Medicine and Health Sciences Commons^™

Characterizing The Combination Of Rpa Inhibitors With Parp Inhibitors In High-Grade Serous Ovarian Cancer, Yat Tang

Theses & Dissertations

High-grade serous ovarian cancer (HGSC) is the most common and deadly gynecologic malignancy. HGSC patients with BRCA1/2 mutations have homologous recombination deficiency (HRD), requiring parallel pathways to maintain genome integrity (e.g., PARP1, PARP2). Approximately 50% of ovarian carcinomas are estimated to exhibit HRD. For the remaining 50% and the large percentage of HRD patients with acquired or innate resistance to single-agent PARP inhibitors, there is a need to develop alternative therapeutic strategies.

Replication Protein A (RPA) is a heterotrimeric protein crucial for genome maintenance. Phosphorylation of RPA in DNA damage response (DDR) is a negative regulator of DNA end resection. …

Enhancing The Identification Of Rheumatoid Arthritis-Associated Lung Disease, Bryant England

Theses & Dissertations

Rheumatoid arthritis (RA) is a systemic autoimmune disease that predisposes afflicted individuals to reduced quality of life, physical disability, and premature mortality. While joint involvement is the primary manifestation of RA, extra-articular features including lung disease are responsible for a significant portion of the excess mortality. In this dissertation I demonstrate the contribution of chronic lung diseases to premature mortality in RA, contrasting with the more widely recognized comorbidity in RA of cardiovascular disease. Then, I establish that a novel serum biomarker, anti-malondialdehyde-acetaldehyde adduct (MAA) antibody, is associated with the presence of interstitial lung disease (ILD) in RA subjects. Further …

The Development Of Hyaluronan-Based Contract Agents For The Intraoperative Detection Of Pancreatic Tumors, Bowen Qi

Theses & Dissertations

Pancreatic ductal adenocarcinoma is highly lethal and surgical resection is the only potential curative treatment for the disease. Tumor-specific intraoperative fluorescence imaging could improve staging and surgical resection, thereby improving prognosis. In the first study, hyaluronic acid derived NPs with physico-chemically entrapped indocyanine green, termed NanoICG, were utilized for intraoperative near infrared fluorescence detection of pancreatic cancer. NanoICG accumulated significantly in an orthotopic pancreatic ductal adenocarcinoma model with safety profile both in vitro and in vivo. To maximize tumor signal, while minimizing signal in healthy pancreas and RES capture of macromolecules, in the next study, we describe the rational …

Theranostics For Antiretroviral Biodistribution And Pharmacokinetics, Brendan M. Ottemann

Theses & Dissertations

RATIONALE: Our laboratories birthed the field of human immunodeficiency virus (HIV) theranostics. The new field allows simultaneous detection (diagnostics) and treatment (therapeutic) for the identification, treatment and inevitable elimination of virus in cell and tissue compartments. By employing theranostics, antiretroviral drugs (ARVs) can be tracked in lymph nodes, gut, spleen and liver. Cellular viral reservoirs including CD4+ T cell populations and mononuclear phagocytes (MP; monocytes, macrophages, microglia and dendritic cells) along with subcellular endosomal structures can now be targeted for drug delivery bringing therapeutics to areas where virus replicates. The overarching idea rests in improving precision targeted ARV delivery. …

Charge-Based Optimization Of Neurotensin For Neurotensin-Receptor-1 Targeting Utilizing A One-Bead One-Compound Peptide Library Approach, Trey Neeley

Theses & Dissertations

Neurotensin-receptor-1 (NTSR1) is regularly overexpressed in various cancers and contributes to the proliferation, survival, migration, invasion, and angiogenesis of tumors. NTSR1-targeting vectors have demonstrated promise in both diagnostic and therapeutic aspects. Unfortunately, the relatively poor in vivo metabolic stability and high renal uptake and retention of NTSR1-targeted compounds have hampered the translation to the clinic. In this research, we utilized a one-bead one-compound (OBOC) peptide library approach to make targeted modifications at the naturally charged residues of an NTS (4-13) sequence to discover an NTS derivative with comparable affinity to NTSR1, acceptable in vivo stability, and tolerable renal retention. Subsequent …

