Day 1 :
Keynote Forum
Henry M. Sobell
University of Rochester, USA
Keynote: The centers of premeltons signal the beginning and ends of genes
Time : 10:00-10:45
Biography:
Henry M Sobell completed his studies at Brooklyn Technical High School (1948-1952), Columbia College (1952-1956), and the University of Virginia School of Medicine (1956-1960). Instead of practicing clinical medicine, he then went to the Massachusetts Institute of Technology (MIT) to join Professor Alexander Rich in the Department of Biology (1960-1965), where, he had a Helen Hay Whitney Postdoctoral Fellowship where he learned the technique of single crystal X-ray analysis. He then joined the Chemistry Department at the University of Rochester, having been subsequently jointly appointed to both the Chemistry and Molecular Biophysics departments (the latter at the University of Rochester School of Medicine and Dentistry), becoming a full tenured Professor in both departments (1965-1993). He is now retired and living in the Adirondacks in New York, USA.
Abstract:
Premeltons are examples of emergent structures (i.e., structural solitons) that arise spontaneously in DNA due to the presence of nonlinear excitations in its structure. They are of two kinds: B-B (or A-A). Premeltons form at specific DNA-regions to nucleate site-specific DNA melting. These are stationary and, being globally non-topological, undergo breather motions that allow drugs and dyes to intercalate into DNA. B-A (or A-B) premeltons, on the other hand, are mobile, and being globally topological, act as phase-boundaries transforming B- into A- DNA during the structural phase-transition. They are not expected to undergo breather-motions. A key feature of both types of premeltons is the presence of an intermediate structural-form in their central regions (proposed as being a transition-state intermediate in DNA-melting and in the B- to A- transition), which differs from either A- or B- DNA. The so called beta-DNA, this is both metastable and hyperflexible–and contains an alternating sugar-puckering pattern along the polymer-backbone combined with the partial-un-stacking (in its lower energy-forms) of every other base-pair. Beta-DNA is connected to either B- or to A- DNA on either side by boundaries possessing a gradation of nonlinear structural-change, these being called the kink and the anti-kink regions. The presence of premeltons in DNA leads to a unifying theory to understand much of DNA physical-chemistry and molecular-biology. In particular, premeltons are predicted to define the 5’ and 3’ ends of genes in naked-DNA and DNA in active-chromatin, this is having important implications for understanding physical aspects of the initiation, elongation and termination of RNA-synthesis during transcription. For these and other reasons, the model will be of broader interest to the general audience working in these areas. The model explains a wide variety of data, and carries within it a number of experimental predictions –all readily testable – as will be described in my talk.
Recent Publications
1. Sobell H M (2016) Premeltons in DNA. Journal of Structural and Functional Genomics 17:17-31.
2. Sobell H M (2009) Premeltons in DNA. A unifying polymer-physics concept to understand DNA physical-chemistry and molecular-biology. Explanatory publications, Lake Luzerne, NY, ISBN 978-0-615-33828-6.
3. Sobell HM (2013) Organization of DNA in Chromatin. Rather than bending uniformly along its length, nucleosomal DNA is proposed to consist of multiple segments of B- and A- DNA held together by kinks when forming its left-handed toroidal superhelical structure. Explanatory publications, Lake Luzerne, NY, ISBN 978-0-692-01974-0.
Keynote Forum
Hiltrud Brauch
Dr. Margarete Fischer Bosch-Institute of Clinical Pharmacology, Germany
Keynote: Tamoxifen pharmacogenomics of breast cancer: the controversy and way forward
Time : 10:45-11:30
Biography:
Hiltrud Brauch has completed herPhDat the University of Heidelberg, Germany, and postdoctoral studies as a Fogarty International Visiting Fellowat the National Institutes of Health (NIH), National Cancer Institute (NCI), Frederick, Maryland, USA. She is the deputy director of Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology in Stuttgart, a non-profit private research institute of the Robert Bosch Foundation. She has published more than 250 papers in reputed journals and has been serving as an editorial board member of Pharmacogenetics and Genomics as well as Pharmacogenomics and Personalized Medicine.
