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THURSDAY, FEBRUARY 26 

7:00am Registration Open and Morning Coffee

7:20 Plenary Keynote Introduction

7:30 Tissue Engineering Strategies for Musculoskeletal Regenerative Medicine in Civilian and Military Applications
Michael J. Yaszemski, M.D., Ph.D., Brigadier General, United States Air Force, Professor, Orthopedic Surgery and Biomedical Engineering, Mayo Clinic College of Medicine
Tissue regeneration via tissue engineering strategies requires some combination of cells, a scaffold upon which the cells can attach and express their phenotypic function, and signaling molecules to direct the cells down the desired differentiation path. This cellular component often includes stem cells. This lecture will present current concepts regarding musculoskeletal tissue regeneration and the issues to be considered for its translation to clinical practice, as well as the unique reconstructive challenges encountered in combat injuries. 

LIVER AND IDIOSYNCRATIC TOXICITIES

8:25 Chairperson’s Remarks 
Paul B. Watkins, M.D., Director of Hamner/U.N.C. Center for Drug Safety Science, University of North Carolina at Chapel Hill

8:30 The Role of Reactive Intermediates in Idiosyncratic Drug Toxicity
John C. L. Erve, Ph.D., Principal Research Scientist II, Wyeth Research, Drug Safety and Metabolism
For drugs that have been withdrawn from the market for toxicity reasons, many have later shown to undergo metabolism to reactive intermediates. Still, there remain unanswered questions regarding the relationship between reactive metabolites and idiosyncratic toxicity. This talk will cover the proposed mechanistic role for reactive metabolites in causing idiosyncratic toxicity and point out areas where further knowledge is needed.

9:00 How to Improve Preclinical Testing for Liver Toxicity
Paul B. Watkins, M.D., Director of Hamner/U.N.C. Center for Drug Safety Science, University of North Carolina at Chapel Hill
Current preclinical liver safety screening has not prevented entry into the clinic of drugs capable of causing catastrophic but rare liver injury. “Humanizing” preclinical screening has shown some promise, but most humans are not good models for this toxicity- only a very small fraction of the human population is susceptible. Major improvements in preclinical screening must await better understanding of the mechanisms that underlie these rare clinical events. Ongoing efforts of networks combined with focused preclinical studies and virtual liver models should provide the understanding necessary to develop better screening techniques.

9:30 Imaging Techniques for Assessing Toxicity in Primary Human Hepatocyte Cell Culture
Eric Tien, Ph.D., Senior Scientist, Biotherapeutics and Bioinnovation Center, Target Generation Unit, Pfizer Research Technology Center
This presentation will discuss the challenges of culturing of primary human hepatocytes in 96 well format and our approach for image capture and analysis. A focus will be on the assessment of positive hepatotoxic compounds.

10:30 Poster Competition Refreshment Break & Raffles in the Exhibit Hall

11:30 Mechanistic Investigation of a Species-specific Liver Toxicity Induced by a Preclinical Drug Candidate
Cindy Xia, Ph.D., Senior Scientist I, DMPK department, Millennium, The Takeda Oncology Company
A selective Aurora A kinase inhibitor under clinical development for the treatment of solid tumors was found to cause, at similar high dose liver concentrations, profound reversible hyperbilirubinemia in SD-rats but not in beagle dog. We’ll present the in vitro and in vivo tools we used to determine which species’ liver toxicity was more predictive of the toxicity the compound would encounter in humans. 

12:00pm Panel – Predicting Liver Toxicity 
Session speakers and John Senior,M.D., FDA. Moderated by Paul Watkins, M.D.

