Other Medical Sciences Commons^™

Investigation Of Radiation Injury In The Esophagus From Definitive Chemoradiation Therapy Using Novel Imaging Biomarkers, Joshua S. Niedzielski

Dissertations & Theses (Open Access)

Radiation injury in the esophagus occurs with high frequency from the treatment of non-small cell lung cancer (NSCLC). Radiation esophagitis is an acute normal tissue toxicity that negatively affects treatment efficacy by limiting dose and potentially interrupting radiation therapy. Clinical quantification of this toxicity is typically achieved by utilizing physician grading scales, assigning complication severity on an ordinal scale of symptom presentation and/or physician chosen interventions. These criteria are subjective in nature, both from the physician assigning the grade and the patient reporting the symptom. Furthermore, radiation therapy planning guidelines for the esophagus are derived from toxicity prediction models utilizing …

Animal-Friendly Affinity Reagents: Replacing The Needless In The Haystack, A. C. Gray, S. S. Sidhu, P. C. Chandrasekera, C. F.M. Hendriksen, C. A.K. Borrebaeck

Biomedicine and Animal Models in Research Collection

The multibillion-dollar global antibody industry produces an indispensable resource but that is generated using millions of animals. Despite the irrefutable maturation and availability of animal-friendly affinity reagents (AFAs) employing na€ive B lymphocyte or synthetic recombinant technologies expressed by phage display, animal immunisation is still authorised for antibody production. Remarkably, replacement opportunities have been overlooked, despite the enormous potential reduction in animal use. Directive 2010/63/EU requires that animals are not used where alternatives exist. To ensure its implementation, we have engaged in discussions with the EU Reference Laboratory for alternatives to animal testing (EURL ECVAM) and the Directorate General for Environment …

Epoxyeicosatrienoic Acids Regulate Adipocyte Differentiation Of Mouse 3t3 Cells, Via Pgc-1Α Activation, Which Is Required For Ho-1 Expression And Increased Mitochondrial Function, Maayan Waldman, Lars Bellner, Luca Vanella, Joseph Schragenheim, Komal Sodhi, Shailendra P. Singh, Daohong Lin, Anand Lakhkar, Jiangwei Li, Edith Hochhauser, Michael Arad, Zbigniew Darzynkiewicz, Attallah Kappas, Nader G. Abraham

Biochemistry and Microbiology

Epoxyeicosatrienoic acid (EET) contributes to browning of white adipose stem cells to ameliorate obesity/diabetes and insulin resistance. In the current study, we show that EET altered preadipocyte function, enhanced peroxisome proliferation-activated receptor γ coactivator α (PGC-1α) expression, and increased mitochondrial function in the 3T3-L1 preadipocyte subjected to adipogenesis. Cells treated with EET resulted in an increase, P < 0.05, in PGC-1α and a decrease in mitochondria-derived ROS (MitoSox), P < 0.05. The EET increase in heme oxygenase-1 (HO-1) levels is dependent on activation of PGC-1α as cells deficient in PGC-1α (PGC-1α knockout adipocyte cell) have an impaired ability to express HO-1, P < 0.02. Additionally, adipocytes treated with EET exhibited an increase in mitochondrial superoxide dismutase (SOD) in a PGC-1α-dependent manner, P < 0.05. The increase in PGC-1α was associated with an increase in β-catenin, P < 0.05, adiponectin expression, P < 0.05, and lipid accumulation, P < 0.02. EET decreased heme levels and mitochondria-derived ROS (MitoSox), P < 0.05, compared to adipocytes that were untreated. EET also decreased mesoderm-specific transcript (MEST) mRNA and protein levels (P < 0.05). Adipocyte secretion of EET act in an autocrine/paracrine manner to increase PGC-1α is required for activation of HO-1 expression. This is the first study to dissect the mechanism by which the antiadipogenic and anti-inflammatory lipid, EET, induces the PGC-1α signaling cascade and reprograms the adipocyte phenotype by regulating mitochondrial function and HO-1 expression, leading to an increase in healthy, that is, small, adipocytes and a decrease in adipocyte enlargement and terminal differentiation. This is manifested by an increase in mitochondrial function and an increase in the canonical Wnt signaling cascade during adipocyte proliferation and terminal differentiation.