Hiv-1 Elimination In Humanized Mice, Hang Su

Theses & Dissertations

Human immunodeficiency virus type one (HIV-1) exclusively infects humans and chimpanzees. Therefore, animal models are required for all investigations of viral pathogenesis, therapy and cure. Immunodeficient mice transplanted with human hematopoietic stem cells, termed humanized mice, support the development of multiple human cell lineages throughout the cell’s life span. To this end, we used humanized mice to evaluate the dynamic changes of host immunologic and viral profiles during both acute and chronic HIV-1 infection. We identified the temporal and spatial distribution of HIV-1 cell and tissue compartment infections and outlined correlations made between viral progression and host immunity by comparing …

Orthodontically Induced External Root Resorption In Extraction Versus Non-Extraction Treatment Modalities – A Retrospective Cone-Beam Computed Tomography (Cbct) Study, Jaykishan Patel

Theses & Dissertations

Purpose of this study was to evaluate orthodontically induced external apical root resorption using cone beam computed tomography in patients receiving orthodontic treatment with or without extractions. Records of 188 consecutively treated patients who received orthodontic treatment with or without extractions were evaluated. Pre-and post-treatment root lengths of maxillary incisors, volumes of maxillary central incisors, and apex displacement of either right or left maxillary central incisors were measured using Invivo 5.4 or ITK-SNAP 3.8.0 software. After adjusting for initial length, treatment duration, tooth, sex, race, bracket type, and malocclusion, maxillary incisor reduction of root length in extraction group was 0.37 …

Identification Of More Potent And Efficacious Analogs Of The Novel Host-Derived Immunostimulant Ep67, Abdul Alshammari

Theses & Dissertations

EP67 is a human C5a-derived decapeptide agonist of C5a Receptor 1 (C5aR1/CD88) that selectively activates mononuclear phagocytes over neutrophils to stimulate protective innate and adaptive immune responses while potentially minimizing neutrophil-mediated toxicity. Two N-alkyl amino acids Pro⁷ and N-methyl-Leu⁸ (nme-Leu⁸) within EP67 induce structural changes that increase potency and selective activation of mononuclear phagocytes over neutrophils. Cis/trans isomerization at these positions, however, likely limits the activity of EP67 and low coupling efficiency between Pro⁷ and nme-Leu⁸ increases scale-up costs for clinical use. Thus, the goals of this study were to …

The Effectiveness Of Resin-Modified Glass Ionomer Varnish In Preventing White Spot Lesions During Fixed Appliance Orthodontic Therapy: An In Vitro Study, Bradley Herman

Theses & Dissertations

The purpose of this investigation was to evaluate the efficacy of a glass ionomer varnish in preventing demineralization of enamel adjacent to and some distance away from an orthodontic bracket. Forty extracted human molars were divided into four different treatment groups (varnish in distilled water, varnish in acetic acid, enamel in acetic acid, and enamel in distilled water). Two 3 x 3 mm graphite windows were drawn on the tooth, one adjacent to the bracket and one 3 mm away from the first window, indicating the scanning area. Varnish was applied to the teeth in the varnish groups and all …

Defining The Role Of Tyrosine Phosphorylation In The Regulation Of Connexin43 In Cardiac Diseases, Li Zheng

Theses & Dissertations

Connexins are integral membrane proteins that oligomerize to form gap junction channels. Ions and small molecules diffuse intercellularly through these channels, allowing individual cellular events to synchronize into the functional response of an entire organ. Gap junction channels composed of Connexin43 (Cx43) mediate electrical coupling and impulse propagation in the normal working myocardium. In the failing heart, Cx43 remodeling (decreased expression, altered phosphorylation state, loss at intercalated discs, and increased presence at lateral membranes) contributes to rhythm disturbances and contractile dysfunction. While there is considerable information regarding key interactions of Cx43 in the regulation of gap junction channels, unfortunately, the …

Delivery Of Small Molecule And Rna Using Synthetic Polymeric Micelles And Multifunctional Exosomes For The Treatment Of Type 1 Diabetes, Yang Peng

Theses & Dissertations

Type 1 diabetes is one of the most challenging chronic autoimmune diseases. The destruction and dysfunction of insulin-secreting β cells are the results of inflammatory infiltration and the synergistic effect of multiple immune cells. The aim of this dissertation is to develop novel and reliable therapeutic approaches to advance the treatment of T1D: including chemical modification of a broad-spectrum immunosuppressant, co-application of small molecule based immune intervention and siRNA based β cell preservative therapy, and administration of a PI3K-δ/γ dual inhibitor to specifically target immune cells, utilizing synthetic polymeric micelles or natural produced multi-functional exosomes derived from human bone marrow …

