Animal Experimentation and Research Commons^™

Paracrine-Rescued Lobulogenesis In Chimeric Outgrowths Comprising Progesterone-Receptor-Null Mammary Epithelium And Redirected Wild-Type Testicular Cells, Robert D. Bruno, Corinne A. Boulanger, Sonia M. Rosenfield, Lisa H. Anderson, John P. Lydon, Gilbert H. Smith

School of Medical Diagnostics & Translational Sciences Publications

We have previously shown that non-mammary and tumorigenic cells can respond to the signals of the mammary niche and alter their cell fate to that of mammary epithelial progenitor cells. Here we tested the hypothesis that paracrine signals from mammary epithelial cells expressing progesterone receptor (PR) are dispensable for redirection of testicular cells, and that re-directed wild-type testicular-derived mammary cells can rescue lobulogenesis of PR-null mammary epithelium by paracrine signaling during pregnancy. We injected PR-null epithelial cells mixed with testicular cells from wild-type adult male mice into cleared fat-pads of recipient mice. The testicular cells were redirected in vivo to …

Arkansas Animal Science Department Report 2013, David L. Kreider, Paul Beck

Arkansas Agricultural Experiment Station Research Series

No abstract provided.

Predeliberation Activity In Prefrontal Cortex And Striatum And The Prediction Of Subsequent Value Judgment, Uri Maoz, Ueli Rutishauser, Soyoun Kim, Xinying Cai, Christof Koch

Psychology Faculty Articles and Research

Rational, value-based decision-making mandates selecting the option with highest subjective expected value after appropriate deliberation. We examined activity in the dorsolateral prefrontal cortex (DLPFC) and striatum of monkeys deciding between smaller, immediate rewards and larger, delayed ones. We previously found neurons that modulated their activity in this task according to the animal's choice, while it deliberated (choice neurons). Here we found neurons whose spiking activities were predictive of the spatial location of the selected target (spatial-bias neurons) or the size of the chosen reward (reward-bias neurons) before the onset of the cue presenting the decision-alternatives, and thus before rational deliberation …

Prolonged Pain Research In Mice: Trends In Reference To The 3rs, Jonathan Balcombe, Hope Ferdowsian, Lauren Briese

Experimentation Collection

This literature review documents trends in the use of mice in prolonged pain research, defined herein as research that subjects mice to a source of pain for at least 14 days. The total amount of prolonged pain research on mice has increased dramatically in the past decade for the 3 pain categories examined: neuropathic, inflammatory, and chronic pain. There has also been a significant rise in the number of prolonged mouse pain studies as a proportion of all mouse studies and of all mouse pain studies. The use of transgenic mice has also risen significantly in prolonged pain research, though …

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

Toxicology and Animal Models in Research Collection

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 …

Bmp7 Gene Transfer Via Gold Nanoparticles Into Stroma Inhibits Corneal Fibrosis In Vivo, Ashish Tandon, Ajay Sharma, Jason T. Rodier, Alexander M. Klibanov, Frank G. Rieger, Rajiv R. Mohan

Pharmacy Faculty Articles and Research

This study examined the effects of BMP7 gene transfer on corneal wound healing and fibrosis inhibition in vivo using a rabbit model. Corneal haze in rabbits was produced with the excimer laser performing -9 diopters photorefractive keratectomy. BMP7 gene was introduced into rabbit keratocytes by polyethylimine-conjugated gold nanoparticles (PEI2- GNPs) transfection solution single 5-minute topical application on the eye. Corneal haze and ocular health in live animals was gauged with stereo- and slit-lamp biomicroscopy. The levels of fibrosis [a-smooth muscle actin (aSMA), F-actin and fibronectin], immune reaction (CD11b and F4/80), keratocyte apoptosis (TUNEL), calcification (alizarin red, vonKossa and osteocalcin), and …

Arkansas Animal Science Department Report 2012, David L. Kreider

Arkansas Agricultural Experiment Station Research Series

No abstract provided.

