Translational Medical Research Commons^™

Developing Radiosensitizers To Enhance Radiotherapy In Treating Gastroenteropancreatic Neuroendocrine Tumor, Zeta Chow

Theses and Dissertations--Clinical and Translational Science

Gastroenteropancreatic Neuroendocrine Tumor (GEP-NET) is a heterogeneous group of malignancies arising from multipotent neuroendocrine stem cells in the gastrointestinal tract. The incidence of GEP-NET continues to rise, possibly due to the advancement of imaging and biomarkers available for diagnosis. However, even though the majority of patients are diagnosed with low-grade and localized disease, a significant percentage of patients present with advanced-stage metastatic disease with poor prognosis in months to a few years. These advanced-stage GEP-NET patients can also present with a variety of debilitating symptoms that significantly impact their quality of life. The role of palliative-intent surgery is limited, and …

Modulating The Mtor Pathway Using Inducible Retrogradely Transported Aavs As A Novel Approach To Improve Motor Recovery In Spinal Cord Injury, Christopher Bosse-Joseph

Theses and Dissertations--Medical Sciences

Spinal cord injury poses multiple regeneration barriers, including neuronal-intrinsic and extrinsic factors. Overcoming these barriers has stood as a longstanding challenge in neuroscience. A well-studied mechanism to promote spinal cord regeneration and locomotor recovery is activating the PI3K/mTOR pathway by knocking out phosphatase and tensin homolog protein (PTEN). PTEN knockout (PTEN-KO) studies have traditionally used adeno-associated virus (AAV) viral vectors to improve functional recovery. The use of traditional AAV serotypes to induce PTEN-KO has shown promise to improve functional recovery in rodent models; however, these approaches show significant limitations for translational utility. Firstly, the use of traditional AAV serotypes to …

Mitochondria As Causes Of And Therapeutic Targets In Chronic Post-Sepsis Skeletal Muscle Weakness, Meagan Scott Kingren

Theses and Dissertations--Pharmacology and Nutritional Sciences

Sepsis, or the organ damage that ensues after the body fails to properly contain a local infection, is the leading cause of in-patient hospitalization in the United States. Advances in critical care medicine over the last 20 years have enabled most sepsis patients to survive the life-threatening dysregulated immune response. However, a majority of survivors report chronic weakness and fatigue years after sepsis, and the cause of this weakness remains largely unknown. This dissertation work focused first on elucidating the major causes of post-sepsis muscle weakness (Aim 1). This aim involved a time-course study to determine when muscle weakness was …

Alzheimer’S Disease Genetics And Short-Chain Fatty Acid Treatment In Studies Of The Murine Gut Microbiome, Diana Zajac

Theses and Dissertations--Physiology

Elucidating the relationship of the gut microbiome in Alzheimer's Disease (AD) risk and pathogenesis is an area of intense interest. Since 60 to 80% of AD risk is related to genetics and APOE alleles represent the most impactful genetic risk factors for AD, their mechanism(s) of action are under intense scrutiny.

First, I conducted a study on APOE targeted replacement mice to investigate the impact of APOE alleles on the murine gut microbiome. The relative abundance of bacteria from the family Ruminococacceae and related genera increased with APOE2 status. The relative abundance of the class Erysipelotrichia increased with APOE4 status, …

Assessment Of The Interplay Between Regional Β-Amyloid Burden And White Matter Hyperintensities On Cognition And Default Mode Network In Clinically Normal Older Participants, Doaa G. Ali

Theses and Dissertations--Clinical and Translational Science

Objective: Alzheimer’s disease (AD) and subcortical vascular dementia are considered the most common pathologic contributors to dementia in the aging population. Both frequently coexist in over 80% of community dwelling adults with dementia. The neuropathological development of AD arguably begins with β-amyloid (Aβ) deposition in the brain. This series of studies aims to test the hypothesis that early focal regional amyloid deposition in the brain is associated with cognitive performance in specific cognitive domain scores in preclinical AD (pAD) (study1). Since mixed dementia is widely recognized as the norm rather than the exception, the second study aimed to explore the …

Regulation Of Skeletal Muscle Plasticity By The Gut Microbiome, Taylor R. Valentino