Burden And Risk Of Non-Aids Defining Cancers In Hiv-Infected Persons Receiving Antiretroviral Therapy, Brittney L. Dickey

Theses & Dissertations

The burden of cancers not previously associated with an HIV infection, called non-AIDS defining cancers (NADCs), have increased in the years since highly active anti-retroviral therapy has been introduced. The studies in this dissertation attempted to quantify this burden via incidence and mortality compared to the general population. Further, an assessment of risk factors and creation of a predictive risk model, a nomogram, were utilized to better understand how factors associated with demographics, lifestyle, and immune response affected risk for an NADC diagnosis once therapy was initiated and HIV better controlled. Standardized incidence and mortality ratios showed that burden of …

Engineering Hyaluronic Acid For Biomedical Applications, Deep S. Bhattacharya

Theses & Dissertations

This work presents research using the naturally available non- sulfated carbohydrate glycosaminoglycan hyaluronic acid (HA) for the synthesis of different chemical derivatives of HA for evaluation of binding kinetics with CD44 and P- selectin proteins for applications in fluorescence image-guided surgery. Chemical derivatives of HA such as deacetylated HA (deHA), sulfated HA (sHA), and deacetylated and sulfated HA (s-deHA) were synthesized by modulating sulfating and deacetylating reagents to alter binding specificities to CD44. Modified HA derivatives and CD44 biophysical interactions were assessed by fluorescence polarization. In silico techniques were also used to determine binding using molecular docking and MM-PBSA approaches. …

The Role Of Histone Chaperone Fact Complex In Base Excision Repair Pathway And Its Therapeutic Potential In Colon Cancer And Medulloblastoma, Heyu Song

Theses & Dissertations

Base excision repair (BER) pathway is required for the removal of damaged bases caused by alkylation, oxidation and ring-saturation. Human apurinic/apyrimidinic endonuclease 1 (APE1) plays a central role in BER pathway. Although repair of damaged bases by recombinant APE1 has been well investigated in vitro, how APE1 gains access to damaged bases in the context of chromatin is largely unknown. A prominent member of the histone chaperone family, FACT (Facilitates Chromatin Transcription) is thought to reorganize nucleosomes through the destabilization of multiple intra-nucleosome contacts. FACT complex is composed of two polypeptides identified as SPT16 (Suppressor of Ty 16) and SSRP1 …

Synthesis And Characterization Of Long Acting Darunavir Prodrugs, Mary Banoub

Theses & Dissertations

Patient adherence is critical for ART success to ensure adequate viral suppression, therefore, long-acting antiretrovirals are soon replacing current daily regimens. In recent years, two drugs were successfully transformed into long-acting injectables; CAB LA and RPV LA. These long-acting nanoformulations made it possible to abandon the daily pill burden, instead approximately a bimonthly injection of both drugs is enough to suppress and maintain viral load suppression. Our laboratory has been instrumental in transforming FDA-approved and experimental-HIV medications into long-acting slow effective release drugs, also known as LASER ART. LASER ART consists of slow drug metabolism and high permeability and retention …

Targeted Inhibition Of Histone Deacetyltransferases For Pancreatic Cancer Therapy, Richard Laschanzky

Theses & Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a dismal five-year survival rate of less than 10%. One major obstacle in PDAC treatment is acquired drug resistance. Pan-histone deacetylase inhibitors (pan-HDACi) are a relatively new class of anti-cancer drugs, with demonstrated ability to overcome drug resistance and re-sensitize PDAC tumors to Gemcitabine (Gem). These agents target HDACs, a family of 18 enzymes (divided into four classes, I-IV) that catalyze the deacetylation of histones and other cellular proteins and have multiple effects on cell growth, differentiation, survival, and tumorigenesis. Although pan-HDACi have shown significant efficacy in preclinical analysis, and some …

Computational Studies And Design Of Pparγ And Glut1 Inhibitors, Suliman Almahmoud

Theses & Dissertations

The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. PPARγ is a target for insulin-sensitizing drugs, and it plays a significant function in prostate cancer. PPARγ antagonists have anti-proliferative effects in a broad range of hematopoietic and epithelial cell lines. The ligand binding domain (LBD) of PPARγ is large and has orthosteric and allosteric binding sites. Several PPARγ-ligand co-crystal structures show two bound molecules, one to the orthosteric pocket and a second to the allosteric …

