Digital Commons Network^™

Modulating Hallmarks Of Cholangiocarcinoma, Cody Wehrkamp

Theses & Dissertations

How are cholangiocarcinoma cells different from non-malignant cholangiocytes?

All of the hallmarks of cancer apply- those reported in this dissertation include cell proliferation, migration, apoptosis, and evasion of growth suppression. My studies began with testing how apoptosis might be regulated through embelin, a small molecule reported to sensitize cells to apoptosis by blocking XIAP. My data however revealed that embelin reduced the proliferative capacity in cholangiocarcinoma cells, but did not increase cell death. Malignant cells exhibit dysregulation of microRNA processing and expression. Hence, my studies seeking ways that cholangiocarcinoma eludes apoptosis transitioned to the oncomiR miR-106b, which is overexpressed in …

Association Between Systemic Inflammation And Nutritional Compounds In Maternal-Infant Dyads, Jessica N. Snowden

Theses & Dissertations

Many events during pregnancy and early infancy can affect infant brain development. Inflammation during pregnancy, around delivery and during early infancy appears to adversely affect infant brain development. As the brain is rapidly growing and developing from conception through early childhood, it is particularly vulnerable during this time to inflammatory insults, which may be exacerbated or ameliorated by nutritional factors. Inflammatory compounds, as well as many nutritional compounds, can be either pro- or anti-inflammatory. These compounds are of particular importance in preterm infants, who are at risk of deficiency in anti-inflammatory micronutrients typically stored as a result of prenatal maternal …

Examining Barriers To Sexual And Reproductive Health Services For Adolescents And Young Adults In Nebraska, Marisa Rosen

Theses & Dissertations

Despite recent declines in unintended pregnancy rates among adolescent and young adult women, barriers to family planning services and contraception continue to exist for young women living in the United States. Various initiatives have been implemented over the years from programmatic interventions to enactment of policies around family planning, yet more work needs to be done to help adolescent and young adult women successfully prevent unintended pregnancy. The Contraceptive Access Project (CAP) is a multi-component initiative in Nebraska to reduce unintended pregnancy among women aged 15-24. This dissertation comprises three separate studies each of which contributes to the overall objective …

Regulation Of Canonical And Non-Canonical Hippo Pathway Components In Mitosis And Cancer, Seth Stauffer

Theses & Dissertations

The Hippo pathway is conserved regulator of organ size through control of proliferation, apoptosis, and stem-cell self-renewal. In addition to this important function, many of the canonical signaling members have also been shown to be regulated during mitosis. Importantly, Hippo pathway components are frequently dysregulated in cancers and have attracted attention as possible targets for improved cancer therapeutics. Further exploration of Hippo-YAP (yes-associated protein) signaling has revealed new regulators and effectors outside the canonical signaling network and has revealed a larger non-canonical network of signaling proteins in which canonical Hippo pathway components crosstalk with important cellular homeostasis and apoptosis signaling …

Development Of Chloroquine-Containing Hpma Copolymers For Drug Delivery, Fei Yu

Theses & Dissertations

Abstract

Development of Chloroquine-containing HPMA Copolymers for Drug Delivery

Fei Yu, Ph.D.

University of Nebraska Medical Center, 2018

Supervisor: David Oupický, Ph.D.

Synthetic polymers have been extensively explored for improved delivery of anticancer agents. Polymers can be designed as either carriers of existing drugs or as polymeric drugs with intrinsic pharmacological activity. Advantages of such polymeric drugs include common positive features of polymer-drug conjugates, such as targeted delivery of drugs, altered pharmacokinetic and biodistribution, improved drug safety, but also favorable pharmacological activities due to multivalent receptor-ligand interactions.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are safe drugs that have been in clinical …

Development Of Macromolecular Prodrugs For The Treatment Of Chronic Inflammatory Pain, Laura Weber

Theses & Dissertations

Chronic pain afflicts millions of people worldwide. Particularly, the inflammatory conditions in the incurable disease rheumatoid arthritis (RA) generate persistent pain in its sufferers, for which a number of different analgesics have been prescribed, such as glucocorticoids (GCs) and opioids. However, administration of these pain- mitigating pharmaceutics is implicated in the development of adverse systemic effects due to their non-specific tissue distribution and quick excretion, eliciting the need for high dosing frequencies. To address this issue, this thesis is focused on the development of prodrugs based on a macromolecular design approach to instill preferential inflammation-targeting and retentive properties to common …

Developing Of Micellar Drug Carriers For The Treatment Of Breast Cancer Bone Metastasis, Tong Liu

Theses & Dissertations

Breast cancer (BC) remains one of the most frequently diagnosed cancer worldwide. Bone is one of the most common sites and often the first clinical indication of metastatic progression of BC. Current treatments including radiation, surgery, and chemotherapy are rarely curative with limited effect in overall survival. The challenge is true especially for patients with triple-negative BC that are not responsive to receptor-targeted therapy, or patients who had exposure to chemotherapy before and might already gain the resistance to some of the drugs.