Theses and Dissertations--Physiology

Recent evidence suggests that the gut microbiome could play a role in skeletal muscle plasticity, providing novel treatments for muscle wasting diseases and/or performance enhancements. I first sought to determine if the gut microbiome is necessary for skeletal muscle adaptation to exercise. Forty-two, four-month old, female C57Bl/6J underwent nine weeks of weighted wheel running or remained in cage with a locked wheel, without or without the administration of antibiotics (treated). In response to wheel running, I found that antibiotic depletion of the microbiome led to a blunted hypertrophic response in the soleus muscle as measured by normalized muscle wet weight …

Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids To Predict Carboplatin Resistance, Justin W. Gorski

Theses and Dissertations--Clinical and Translational Science

The development of patient-derived tumor organoids (TOs) from epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine.

Here, we utilize TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high grade serous epithelial ovarian cancer tumor organoids from tissue obtained during debulking surgery (2 neoadjuvant carboplatin exposed, 4 chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1 and 0.1µM). Cell viability curves and resultant EC50 values were determined …

Human Regulatory T Cells Control Inflammation From Effector T Cells In Prediabetes, Rui Liu

Theses and Dissertations--Pharmacy

Type 2 diabetes (T2D) is a chronic low-grade inflammatory disease. A T cell cytokine profile (Th17) from PBMCs can distinguish obese T2D from obese non-diabetes subjects. Individual T cell subsets interact with each other and the diverse subsets jointly determine overall inflammation. Cellular metabolism drives cytokine production of CD4⁺ T cells, and therefore contributes to inflammation in T2D. However, specific changes in metabolism and function of CD4⁺ T cells during the progression from lean healthy to obese and diabetic stages in people have not been clarified.

We hypothesize that human regulatory T cells (Treg) impact metabolism of effector …

The Use Of Mechanotherapy To Promote The Recovery From Disuse Atrophy In Aging Rat Skeletal Muscle, Zachary Hettinger

Theses and Dissertations--Rehabilitation Sciences

The combination of age and disuse-related skeletal muscle atrophy predisposes older adults to reduced mobility, loss of independence, and poor quality of life. Poor health outcomes resulting from periods of disuse in older adults are exacerbated by an inability to fully recover, ultimately accelerating geriatric populations towards further functional decline. Aged-related changes to skeletal muscle viscoelastic properties, specifically of muscle extracellular matrix (ECM) stiffness, may not only impact how muscle responds during recovery, but also to interventions intended to augment recovery. Remodeling of muscle ECM in the aged may therefore benefit muscle mass recovery, yet therapies focused on ECM remodeling …

Atv Dynamics And Pediatric Rider Safety, James T. Auxier Ii

Theses and Dissertations--Biomedical Engineering

It has been observed through numerous academic and governmental agency studies that pediatric all-terrain vehicle ridership carries significant risk of injury and death. While no doubt valuable to safety, the post-hoc approach employed in these studies does little to explain the why and how behind the risk factors. Furthermore, there has been no prolonged, widespread, organized, and concerted effort to reconstruct and catalog the details and causes of the large (20,000+) number of ATV-related injuries that occur each year as has been done for road-based motor vehicle accidents. This dissertation takes the opposite approach from a meta-analysis and instead examines …

Transcriptomic And Cellular Response To Mechanical Overload And The Underlying Role Of Macrophages In Extracellular Matrix Remodeling, Bailey D. Peck

Theses and Dissertations--Rehabilitation Sciences

The extracellular matrix (ECM) in skeletal muscle plays an integral role in tissue development, structural support, and force transmission. Upon mechanical loading, including resistance exercise, which alter muscle fiber contractile activity, size, orientation and connectivity, remodeling processes must occur that involve both ECM deposition and degradation. ECM remodeling involves many cell types in muscle, but the focus of our research was directed towards macrophages, which participate in the early immune response to damage and loading. We have consistently demonstrated a significant increase in skeletal muscle macrophage abundance using pan macrophage markers (CD11b/CD68) and anti-inflammatory markers (CD206/CD163) following exercise training in …

Knee Joint Loading Following Anterior Cruciate Ligament Reconstruction: Link To Patient Reported Outcomes And A Novel Method To Monitor With Wearable Sensors, Alex Spencer