Implementing The Patient-Centered Care Paradigm In An Academic Research Environment, Fernando Orgas

Theses & Dissertations

Research Focus. The healthcare landscape is transitioning from a provider-centered care model toward greater emphasis on patient-centered care (PCC). The shift to PCC reflects efforts to increase the quality of healthcare and the care experience. The current state of research within healthcare remains focused on how to provide high-quality and sound research that will bring new equipment, procedures, and verify strategies that may benefit healthcare globally. However, changes in the healthcare atmosphere bring a new perspective to research. How is the paradigm shift to patient-centered care implemented in an academic research environment? Does this holistic mindset fully cross into …

Affordable Care Act And Preventive Care Usage: A Mixed Method Analysis Of Cardiovascular Care, Brit Peek

Theses & Dissertations

It is a commonly held belief that access to health insurance affects the level of utilization of preventive care services, and thus plays a crucial role in the effective management of avoidable chronic illnesses, decreasing levels of premature mortality, and enabling individuals to live wholesome long lives. Based on this belief, among other goals, the Affordable Care Act (ACA) was designed to increase access to health insurance and related medical services for the population of the United States. This dissertation attempts to identify whether this belief is valid or not by testing whether the usage of preventive care changed between …

Preventive Healthcare Usage In The United States: Does Health Insurance Matter, Diane Rodriguez

Theses & Dissertations

The Centers for Disease Control in the United States has maintained that adults who avoid preventive care services are more likely to suffer from long term chronic diseases because they are not addressed or treated in a timely manner. Examining the effects of providing access to healthcare to uninsured adults and increasing preventive services can help in reducing chronic diseases and enable adults to live longer, healthier lives. The purpose of this study was to identify the relationship between the utilization of preventive health services and socioeconomic factors such as insurance status, race/ethnicity, household income, marital status, education, gender, age, …

Impediments To The Historical Development Of The Clinical Pap Test In The United States: Their Relevance In Optimizing Cervical Cancer Screening In The State Of Qatar, Nikolaos Chantziantoniou

Theses & Dissertations

Three hundred surveys listing 31 questions were distributed amongst women and men at Sidra Medicine, Doha, State of Qatar, to assess knowledge and perceptions of: Cervical cancer (CxCa); preventive Pap test screening; Human Papilloma Virus (HPV) vaccination; and, need for population-based screening. Survey questions captured categorical statistical data through four categories: (1) Socio-demographic; (2) Healthcare Services; (3) Health Literacy; and, (4) Self-efficacy and Perceptions. Hypothesis 1: 12 survey questions pertaining to CxCa and Pap testing revealed 8 statistically-significant dependencies; notably, 70% of respondents were aware of CxCa; however, 31.8% were unaware that CxCa may be curable; 33.7% were unaware …

Macromolecular Prodrug For The Treatment Of Ulcerative Colitis, Yuanyuan Sun

Theses & Dissertations

Ulcerative colitis is a chronic inflammatory bowel disease affecting the colon. More than 1 million Americans are affected, with the annual economic burden up to 14.9 billion in the United States. By far, ulcerative colitis still lacks the cure and the current treatment strategies are limited due to severe side effects and in-sufficient efficacy. The tofacitinib (Xeljanz) is the only approved oral medication by for adults with moderately-to-severely-active ulcerative colitis. But the related side effects and serious infections still have to be resolved. In the previous study in our lab, the researchers have successfully developed and characterized multiple hy-drophilic prodrug …

Health Literacy Changes In A Technology-Enhanced Diabetes Prevention Program, Cody Goessl

Theses & Dissertations

Background: In 2001, the Diabetes Prevention Program was published evaluating the efficacy of a pharmaceutical intervention, Metformin, and a behavioral lifestyle intervention (LI) to reduce incidence of Type 2 diabetes mellitus. The LI was observed to reduce the incidence of the disease by 58% relative to 31% in the medication treatment. Amongst technology based LIs, little has been done to address different health literacy populations.

Objectives: This dissertation evaluated how teach-back and teach-to-goal can influence the uptake of information obtained in each health education lesson, behaviors and its influence on engagement and weight loss.

Methods: Four hundred forty-two participants …

Delineating Phenotypes Of Rare Disease, Lois J. Starr

Theses & Dissertations

Not available.