Late Developing Mammary Tumors And Hyperplasia Induced By A Low-Oncogenic Variant Of Mouse Mammary Tumor Virus (Mmtv) Express Genes Identical To Those Induced By Canonical Mmtv, Robert D. Bruno

School of Medical Diagnostics & Translational Sciences Publications

Background: The canonical milk-transmitted mouse mammary tumor virus (MMTV) of C3H mice (C3H-MMTV) rapidly induces tumors in 90% of infected animals by 8 months of age. Pro-viral insertions of C3H-MMTV into genomic DNA results in the overexpression of common core insertion site (CIS) genes, including Wnt1/10b, Rspo2, and Fgf3. Conversely, infection by either the endogenous Mtv-1 virus (in C3Hf) or the exogenous nodule-inducing virus (NIV) (in Balb/c NIV) induces premalignant mammary lesions and tumors with reduced incidence and longer latency than C3H-MMTV. Here, we asked whether Mtv-1/NIV affected the expression of core CIS genes.

Findings: We confirmed the presence of …

Pharmacokinetics And Brain Uptake In The Rhesus Monkey Of A Fusion Protein Of Arylsulfatase A And A Monoclonal Antibody Against The Human Insulin Receptor, Ruben J. Boado, Jeff Zhiqiang Lu, Eric Ka-Wai Hui, Rachita K. Sumbria, William M. Pardridge

Pharmacy Faculty Articles and Research

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder of the brain caused by mutations in the gene encoding the lysosomal sulfatase, arylsulfatase A (ASA). It is not possible to treat the brain in MLD with recombinant ASA, because the enzyme does not cross the blood-brain barrier (BBB). In the present investigation, a BBB-penetrating IgG-ASA fusion protein is engineered and expressed, where the ASA monomer is fused to the carboxyl terminus of each heavy chain of an engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb crosses the BBB via receptor-mediated transport on the endogenous BBB insulin receptor, …

The Moral Status Of Invasive Animal Research, Bernard E. Rollin

Experimentation Collection

No abstract provided.

Bias During The Evaluation Of Animal Studies, Andrew Knight

Morality and Ethics of Animal Experimentation Collection

My recent book entitled The Costs and Benefits of Animal Experiments seeks to answer a key question within animal ethics, namely: is animal experimentation ethically justifiable? Or, more precisely, is it justifiable within the utilitarian cost:benefit framework that fundamentally underpins most regulations governing animal experimentation? To answer this question I reviewed more than 500 scientific publications describing animal studies, animal welfare impacts, and alternative research, toxicity testing and educational methodologies. To minimise bias I focused primarily on large-scale systematic reviews that had examined the human clinical and toxicological utility of animal studies. Despite this, Dr. Susanne Prankel recently reviewed my …

Arkansas Animal Science Department Report 2011, David L. Kreider

Arkansas Agricultural Experiment Station Research Series

No abstract provided.

Ginkgo Extract Egb761 Confers Neuroprotection By Reduction Of Glutamate Release In Ischemic Brain, Alexander Mdzinarishvili, Rachita K. Sumbria, Dorothee Lang, Jochen Klein

Pharmacy Faculty Articles and Research

Purpose - Ginkgo extract EGb761 has shown anti-edema and anti-ischemic effects in various experimental models. In the present study, we demonstrate neuroprotective effects of EGb761 in experimental stroke while monitoring brain metabolism by microdialysis. Methods - We have used oxygen-glucose deprivation in brain slices in vitro and middle cerebral artery occlusion (MCAO) in vivo to induce ischemia in mouse brain. We used microdialysis in mouse striatum to monitor extracellular concentrations of glucose and glutamate. Results - In vitro, EGb761 reduced ischemia-induced cell swelling in hippocampal slices by 60%. In vivo, administration of EGb761 (300 mg/kg) reduced cell degeneration and edema …

Rational Engagement, Emotional Response, And The Prospects For Moral Progress In Animal Use “Debates”, Nathan Nobis

Animal Welfare Collection

This chapter is designed to help people rationally engage moral issues regarding the treatment of animals, specifically in experimentation, research, product testing, and education. Little “new” philosophy is offered here, strictly speaking. New arguments are unnecessary to help make progress in how people think about these issues. What is needed are improved abilities to engage the arguments already on the table, for example, stronger skills at identifying and evaluating the existing reasons given for and against conclusions on the morality of various uses of animals. To help improve these abilities, this chapter sets forth a set of basic but powerful …

Vorinostat: A Potent Agent To Prevent And Treat Laser-Induced Corneal Haze, Ashish Tandon, Jonathan C. K. Tovey, Michael R. Waggoner, Ajay Sharma, John W. Cowden, Daniel J. Gibson, Yuanjing Liu, Gregory S. Schultz, Rajiv R. Mohan

Pharmacy Faculty Articles and Research

PURPOSE—This study investigated the efficacy and safety of vorinostat, a deacetylase (HDAC) inhibitor, in the treatment of laser-induced corneal haze following photorefractive keratectomy (PRK) in rabbits in vivo and transforming growth factor beta 1 (TGFβ1) -induced corneal fibrosis in vitro.

