenous leukemia (AML), it is generally believed that these patients if they survive long enough will eventually transform and in the past named as a preleukemic syndrome. Basic knowledge regarding the molecular mechanism of the evolution of MDS into AML, development of epigenetic and immunomodulatory agents in its management may give us opportunities of better management of the disease as well as opportunities to prevention of its evolution to a fatal condition given the right circumstances. Continued improvement in classification and prognostication by inclusion of new data including cytogenetics and molecular markers, we are now able to tailor specific treatment for subgroups of patients leading to a more specific and personal approach to their management. Patients with del5q-cytogeneticsis responsive to a specific immunomodulatory agent called lenalidomide.MDS which for the past decade had no standard therapy has now shown a doubling overall survival with azacytidine. Meanwhile in AML, a completely different approach such as using a retinoid and arsenic trioxide can now cure some patients with acute promyelocytic leukemia (APL) with the translocation 15;17and those with core binding factor chromosomes such as inverted 16 as a good prognostic marker treated specifically with standard induction and high dose cytosine arabinoside consolidation. The intermediate group in AML with normal cytogenetics is a mixture of good and bad prognostic patients and with the help of molecular markers such as FLT3/ITD and NPM markers. We an also identify up front patients who will not respond to our available therapies and should be prepared early for possible hematopoietic stem cell transplantation.