Theses and Dissertations--Kinesiology and Health Promotion

Recovery from anterior cruciate ligament reconstruction (ACLR) commonly results in undesirable physical and patient-reported outcomes (PROs). Identification of modifiable factors such as knee contact force (KCF) early in rehabilitation that can improve these outcomes is important due to the rapid decrease in function, quality of life, and joint health in this population. Additionally, if noninvasive measurement of KCFs outside of a traditional laboratory were possible, clinicians could optimize patient treatment with personalized care. Therefore, there are two primary aims to this thesis: 1) quantify the link between KCF and PROs which measure pain, ability to perform activities of daily living, …

A Brain-Computer Interface For Closed-Loop Sensory Stimulation During Motor Training In Patients With Tetraplegia, Sarah Helen Thomas

Theses and Dissertations--Biomedical Engineering

Normal movement execution requires proper coupling of motor and sensory activation. An increasing body of literature supports the idea that incorporation of sensory stimulation into motor rehabilitation practices increases its effectiveness. Paired associative stimulation (PAS) studies, in which afferent and efferent pathways are activated in tandem, have brought attention to the importance of well-timed stimulation rather than non-associative (i.e., open-loop) activation. In patients with tetraplegia resulting from spinal cord injury (SCI), varying degrees of upper limb function may remain and could be harnessed for rehabilitation. Incorporating associative sensory stimulation coupled with self-paced motor training would be a means for supplementing …

Development Of Mithramycin Analogues With Improved Efficacy And Reduced Toxicity For Treatment Of Ets-Dependent Tumors In Ewing Sarcoma And Prostate Cancer, Joseph Michael Eckenrode

Theses and Dissertations--Pharmacy

Introduction: Genetic rearrangements in Ewing sarcoma, prostate, and leukemia cells result in activation of oncogenic ETS transcription factor fusions. Mithramycin (MTM) has been identified as an inhibitor of EWS-FLI1 transcription factor, a gene fusion product responsible for oncogenesis in Ewing sarcoma. Despite preclinical success, a phase I/II clinical trial testing MTM therapy in refractory Ewing sarcoma was terminated. Liver and blood toxicities resulted in dose de-escalation and sub-therapeutic exposures. However, the promise of selectively targeting oncogenic ETS transcription factors like EWS-FLI1 prompted us to undertake the discovery of more selective, less toxic analogues of MTM. MTM is a potent inhibitor …

Integrin Α5Β1 As A Novel Target With The Small Peptide, Atn-161, In The Treatment Of Ischemic Stroke, Danielle Nichele Edwards

Theses and Dissertations--Neuroscience

Stroke is the 5^th leading cause of death and the leading cause of disability in the United States, but there are only two available therapies, tissue plasminogen activator and endovascular thrombectomy. As both therapies focus on removal of the clot, the subsequent pathologic processes, i.e. inflammation, cerebrovascular breakdown, ATP depletion, etc. are left untreated, contributing to worsened patient outcome. Many clinical trials have unsuccessfully attempted to address these mechanisms. The blood-brain barrier (BBB), a system of non-fenestrated endothelial cells, extracellular matrix, and astrocytic endfeet, is significantly impacted after ischemic stroke in its role of preventing the free movement of …

Autologous Peripheral Nerve Grafts To The Brain For The Treatment Of Parkinson's Disease, Andrew Welleford

Theses and Dissertations--Neuroscience

Parkinson’s disease (PD) is a disorder of the nervous system that causes problems with movement (motor symptoms) as well as other problems such as mood disorders, cognitive changes, sleep disorders, constipation, pain, and other non-motor symptoms. The severity of PD symptoms worsens over time as the disease progresses, and while there are treatments for the motor and some non-motor symptoms there is no known cure for PD. Thus there is a high demand for therapies to slow the progressive neurodegeneration observed in PD. Two clinical trials at the University of Kentucky College of Medicine (NCT02369003, NCT01833364) are currently underway that …

A Pilot Study Of A Multiple Health Behavior Change Intervention For Smokers, Srihari Seshadri

Theses and Dissertations--Clinical and Translational Science

Background: Being both obese and a smoker increases the probability of developing type 2 diabetes, cardiovascular disease, and cancer, diseases that impact Kentucky residents disproportionately. Kentucky (KY) has a high incidence of obesity (34.2%) and smoking (24.5 %). Weight gain associated with smoking cessation also can undermine health benefits of quitting, and may lead to smoking relapse.