METHODS—Corneal haze in rabbits was produced with −9.00 diopters (D) PRK. Fibrosis in cultured human and rabbit corneal fibroblasts was activated with TGFβ1. Vorinostat (25 μm) was topically applied once for 5 minutes on rabbit cornea immediately after PRK for in vivo studies. Vorinostat (0 to 25 μm) was given to human/rabbit corneal fibroblasts for 5 minutes or 48 …

Attenuation Of Corneal Myofibroblast Development Through Nanoparticle-Mediated Soluble Transforming Growth Factor-Β Type Ii Receptor (Stgfβrii) Gene Transfer, Ajay Sharma, Jason T. Rodier, Ashish Tandon, Alexander M. Klibanov, Rajiv R. Mohan

Pharmacy Faculty Articles and Research

Purpose: To explore (i) the potential of polyethylenimine (PEI)-DNA nanoparticles as a vector for delivering genes into human corneal fibroblasts, and (ii) whether the nanoparticle-mediated soluble extracellular domain of the transforming growth factor–β type II receptor (sTGFβRII) gene therapy could be used to reduce myofibroblasts and fibrosis in the cornea using an in vitro model.

Methods: PEI-DNA nanoparticles were prepared at a nitrogen-to-phosphate ratio of 30 by mixing linear PEI and a plasmid encoding sTGFβRII conjugated to the fragment crystallizable (Fc) portion of human immunoglobulin. The PEI-DNA polyplex formation was confirmed through gel retardation assay. Human corneal fibroblasts (HCFs) were …

Lessons From Chimpanzee-Based Research On Human Disease: The Implications Of Genetic Differences, Jarrod Bailey

Laboratory Experiments Collection

Assertions that the use of chimpanzees to investigate human diseases is valid scientifically are frequently based on a reported 98–99% genetic similarity between the species. Critical analyses of the relevance of chimpanzee studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for the chimpanzee to constitute a good model for research, and furthermore, that chimpanzee data do not translate well to progress in clinical practice for humans. Leading examples include the minimal citations of chimpanzee research that is relevant to human medicine, the highly different pathology of HIV/AIDS and hepatitis C virus …

Neuroprotective Effects Of Bilobalide Are Accompanied By A Reduction Of Ischemia-Induced Glutamate Release In Vivo, Dorothee Lang, Cornelia Kiewert, Alexander Mdzinarishvili, Tina Maria Schwarzkopf, Rachita K. Sumbria, Joachim Hartmann, Jochen Klein

Pharmacy Faculty Articles and Research

Neuroprotective properties of bilobalide, a specific constituent of Ginkgo extracts, were tested in a mouse model of stroke. After 24 h of middle cerebral artery occlusion (MCAO), bilobalide reduced infarct areas in the core region (striatum) by 40–50% when given at 10 mg/kg 1 h prior to MCAO. Neuroprotection was also observed at lower doses, or when the drug was given 1 h past stroke induction. Sensorimotor function in mice was improved by bilobalide as shown by corner and chimney tests. When brain metabolism in situ was monitored by microdialysis, MCAO caused a rapid disappearance of extracellular glucose in the …

Towards A New Paradigm Of Non-Captive Research On Cetacean Cognition, Lori Marino, Toni Frohoff

Experimentation Collection

Contemporary knowledge of impressive neurophysiology and behavior in cetaceans, combined with increasing opportunities for studying free-ranging cetaceans who initiate sociable interaction with humans, are converging to highlight serious ethical considerations and emerging opportunities for a new era of progressive and less-invasive cetacean research. Most research on cetacean cognition has taken place in controlled captive settings, e.g., research labs, marine parks. While these environments afford a certain amount of experimental rigor and logistical control they are fraught with limitations in external validity, impose tremendous stress on the part of the captive animals, and place burdens on populations from which they are …

Ethical And Scientific Considerations Regarding Animal Testing And Research, Hope Ferdowsian, Nancy Beck

Experimentation Collection

In 1959, William Russell and Rex Burch published the seminal book, The Principles of Humane Experimental Technique, which emphasized reduction, refinement, and replacement of animal use, principles which have since been referred to as the ‘‘3 Rs’’. These principles encouraged researchers to work to reduce the number of animals used in experiments to the minimum considered necessary, refine or limit the pain and distress to which animals are exposed, and replace the use of animals with non-animal alternatives when possible. Despite the attention brought to this issue by Russell and Burch and since, the number of animals used in research …

