Animal Experimentation and Research Commons^™

Evidence-Based Toxicology For The 21st Century: Opportunities And Challenges, Martin L. Stephens, Melvin E. Andersen, Richard A. Becker, Kellyn Betts, Kim Boekelheide, Ed Carney, Robert Chapin, Dennis Devlin, Suzanne C. Fitzpatrick, John R. Fowle Iii, Patricia Harlow, Thomas Hartung, Sebastian Hoffman, Michael P. Holsapple, Abigail Jacobs, Richard Judson, Olga Naidenko, Tim Pastoor, Grace Patlewicz, Andrew Rowan, Roberta Scherer, Rashid Shaikh, Ted Simon, Douglas Wolf, Joanne Zurlo

Martin Stephens, PhD

The Evidence-based Toxicology Collaboration (EBTC) was established recently to translate evidence-based approaches from medicine and health care to toxicology in an organized and sustained effort. The EBTC held a workshop on “Evidence-based Toxicology for the 21st Century: Opportunities and Challenges” in Research Triangle Park, North Carolina, USA on January 24-25, 2012. The presentations largely reflected two EBTC priorities: to apply evidence-based methods to assessing the performance of emerging pathwaybased testing methods consistent with the 2007 National Research Council report on “Toxicity Testing in the 21st Century” as well as to adopt a governance structure and work processes to move that …

Adaptation Of The Systematic Review Framework To The Assessment Of Toxicological Test Methods: Challenges And Lessons Learned With The Zebrafish Embryotoxicity Test, Martin L. Stephens, Sevcan Gül Akgün-Ölmez, Sebastian Hoffman, Rob De Vries, Burkhard Flick, Thomas Hartung, Manoj Lalu, Alexandra Maertens, Hilda Witters, Robert Wright, Katya Tsaioun

Martin Stephens, PhD

Systematic review methodology is a means of addressing specific questions through structured, consistent, and transparent examinations of the relevant scientific evidence. This methodology has been used to advantage in clinical medicine, and is being adapted for use in other disciplines. Although some applications to toxicology have been explored, especially for hazard identification, the present preparatory study is, to our knowledge, the first attempt to adapt it to the assessment of toxicological test methods. As our test case, we chose the zebrafish embryotoxicity test (ZET) for developmental toxicity and its mammalian counterpart, the standard mammalian prenatal development toxicity study, focusing the …

Effects Of Dabigatran In Mouse Models Of Aging And Cerebral Amyloid Angiopathy, Neethu Michael, Mher Mahoney Grigoryan, Kelley Kilday, Rachita K. Sumbria, Vitaly Vasilevko, Joanne Van Ryn, David H. Cribbs, Annlia Paganini-Hill, Mark J. Fisher

Pharmacy Faculty Articles and Research

Oral anticoagulants are a critical component of stroke prevention, but carry a risk of brain hemorrhage. These hemorrhagic complications tend to occur in elderly individuals, especially those with predisposing conditions such as cerebral amyloid angiopathy (CAA). Clinical evidence suggests that non-vitamin K antagonist oral anticoagulants are safer than traditional oral anticoagulants. We analyzed whether the anticoagulant dabigatran produces cerebral microhemorrhage (the pathological substrate of MRI-demonstrable cerebral microbleeds) or intracerebral hemorrhage in aged mice with and without hemorrhage-predisposing angiopathy. We studied aged (22 months old) Tg2576 (a model of CAA) and wild-type (WT) littermate mice. Mice received either dabigatran etexilate (DE) …

Practical Considerations In Regenerative Medicine Research: Iacucs, Ethics, And The Use Of Animals In Stem Cell Studies, Susan Vandewoude, Bernard E. Rollin