Here we took advantage of the aminobisphosphonate, alendronate (ALN), that can bind to the bone mineral efficiently …

Development Of Preclinical Magnetic Resonance Imaging Relational Database And Interactive Analytical Tool For Diffusion Tensor Imaging, Ahmad Tanwir

Theses & Dissertations

Databases have become an essential component for any organization to collect and manage the information. Similar to other domains, by implementing a database management system (DBMS), data storage, access, analysis and updates can be automated and optimized in the biological, medical and preclinical research areas. This work demonstrated the development of a preclinical database, which contains the processed results from different magnetic resonance imaging (MRI) techniques with relevant biological information. In addition, we designed and implemented an interactive analytical tool to format and analyze diffusion tensor imaging (DTI) data and automatically generate results in the forms of box plot, bar …

An Assessment Of Preparations Made In The United States For Highly Hazardous Communicable Diseases Following The 2014-2016 Ebola Virus Disease Epidemic, Jocelyn J. Herstein

Theses & Dissertations

The 2014-2016 Ebola virus disease (EVD) epidemic in West Africa was unprecedented in magnitude and scope. The threat of imported cases of EVD in the United States prompted the Centers for Disease Control and Prevention (CDC) to establish a tiered network of hospitals to enhance domestic isolation capacity, including the designation of select hospitals as Ebola treatment centers (ETCs). As of spring 2015, no information existed on the capacity, physical infrastructure, staffing models, or infection control protocols of these newly-established ETCs, nor was there information on other highly hazardous communicable diseases (HHCDs) these units would admit. Moreover, no documentation was …

Development Of Polymeric Carriers For The Treatment Of Acute Kidney Injury, Yi Chen

Theses & Dissertations

Acute kidney injury (AKI) is a major kidney disease associated with high mortality and morbidity. Long-term AKI may lead to chronic kidney disease and end-stage renal disease. Several clinical trials failed due to lack of efficacy and undesired side effects. Studies showed that macromolecular delivery systems would be a promising method to target kidney, however, little is known about how physicochemical properties affects the polymers deposition in ischemia-reperfusion (I/R) AKI.

Gene therapy has been well studied as a promising therapeutic agent for several diseases, including cancer and AKI. Although small interfering RNA (siRNA) has been commonly used to treat AKI …

Red Panda: A Novel Method For Detecting Variation In Single-Cell Rna Sequencing, Adam Cornish

Theses & Dissertations

Single-cell sequencing enables the rapid acquisition of genomic and transcriptomic data from individual cells to better understand genetic diseases, such as cancer or autoimmune disorders, which are often affected by changes in rare cells. Currently, no existing software is aimed at identifying single nucleotide variations or micro (1-50bp) insertions and deletions in single-cell RNA sequencing (scRNA-seq) data. However, generating high quality data is vital to the study of the aforementioned diseases, among others. Our goal is to create such a tool and use in-house sequencing to validate its effectiveness. Our software employs the unique information found in scRNA-seq data to …

Delineation Of New Mechanisms Of Dna Double Strand Break Repair, Songli Zhu

Theses & Dissertations

DNA damage is frequently induced in cells by both endogenous and exogenous agents. DNA damage, particular double strand breaks (DSBs) may lead to genomic instability, and the progression of cancer, aging, neurodegeneration, and other human diseases. The cell employs two major DSB repair pathways, including homologous recombination (HR) and Non-homologous end joining (NHEJ), but the detailed mechanisms of DSB repair remain to be further revealed.

In the first part of this study, we characterized a plasmid-based assay to investigate NHEJ repair in Xenopus egg extracts. Our data argued for a preference for the precise repair by the NHEJ machinery and …

Intra- And Inter-Molecular Signaling In A Cardiac Connexin: Role Of Cytoplasmic Domain Dimerization And Phosphorylation, Andrew J. Trease

Theses & Dissertations

As critical mediators of cell-to-cell communication, gap junctions (GJs) are comprised of membrane channels that directly link the cytoplasm of adjacent coupled cells thereby allowing for the passage of ions, small metabolites, and secondary messengers. Each channel is formed by the apposition of two connexons from adjacent cells, each composed of six connexin (Cx) proteins. Each GJ channel functions to promote signal propagation and synchronization of cells and tissues in organs. Furthermore, GJs are essential for proper propagation of cardiac action potentials from one cell to the next, leading to the coordinated contraction and relaxation of heart muscle powering circulation. …

Effects Of Class Ii Correctors And Functional Appliances On The Periodontal Health Of The Mandibular Incisors – A Prospective Cone-Beam Computed Tomography (Cbct) Study, David C. Duevel

