Daily Pocket Calendar
Plenary Opening Lecture
Genetic Analysis of Innate Immune Sensing
Exhibit Hall A
Monday, March 11, 8:00 AM–9:00 AM
Lecturer: Dr. Bruce A. Beutler, University of Texas Southwestern Medical Center, Dallas, TX.
Microbes were known to be the causative agents of infectious diseases since the mid-nineteenth century, and infections were known since antiquity for their inflammatory character. However, the molecular interactions through which microbes were recognized, and through which they triggered an inflammatory response on the part of the host, remained unknown until much more recently. A genetic approach was required to elucidate them. Applying a positional cloning approach to mice that were refractory to lipopolysaccharide (LPS), we identified the LPS receptor, and with it, a family of receptors responsible for sensing diverse molecules of microbial origin. These, the Toll-like receptors, signal by way of a system of adaptors, protein kinases, and transcription factors to induce the biosynthesis of hundreds of cytokines that orchestrate inflammation. Subsequently RIG-I-like helicases, NOD-like receptors, and C-type lectin receptors also were found to respond to infection. A number of common inflammatory diseases appear to depend upon these molecular pathways, which evolved to check the spread of micro-organisms prior to the advent of adaptive immunity.
Bruce Beutler is a Regental Professor and Director of the Center for the Genetics of Host Defense at University of Texas Southwestern Medical Center. He received his MD from the University of Chicago in 1981. As a postdoctoral associate at Rockefeller University (1983–1986), he isolated mouse tumor necrosis factor (TNF) and discovered its importance as a mediator of inflammation. Subsequently at UT Southwestern he analyzed mammalian responses to bacterial lipopolysaccharide. This work culminated in the discovery of Toll-like receptors as key sensors of the innate immune system, capable of detecting infection within minutes of the time the host is inoculated with microbes. In further studies, Beutler has used a forward genetic strategy to elucidate many aspects of mammalian immunity. He received numerous awards for his work, among them the Balzan Prize (2007), the Albany Medical Center Prize (2009), the Shaw Prize (2011), and election to the US National Academy of Sciences (2008), the Institute of Medicine (2008), and EMBO. In 2011, he shared the Nobel Prize in Physiology or Medicine for “discoveries concerning the activation of innate immunity.”
Keynote Medical Research Council (MRC) Lecture
Phenotyping the Patient Journey: Making Systems Medicine Work in the Real World
Grand Ballroom C1
Wednesday, March 13, 8:00 AM–9:00 AM
Lecturer: Prof. Jeremy K. Nicholson, Imperial College London, United Kingdom.
Systems biology tools can be applied at both individual and population levels to understand integrated biochemical function in relation to disease pathogenesis. Metabolic phenotyping offers an important window on systemic activity and both advanced spectroscopic approaches can be used to characterize disease processes and responses to therapy. There is now wide recognition that the extensive cross-talk and signalling between the host and the symbiotic gut microbiome links to both the responses to therapy and disease risk factors and indeed these also modulate drug toxicity. Such symbiotic supraorganismal interactions greatly increase the degrees of freedom of the metabolic system that poses significant challenges to fundamental notions on the nature of the human diseased state, the aetiopathogenesis of common diseases, and current systems modelling requirements for personalized medicine. We have developed scalable and translatable strategies for phenotyping the hospital patient journey using top-down systems biology tools that capitalize on the use of both metabolic modelling and pharmaco-metabonomics for diagnostic and prognostic biomarker generation to aid clinical decision making at point-of-care. Such diagnostics (including those for near real-time applications, as in surgery and critical care) can be extremely sensitive for the detection of diagnostic and prognostic biomarkers in a variety of conditions and are a powerful adjunct to conventional procedures for disease assessment that are required for future developments in precision medicine including understanding of the symbiotic influences on patient state. Many biomarkers also have deeper mechanistic significance and may also generate new therapeutic leads or metrics of efficacy for clinical trial deployment. Furthermore, the complex and subtle gene-environment interactions that generate disease risks in the general human population also express themselves in the metabolic phenotype, and, as such, the Metabolome Wide Association Study approach gives us a powerful new tool to generate disease risk biomarkers from epidemiological sample collections and for assessing the health of whole populations. Such population risk models and biomarkers can also feedback to individual patient healthcare models thus closing the personal and public healthcare modelling triangle.
