Medicine and Health Sciences Commons^™

Characterization Of 1,1-Diarylethylene Foxm1 Inhibitors Against High-Grade Serous Ovarian Carcinoma Cells, Cassie Liu

Theses & Dissertations

Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases, and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell …

Tourniquet-Induced Ischemia-Reperfusion Injury, Junliang Qian

Theses & Dissertations

Ischemia-reperfusion (IR) is a pathological condition characterized by an initial restriction of blood supply to an organ followed by subsequent restoration of reperfusion associated with exacerbation of tissue damage. For pre-hospital emergency situations and surgical procedures, tourniquet or femoral artery ligation are widely used to stop extremity hemorrhage or create a bloodless operating field. To fully evaluate the underlying mechanisms in IR pathophysiology and potential therapeutic options, we compared tourniquet- and femoral artery ligation-induced IR injuries in the hindlimb of mice. We found that tourniquet/IR-induced acute hindlimb injuries are more severe than those induced by femoral artery ligation/IR, including alteration …

Investigation Of Cumulative Genetic Risk And Cc16 In Adult Asthma And Copd Populations, Kelli C. Gribben

Theses & Dissertations

INVESTIGATION OF CUMULATIVE GENETIC RISK AND CC16 IN ADULT ASTHMA AND COPD POPULATIONS

Kelli C. Gribben, Ph.D.

University of Nebraska Medical Center, 2022

Supervisors: Paraskevi A. Farazi and Tricia D. LeVan, Ph.D.

Asthma and Chronic Obstructive Pulmonary Disease (COPD) have complex etiologies and lack biological predictors that can be used for primary prevention, early detection, progression, or monitoring. Genetic risk scores (GRS) aggregate genetic effects from GWAS-identified susceptibility variants associated with a trait. GRS may provide opportunities to improve disease prediction to inform public health and clinical interventions. Asthma GRS studies utilizing multi-ethnic populations are scarce and there is a …

Design, Synthesis, And Biological Investigation Of Pyridine Sulfones As Anti-Chlamydia Trachomatis Agents, Mohamed A. Seleem

Theses & Dissertations

Chlamydia trachomatis is the most prominent cause of sexually transmitted bacterial infections worldwide, with around 128 million reported cases annually. This pathogen can cause severe urogenital and ocular consequences, resulting in infertility and trachoma. In its unique developmental cycle, Chlamydia fluctuates between two distinct forms, elementary bodies (EBs) and reticulate bodies (RBs). We hypothesized that caseinolytic protease P (ClpP), a conserved protease among bacterial species, drives the Chlamydia developmental cycle. Earlier work by the Ouellette group demonstrated that Chlamydia relies on its ClpP2 paralogue (ctClpP2) to differentiate between its developmental forms. Dysregulation of ctClpP2 had a significant …

The Development Of Polymeric Dexamethasone Prodrug Nanomedicines For The Treatment Of Lupus Nephritis, Zhifeng Zhao

Theses & Dissertations

Lupus nephritis (LN) is a significant cause of morbidity and mortality among lupus patients. Glucocorticoids (GCs) are uniformly used in clinical LN management. Their notorious toxicities, however, have hampered the long-term clinical application. To circumvent GCs’ adverse effects while maintaining their potent therapeutic efficacy, we have developed a micelle-forming polyethylene glycol (PEG)-conjugated dexamethasone prodrug (ZSJ-0228), which could passively target the inflamed kidney in NZB/W F1 lupus-prone mice. It was found that monthly ZSJ-0228 treatment for five months significantly reduced the incidence of nephritis in NZB/W F1 mice with an improved survival rate. Unlike the dose equivalent daily dexamethasone treatment, long-term …

Linking Spinal Cord Circuits With Upper Limb Sensorimotor Control In Adults With Cerebral Palsy, Saihari Dukkipati

Theses & Dissertations

Cerebral palsy (CP) is the most common neurological disorder originating in childhood, but most of the people living with CP are currently adults. While people with CP continue to get older, the amount of research focused on adults has been rather limited. The early childhood insults leading to CP are thought to originate in the brain, but the effects on the entire neuromuscular system across the lifespan have only recently started to be explored. Of note, recent neuroimaging evidence suggests that the cervical spinal cord structure is atypical in adults with CP. However, it is largely unclear how the neurophysiological …