Bernard Rollin, PhD

The intent of US federal laws mandating IACUC review of animal-related activities was to satisfy contemporary socioethical concerns by introducing deliberations about ethics and animal welfare into the research process when animals are used. These laws and the system they chartered have worked well for the most part in providing opportunities for consideration of animal welfare as a vital part of animal research. As a result, investigators today are far less naïve about the ethical issues raised by research on animals and typically more sympathetic about the need for such consideration. As evidence of this growing awareness, the literature on …

Adaptation Of The Systematic Review Framework To The Assessment Of Toxicological Test Methods: Challenges And Lessons Learned With The Zebrafish Embryotoxicity Test, Martin L. Stephens, Sevcan Gül Akgün-Ölmez, Sebastian Hoffman, Rob De Vries, Burkhard Flick, Thomas Hartung, Manoj Lalu, Alexandra Maertens, Hilda Witters, Robert Wright, Katya Tsaioun

Toxicology and Animal Models in Research Collection

Systematic review methodology is a means of addressing specific questions through structured, consistent, and transparent examinations of the relevant scientific evidence. This methodology has been used to advantage in clinical medicine, and is being adapted for use in other disciplines. Although some applications to toxicology have been explored, especially for hazard identification, the present preparatory study is, to our knowledge, the first attempt to adapt it to the assessment of toxicological test methods. As our test case, we chose the zebrafish embryotoxicity test (ZET) for developmental toxicity and its mammalian counterpart, the standard mammalian prenatal development toxicity study, focusing the …

Animal Organs In Humans: Uncalculated Risks And Unanswered Questions, Gillian R. Langley, Joyce D'Silva

Gill Langley, PhD

This report, produced jointly by the British Union for the Abolition of Vivisection and Compassion in World Farming, fills a number of significant gaps in the current debate about xenotransplantation.

In this report we also summarise the ethical and welfare issues concerning experiments on animals for xenotransplant research and their possible use as source animals for organs. Both these aspects are responsible for much pain and distress caused to many animals. We prefer the term “source animals” to “donor animals”, because animals do not choose to donate their organs for xenotransplantation.

Short Amylin Receptor Antagonist Peptides Improve Memory Deficits In Alzheimer’S Disease Mouse Model, Rania Soudy, Ryoichi Kimura, Aarti Patel, Wen Fu, Kamaljit Kaur, David Westaway, Jing Yang, Jack Jhamandas

Pharmacy Faculty Articles and Research

Recent evidence supports involvement of amylin and the amylin receptor in the pathogenesis of Alzheimer’s disease (AD). We have previously shown that amylin receptor antagonist, AC253, improves spatial memory in AD mouse models. Herein, we generated and screened a peptide library and identified two short sequence amylin peptides (12–14 aa) that are proteolytically stable, brain penetrant when administered intraperitoneally, neuroprotective against Aβ toxicity and restore diminished levels of hippocampal long term potentiation in AD mice. Systemic administration of the peptides for five weeks in aged 5XFAD mice improved spatial memory, reduced amyloid plaque burden, and neuroinflammation. The common residue SQELHRLQTY …

Contribution Of Animal Models To Contemporary Understanding Of Attention Deficit Hyperactivity Disorder, Constança Carvalho, Mariana Vieira Crespo, Luísa Ferreira Bastos, Andrew Knight, Luís Vincente

Andrew Knight, PhD

Attention Deficit Hyperactivity Disorder (ADHD) is a poorly understood neurodevelopmental disorder of multifactorial origin. Animal-based research has been used to investigate ADHD etiology, pathogenesis and treatment, but the efficacy of this research for patients has not yet been systematically evaluated. Such evaluation is important given the resource consumption and ethical concerns incurred by animal use.

