Medicine and Health Sciences 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 …

Enhancing Dna-Damaging Therapy Through The Inhibition Of Dntp Synthesis Using A Synergistic Drug Combination To Treat Pancreatic Neuroendocrine Neoplasms, Jennifer Castle Md

Theses and Dissertations--Clinical and Translational Science

Despite clinical advances, pancreatic neuroendocrine neoplasms (pNEN) remain a difficult clinical entity to treat and can carry a poor prognosis. Systemic therapy is used to treat pNENs which are not amenable to surgical resection. Peptide receptor radionuclide therapy, a form of radiation therapy (RT) and cisplatin are two different forms of DNA-damaging therapy in current use to treat pNENs. However, their efficacy remains poor as single agents. This study aimed to increase the sensitivity of pNENs to the DNA-damaging agents, RT and cisplatin, by inhibiting deoxynucleotide triphosphate (dNTP) synthesis. Triapine, a ribonucleotide reductase inhibitor (RNRi), and ataxia telangiectasia and Rad3-related …

Novel Mechanism Of Endogenous Pancreatic Cancer Cell Expression Of Immune Checkpoint Programmed Cell-Death 1 Protein (Pd-1) Inducing Epithelial-To-Mesenchymal Transition (Emt) Through The Met Pathway And Promoting Cancer Progression In An Immune-Independent Process, Megan M. Harper

Theses and Dissertations--Clinical and Translational Science

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with few treatment options, necessitating an urgent need for novel therapeutics. Immuno-oncologic (IO) therapies have revolutionized anti-cancer regimens in the past decade but typically involve reactivation of adaptive immune responses. In particular, immune checkpoint PD-1 is traditionally expressed only on immune cells while PD-L1 (PD-1 ligand) is overexpressed on cancer cells. When tumor-endogenous PD-L1 binds the PD-1 receptor on T-cells, the immune cells undergo anergy resulting in self-tolerance and cancer cell immune evasion. However, contrary to standard dogma, we previously demonstrated tumor-endogenous PD-1 expression in PDAC. Our data indicated that …

Progressive Endoscopic Approach To Balloon Dilation For Benign Esophageal Strictures, Chad J. Cooper

Theses and Dissertations--Clinical and Translational Science

Benign esophageal strictures are a frequently encountered problem in clinical practice. The management of benign esophageal strictures have slowly evolved over the decades based on “expert opinion.” Despite vast amounts of data about the efficacy and safety of dilation, unfortunately there is no consensus on a systematic and safe approach that is efficient, limits complications and provides long lasting improvement of dysphagia. Our group designed a progressive approach to endoscopic balloon dilation based on tailoring certain technical aspects of the dilation process.

Most studies in the literature concluded that endoscopic dilation is safe and effective in relieving dysphagia caused by …

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 …

Precision Drug Delivery For Vancomycin Efficacy And Safety In Critically Ill Patients, Alexander Flannery

Theses and Dissertations--Clinical and Translational Science

Vancomycin is the most commonly prescribed antibiotic for hospitalized patients. Despite this fact and decades of clinical use, clinicians remain challenged to meet dosing targets of this narrow therapeutic index drug as well as minimize the risks of therapy, primarily nephrotoxicity. These concerns are magnified in critically ill patients given their severity. Accordingly, in a series of five clinical studies, we sought to identify optimal methods of vancomycin administration in critically ill patients to maximize efficacy and minimize nephrotoxicity via three techniques: use of continuous versus intermittent infusion, use of first-dose pharmacokinetic calculations to guide dosing, and use of loading …

The Effect Of Haptoglobin Phenotypes On Markers Of Neuroinflammation In Patients With Aneurysmal Subarachnoid Hemorrhage, Kevin Hatton

Theses and Dissertations--Clinical and Translational Science

Aneurysmal subarachnoid hemorrhage (aSAH) is a severe form of hemorrhagic stroke resulting from the spontaneous rupture of an intracranial aneurysm and release of oxygenated blood into the subarachnoid space. In the United States alone, aSAH occurs in approximately 30,000 patients each year and occurs, primarily, in otherwise healthy adults, frequently without warning. Sadly, approximately 40% of patients with aSAH will die in the first 30 days. Of those who survive, only about 75% will be able to live semi-independently again and only about 60% will be able to return to work.