Macromolecular Fluorescent Conjugates For Bioimaging Applications, Paul Lovell

Theses & Dissertations

Bioimaging tools enable the visualization of small anatomical features as well as structures that may be obscured by other tissue. One such group of tools are fluorescent probes, molecules that emit detectable signals when stimulated by an excitation source. Incorporating fluorescent conjugates for clinical purposes would enable direct usage for the diagnosis, detection, or treatment of diseases. The development of specific targeting agents is feasible due to the number of nanomaterials and biological products that contain fluorophores. Specific targeting agents can target a particular region of interest, such as a cancerous tumor for removal or vital nerve structure for avoidance …

Erα As A Modulator Of The Sle1b Lupus Susceptibility Locus And B Cell Receptor Signaling, Jared H. Graham

Theses & Dissertations

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by loss of immune tolerance and the production of anti-nuclear autoantibodies. 90% of lupus patients are women, and this sex bias is due to the actions of estrogens, which promote lupus pathogenesis. Our lab has shown that estrogen receptor alpha (ERα) mediates the effect of estrogens in lupus and that ERa acts in a B cell intrinsic manner to promote the development of autoantibodies and SLE. Genetic factors also contribute to lupus. One major lupus susceptibility locus, Sle1, controls loss of tolerance and autoantibody development as well as immune cell …

The Role Of Calprotectin In T-Lymphocyte Driven Inflammation In A Mouse Model Of Psychological Trauma, Cassandra Moshfegh

Theses & Dissertations

Post-traumatic stress disorder (PTSD) is a debilitating psychological disorder that affects nearly 45 million Americans. This mental disorder is characterized by behavioral symptoms such as learned helplessness, hyperarousal, withdrawal, and flashbacks. The deleterious effects of PTSD are far-reaching and go beyond behavioral dysfunction, as these individuals are at a three-fold higher risk of comorbid inflammatory diseases. Autonomic, metabolic, and cardiovascular diseases plague these individuals later in their lifetime, however, the mechanistic link connecting psychological trauma to this systemic peripheral immunological dysfunction remains elusive. T-lymphocyte-induced inflammation plays a significant role in all these disease pathologies. Previous work from our laboratory demonstrated …

Gut Commensals Modulate Siv/Shiv Pathogenesis And Therapeutics, Samuel Johnson

Theses & Dissertations

Despite significant advancements in combination antiretroviral therapy (cART), ongoing inflammation in the brain and gut remain two of the most significant hurdles in the health of people living with human immunodeficiency virus (HIV). Additionally, a viral reservoir in each compartment inhibits cure efforts by allowing rapid viral rebound following cART interruption. Emerging understanding of the gut-brain axis (GBA) implicates each compartment in the modulation of the other in a complex bi-directional interaction mediated by vagus innervation, circulating lymphocytes, and microbiome composition and biproducts. Using multiple models of the simian (and simian-human) immunodeficiency virus (SIV/SHIV) and therapeutic intervention, I present how …

The Development Of Thermoresponsive Hydrogel-Based Drug Delivery Systems For The Treatment Of Musculoskeletal Diseases, Ningrong Chen

Theses & Dissertations

Water-soluble polymers are one of the most commonly used drug delivery vehicles for musculoskeletal diseases. During the past few decades, various biocompatible polymers have been employed in the development of thermoresponsive hydrogels as drug delivery systems for the treatment of local musculoskeletal pathologies. As part of our laboratory’s contribution to this field of study, I have successfully developed three thermoresponsive hydrogel-based formulations for the treatment of three different pathologies associated with the musculoskeletal system.

As my initial effort, I have developed a bone-targeting injectable hydrogel drug delivery system based on Pluronic 127 (Poloxamer 407), which is a Generally Recognized As …

Ethical Sensitivity Of Padis Care Among Critical Care Nurses: A Mixed Methods Study, Denise Waterfield

Theses & Dissertations

Critically ill patients often experience distressful and impactful symptoms and conditions that include pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS). The presence of PADIS can affect recovery and long-term patient outcomes. An integral part of critical care nursing is PADIS prevention, assessment, and management. To better understand the complexities of PADIS care, two reviews of the literature were completed. The first is an integrative review of the use of PADIS assessment tools by critical care nurses. The second is a qualitative systematic review of the literature on the integration of care ethics and nursing workload. Ethical sensitivity of everyday …

Feasibility And Efficacy Of Bisphosphonate Use For The Prevention Of Bone And Muscle Loss, Laura E. Flores