Pnaktide Inhibits Na/K-Atpase Reactive Oxygen Species Amplification And Attenuates Adipogenesis, Komal Sodhi, Kyle Maxwell, Yanling Yan, Jiang Liu, Muhammad Chaudhry, Morgan Getty, Zijian Xie, Nader G. Abraham, Joseph I. Shapiro Md

Yanling Yan

Obesity has become a worldwide epidemic and is a major risk factor for metabolic syndrome. Oxidative stress is known to play a role in the generation and maintenance of an obesity phenotype in both isolated adipocytes and intact animals. Because we had identified that the Na/K-ATPase can amplify oxidant signaling, we speculated that a peptide designed to inhibit this pathway, pNaKtide, might ameliorate an obesity phenotype. To test this hypothesis, we first performed studies in isolated murine preadipocytes (3T3L1 cells) and found that pNaKtide attenuated oxidant stress and lipid accumulation in a dose-dependent manner. Complementary experiments in C57Bl6 mice fed …

Cell-To-Cell Transmission Of Dipeptide Repeat Proteins Linked To C9orf72-Als/Ftd., Thomas Westergard, Brigid K Jensen, Xinmei Wen, Jingli Cai, Elizabeth Kropf, Lorraine Iacovitti, Piera Pasinelli, Davide Trotti

Farber Institute for Neuroscience Faculty Papers

Aberrant hexanucleotide repeat expansions in C9orf72 are the most common genetic change underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). RNA transcripts containing these expansions undergo repeat-associated non-ATG translation (RAN-T) to form five dipeptide repeat proteins (DPRs). DPRs are found as aggregates throughout the CNS of C9orf72-ALS/FTD patients, and some cause degeneration when expressed in vitro in neuronal cultures and in vivo in animal models. The spread of characteristic disease-related proteins drives the progression of pathology in many neurodegenerative diseases. While DPR toxic mechanisms continue to be investigated, the potential for DPRs to spread has yet to be determined. …

Continuous Care In Complex Contexts: Access To Health Services For Noncommunicable Diseases Among Syrian Refugee Women In Jordanian Host Communities, Jennifer Ostrowski

Independent Study Project (ISP) Collection

This study examines how, when and where Syrian refugee women living in a host community in central Jordan access health services related to noncommunicable diseases. Noncommunicable diseases are the leading cause of death and disability worldwide, but can be effectively managed through timely treatment. Examining access to care for these diseases in the context of humanitarian emergencies, such as war and displacement, is particularly important because they require continuous care, which may be interrupted during emergencies, and because they can cause acute complications, which may be exacerbated by emergencies (WHO, 2016).

Previous studies indicate a high burden of NCDs among …

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

Jonathan Balcombe, 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 Examination Of Chimpanzee Use In Human Cancer Research, Jarrod Bailey

Jarrod Bailey, PhD

Advocates of chimpanzee research claim the genetic similarity of humans and chimpanzees make them an indispensable research tool to combat human diseases. Given that cancer is a leading cause of human death worldwide, one might expect that if chimpanzees were needed for, or were productive in, cancer research, then they would have been widely used. This comprehensive literature analysis reveals that chimpanzees have scarcely been used in any form of cancer research, and that chimpanzee tumours are extremely rare and biologically different from human cancers. Often, chimpanzee citations described peripheral use of chimpanzee cells and genetic material in predominantly human …

Monkey-Based Research On Human Disease: The Implications Of Genetic Differences, Jarrod Bailey

Jarrod Bailey, PhD

Assertions that the use of monkeys to investigate human diseases is valid scientifically are frequently based on a reported 90–93% genetic similarity between the species. Critical analyses of the relevance of monkey studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for monkeys to constitute good models for research, and that monkey data do not translate well to progress in clinical practice for humans. Salient examples include the failure of new drugs in clinical trials, the highly different infectivity and pathology of SIV/HIV, and poor extrapolation of research on Alzheimer’s disease, Parkinson’s …

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

Jarrod Bailey, PhD

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 …

Animal Carcinogenicity Studies: Implications For The Reach System, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, PhD

The 2001 European Commission proposal for the Registration, Evaluation and Authorisation of Chemicals (REACH) aims to improve public and environmental health by assessing the toxicity of, and restricting exposure to, potentially toxic chemicals. The greatest benefits are expected to accrue from decreased cancer incidences. Hence the accurate identification of chemical carcinogens must be a top priority for the REACH system. Due to a paucity of human clinical data, the identification of potential human carcinogens has conventionally relied on animal tests. However, our survey of the US Environmental Protection Agency’s (EPA’s) toxic chemicals database revealed that, for a majority of the …

Animal Carcinogenicity Studies: 3. Alternatives To The Bioassay, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, PhD

Conventional animal carcinogenicity tests take around three years to design, conduct and interpret. Consequently, only a tiny fraction of the thousands of industrial chemicals currently in use have been tested for carcinogenicity. Despite the costs of hundreds of millions of dollars and millions of skilled personnel hours, as well as millions of animal lives, several investigations have revealed that animal carcinogenicity data lack human specificity (i.e. the ability to identify human non-carcinogens), which severely limits the human predictivity of the bioassay. This is due to the scientific inadequacies of many carcinogenicity bioassays, and numerous serious biological obstacles, which render profoundly …

Animal Carcinogenicity Studies: 1. Poor Human Predictivity, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, PhD

The regulation of human exposure to potentially carcinogenic chemicals constitutes society’s most important use of animal carcinogenicity data. Environmental contaminants of greatest concern within the USA are listed in the Environmental Protection Agency’s (EPA’s) Integrated Risk Information System (IRIS) chemicals database. However, of the 160 IRIS chemicals lacking even limited human exposure data but possessing animal data that had received a human carcinogenicity assessment by 1 January 2004, we found that in most cases (58.1%; 93/160), the EPA considered animal carcinogenicity data inadequate to support a classification of probable human carcinogen or non-carcinogen. For the 128 chemicals with human or …

Which Drugs Cause Cancer?, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, PhD

Animal tests yield misleading results.

