Doctor of Philosophy, The Ohio State University, 2022, Biomedical Sciences

Recently an increased appreciation for the systemic consequences of spinal cord injury (SCI) has re-emerged. These pathophysiological processes provide novel therapeutic targets, beyond central nervous system (CNS) regeneration, to improve clinical outcomes. This includes muscle wasting, an endemic consequence of SCI. Muscle tissue, even when not actively participating in movement of a limb, hosts additional crucial functions for SCI patients beginning already immediately after injury, as the loss of muscle tissue contributes to mortality, impaired functional recovery and the development of additional secondary complications. A deeper understanding of muscle pathophysiology early after SCI is necessary since current interventions are minimally effective and are not started until after considerable muscle wasting has already occurred. SCI disrupts connectivity between the nervous system and muscles, resulting in paralysis of muscles at and below the injury lesion level. Though denervation and inactivity of paralyzed muscles are common explanations for localized sublesional muscle atrophy, they cannot explain the rapid systemic wasting of non-paralyzed muscles retaining fully intact motor innervation from spinal cord levels rostral to the SCI lesion. Therefore, unidentified systemic mechanisms of muscle wasting present novel therapeutic targets to rescue muscle tissue during the critical acute period ‘bridging' between SCI and rehabilitation. To investigate systemic mechanism originating in the spinal cord we evaluated muscle after rodent SCI at two different thoracic levels. Both high and low thoracic SCI retain full forelimb innervation, but muscle wasting was further exacerbated by high thoracic SCI. Concurrently, high, compared to low, thoracic SCI exacerbates acute hypercortisolism. Accordingly, we hypothesized that glucocorticoid excess, by means of a putative SCI level-dependent hypercortisolism mechanism, represents a candidate catabolic signal exacerbating (open full item for complete abstract)

Committee: Jan Schwab (Advisor); Andrea Tedeschi (Committee Member); Phillip Popovich (Committee Member); William Arnold (Committee Member); Harold Fisk (Other) Subjects: Biomedical Research; Endocrinology; Experiments; Health; Health Sciences; Medicine; Neurobiology; Neurosciences; Rehabilitation

Master of Science, The Ohio State University, 2019, Allied Medicine

Chronic kidney disease (CKD) is a complex condition that leads to alterations in metabolism, nutrient requirements, and body composition due to progressive damage and loss of function to the kidneys. CKD is defined by the presence of kidney damage or decreased glomerular filtration rate (GFR 60 ml/min per 1.73 m2 ) for 3 months independent of etiology. This classification is further classified into five progressive stages based on the level of GFR. Individuals with CKD are at greater nutritional risk than healthy individuals. Undernutrition and malnutrition in patients with CKD may be due to inadequate energy and nutrient intake or due to metabolic changes and increased nutritional needs. Inadequate oral intake related to anorexia is common in patients with CKD. The metabolic changes of CKD require a constant balance of numerous nutrients in addition to assuring adequacy of protein to remain healthy enough for treatment options, including transplant. Malnutrition prevalence rates in individuals with CKD have been estimated to be anywhere from 18-75% This case series was designed to describe the use of portable ultrasound as a nutritional assessment tool in addition to standard practice in kidney transplant candidates. Each participant's nutrition status was assessed through anthropometric data, renal function laboratory values, and nutritional status screening including hand grip strength assessment, timed up and go test, triceps skinfold measurements, and a nutrition focused physical exam. Lastly, ultrasound measurements of the biceps and triceps muscles were measured. Results of this study indicate that no participants were diagnosed with malnutrition across all assessment tools. Muscle measurements completed through ultrasound imaging were not equivalent to other measurements taken. Further research on the use of this technology as a tool for nutritional assessment is necessary.