Aim: The aim of the pilot study was to implement and evaluate a Multiple Health Behavioral Change (MHBC) program that combines Cooper Clayton Method to Stop Smoking (CCMSS) and the Diabetes Prevention Program (DPP) for weight control.

Method: A 15-week intervention was administered …

Design And Analysis Of A 3d-Printed, Thermoplastic Elastomer (Tpe) Spring Element For Use In Corrective Hand Orthotics, Kevin Thomas Richardson

Theses and Dissertations--Mechanical Engineering

This thesis proposes an algorithm that determine the geometry of 3D-printed, custom-designed spring element bands made of thermoplastic elastomer (TPE) for use in a wearable orthotic device to aid in the physical therapy of a human hand exhibiting spasticity after stroke. Each finger of the hand is modeled as a mechanical system consisting of a triple-rod pendulum with nonlinear stiffness at each joint and forces applied at the attachment point of each flexor muscle. The system is assumed quasi-static, which leads to a torque balance between the flexor tendons in the hand, joint stiffness and the design force applied to …

Scalable Feature Selection And Extraction With Applications In Kinase Polypharmacology, Derek Jones

Theses and Dissertations--Computer Science

In order to reduce the time associated with and the costs of drug discovery, machine learning is being used to automate much of the work in this process. However the size and complex nature of molecular data makes the application of machine learning especially challenging. Much work must go into the process of engineering features that are then used to train machine learning models, costing considerable amounts of time and requiring the knowledge of domain experts to be most effective. The purpose of this work is to demonstrate data driven approaches to perform the feature selection and extraction steps in …

The Mechanical Properties Of Non-Failing And Failing Human Myocardium, Cheavar A. Blair

Theses and Dissertations--Physiology

Heart failure is a clinical syndrome that manifests when there are structural and functional impairments to the heart that reduces the ability of the ventricles to fill or eject blood. The syndrome affects ~6 million Americans and is responsible for nearly 300,000 deaths annually. At the core of the syndrome are dysfunctional sarcomeres, the machinery that drives cardiac contraction and relaxation. By assessing the mechanical properties of human cardiac tissue, the information provided in this dissertation will provide data that demonstrates how sarcomeric dysfunction contributes to heart failure in the left and right ventricles. Additionally, these data will supply information …

New Insights Into Post-Sepsis Muscle Weakness Elucidated Using A Novel Animal Model, Allison M. Steele

Theses and Dissertations--Physiology

Sepsis is a severe life-threatening critical illness that damages multiple physiological systems. After hospital discharge, more than 70% of severe sepsis survivors report profound weakness which significantly impacts quality of life. Such weakness gives rise to new limitations of daily living, which ultimately leads to loss of independence in many patients. Despite wide recognition of this serious issue by clinicians and researchers alike, the mechanisms contributing to chronic skeletal muscle dysfunction after sepsis are not well understood. Lack of progress in this field is largely due to the absence of an appropriate animal model; current models are either too mild …

Overcoming Treatment Resistance In Heterogeneous Tumors, Nikhil Hebbar

Theses and Dissertations--Toxicology and Cancer Biology

Most primary tumors are heterogeneous and are often composed of therapy-sensitive and emerging therapy-resistant cancer cells. Rather unexpectedly, treatment of therapy-sensitive tumor cells in heterogeneous tumor microenvironments resulted in apoptosis of the therapy-resistant cancer cells. We identified a novel Par-4 amino-terminal fragment (PAF, which includes amino acids 1-131 of Par-4) that is produced and released by therapy-sensitive cancer cells following therapy-induced caspase-dependent cleavage of the tumor suppressor Par-4. PAF caused paracrine apoptosis in therapy-resistant cancer cells. Unlike Par-4-inducible apoptosis, which is dependent on the cell surface GRP78 receptor, PAF produced cancer-selective apoptosis independent of cell surface GRP78 function. Par-4 contains …

Surface-Initiated Polymerizations For The Rapid Sorting Of Rare Cancer Cells, Jacob L. Lilly