Critical Evaluation Of The Use Of Dogs In Biomedical Research And Testing In Europe, Nina Hasiwa, Jarrod Bailey, Peter Clausing, Mardas Daneshian, Sándor Farkas, István Gyertyán, Robert Hubrecht, Werner Kobel, Goran Krummenacher, Marcel Leist, Hannes Lohi, Adám Miklósi, Frauke Ohl, Klaus Olejniczak, Georg Schmitt, Patrick Sinnett-Smith, David Smith, Kristina Wagner, James D. Yager, Joanne Zurlo, Thomas Hartung

Companion Animals as Laboratory Research Subjects Collection

Dogs are sometimes referred to as “man’s best friend” and with the increase in urbanization and lifestyle changes, dogs are seen by their owners as family members. Society expresses specific concerns about the experimental use of dogs, as they are sometimes perceived to have a special status for humans. This may appear somewhat conflicting with the idea that the intrinsic value of all animals is the same, and that also several other animal species are used in biomedical research and toxicology. This aspect and many others are discussed in an introductory chapter dealing with ethical considerations on the use of …

Unifying The Mathematical Modeling Of In Vivo And In Vitro Microdialysis, Peter M. Bungay, Rachita K. Sumbria, Ulrich Bickel

Pharmacy Faculty Articles and Research

A unifying approach is presented for developing mathematical models of microdialysis that are applicable to both in vitro and in vivo situations. Previous models for cylindrical probes have been limited by accommodating analyte diffusion through the surrounding medium in the radial direction only, i.e., perpendicular to the probe axis, or by incomplete incorporation of diffusion in the axial direction. Both radial and axial diffusion are included in the present work by employing two-dimensional finite element analysis. As in previous models, the nondimensional clearance modulus (Θ) represents the degree to which analyte clearance from the external medium influences diffusion through the …

The Harmful, Nontherapeutic Use Of Animals In Research Is Morally Wrong, Nathan Nobis

Experimentation Collection

It is argued that using animals in research is morally wrong when the research is nontherapeutic and harmful to the animals. This article discusses methods of moral reasoning and discusses how arguments on this and other bioethical issues might be defended and critiqued. A basic method of moral argument analysis is presented and used to show that common objections to the view that “animal research is morally wrong” fail: ie, common arguments for the view that “animal research is morally permissible” are demonstrably unsound or in need of defense. It is argued that the best explanations why harmful, nontherapeutic research …

Systematic Review Of Chimpanzee Use In Monoclonal Antibody Research And Drug Development: 1981-2010, Raija Bettauer

Experimentation Collection

This survey examines the extent to which live chimpanzees have been used in monoclonal antibody (mAb) research and the drug approval process. The survey covers 193 scientific articles published during the years 1981-2010, as well as preclinical studies leading to the approval of mAb drugs by the Food and Drug Administration of the United States. The frequency of the articles has decreased by more than two-thirds from their highs in the late 1980’s, and the aggregate number of chimpanzees used in these studies has decreased by more than 90%.

The experimental protocols ranged from single or multiple blood draws to …

A Kenyan Perspective On The Use Of Animals In Science Education And Scientific Research In Africa And Prospects For Improvement, Charles Kimwele, Duncan Matheka, Hope Ferdowsian

Experimentation Collection

Introduction: Animal experimentation is common in Africa, a region that accords little priority on animal protection in comparison to economic and social development. The current study aimed at investigating the prevalence of animal experimentation in Kenya, and to review shortfalls in policy, legislation, implementation and enforcement that result in inadequate animal care in Kenya and other African nations. Methods: Data was collected using questionnaires, administered at 39 highly ranked academic and research institutions aiming to identify those that used animals, their sources of animals, and application of the three Rs. Perceived challenges to the use of non-animal alternatives and common …

Self-Harm In Laboratory-Housed Primates: Where Is The Evidence That The Animal Welfare Act Amendment Has Worked?, Jonathan Balcombe, Hope Ferdowsian, Debra Durham

Animal Welfare Collection

The 1985 amendment to the United States Animal Welfare Act (AWA) to promote psychological well being of primates in the laboratory represents an acknowledgment of an important welfare problem concerning nonhuman animals. How effective has this amendment been? Perhaps the best-known contributor to psychological distress in primates in the laboratory is nonsocial housing; yet, available analyses suggest that little progress has been made in avoiding single-caging of these animals. Another way to assess psychological well being is to examine rates of self-abusive behavior in laboratory primates. If the AWA has been effective, then post-AWA self-harm rates might be lower than …