Perception Of Bone Mineral Loss On Cone-Beam Computed Tomography (Cbct) & Digital Periapical (Pa) Film: An Ex-Vivo Comparison, David P. Hamm

Theses & Dissertations

Using micro computed tomography (micro-CT) as a reference standard, the purpose of this investigation was to evaluate the influences of bone mineral loss and radiographic contrast in digital periapical (PA) film and cone-beam computed tomography (CBCT). Seven dog and human mandibles were sectioned, followed by modification via cortical bone drilling to create 248 lesions and/or trabecular bone acid demineralization to create 96 coronal slice pairs. Pretreatment and post-treatment radiographs (PA, CBCT, and/or micro-CT) were taken for lesion rating/perception in addition to two-dimensional (area) and three-dimensional (volumetric) measurements of 50 drilling lesions and 20 coronal slice pairs. 4-7% bone mineral loss …

The Effectiveness Of Registered Dietitians In Diabetes Case Management, Meghan C. Mclarney

Theses & Dissertations

OBJECTIVE: The objective of this paper is to investigate the effectiveness of diabetes education provided by registered dietitians (RD) in a diabetes case management (DCMs) model, compared to diabetes education provided by RDs in the usual care model (UCM) at an outpatient endocrinology clinic in Omaha, Nebraska. This study hypothesizes that education by RD DCMs will be equal or more efficacious in regards to primary outcomes of A1C and BMI and secondarily, lipid results and adherence (total encounters) when compared to outcomes of UC.

METHODS: This is a cross sectional retrospective review of patients with diabetes (n=946), receiving traditional RD …

Maternal Cognitions And The Origins Of Early Sensorimotor Based Play In Infants Born Preterm, Sandra L. Willett

Theses & Dissertations

Maternal cognitions are beliefs, perceptions, and expectations that guide parenting practices. For at-risk infants born prematurely, these maternal constructs may influence the caregiving environment and opportunities for motor experience. The impact of maternal cognitions on motor development in infants born preterm is not well-documented. This three-part dissertation systematically explores: 1) the nature and extent of existing evidence supporting the link between maternal cognitions and motor development of infants born preterm, 2) if maternal perception of infant vulnerability as measured by an adapted Vulnerable Baby Scale (VBS) can be validly and reliably quantified in mothers of infants born preterm and near …

Synthesis And Characterization Of Long-Acting Rilpivirine Prodrugs, James R. Hilaire

Theses & Dissertations

Antiretroviral therapy (ART) requires lifelong daily dosing to suppress viral replication, restore or maintain immune function and improve quality of life. As an alternative, long-acting (LA) antiretrovirals (ARVs) aim to deliver therapeutic drug concentrations over an extended period, ultimately requiring monthly or even more extended dosing intervals. Specifically, the success of recent clinical trials examining LA cabotegravir and rilpivirine (CAB and RPV LA) highlight the advent of these novel HIV-1 therapeutics. Further optimization of LA dosage forms are required and rests upon improving dosing frequency, injection volumes and tissue distribution to viral compartments. To this end, we report the synthesis …

Female Genital Mutilation And Its Medicalizationa Qualitative Study Among Healthcare Professionals And Community Leaders In Kisii County, Douglas Oimeke Mariita

Theses & Dissertations

Background: According to the World Health Organization (WHO), female genital mutilation (FGM) includes all procedures that involve removal of the female genitalia and / or injury to the female genital organs for cultural and / or any other nonmedical reason. The practice poses serious threats to women’s health hence violating their health and rights. FGM, also referred to as genital cutting, is deeply rooted amongst the Abagusii community of Kenya, with 84% of the girls cut as per Kenya Demographic Health Survey report of 2014 and the medicalized form slowly replacing the traditional cut. Overall in Kenya, the medicalized form …

Prevalence And Outcome Of Asymptomatic Cryptococcal Antigenemia In Art Naive And Art Experienced Hiv Patients In Dar Es Salaam, Tanzania, Charles Mandela Makakala

Theses & Dissertations

Introduction: Cryptococcal meningitis (CM) is a highly fatal disease and contributes to about 20% of all-cause mortality in HIV/AIDS. Sub-Saharan Africa is facing substantial challenges in the treatment of the disease; the focus has been shifted towards prevention of the condition in ART-naive patients with CD4 counts of less than 100 cells/μL. Most studies and interventions have been conducted on ART-naive HIV patients despite there being cases and deaths due to cryptococcal meningitis among ART-experienced patients. Recent studies have shown that although there is an increase in ART coverage among HIV patients, this has not affected the incidence of cryptococcal …