Jeremy K. Nicholson has won many accolades and international prizes for his work, which spans three decades, and is the author of over 500 peer-reviewed scientific papers and many other articles/patents on the development and application of novel spectroscopic and systems
biology approaches to the investigation of disturbed metabolic processes in complex organisms. He was elected as a Fellow of the Academy of Medical Sciences in 2010 and currently holds honorary professorships at eight overseas universities and the Chinese Academy of Sciences, and is on the editorial board of eight international scientific journals. He is head of Department of Surgery and Cancer at Imperial College London. He is also a consultant for many pharmaceutical/healthcare companies in the United Kingdom, Europe, and the United States, and is a founder director of Metabometrix, an Imperial College spin-off company specializing in molecular phenotyping, clinical diagnostics, and toxicological screening via metabonomics and metabolomics.
Frontiers for Toxicology Session
Systems and Computational Biology As Foundations for Toxicology Research
Application of Systems Biology to Toxicology
Grand Ballroom C1
Tuesday, March 12, 2013, 9:00 AM–11:45 AM
Chairperson(s): Annie M. Jarabek, US EPA, Research Triangle Park, NC and James L. Stevens, Eli Lilly Corporation, Indianapolis, IN.
Sponsor: Scientific Program Committee
Systems and computational approaches are holistic methods to elucidate and understand the complex interactions among components of a biologic response network and are central to the comprehensive understanding of all biological processes. The field requires the integration of concepts from biology and physiology, computer science and applied mathematics, as well as physics and engineering. Toxicology is also a multidisciplinary science and application of systems and computational approaches can aid in unraveling the dynamic and complex nature of toxic responses. In light of the broad utility of systems biology approaches to toxicology and risk assessment, the goal of this session is to feature eminent scientists who have made seminal contributions and advances in systems and computational biology. The broad areas to be addressed include:
- general concepts of systems biology tools including network mapping and statistical challenges in assuring the validity of network analyses along with the newest tools and approaches for gaining insight into the regulation and function of complex systems;
- applications of systems biology approaches to studying fundamental biological responses such as cell signaling and kinase networks;
- perspectives on the application of systems networks to biomedical research and particularly for studying disease etiology and prevention;
- computational strategies that inform the prediction of pharmacologic and toxicologic responses including the prediction of adverse drug reactions; and,
- novel applications of machine learning and cell imaging to evaluate subcellular organization and function that inform hypothesis testing and translational details that may be useful in drug development.
Turning Protein Networks into Gene Ontologies. Trey Ideker, University of California, San Diego, La Jolla, CA.
Network2Canvas: Network Visualization on a Canvas with Enrichment Analysis. Avi Ma’ayan, Mt. Sinai School of Medicine, New York, NY.
Computational Approaches to Predicting Adverse Drug Reactions and Mitigating Off-Target Liabilities in Early-Stage Drug Discovery. Laszlo Urban, Novartis Institutes for Biomedical Research, Cambridge, MA.
Image-Derived Models of Subcellular Organization and Perturbation. Robert Murphy, Carnegie Mellon University, Pittsburgh, PA.
Distinguished Toxicology Scholar Award Lecture
Mitochondria: Crossroads of Cell Survival, Death, and
Grand Ballroom C2
Wednesday, March 13, 12:30 PM–1:30 PM
Lecturer: John J. Lemasters, Medical University of South Carolina, Charleston, SC
Increased Ca2+, formation of reactive oxygen and
nitrogen species, and oxidation of pyridine nucleotides
and glutathione promote a phenomenon
called the mitochondrial permeability transition
that in turn leads to mitochondrial depolarization
and swelling with outer membrane rupture. The
MPT initially promotes degradation of mitochondria
by autophagy (mitophagy). However, excess MPT induction causes
both ATP depletion-dependent necrotic cell death and caspase-dependent
apoptosis during reperfusion injury, hepatotoxicity and other
stresses. Cellular stresses also cause lysosomal alkalinization and/or
disintegration, leading to release of iron, which is taken into mitochondria
by the mitochondrial calcium uniporter to enhance hydroxyl
radical formation and MPT onset. Suppressed mitochondrial metabolism
with activation of glycolysis called the Warburg phenomenon is
a hallmark feature of transformed cancer cells. Free tubulin, which is
high in proliferating cells, blocks voltage dependent anion channels
(VDAC) in the mitochondrial outer membrane, which accounts for this
global mitochondrial suppression. Thus, both increases and decreases
of mitochondrial membrane permeability contribute to pathobiology.
Understanding these processes offers new strategies to rescue cells and
tissues from irreversible toxic and ischemic injury and to develop antiproliferative,
anti-Warburg cancer drugs.