12:30 Luncheon Presentation (Opportunity Available) or Lunch on your own

1:30 Plenary Keynote Introduction 

1:40 PLENARY KEYNOTES
Engineering Cells to Death 
James A. Wells, Ph.D., Chair, Department of Pharmaceutical Chemistry; Professor of Pharmaceutical Sciences, Departments of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology; and Director of the Small Molecule Discovery Center, University of California, San Francisco
Apoptosis, or programmed cell death, represents an ultimate fate decision in cell biology. This process is critical for cellular differentiation and remodeling of tissues, and for anti-viral and anti-tumor defense. The study of apoptotic pathways has important ramifications for determining what is critical for cellular homeostasis, and for the development of potential anti-cancer therapeutics. A distinct molecular feature of apoptosis is the widespread but controlled cellular proteolysis, that is predominantly mediated by eight members of the caspase family of cysteine proteases. These enzymes are like demolition experts that cleave protein targets critical for cellular life. We have designed new enzymes, and antibodies, and small molecules to study and activate individual caspases and the proteins they cleave. For example, a robust proteomic method for global profiling of proteolysis ("degradomics") in cells has been developed. Key to this is an engineered enzyme, subtiligase, that permits selective labeling and enrichment for the protein N-termini created as a result of proteolysis. Using this approach we have already identified >300 caspase substrates from Jurkat cells that were induced to undergo apoptosis by treatment with the chemotherapeutic agent etoposide. The proteins fall into a wide range of functional classes, and reveal much about the molecular components, logic, and timed sequence of events that drive a cell from life to death. We believe these engineered enzymes and proteomic approaches will be useful for characterizing the proteolysis of apoptosis induced by various agents or in different cell types, and will be generally useful for dissecting protease signaling pathways

2:25 The Brave New World of Personalized Medicine: The Experimental Man Project, One Man Takes the Ultimate High-Tech Exam
David Ewing Duncan, Chief Corresponsent, NPR Talk’s “Biotech Nation” and Best Selling Author “Masterminds” 
This focus of this presentation will be on "Creative Disruptions", and will demonstrate the walking scientific response to the question: "Can they really do that?" The most important and controversial topics of today’s scientific research will be discussed, from stem cells and synthetic biology, to rising drug prices and reforming the FDA. Recently, there has been attention on science’s most significant story: a species’ potential to self-evolve. As the founder of the independent BioAgenda Institute for Life Science Studies and, more recently, as the founder of the new Center for Life Science Policy at UC Berkeley, the passion for what comes next after new technologies appear will be explored -- what happens in business, politics, science, philosophy, the media, the arts, and to society as a whole.

3:05 Ice Cream Refreshment Break in the Exhibit Hall with BEST OF SHOW AWARDS (Last Chance for Viewing Exhibits & Posters)

EMERGING ASSAYS AND TRENDS IN TOXICOLOGY/DRUG SAFETY

3:55 Chairperson’s Remarks
Dina Andrews-Cleavenger, Ph.D., Director of Pathology, Amgen

4:00 Utility and Positioning of the Comet Assay in Toxicologicy Testing
Patricia Escobar, Ph.D., Senior Scientist, Toxicology and Safety Assessment, Boehringer-Ingelheim Pharmaceuticals, Inc. 
The Comet Assay, also known as Single Cell Gel Electrophoresis (SCGE), is a microgel electrophoretic technique that has the ability to detect DNA damage at a single cell level. The comet assay is increasingly being used to evaluate the genotoxic potential of pharmaceutical compounds. An update on the applications of the rodent Comet Assay, including its use in regulatory applications, will be provided. 

4:30 Applying Improved Nephrotoxicity Markers in Preclinical Safety Studies: An Industry Perspective 
Dina A. Andrews, D.V.M., Ph.D., D.A.C.V.P., Director of Pathology, Amgen
This presentation will review the seven rodent kidney safety biomarkers recently submitted by the Preclinical Safety Testing Consortium Nephrotoxicity Working Group and how pharmaceutical companies can use them to strategically and appropriately communicate with regulatory agencies about a new drug’s safety profile. 

5:00 Understanding and Avoiding Mitochondrial Toxicity
Yvonne Will, Ph.D., Senior Principal Scientist, Exploratory Safety Differentiation, Pfizer Global R&D
Conventional in vitro approaches often fail to detect mitochondrial dysfunction early in a drug candidate’s development, and there are few animal models which would readily reveal mitochondrial liability. Organelle and cell based in vitro screens we’ve developed to detect potential mitochondrial toxicities and other new approaches will be presented.

5:30 Expanded Scope of Animal Disease Models for Preclinical Toxicology
Alain Stricker-Krongrad, Ph.D., Chief Scientific Officer, Preclinical Services, Charles River 
Animal models of human disease are widely used to study the efficacy of therapeutics. However healthy animals are usually used for safety studies. This largely ignores the potential impact of a disease state on results. Animal models of human disease may predict and reveal potential human toxicities or adverse side effects that are present in the human diseased population but not observed in healthy animals. 

6:00 Close of Day

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