Theses & Dissertations

Loss of bone and muscle mass often occurs in tandem, increasing the risk of fragility fractures. Whereas many drugs are approved for the treatment of bone loss, there are few treatments available for the concomitant loss of bone and muscle. Identification of a treatment to mitigate pathologic bone and muscle atrophy has the potential to impact countless populations and influence approaches for healthy aging. Bisphosphonates have emerged as a potential treatment for both bone and muscle loss in cellular, murine, and observational human studies. Our findings of modest weight maintenance in postmenopausal women treated with 12-months of risedronate, relative to …

Maternal Distress In The Neonatal Intensive Care Unit, Morgan A. Staver

Theses & Dissertations

Maternal distress in the NICU is a common and potentially harmful phenomenon for mothers with a sick infant. The overall purpose of this dissertation was to describe maternal distress and to examine maternal distress among mothers who have infants greater than or equal to 34 weeks of gestation at birth in the NICU. This was accomplished by first conducting a concept analysis of maternal distress in the NICU. Next, an integrative review of the literature was done to assess maternal distress and associated variables in response to infant hospitalization in the NICU. Finally, a mixed methods study was done to …

1-Check Unmc Mobile App Usage: A Quantitative Analysis Of The Data, Molly Pofahl

Theses & Dissertations

As COVID-19 cases continued to rise in Nebraska, universities and colleges were faced with unique challenges in the effort to continue providing quality education for students. The University of Nebraska Medical Center (UNMC) took on especially difficult challenges due to its status as an academic medical center. By the Fall of 2021, students, faculty, and staff were beginning to return to campus. The 1-Check UNMC app was created to help keep sick people from coming to campus. The UNMC community was expected to screen themselves for COVID-19 using this app each day before coming to campus. This thesis is an …

Modulation Of Immune Homeostasis In Neurodegenerative Diseases, Pravin Yeapuri

Theses & Dissertations

Modulating the immune system via. transformation of CD4+ T cell effector to regulatory (Teff to Treg) or promoting microglial clearance of abnormal disease proteins are attractive therapeutic strategies to restore immunological balance in neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease (AD). In the past decade, we defined a safe and effective pathway for Treg induction through the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF was developed in PD animal models and early phase I human studies demonstrating proof-of-concept efficacy for ameliorating disease signs and symptoms. Despite the recorded efficacy, the medicine’s short half-life, limited bioavailability, and injection site reactions …

Modulating Cardiac Remodeling After Myocardial Infarction, Upendra Chalise

Theses & Dissertations

Cardiac remodeling after myocardial infarction (MI) is indicated by infarct wall thinning, reduced ejection fraction, and dilation of the left ventricle (LV). Inflammation presides in the early days of MI as a key event in cardiac wound healing. Infiltration of inflammatory cells, predominantly neutrophils and macrophages, is stimulated by ischemic cardiomyocytes that secrete inflammatory cues. This dissertation focused on identifying factors that influence cardiac remodeling after MI. S100A9 is a neutrophil-derived factor identified that exacerbated infarct wall thinning and cardiac dilation by increasing neutrophil and macrophage infiltration. Similarly, murinoglobulin 1 (Mug1) and galectin (Lgals)3 were macrophage-derived factors identified that regulate …

Psychological Trauma Alters T-Lymphocyte Inflammation And Redox Through Sympathetic Mechanisms, Safwan K. Elkhatib

Theses & Dissertations

Posttraumatic stress disorder (PTSD) is a devastating psychiatric disorder characterized by distinctive symptom clusters, including intrusive memories (i.e., flashbacks), avoidance of related stimuli, affective changes, and hyperarousal. Strikingly, patients with PTSD face a significantly increased risk for a number of inflammation-driven pathologies, ranging from cardiovascular to autoimmune disease. Yet, the exact etiology of this increased risk remains unknown. The immune system is known to be strongly influenced by the sympathetic nervous system, and sympathetic overactivity is a hallmark of PTSD. Lymphoid organs, such as the spleen, are richly innervated by sympathetic nerve fibers which terminate near adaptive immune …

Leukocyte Subsets In The Peripheral Blood And Spleen Of Gastrointestinal Cancer Patients, Kathryn E. Cole