Committee: Marcia Nahikian-Nelms (Advisor) Subjects: Nutrition

Doctor of Philosophy, The Ohio State University, 2017, Comparative and Veterinary Medicine

Pancreatic cancer is the 3rd leading cause of cancer death in the United States and has a 5-year survival of less than 9% for all stages. Furthermore, cachexia, defined as severe weight loss due to depletion of muscle mass that is not reversible with conventional nutritional support, is seen in 85% of pancreatic cancer patients and contributes significantly to morbidity and mortality. Therefore, there is an urgent need to develop novel therapeutics that target tumor growth and muscle wasting in order to improve clinical outcomes. The first part of this study was aimed at evaluating the efficacy of AR-42, a novel histone deacetylase (HDAC) inhibitor developed in our laboratory, in suppressing tumor growth in mouse models of pancreatic cancer. The in vitro anti-proliferative activity of AR-42 was evaluated in six human pancreatic cancer cell lines. An AsPC-1 subcutaneous xenograft and transgenic KPfl/flC (LSL-KrasG12D;Trp53flox/flox;Pdx-1-Cre) mouse models of pancreatic cancer were used to evaluate the in vivo efficacy of AR-42 in suppressing tumor growth and/or muscle wasting. Growth suppression in AR-42-treated cells was observed in all six human pancreatic cancer cell lines with dose-dependent modulation of proliferation and apoptotic markers and hallmark features of HDAC inhibition, including p21 up-regulation and histone H3 hyperacetylation. Oral administration of AR-42 at 50 mg/kg every other day resulted in suppression of tumor burden in AsPC-1 xenograft and KPfl/flC models by 78% and 55%, respectively. Tumor suppression was associated with HDAC inhibition, increased apoptosis, and inhibition of proliferation. AR-42 as a single agent preserved muscle size and increased grip strength in KPfl/flC mice. Finally, the combination of AR-42 and gemcitabine in transgenic mice demonstrated a significant increase in survival than either agent alone. These results suggest that AR-42 represents a therapeutically promising strategy for the treatment of pancreatic cancer. (open full item for complete abstract)

Committee: Ching-Shih Chen PhD (Advisor); Mary-Jo Burkhard DVM, PhD, DACVP (clinical) (Committee Member); Thomas Ludwig PhD (Committee Member); Sue Knoblaugh DVM, DACVP (anatomic) (Committee Member) Subjects: Cellular Biology; Molecular Biology; Pharmacology

Doctor of Philosophy, The Ohio State University, 2013, Nursing

Purpose: Fatigue is the most common and distressing symptom reported by cancer patients, significantly reducing quality of life. While the mechanisms of cancer-related fatigue (CRF) are poorly understood, evidence indicates that pro-inflammatory cytokines and reactive oxygen species, produced by the tumor and/or host, alter muscle metabolism to cause muscle wasting and cardiac dysfunction. Symptoms of muscle wasting and cardiac dysfunction are weakness and decreased effort tolerance, similar to patients with CRF. Ubiquinol, an endogenously produced, lipid soluble antioxidant, protects against lipid peroxidation to cellular lipid membranes, proteins and DNA, and regenerates active forms of other antioxidants such as vitamins C and E. The purpose of this study was to determine if treatment with ubiquinol, might preserve muscle mass, improve cardiac function, and reduce fatigue in an animal model of CRF. The following hypotheses were tested in mice bearing the colon26 (C26) adenocarcinoma: 1. Ubiquinol will reduce the expression of biomarkers of muscle protein degradation and increase protein synthesis in the gastrocnemius and cardiac muscles of tumor-bearing mice; 2. Ubiquinol will increase: (a) muscle mass, (b) fore-limb grip strength, (c) in vivo cardiac function, and (d) voluntary running activity (VRA) in tumor-bearing mice and; 3. Ubiquinol will not affect tumor growth. Method: Eight week old adult female CD2F1 mice were acclimated to running wheels and grip strength 1 week prior to being inoculated with the tumor cells. Half of the control and half of the tumor bearing mice received ubiquinol 500 mg/kg/day in their drinking water. VRA and grip strength were measured on days 0, 8, 14 and 17 of tumor growth. Cardiac function was measured by echocardiography on day 18 or 19 after which the mice were euthanized. The heart and gastrocnemius muscles were weighed and normalized to body weight. Serum levels of proinflammatory cytokines were measured by ELISA. Oxid (open full item for complete abstract)

Committee: Donna McCarthy PhD (Advisor); Loren Wold PhD (Committee Member); Jodi McDaniel PhD (Committee Member); Laura Szalacha PhD (Committee Member) Subjects: Physiology