An Analysis Of The Use Of Animal Models In Predicting Human Toxicology And Drug Safety, Jarrod Bailey, Michelle Thew, Michael Balls

Jarrod Bailey, PhD

Animal use continues to be central to preclinical drug development, in spite of a lack of its demonstrable validity. The current nadir of new drug approvals and the drying-up of pipelines may be a direct consequence of this. To estimate the evidential weight given by animal data to the probability that a new drug may be toxic to humans, we have calculated Likelihood Ratios (LRs) for an extensive data set of 2,366 drugs, for which both animal and human data are available, including tissue-level effects and MedDRA Level 1–4 biomedical observations. This was done for three preclinical species (rat, mouse …

Cancerous Contradictions: The Mis-Regulation Of Human Carcinogens Based On Animal Data, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, PhD

The regulation of human exposures to potential carcinogens constitutes society’s most important use of animal carcinogenicity data. However, for environmental contaminants of greatest U.S. concern, we found that in most cases (58.1%; 93/160) the U.S. Environmental Protection Agency (EPA) considered the animal data inadequate to support a classification of probable human carcinogen or noncarcinogen.

The World Health Organisation’s International Agency for Research on Cancer (IARC) is a leading international authority on carcinogenicity assessments. For chemicals lacking human exposure data (the great majority), IARC classifications of identical chemicals were significantly more conservative than EPA classifications (p

Animal Carcinogenicity Studies: 2. Obstacles To Extrapolation Of Data To Humans, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, PhD

Due to limited human exposure data, risk classification and the consequent regulation of exposure to potential carcinogens has conventionally relied mainly upon animal tests. However, several investigations have revealed animal carcinogenicity data to be lacking in human predictivity. To investigate the reasons for this, we surveyed 160 chemicals possessing animal but not human exposure data within the US Environmental Protection Agency chemicals database, but which had received human carcinogenicity assessments by 1 January 2004. We discovered the use of a wide variety of species, with rodents predominating, and of a wide variety of routes of administration, and that there were …

Sample Size Formulas For Estimating Intraclass Correlation Coefficients In Reliability Studies With Binary Outcomes, Mengxiao Xu

Electronic Thesis and Dissertation Repository

Introduction: Measurement errors can seriously affect quality of clinical practice and medical research. It is therefore important to assess such errors by conduct- ing studies to estimate a coefficients reliability and assessing its precision. The intraclass correlation coefficient (ICC), defined on a model that an observation is a sum of information and random error, has been widely used to quantify reliability for continuous measurements. Sample formulas have been derived for explicitly incorporation of a prespecified probability of achieving the prespecified precision, i.e., the width or lower limit of a confidence interval for ICC. Although the concept of ICC is applicable …

Oncology Edge Task Force On Prostate Cancer Outcomes: A Systematic Review Of Outcome Measures For Functional Mobility, Claire Davies, Genevieve Colon, Hannah Geyer, Lucinda Pfalzer, Mary Insana Fisher

Mary Insana Fisher

Background: The medical treatment of prostate cancer results in multiple impairments in body structure and declines functional abilities, resulting in activity limitations and participation restrictions. Measurement of functional mobility is an essential outcome measure in survivorship care. Purpose: The purpose of this systematic review is to make recommendations of the best measurement tools to assess functional mobility in men treated for prostate cancer based on psychometric properties and clinical utility. Methods: Multiple electronic databases were searched from February to March 2014. Studies of tools used to assess functional mobility were included if they met the following criteria: reported psychometric properties, …

Pnaktide Inhibits Na/K-Atpase Reactive Oxygen Species Amplification And Attenuates Adipogenesis, Komal Sodhi, Kyle Maxwell, Yanling Yan, Jiang Liu, Muhammad Chaudhry, Morgan Getty, Zijian Xie, Nader G. Abraham, Joseph I. Shapiro Md

Zijian Xie

Obesity has become a worldwide epidemic and is a major risk factor for metabolic syndrome. Oxidative stress is known to play a role in the generation and maintenance of an obesity phenotype in both isolated adipocytes and intact animals. Because we had identified that the Na/K-ATPase can amplify oxidant signaling, we speculated that a peptide designed to inhibit this pathway, pNaKtide, might ameliorate an obesity phenotype. To test this hypothesis, we first performed studies in isolated murine preadipocytes (3T3L1 cells) and found that pNaKtide attenuated oxidant stress and lipid accumulation in a dose-dependent manner. Complementary experiments in C57Bl6 mice fed …