Abstract:
Breast cancer is a global health burden with 1.7 million newly diagnosed patients and more than half a million patients dying from the disease each year. The large majority (75%) of breast cancers express the estrogen receptor (ER) making them amenable to targeted endocrine therapy. Standard of care is the blockade of estrogen signaling via long-term estrogen deprivation. Two proven treatment options are available: tamoxifen, a selective ER modulator which blocks 17ß-estradiol binding to ER to stop tumor growth, and aromatase inhibitors (AI), which block the aromatase enzyme that prevents the conversion of androgens to estrogens. Despite the well-established effectiveness of endocrine treatments every other patient displays de novo or acquired resistance which ultimately leads to disease progression and death. Based on its well-known metabolism and drug action, tamoxifen has been in the spotlight of pharmacogenomics investigations within the past decade. The goal is to identify biomarkers that can predict tamoxifen outcome and facilitate personalized treatment schemes in order to avoid drug failure. Tamoxifen failure has been in part attributed to a lack of bio-activation towards its active metabolite, endoxifen. Pharmacological and pharmacogenetics evidence strongly support the view that in vivo endoxifen formation is mainly mediated from the primary metabolite N-desmethyl-tamoxifen by the polymorphic cytochrome P450 (CYP) 2D6 enzyme. Distinct genetically determined functional CYP2D6 variants are present in the general population and inter-individual differences in enzyme activities can be grouped into the four CYP2D6 phenotypes ultra-rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. We and others provided strong evidence that tamoxifen treated EM breast cancer patients have high levels of endoxifen and that they are likely to benefit from the treatment. In contrast, PM patients have low endoxifen levels and a significant risk to relapse. Thus, CYP2D6 polymorphism and plasma endoxifen levels have a great potential as suitable tamoxifen outcome predictors. However, due to controversies from negative studies, the translation into the clinic has been hampered. In my talk, I will discuss the current status of the debate and emphasize the need for uniform study design, technology and statistical procedures in the conduct of pharmacogenomics analyses in order to avoid shortcomings and delay in clinical implementation. Moreover, I will present a way forward towards the clarification of the CYP2D6 tamoxifen pharmacogenomic issue via a novel strategy for the optimization of endoxifen plasma levels in CYP2D6 compromised breast cancer patients currently investigated in our ongoing phase II clinical trial.
- Cancer Genomics| Functional Genomics| Next Generation Sequencing |Biomarkers| Pharmacogenomics | Proteomics| Clinical Genomics| Human Genomics | Genome Engineering
Location:
Session Introduction
Jatinder Lamba
University of Florida, USA
Title: Integrated genetic and epigenetic analysis identifies biomarkers of prognostic significance in pediatric acute myeloid leukemia
Time : 11:45-12:15
Biography:
Jatinder Lamba is an Associate Professor in Department of Pharmacotherapy and Translational Research. She completed her PhD in the field of Pharmacogenomics at Postgraduate Institute of Medical Education and Research in Chandigarh, India and Post-doctoral training at St. Jude Children’s Research Hospital, Memphis. Her research has been funded from NIH/NCI since 2008 and focuses on “Identification, characterization and clinical validation of genomic/epigenomic markers predictive of therapeutic outcome in cancer patients specifically Acute Myeloid Leukemia. Her research spans from preclinical basic research comprising the discovery phase to translational/clinical phase in patient populations from multi-institute clinical trials.
Abstract:
Epigenetic mechanisms such as DNA methylation are deregulated in cancer. Aberrant DNA methylation is reported to have clinical significance in acute myeloid leukemia (AML) in adults; however, its impact on pediatric AML is relatively unknown. Our research focuses on integrated genome-wide DNA methylation and gene expression analyses to identify the epigenetic signatures that are associated with gene expression and prognosis in pediatric patients with AML. We developed and applied a novel method that integrates canonical correlation analysis with projection onto the most interesting statistical evidence (CC-PROMISE) to identify genes with methylation and expression values that exhibit a biologically concordant and clinically meaningful pattern of associations’ treatment outcome in pediatric AML patients. Our results identified several genes of significant importance in cell growth, proliferation, apoptosis as well as AML biology as top candidates. Of special interest was the gene DNA methyl-transferase gene DNMT3B, which has been previously implicated in adult AML, significant methylation-expression correlation and was strongly predictive of poor outcome in pediatric AML. Furthermore, consistent with its biological function, greater DNMT3B expression associated with greater genome-wide methylation burden. Collectively, these results indicate that deregulated methylation of the DNMT3B locus may modulate DNMT3B expression which subsequently alters the methylome, transcriptome, disease progression, and clinical prognosis of childhood AML. Overall understanding epigenetic and transcriptomic landscape of childhood AML can help in better designing the incorporation of epigenetic modifier drugs to standard chemotherapy regimens as well as help in identifying patients that would likely be better candidates to receive such a combination treatment.