Leading Edge in Basic Science Award Lecture
Human Organs on Chips As Replacements for Animal Testing
Grand Ballroom C2
Tuesday, March 12, 8:00 AM–8:50 AM
Lecturer: Donald E. Ingber, Harvard University, Boston, MA
In this presentation, Dr. Ingber will describe the work he and his colleagues have
been carrying out in the Biomimetic Microsystems
platform at the Wyss Institute for Biologically
Inspired Engineering at Harvard University. The
goal of this platform is to engineer “Organs-on-Chips”: microchips lined by living human cells
created with microfabrication techniques that recapitulate
organ-level functions as a way to replace animal testing for drug
development. He will review recent advances we have made in development
of multiple organ chips, including human lung, gut, and bone
marrow chips. Dr. Ingber will also describe the ongoing efforts to develop more
than 10 different organ chips, to integrate them into a “human body-ona-chip,” and to engineer an automated instrument for real-time analysis of
cellular responses to pharmaceutics, toxins, and other chemicals.
Meet the Directors
Grand Ballroom C1
Monday, March 11, 1:00 PM–3:30 PM
Chairperson(s): Lois D. Lehman-McKeeman, Bristol-Myers Squibb Company, Princeton, NJ, and Norbert E. Kaminski, Michigan State University, East Lansing, MI.
This important session is designed to provide an opportunity for the leaders of agencies to discuss the scientific directions and strategies along with relevant concepts and achievements of their organizations. An important issue for many SOT members is the funding opportunities that various agencies can provide for toxicology research. This year, our panel of experts will focus the scientific strategies and initiatives of their respective agencies and provide relevant information on the funding opportunities that are available to support basic and applied research. Representatives and leaders from the National Institute of Environmental Health Science (NIEHS), US Environmental Protection Agency (US EPA), National Institute for General Medical Sciences (NIGMS), and the National Institute for Occupational Safety and Health (NIOSH) will share their perspectives on these matters. The session is intended to be highly interactive, providing the audience with an opportunity to query the panel on issues concerning extramural funding, and other relevant topics. We hope you’ll join them as they deliver recent updates related to issues that have an impact on toxicology.
In the Near Foreseeable Future, Much of Toxicity Testing Can Be Replaced by Computational Approaches
Grand Ballroom C1
Monday, March 11, 4:45 PM–6:00 PM
Chairperson(s): Norbert E. Kaminski, Michigan State University, East Lansing, MI, and Aristidis Tsatsakis, University of Crete, Heraklion, Greece.
SOT Debater: Rory Conolly, US EPA, Research Triangle Park, NC.
EUROTOX Debater: George Loizou, Health and Safety Laboratory, Buxton, United Kingdom
Endorsed by: Society of Toxicology (SOT)
European Societies of Toxicology (EUROTOX)
Each year the SOT Annual Meeting includes a debate that continues a tradition that originated in the early 1990s in which leading toxicologists advocate opposing sides of an issue of great toxicological importance. This year, our debaters will address the proposition: In the Near Foreseeable Future, Much of Toxicity Testing Can Be Replaced by Computational Approaches.
During the past decade significant advances have been made in the development and application of mathematical modeling and computational simulation approaches to describing as well as predicting biological events. To a large extent, the application of computational approaches to biological systems has been driven by the exponential growth in knowledge of the underlying biological processes in living organisms. Similarly, major advances have also been made in the understanding of the molecular mechanisms by which xenobiotics modify biological processes, hence the vision and desire of applying computational approaches to toxicology. In fact, many benefits could be envisioned in applying in silico approaches to toxicity testing including a reduction in animal use, decreased costs of testing, and more rapid assessments of potential toxicity, to mention a few. In contrast, skepticism and serious concerns exist that the current understanding of the underlying biology and toxicology, especially at the organismal level, make replacement of toxicity testing by computational approaches a distant dream of the future. The debate will present some of the challenges investigators and regulators will face in the integration of computational approaches to toxicity testing.
Regardless of framework differences and personal convictions, each scientific delegate will present relevant evidence and compelling scientific arguments to persuade and appeal to the response of the audience in order to obtain the approval or refusal of the motion. In addition to being a featured session at the SOT Annual Meeting, this debate will again take place in Interlaken, Switzerland during the 2013 Eurotox Annual Congress, September 1–4.
Regional Interests Sessions
Toxicological Challenges in Food Production in Texas and the Gulf Coast
Room 217 C&D
Monday, March 11, 9:15 AM to 12:00 Noon
Chairperson(s): Erica D. Bruce, Baylor University, Waco, TX, and Laura M. Plunkett, Integrative Biostrategies LLC, Houston, TX.