Delayed brain injuries (DBI), which may affect up to …

Breast Implant-Associated Anaplastic Large Cell Lymphoma: Molecular Features, Epidemiological Risk Factors, And Evidence-Based Clinical Recommendations, Ryan Decoster

Theses and Dissertations--Clinical and Translational Science

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an emerging cancer of the immune system that can form around textured-surface breast implants. In this dissertation, the cellular and molecular mechanisms of BIA-ALCL are reviewed with a focus on the role of oncogenic JAK-STAT3 signaling in BIA-ALCL tumorigenesis and progression. Herein, the epidemiology of BIA-ALCL is systematically studied to better define the risk of BIA-ALCL and to determine the oncologic safety of smooth surface devices relative to BIA-ALCL formation. Next, a systematic review is conducted which critically appraises current clinical guidelines in order to establish an evidence base to better inform …

Understanding The Contributions Of Alzheimer’S Disease & Cardiovascular Risks To Cerebral Small Vessel Disease Manifest As White Matter Hyperintensities On Magnetic Resonance Imaging (Mri), Omar M. Al-Janabi

Theses and Dissertations--Clinical and Translational Science

Introduction: Alzheimer’s Diseases (AD) & cerebral small vessel disease associated with cardiovascular risk factors (cSVD) frequently coexist, differentially affecting both imaging and clinical features associated with aging and dementia. We hypothesized that Magnetic Resonance Imaging (MRI) can be used in novel ways to identify relative contributions of AD & cardiovascular risks to cSVD and brain atrophy, generating new biomarkers & insights into mixed disease states associated with cognitive decline and dementia.

Methods: Three experiments were conducted to address the overarching hypothesis. First, we visually rated the clinical MRI of 325 participants from a community-based cross-sectional sample to elucidate the relative …

Protocolized Volume De-Resuscitation In Critically Ill Patients, Brittany Dawn Bissell

Theses and Dissertations--Clinical and Translational Science

While early fluid resuscitation may be a necessary component to decrease mortality in the majority of critically ill patients admitted to the intensive care unit, the benefit of continued administration after the first 24 hours is less clear. Paradoxically, a positive fluid balance secondary to intravenous fluid receipt has been associated with diverse and persistent perpetuating detriment on a multitude of organ systems. Continued clinical harm has been demonstrated on pulmonary and renal function as well as patient outcomes such as rates of mortality and length of stay. Despite the growing body of evidence supporting the potential adverse aspects of …

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 …

Intermittent Hypoxemia In Preterm Infants, Elie G. Abu Jawdeh

Theses and Dissertations--Clinical and Translational Science

Intermittent hypoxemia (IH) is defined as episodic drops in oxygen saturation (SpO₂). Virtually all preterm infants have IH events. Extremely preterm infants have hundreds of IH events per day. The extent of IH is not apparent clinically as accurately documenting cardiorespiratory events for day-to-day patient care management is challenging. High resolution pulse oximeters with 2 second averaging time are currently the ideal methods to measure IH. We have developed novel methods and processes to accurately and efficiently calculate an IH profile that reflects to spectrum of the problem.

The natural progression of IH is dynamic. There is low …

Promotion Of Early Pediatric Hearing Detection Through Patient Navigation, Matthew L. Bush

Theses and Dissertations--Clinical and Translational Science

Congenital hearing loss is the most common neonatal sensory disorder and it is crucial to diagnose hearing loss as soon as possible after birth in order to facilitate rapid treatment. Universal standards of infant hearing healthcare dictate that infant hearing screening should be completed by one month of age and abnormal screening tests should be followed with definitive audiological testing by three months of age. Obtaining diagnostic testing can be complicated by limited access to care in rural areas, breakdowns in communication, lack of parental support, and poor coordination of care. There is no established method to address appointment non-adherence …

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 …

Clinical And Pathologic Significance Of Integrin Α6Β4 Expression In Human Malignancies, Rachel L. Stewart

Theses and Dissertations--Clinical and Translational Science

Integrins are cellular adhesion molecules that bind cells to the extracellular matrix. The integrin α6β4, a receptor for laminins, is predominantly expressed on epithelial cells where it is present at the basal surface adjacent to the basement membrane. This integrin plays a critical role in maintaining normal cellular functions, yet has also been implicated in promoting invasion and metastasis in human malignancies. While overexpression of the integrin α6β4 has been detected in select human cancers, the clinical significance of integrin α6β4 expression in a number of malignancies has not been determined. The purpose of this study was to examine integrin …

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 …