Theses & Dissertations

In 2022, an estimated 62,210 people will be diagnosed with pancreatic ductal adenocarcinoma (PDAC) and approximately 49,830 will die from the disease. Current treatment strategies for gastrointestinal (GI) cancer patients, such as PDAC, have shown limited benefit, suggesting the need to develop novel, multimodality therapeutic approaches. Adoptive cellular therapy (ACT) using autologous tumor infiltrating lymphocytes (TILs) has shown efficacy in patients with melanoma; however, this approach is costly and requires extensive cell culture for sufficient numbers of T-cells for infusion. GI cancer patients with borderline resectable disease, whose primary tumor is adjacent to the splenic vasculature, can sometimes undergo a …

Evaluation Of Awareness, Knowledge, And Preventive Intervention Of Nonalcoholic Fatty Liver Disease Among Chinese Young Adults, Yi Du

Theses & Dissertations

The prevalence of nonalcoholic fatty liver disease (NAFLD) among Chinese young adults (CYA) aged 18-25 years ranges from 4.7% to 15.1% and has kept increasing in recent years. Previous studies reported limited awareness and knowledge of NALFD among middle-aged and older Chinese populations, however, they have not investigated awareness in CYA, for which there is no well-validated questionnaire. There is currently no efficacious educational intervention on NAFLD for CYA.

The objectives were 1) to develop and validate a questionnaire which can be used to assess the awareness and knowledge of NAFLD among CYA; 2) to assess the awareness and knowledge …

Building An Artificial Intelligence Framework For Hypertension Diagnosis: A Use Case Of The Problem List Curation, Ketemwabi Yves Shamavu

Theses & Dissertations

Hypertension is the world's leading factor in cardiovascular disease. Forty-seven percent or close to one in two Americans aged 18 and older are affected. It predicts approximately a thousand deaths per day. Based on recent statistics from the Centers for Disease Control and Prevention, one in three patients with hypertension does not know they are hypertensive. Seventy-five percent of hypertensive patients have uncontrolled hypertension - meaning that they are not treated to target. While there is extensive literature on hypertension diagnosis and management, there is an apparent gap in understanding and acknowledging that a person is hypertensive. Moreover, blood pressure …

Contextual Factors And Sti/Hiv Sexual Risk Behaviors Among Hispanic Youths Aged 13 To 24 Years, Mariam Taiwo

Theses & Dissertations

Despite the growing population of Hispanics and several efforts to combat the high STI/HIV rates among Hispanic youths aged 13 to 24 years in the United States, this population continues to experience stark disparities in STI/HIV and is underrepresented in STI/HIV research relative to their White peers. This dissertation consists of three distinct studies designed to identify and understand the contextual factors of STI/HIV sexual risk behaviors across the social-ecological model that are pertinent to Hispanic youths.

Results from the first study showed that STI/HIV sexual risk behavior varied by Hispanic youths’ acculturation types and moderated by gender. We found …

Polymeric Nanocarriers For Delivery Of Small Molecules Inhibiting Tubulin Polymerization For The Treatment Of Pancreatic Cancer And Lung Metastatic Melanoma, Rajan Sharma Bhattarai

Theses & Dissertations

The aim of this thesis is to develop delivery systems for the novel small molecules which inhibit tubulin polymerization. One of the small molecules was modified to lipid conjugate to increase the lipophilicity of the molecules which in turn drastically improved the drug loading in amphiphilic polymeric system. The second molecule was conjugated to the amphiphilic polymeric backbone with pH sensitive Schiff’s linker for the tumor site specific delivery in lung metastatic melanoma model.

Chapter 1 discusses the tumor microenvironment for the solid tumor especially focusing on Pancreatic Ductal Adenocarcinoma (PDAC). Further the drug delivery system currently researched for addressing …

Frailty And Neurocognition In Prostate Cancer, Lindsey Hanson

Theses & Dissertations

Prostate cancer (PCa) treatment often leads to distressing side effects ranging from muscle loss, physical inactivity, and fatigue to cancer associated cognitive decline (CACD). Evidence suggests that men treated with androgen deprivation therapy (ADT) may have a specifically high risk of CACD, partially due to increased frailty. However, the current literature on cognitive effects of ADT is equivocal. Therefore, the primary objectives of this study were to (1) compare cognitive function, physical activity (PA), and fitness in men receiving ADT, men scheduled to receive radiation, and men under active surveillance for PCa; (2) examine changes in cognitive performance and PA …