Sponsor: Lone Star Regional Chapter
Endorsed by: Food Safety Specialty Section
With recent media attention on episodes of food contamination and
the impact of chemicals in the environment on the food supply (i.e.,
bacterial contamination of food, as well as the 2010 BP oil spill),
public awareness of food safety issues has grown. This symposium
will explore the topic of food safety as it relates to unique features of food production in Texas and the Gulf Coast. Texas is a major source of fresh fruit and vegetable production for both regional and countrywide consumption, while the Gulf Coast is a major source of fresh fish and seafood for many parts of the United States. Topics covered in the symposium will include recent legislative initiatives such as the Food Safety and Modernization Act of 2010, current regulatory oversight of food safety in the Gulf Coast region, and key public and/or worker health issues associated with food production in the region. The goal of the symposium is to describe the strengths and weaknesses of current regulations and practices to ensure a safe food supply as well as worker safety, and provide dialog for ways to address unique concerns related to food production in Texas and the Gulf Coast. Symposium speakers work in academia, for the United States government (US FDA), and an organization representing the interests of the public (Center for Science in the Public Interest), which will allow for discussion of the topics from a variety of perspectives.
- Multiagency Response to Seafood Safety Concerns following
the 2010 Deepwater Horizon Oil Spill. Robert Dickey, US FDA,
Dauphin Island, AL.
- Seafood Safety Challenges for the Texas Gulf Coast.
David Plunkett, Center for Science in the Public Interest,
- Occupational Hazards in Texas Food Production. Eva Shipp,
Texas A&M School of Rural Public Health, College Station, TX.
- Occupational Heat Stress in Agricultural Settings. Jeffrey Levine, The University of Texas Health Science Center at Tyler, Tyler, TX.
Assessment of Environmental, Dietary, and Biological Risk Factors Impacting Liver Cancer Incidence in Texas
Grand Ballroom C2
Wednesday, March 13, 1:30 PM to 4:15 PM
Chairperson(s): Erica D. Bruce, Baylor University, Waco, TX, and
Amelia Romoser, Texas A&M University, College Station, TX.
Sponsor: Lone Star Regional Chapter
Endorsed by: Food Safety Specialty Section
Hispanic Organization of Toxicologists Special Interest Group
Mixtures Specialty Section
Risk Assessment Specialty Section
The increasing incidence of primary liver cancer in Texas is a result of multiple risk factors, including environmental and dietary exposures to carcinogens, as well as biological factors, such as hepatitis C infection. Texas has the highest liver cancer mortality rate in the United States, affecting the Hispanic portion of the population most acutely. It is speculated that the increased incidence of primary liver cancer observed in these Hispanic communities is due to occupational exposures to pesticides, polycyclic aromatic hydrocarbons (PAHs), and dietary risk factors from contaminated maize. Current research and risk assessment in this field is focused on cancer epidemiology within these populations to determine those risk factors that are most hazardous to the community health of south Texas. Many pesticides used in farming and households are labeled as probable carcinogens and can cause many other negative health effects in people chronically exposed. Research and educational programs in Texas are striving to increase awareness of health effects from exposure and pesticide safety. PAHs are also known hepatic carcinogens, forming DNA adducts within the liver. Health effects observed in Texas from chronic PAH exposure through foods and poor air quality are being assessed. Additionally, mycotoxin occurrence is heightened in the southern portion of the state where drought conditions and excessive heat contribute to fungal growth on staple crops (i.e., maize). Specifically, aflatoxin and fumonisin exposures have been observed in various communities in San Antonio and along the Texas-Mexico border. These mycotoxins are known to both initiate and promote hepatocellular carcinoma. Understanding the risk factors for primary liver cancer in Texas is essential to developing future remediation, prevention, and treatment strategies, as well as identifying and establishing necessary changes in state regulations.
- Liver Cancer Incidence Trends in Texas 1995–2009. John Villanacci, Texas Department of State Health Services, Austin,
- A Lay Health Worker-Based Intervention for Reducing Families’ Environmental Exposures. L. Cizmas, Texas A&M University, College Station, TX.
- Early Obesity and Risk of Hepatocellular Carcinoma in USA. M. Hassan, The University of Texas MD Anderson Cancer Center,
- Biomarkers of Hepatocellular Cancer Risk and Diagnosis. Regina M. Santella, Columbia University Mailman School of Public Health, New York, NY.
- Mitigation of Aflatoxin Exposures Using a Clay-Based
Enterosorbent. Timothy D. Phillips, Texas A&M University, College Station, TX.
- Risk Factors Influencing the Incidence of Liver Cancer in
San Antonio. Fernando Guerra, University of Texas Health Science Center San Antonio, San Antonio, TX.
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