We used the citation tracking facility within Web of Science to locate citations of original research papers on animal models related to ADHD published prior to 2010 identified in PubMed by relevant search terms. Human medical papers citing those animal studies were carefully analyzed by …

Contribution Of Animal Models To Contemporary Understanding Of Attention Deficit Hyperactivity Disorder, Constança Carvalho, Mariana Vieira Crespo, Luísa Ferreira Bastos, Andrew Knight, Luís Vincente

Biomedicine and Animal Models in Research Collection

Attention Deficit Hyperactivity Disorder (ADHD) is a poorly understood neurodevelopmental disorder of multifactorial origin. Animal-based research has been used to investigate ADHD etiology, pathogenesis and treatment, but the efficacy of this research for patients has not yet been systematically evaluated. Such evaluation is important given the resource consumption and ethical concerns incurred by animal use.

We used the citation tracking facility within Web of Science to locate citations of original research papers on animal models related to ADHD published prior to 2010 identified in PubMed by relevant search terms. Human medical papers citing those animal studies were carefully analyzed by …

Cyclin C Regulated Oxidative Stress Responsive Transcriptome In Mus Musculus Embryonic Fibroblasts, David C Stieg, Kai-Ti Chang, Katrina F Cooper, Randy Strich

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

The transcriptional changes that occur in response to oxidative stress help direct the decision to maintain cell viability or enter a cell death pathway. Cyclin C-Cdk8 is a conserved kinase that associates with the RNA polymerase II Mediator complex that stimulates or represses transcription depending on the locus. In response to oxidative stress, cyclin C, but not Cdk8, displays partial translocation into the cytoplasm. These findings open the possibility that cyclin C relocalization is a regulatory mechanism governing oxidative stress-induced transcriptional changes. In the present study, the cyclin C-dependent transcriptome was determined and compared to transcriptional changes occurring in oxidatively …

An Assessment Of The Use Of Chimpanzees In Hepatitis C Research Past, Present And Future: 1. Validity Of The Chimpanzee Model, Jarrod Bailey

Jarrod Bailey, PhD

The USA is the only significant user of chimpanzees in biomedical research in the world, since many countries have banned or limited the practice due to substantial ethical, economic and scientific concerns. Advocates of chimpanzee use cite hepatitis C research as a major reason for its necessity and continuation, in spite of supporting evidence that is scant and often anecdotal. This paper examines the scientific and ethical issues surrounding chimpanzee hepatitis C research, and concludes that claims of the necessity of chimpanzees in historical and future hepatitis C research are exaggerated and unjustifiable, respectively. The chimpanzee model has several major …

Chimpanzee Research: An Examination Of Its Contribution To Biomedical Knowledge And Efficacy In Combating Human Diseases, Jarrod Bailey, Jonathan Balcombe, Theodora Capaldo

Jarrod Bailey, PhD

Research on captive chimpanzees incurs considerable animal welfare, ethical and financial costs. Advocates of such research claim these costs are outweighed by substantial advancements in biomedical knowledge, and that the genetic similarity of chimpanzees to humans enables the former to make critical contributions to preventing, diagnosing and combating human diseases. To assess these claims, we examined the disciplines investigated in 749 studies of captive chimpanzees published from 1995-2004 inclusive, and subjected 95 randomly selected papers to a detailed citation analysis:

49.5% (47/95) of papers had not been cited at the time of this study; 38.5% (34/95) were cited by 116 …

An Assessment Of The Use Of Chimpanzees In Hepatitis C Research Past, Present And Future: 2. Alternative Replacement Methods, Jarrod Bailey

Jarrod Bailey, PhD

The use of chimpanzees in hepatitis C virus (HCV) research was examined in the report associated with this paper (1: Validity of the Chimpanzee Model), in which it was concluded that claims of past necessity of chimpanzee use were exaggerated, and that claims of current and future indispensability were unjustifiable. Furthermore, given the serious scientific and ethical issues surrounding chimpanzee experimentation, it was proposed that it must now be considered redundant — particularly in light of the demonstrable contribution of alternative methods to past and current scientific progress, and the future promise that these methods hold. This paper builds on …