Theses and Dissertations--Chemical and Materials Engineering

Cancer metastasis directly accounts for an estimated 90% of all cancer related deaths and is correlated with the presence of malignant cells in systemic circulation. This observed relationship has prompted efforts to develop a fluid biopsy, with the goal of detecting these rare cells in patient peripheral blood as surrogate markers for metastatic disease as a partial replacement or supplement to tissue biopsies. Numerous platforms have been designed, yet these have generally failed to support a reliable fluid biopsy due to poor performance parameters such as low throughput, low purity of enriched antigen positive cells, and insufficiently low detection thresholds …

The Role Of Fat Grafting And Adipose-Derived Stem Cells In Breast Reconstruction, Krishna S. Vyas

Theses and Dissertations--Clinical and Translational Science

Fat grafting is a common surgical procedure that involves the transfer of fat from one area of the body to another in order to improve contour deformities, such as in breast reconstruction. Advantages of the technique include using autologous tissue rather than a foreign body and the added benefit of having liposuction to remove fat from an undesirable location. Although adipose tissue could be the ideal soft tissue filler, fat grafting is plagued by tremendous variability in long-term retention, with volume survival rates of 20-80%, resulting in suboptimal outcomes and repetitive procedures.

The mechanisms contributing to long-term fat graft survival …

The Metabolomic Effects Of Metformin On Colon Cancer, Jennifer W. Harris

Theses and Dissertations--Clinical and Translational Science

Metformin is an oral biguanide that is prescribed to over 120 million people worldwide for the treatment of conditions including type II diabetes mellitus, polycystic ovarian syndrome, and gestational diabetes. This hypoglycemic agent is rapidly emerging as a potential cost-effective anti-oncogenic agent. Over the past decade multiple epidemiologic studies have consistently associated metformin with decreased cancer incidence and cancer-related mortality. More recently numerous preclinical and clinical studies have demonstrated anti-cancer effects of metformin, leading to the proposal of numerous clinical trials to better understand this drug and its mechanism of action.

Previously experts believed metformin primarily targeted AMP-activated protein kinase …

Exploration Of Factors Associated With Patient Adherence In Upper Extremity Rehabilitation: A Mixed-Methods Embedded Design, Enrique V. Smith-Forbes

Theses and Dissertations--Rehabilitation Sciences

Adherence is considered a prerequisite for the success of exercise programs for musculoskeletal disorders. The negative effects of non-adherence to exercise recommendations impact the cost of care, and also treatment effectiveness, treatment duration, the therapeutic relationship, waiting times, the efficiency of personnel and use of equipment. Adherence to therapeutic exercise intervention is a multifaceted problem.

The World Health Organization (WHO) established the multidimensional adherence model (MAM). The MAM describes five interactive dimensions (socioeconomic, healthcare team and system, condition-related, therapy-related, and patient-related factors) that have an effect on patient adherence.

The first purpose of this dissertation was to explore the MAM …

Emergency Nurses' Knowledge Of Pediatric Complaints, Kari J. Blackburn

DNP Projects

Each year there are more than 25 million pediatric emergency department (ED) visits, with 37-60% of the complaints being non-urgent (Brosseau, Hoffman, Nattinger, Flores, Zhang and Gorelick, 2007). Injury is the number one reason children present to the ED and is strongly associated with a complaint of pain (AHRQ, 2013). While pain is a high volume reason for visiting the ED, there are other presentation causes that may pose a high risk to pediatric patients. Nausea and vomiting is not typically viewed as a high risk complaint, yet there are some high risk etiologies resulting in nausea and vomiting that …

Primary And Secondary Prevention Of Hepatitis C Virus Among Rural Appalachian People Who Use Drugs, Dustin B. Stephens

Theses and Dissertations--Clinical and Translational Science

Hepatitis C virus (HCV) remains a major cause of morbidity and mortality worldwide, with 3% of the global population chronically infected. Clinical impacts in the United States are projected to increase for two decades, and mortality attributed to HCV now exceeds HIV. Injection drug use (IDU) is the most common route of transmission in the developed world. Advances in treatment offer hope of mitigating HCV impacts, but substantial barriers obstruct people who inject drugs (PWID) from receiving care, particularly in medically underserved regions including Central Appalachia. This study assessed IDU paraphernalia sharing longitudinally over 24 months in a sample of …