Yong Yu
Wellcome Trust Sanger Institute, United Kingdom
Title: Single cell RNA sequencing analysis of bone marrow innate lymphoid progenitors
Time : 12:15-12:45
Biography:
Yong Yu did his PhD training with Dr Pentao Liu, Wellcome Trust Sanger Institute where he focused on the role of Bcl11a in early lymphocyte cell development (2010-2012). Subsequently, he was recruited by Dr Pentao Liu as a Postdoctoral Research Fellow to continue to explore the molecular and cellular mechanisms of hematopoiesis. Recently, he transcriptomically profiled hundreds of innate lymphoid progenitors at the single cell level and discovered PD-1hi marks ILC progenitors and effectors. This work was published in Nature.
Abstract:
Innate lymphoid cells (ILCs) are a new family of immune cells and play fundamental roles in the development of immune system and protect host from pathogens infection but ILC progenitor development in the bone marrow was not clear. We used single cell RNA sequencing to dissect BM ILC progenitors and identified PD-1 marked a committed ILC progenitor. We further found that activated ILCs in particular ILC2s expressed high levels of PD-1. Indeed, depleting PD-1-high ILC2s substantially reduced type 2 cytokines in immune responses, and inhibited acute lung inflammation induced by papain. Our data therefore demonstrate the value of single cell RNA sequencing in dissecting development and present a new perspective for targeting PD-1 in immunotherapies.
Rozana Oliveira Goncalves
Gonçalo Moniz Research Center, Brazil
Title: Pharmacogenetics: advanced drug administration
Time : 12:45-13:15
Biography:
Rozana Oliveira Goncalves is currently a Biology Teacher in the city of Salvador in Brazil. In 1997, she completed a course in Biological Sciences at Catholic University of Salvador. In 2001, she began her career in research as an intern in the Laboratory of Human Genetics and at Maternidade Climério de Oliveira. In 2006, she started her Master's degree in Biotechnology and Investigative Medicine at Gonçalo Muniz Research Center/Fiocruz. She has experience in Genetics, working mainly in the following subjects: “Occupational exposure, bio-indicators, exchanges between chromatid sisters, and recurrent abortion”.
Abstract:
Adverse drug reactions are influenced by multiple factors, including health, environmental influences and genetic characteristics. Pharmacogenetics studies how inter-individual genetic variations may affect drug responses. It is the technology that researches the influence of genetic variation on drug response in patients by correlating gene expression or polymorphisms with a drug's efficacy or toxicity. It is well known that Adverse Drug Reactions (ADRs) are a relevant health matter, being the fourth cause of demise in hospitalized patients. Important drug agencies have demonstrated a great interest in the early detection of ADRs due to their high incidence and increasing health care costs. Pharmacogenetics aims to develop the means to optimize drug therapy with respect to the patients’ genotype, to ensure maximum efficacy with minimal adverse effects. Pharmacogenetics is a research field still in development and therapy individualization remain a challenge for the future. It is important to appreciate that many genes may influence the response to drugs, and the genetic polymorphisms present ethnic variation, which complicates the identification of genetic variations which are most relevant. Clinical validation of genetic markers of the greatest clinical relevance is perhaps one of the major limiting factors in the use of genetic information when making treatment decisions.
Anat Achiron
Tel-Aviv University Sackler School of Medicine, Israel
Title: From translational research to a new molecule for the treatment of multiple sclerosis
Time : 14:00-14:30
Biography:
Anat Achiron is a full Professor of Neurology at Tel-Aviv University, Sackler School of Medicine and Director of the Multiple Sclerosis Center at Sheba Medical Center, Israel. Her research interests are within the fields of Gene Expression and Neuro-immunology in relation to multiple sclerosis. She has extensively studied biological markers in the very early stages of the disease and is involved in studies evaluating disease related outcome variables and prediction of disease activity and treatment response. She has published over 200 publications in the scientific literature and received numerous grants and scientific awards.