The Promises And Challenges Of Erythropoietin For Treatment Of Alzheimer's Disease, Jiahong Sun, Jan Michelle Martin, Victoria Vanderpoel, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder in the world, and intracellular neurofibrillary tangles and extracellular amyloid-beta protein deposits represent the major pathological hallmarks of the disease. Currently available treatments provide some symptomatic relief but fail to modify primary pathological processes that underlie the disease. Erythropoietin (EPO), a hematopoietic growth factor, acts primarily to stimulate erythroid cell production, and is clinically used to treat anemia. EPO has evolved as a therapeutic agent for neurodegeneration and has improved neurological outcomes and AD pathology in rodents. However, penetration of the blood–brain barrier (BBB) and negative hematopoietic effects are the two …

Modernizing Biomedical Training: Replacing Live Animal Laboratories With Human Simulation, John Pawlowski, David Feinstein, Marie L. Crandall, Shalin Gala

Biomedicine and Animal Models in Research Collection

This chapter reviews the global trend towards a modernization of biomedical education in favor of simulation-based training methods, which studies confirm improve student learning and transference of applied skills to clinical practice, reduce laboratory costs, and spare animals from harmful procedures.

Wasted Money In United States Biomedical And Agricultural Animal Research, Jim Keen

Biomedicine and Animal Models in Research Collection

Biomedical and agricultural animal research uses millions of experimental animals and dozens of animal species each year by choice, precedent, or regulatory mandate in basic and applied life science research and toxicity testing of drugs, chemicals, and consumer products. Animal research is a large component of the international us$270 billion government-subsidized, biomedical industrial ecosystem (Chakma et al., 2014). In the United States (us) and presumably elsewhere, about half of these funds support animal research and testing (Institute of Medicine and National Research Council, 2012). Each year at least 115 million experimental animals (mostly mice and likely a significant underestimate) are …

Animal Research For Alzheimer Disease: Failures Of Science And Ethics, John J. Pippin, Sarah E. Cavanaugh, Francesca Pistollato

Biomedicine and Animal Models in Research Collection

This chapter addresses the epidemiology and current understanding of AD as a scientific and societal challenge, reviews the uses and results of animal research in basic science and drug development, and discusses risk factors and funding. Important follow-up topics, including current and in-development, human-relevant approaches for replacement of the failed animal research paradigm, deserve comparable treatment and hence are not addressed here. The reader is referred to the list of recommended readings at the end of the chapter for further discussion of these topics.

Development Of A Functional Testing Platform For The Sensory Segment Of The Neuromuscular Reflex Arc, Alisha Colon

Electronic Theses and Dissertations

Investigations of human biology and disease have been hindered by the use of animal models. The information obtained from such studies often results in clinically irrelevant results and drug trial failures. Additionally, several governing bodies have been formulating legislation to move away from animal models and toward more ethical and efficient testing platforms for drug discovery and cosmetic research. As an answer to these issues, "body-on-a-chip" systems have been a rapidly developing field which easily recapitulates in vivo functionality, providing a more relevant, repeatable, and ethical testing platform to better predict biology. These systems can be used as human-based testing …

Hematologic Safety Of Chronic Brain-Penetrating Erythropoietin Dosing In App/Ps1 Mice, Jiahong Sun, Joshua Yang, Kathrine Whitman, Charlene Zhu, David H. Cribbs, Ruben J. Boado, William M. Pardridge, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Introduction: Low blood-brain barrier (BBB) penetration and hematopoietic side effects limit the therapeutic development of erythropoietin (EPO) for Alzheimer's disease (AD). A fusion protein of EPO and a chimeric monoclonal antibody targeting the mouse transferrin receptor (cTfRMAb) has been engineered. The latter drives EPO into the brain via receptor-mediated transcytosis across the BBB and increases its peripheral clearance to reduce hematopoietic side effects of EPO. Our previous work shows the protective effects of this BBB-penetrating EPO in AD mice but hematologic effects have not been studied. Herein, we investigate the hematologic safety and therapeutic effects of chronic cTfRMAb-EPO dosing, …