Targeted Decorin Gene Therapy Delivered With Adeno-Associated Virus Effectively Retards Corneal Neovascularization In Vivo, Rajiv R. Mohan, Jonathan C. K. Tovey, Ajay Sharma, Gregory S. Schultz, John W. Cowden, Ashish Tandon

Pharmacy Faculty Articles and Research

Decorin, small leucine-rich proteoglycan, has been shown to modulate angiogenesis in nonocular tissues. This study tested a hypothesis that tissue-selective targeted decorin gene therapy delivered to the rabbit stroma with adeno-associated virus serotype 5 (AAV5) impedes corneal neovascularization (CNV) in vivo without significant side effects. An established rabbit CNV model was used. Targeted decorin gene therapy in the rabbit stroma was delivered with a single topical AAV5 titer (100 μl; 5x10^12 vg/ml) application onto the stroma for two minutes after removing corneal epithelium. The levels of CNV were examined with stereomicroscopy, H&E staining, lectin, collagen type IV, CD31 immunocytochemistry and …

Polyethylenimine-Conjugated Gold Nanoparticles: Gene Transfer Potential And Low Toxicity In The Cornea, Ajay Sharma, Ashish Tandon, Jonathan C. K. Tovey, Rangan Gupta, J. David Robertson, Jennifer A. Fortune, Alexander M. Klibanov, John W. Cowden, Frank G. Rieger, Rajiv R. Mohan

Pharmacy Faculty Articles and Research

This study examined the gene transfer efficiency and toxicity of 2-kDa polyethylenimine conjugated to gold nanoparticles (PEI2-GNP) in the human cornea in vitro and rabbit cornea in vivo. PEI2-GNP with nitrogen-to-phosphorus (N/P) ratios of up to 180 exhibited significant transgene delivery in the human cornea without altering the viability or phenotype of these cells. Similarly, PEI2-GNP applied to corneal tissues collected after 12 h, 72 h, or 7 days exhibited appreciable gold uptake throughout the rabbit stroma with gradual clearance of GNP over time. Transmission electron microscopy detected GNP in the keratocytes and the extracellular matrix of the rabbit corneas. …

Significant Inhibition Of Corneal Scarring In Vivo With Tissue-Selective, Targeted Aav5 Decorin Gene Therapy, Rajiv R. Mohan, Ashish Tandon, Ajay Sharma, John W. Cowden, Jonathan C. K. Tovey

Pharmacy Faculty Articles and Research

PURPOSE. This study tested a hypothesis that tissue-selective targeted decorin gene therapy delivered to the stroma with adeno-associated virus serotype 5 (AAV5) inhibits corneal fibrosis in vivo without significant side effects.

METHODS. An in vivo rabbit model of corneal fibrosis was used. Targeted decorin gene therapy was delivered to the rabbit cornea by a single topical application of AAV5 (100 L; 6.5 1012 g/mL) onto the bare stroma for 2 minutes. The levels of corneal fibrosis were determined with stereomicroscopy, slit lamp biomicroscopy, -smooth muscle actin ( SMA), fibronectin, and F-actin immunocytochemistry, and/or immunoblotting. CD11b, F4/80 immunocytochemistry, and TUNEL assay …

Efficacious And Safe Tissue-Selective Controlled Gene Therapy Approaches For The Cornea, Rajiv R. Mohan, Sunilima Sinha, Ashish Tandon, Rangan Gupta, Jonathan C. K. Tovey, Ajay Sharma

Pharmacy Faculty Articles and Research

Untargeted and uncontrolled gene delivery is a major cause of gene therapy failure. This study aimed to define efficient and safe tissue-selective targeted gene therapy approaches for delivering genes into keratocytes of the cornea in vivo using a normal or diseased rabbit model. New Zealand White rabbits, adeno-associated virus serotype 5 (AAV5), and a minimally invasive hair-dryer based vector-delivery technique were used. Fifty microliters of AAV5 titer (6.561012 vg/ml) expressing green fluorescent protein gene (GFP) was topically applied onto normal or diseased (fibrotic or neovascularized) rabbit corneas for 2-minutes with a custom vector-delivery technique. Corneal fibrosis and neovascularization in rabbit …