Abstract:
Applying high throughput gene expression microarrays, we identified that suppression of RNA polymerase 1 (POL1) pathway is associated with benign course of multiple sclerosis (MS). This finding supported the rationale for direct targeting of POL1 transcription machinery as an innovative strategy to suppress MS. Benign multiple sclerosis (BMS) occurs in about 15% of patients with relapsing-remitting MS (RRMS) that over time do not develop significant neurological disability. Aim of this study is to evaluate the biological mechanisms associated with and analyzed by Partek and pathway reconstruction performed by Ingenuity software the most informative genes. BMS signature was enriched by genes related to POL1 transcription that result in activation of the apoptotic cell death machinery. Verification of POL1 pathway key genes RRN3, POLR1D, and LRPPRC was confirmed by qRT-PCR, and RRN3 silencing resulted in significant increase in the apoptosis level of peripheral blood mononuclear cells sub-populations in RRMS patients. To target POL1 transcription machinery as a new strategy for suppression of MS disease activity, we developed and synthetized an oral POL1 inhibiting compound RAM-589.555, that selectively suppressed ribosomal biogenesis of activated immunocompetent cells. RAM-589.555 demonstrated high permeability, specificity to POL1 pathway, ability to induce apoptosis and to inhibit proliferation and viability of activated lymphocytes both in vitro and in vivo. Moreover, oral administration of RAM-589.555 blocked ribosomal RNA transcription and significantly suppressed and ameliorated experimental autoimmune encephalomyelitis the animal model of MS. Our findings demonstrate the application of translational research to target a new molecule for the treatment of MS.
Gurevich Michael
Multiple Sclerosis Center, Sheba Medical Center, Israel
Title: Optimizing multiple sclerosis diagnosis using gene expression and genomic association data
Time : 14:30-15:00
Biography:
Gurevich Michael is the Head of the Neuro-genomics Laboratory at Sheba Multiple Sclerosis Center, Israel. His research primarily focuses on “The study of translational medicine and functional genomics in neurological diseases and multiple sclerosis”. He has gained extensive knowledge and experience working with DNA microarray technology, discovering multiple sclerosis related molecular disease pathogenesis and finding biomarkers that may assist in disease diagnosis, monitoring and prognosis of clinical outcome.
Abstract:
The diagnosis of multiple sclerosis (MS) is based on the neurological symptomatology in combination with the presence of central nervous system lesions disseminated in time and space. However, the clinical, imaging and/or laboratory findings of patients with MS may mimic a wide array of other vascular, inflammatory and demyelinating diseases, hereby defined as NonMS. This overlap may pose a significant diagnostic challenge especially in the process of diagnosis at the early disease stage. We utilized findings of large-scale Genome Wide Association Studies (GWAS) to develop a blood gene expression based classification tool to assist in the diagnosis during the first demyelinating event suggestive of MS. We merged knowledge of 110 MS susceptibility genes gained from MS GWAS studies together with our experimental results of differential blood gene expression profiling between 80 MS patients and 31 NonMS patients. Multiple classification algorithms were applied to this cohort to construct a diagnostic classifier that correctly distinguished between MS and NonMS patients. The overall accuracy of the constructed 42-gene classifier was tested on an independent patients population consisting of diagnostically challenging cases including NonMS patients with positive MRI findings and achieved a correct classification rate of 76.0±3.5%. The presented diagnostic classification tool complements the existing diagnostic McDonald criteria by assisting in the accurate exclusion of other neurological diseases at presentation of the first demyelinating event suggestive of MS.
Hanadi Al-Hashash
Kuwait Institute for Scientific Research, Kuwait
Title: Characterizing TYLCV in cucumber through the application of molecular techniques
Time : 15:00-15:30
Biography:
Hanadi K Al-Hashash completed her Graduation at Kuwait University. She completed her BSc in Microbiology (major) and Biochemistry (minor), then joined Kuwait Institute for Scientific Research (KISR) since May, 2001 till present. Since then, she worked as a task Leader in several project within Biotechnology program. She leads one general research activity (FB067G). She has an excellent experience in “Microbial isolation and identification using conventional as well as molecular techniques, DNA, RNA, and protein extraction, using restriction enzymes, and using ELISA”.
Abstract:
Cucumber is one of the most important vegetable crops in Kuwait, but unfortunately dramatic losses were recorded during the growing season. The majority of these losses are caused by viral infections. Mixed viral infections were reported in cucumber and the main one which was Tomato yellow leaf curl virus (TYLCV). Molecular study was carried on to certify and diagnose the viral infections on cucumber and the study started with characterizing TYLCV. During the study, 50 samples of cucumber leaves were collected, and the symptoms resulting from viral diseases were recorded and documented. DNA extraction and polymerase chain reaction (PCR) tests were performed on the collected samples. PCR tests revealed that 40 out of the 50 samples were positive for the presence of TYLCV. TYLCV was characterized and reported to be infecting cucumber crops which was only reported in tomato crops, which revealed the second report of TYLCV on cucumber in the world.