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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For drugs that have been withdrawn from the market for toxicity reasons, many have later shown to undergo metabolism to reactive intermediates.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.
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10:00 Drug-Induced
Nephrotoxicity – Multiplex Detection of Key Kidney
Damage Biomarkers in Rat Urine
Christopher McMahon, Ph.D., Research &
Development Group Leader, EMD Chemicals
In 2008 the Predictive Safety Testing Consortium (PSTC),
a public-private consortium led by the Critical Path
Institute (C-Path) submitted a list of urinary biomarkers
indicative of drug-induced kidney damage to the FDA and
EMEA regulatory authorities. The FDA and EMEA have issued
new guidelines on the submission of the biomarkers as
indicators of kidney damage in pre-clinical studies. Rules
Based Medicine worked with the members of the PSTC to
develop the assays used in the kidney toxicity study, and
made the assays available in the Rat Kidney MAP testing
service. EMD and Rules Based Medicine have collaborated to
develop these assays as commercially available kits,
exclusively for the Luminex® xMAP® Technology platform,
to support preclinical rat nephrotoxicity studies.This
presentation will describe the assessment of temporal and
dose-dependent changes in biomarker levels in response to
known kidney damaging agents.
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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
Overview
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For questions or suggestions about
the meeting, please contact:
Edel O'Regan
Cambridge Healthtech Institute
250 First Avenue, Suite #300
Needham, MA 02494
Tel: 781-972-5423
Fax: 781-972-5425
email: eoregan@healthtech.com
For sales information, contact:
Carol Dinerstein
Tel: 781-972-5471
email: Dinerstein@healthtech.com
OR
Jon Stroup
Tel: 781-972-5483
email: jstroup@healthtech.com
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