Regulation Of Pancreatic Cancer Progression By Micronutrients, Chunbo He

Theses & Dissertations

Cancer cells rely on altered metabolism to support their uncontrolled proliferation under harsh conditions. Understanding the mechanisms of how metabolic alterations support tumor growth may provide a way to enhance current therapies. Vitamins are micronutrients that our body needs in small quantities but are essential for health maintenance. A number of metabolic processes relevant to cancer initiation and progression are also regulated by vitamins. Here, our studies showed that pancreatic ductal adenocarcinoma (PDAC) cells display an aberrant metabolism of vitamin B6 (VB6) to support their fast proliferation. VB6 was highly demanded and rapidly metabolized by PDAC cells. Depletion of VB6 …

Development Of Bioactive Polymers For Anticancer Sirna Therapy, Siyuan Tang

Theses & Dissertations

Pancreatic ductal adenocarcinoma is a deadly disease with limited treatment options due to late diagnosis and resistance to conventional chemotherapy. Moreover, with the decreased survival rate in the past several years, pancreatic cancer may become the second leading cause of cancer-related death by surpassing breast cancer in 2030. CXCR4/CXCL12 pathway is crucial in tumor-supporting microenvironment, tumor progression, angiogenesis, metastasis and chemotherapy resistance. Small interfering RNA (siRNA) is one of the interfering RNA (RNAi), which targets mRNA specifically then knockdowns the overexpressed oncogene. Thus, siRNA has been widely used as a therapeutic strategy for various diseases including PDAC. In the research …

Mixed Method- How Do Medical-Surgical Nurses Provide Compassionate Care To Patients In The Face Of Adversity?, Diane D. Kret

Theses & Dissertations

Compassion is a quality that is the very essence of nursing. Nurses, as professionals, seek to alleviate suffering. It is through providing compassionate, connected care that nurses can relieve their patients’ suffering. In the midst of adversity such as taking care of ill and dying patients, especially in the Covid-19 pandemic, nurses have been challenged with providing compassionate care despite the increased toll that this may have on them. There is evidence that exposure to these events can cause compassion fatigue and burnout. When these signs of compassion fatigue or compassion burnout are not addressed, nurses have decreased job satisfaction …

Association Between Ct Severity Score And Clinical Severity Score Of Covid-19 Pneumonia At Aga Khan University Hospital, Nairobi, Paul Kareithi Nduati

Theses & Dissertations

Background: Imaging with chest computed tomography (CT) has demonstrated a role in stratifying COVID-19 patients into different clinical severity groups thus facilitating appropriate care decisions. In a limited number of settings, the wider applicability and reproducibility of these findings is unclear.

Objectives: To determine the association between chest CT severity score and clinical severity of illness in RT-PCR confirmed SARS-CoV2 patients. To evaluate the relationship of CT chest severity score with short term clinical outcome of patients.

Methods: CT chest of 172 SARS-CoV2 patients who accessed care at Aga Khan University Hospital Nairobi between 14th March and 31st December 2020 …

Diagnostic Utility Of Red Cell Indices In Relation To Serum Iron Indices For Evaluation Of Iron Deficiency In Heart Failure, Larry Wangai Mburu

Theses & Dissertations

Background: Iron deficiency (ID) in heart failure (HF) causes poorer outcomes, and evaluation using ferritin and transferrin saturation (TSAT) in our setting is hampered by cost and availability. Though the red cell indices (RCIs), routinely used for assessment of ID anaemia, have shown utility in predicting outcomes in HF, they have not been evaluated in this population for prediction of ID relative to the iron indices. A combination of the RCIs, the combined cell index (CCI), may be more accurate. Validating the diagnostic accuracy of the RCIs would improve evaluation of ID in low-resource settings and improve uptake of iron …

Dysglycemia In Patients Presenting With Stroke And Acute Coronary Syndrome At Aga Khan University Hospital, Nairobi, Beverly Yongo Owino

Theses & Dissertations

Background: Dysglycemia is often diagnosed late in sub-Saharan Africa with a significant number of patients presenting with complications. Data is needed to expand knowledge on the impact diabetes has on major adverse cardiovascular outcomes.

Objective: We aimed to determine the prevalence of dysglycemia in patients with stroke and Acute Coronary Syndrome (ACS) and define characteristics of the patients with dysglycemia.

Methods: A prospective cross-sectional study was conducted at Aga Khan University Hospital, Nairobi which is a tertiary facility. Consenting adults above 18 years (n=211) with stroke and acute coronary syndrome were recruited in the study in the period of April …