Theses & Dissertations

The purpose of this investigation was to evaluate the effects of Class II correctors and functional appliances on the dentoalveolar support of the mandibular incisors during orthodontic treatment. Twenty six patients who were treated with a Forsus^TM, Herbst, or MARA participated this study. Lateral cephalometric radiographs, limited field-of-view CBCTs, and periodontal measurements were collected both the day of appliance activation and day of appliance deactivation. Ten hard tissue measurements on all four mandibular incisors were collected at each time point on CBCT images. Bone thickness increased at 6 and 9 mm apical from the cementoenamel junction (CEJ) on …

The Opposing Roles Of Glun2c And Glun2d Nmda Receptor Subunits In Modulating Neuronal Oscillations, Zhihao Mao

Theses & Dissertations

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels consisting of two GluN1 subunits and two other subunits from among GluN2A-2D and GluN3A-3B subunits. NMDARs play critical roles in synaptic plasticity, learning and memory, and higher brain function such as cognition and perception. Dysfunction of NMDARs (hyper-function and hypo-function of NMDARs) are related to various diseases, including stroke, schizophrenia, Alzheimer’s disease, and others. However, to date, NMDARs antagonists have mostly failed in clinical trials due to adverse effects.

NMDARs antagonists replicate the core symptoms of schizophrenia which may underlie its ability to alter neuronal oscillations in the neural circuitry of different brain …

Early Career Physical Therapy Faculty Networking And Scholarly Productivity: A Mixed-Methods Study, Betsy J. Becker

Theses & Dissertations

While it is well-known that physical therapist (PT) faculty must retain a scholarly agenda, few report being activity engaged and many programs have low scholarly dissemination. There is evidence that knowledge of the make-up of a faculty network leads to improved performance and innovation. The purpose of this explanatory sequential mixed methods study was to explore agency (behaviors and perspectives about career advancement) and the professional network structure and composition of early career PT faculty as they relate to scholarly activity. This dissertation research study included 50 early career faculty who worked in accredited entry-level physical therapy programs.

The quantitative …

Changes In The Transverse Dimension Of The Nasomaxillary Complex Following Rapid Palatal Expansion – A Post-Retention, Cbct Evaluation, Allison Schubert

Theses & Dissertations

Purpose: The purpose of this investigation was to evaluate the immediate and long-term effects of palatal expansion on the transverse dimension of the nasomaxillary complex.

Materials and Methods: Twenty-eight patients’ CBCTs were obtained at four time points: pre-expansion (T₁), post-expansion (T₂), pre-treatment (T₃), and middle or end of orthodontic treatment (T₄). The patients’ age, sex, cervical vertebral maturation stage, and the number of instructed expander turns were recorded. Measurements of the nasal floor, nasal passage, maxillary sinus, maxillary first molar mesiolingual cusp, maxillary first molar palatal cusp, maxillary first molar buccal cortical …

Sequence-Specific Extracellular Micrornas Activate Tlr7, Niming Wu

Theses & Dissertations

Toll-like receptors (TLRs) play an important role in the innate immune system. Emerging evidence shows that TLRs, especially endosomal TLRs, can participate in CNS diseases by increasing the production of proinflammatory cytokines via recognition of microRNAs (miRNAs), however which of the miRNAs are able to activate signaling and whether specific sequence motifs are involved remains incompletely defined. Here we found that numerous miRNAs induced TNF-a production across multiple myeloid cell types, including microglia, and that this effect was abolished in cells deficient of TLR7. In particular, miR-20a-5p and miR-148b-3p preferentially stimulate cytokine secretion compared to miR-20b-5p and miR-148a-3p, respectively, despite …

Attitudes Of Sinjari Yezidis In Iraq Regarding The Rape Of Yezidi Women And The Babies Born From Rape During The Isis Genocide, Jordan Greaser

Theses & Dissertations

This thesis evaluated the attitude of acceptance among Sinjari Yezidis toward Yezidi women who were captured and raped by ISIS captors. In addition, attitudes of acceptance were also studied on behalf of the children born due to rape. These attitudes were recorded by a 25-question attitudinal survey and then analyzed on a question by question bases. The outcome of the following study showed an overwhelming acceptance of the women but a mixed acceptance of their children. Based on the study findings, religious beliefs may be the best way to understand the level of acceptance the Yezidi community has toward the …

Development Of Glucocorticoid Prodrug For The Treatment Of Lupus Nephritis, Xiaobei Wang

Theses & Dissertations

Nephritis is one of the major complications of systemic lupus erythematosus (SLE). While glucocorticoids (GC) are frequently used as the first line treatment for lupus nephritis, long-term GC usage is often complicated by severe adverse effects. To address this challenge, we have developed a polyethylene glycol (PEG)-based macromolecular prodrug (ZSJ-0228) of dexamethasone, which self-assembles into micelles in aqueous media. When compared to the dose equivalent daily dexamethasone 21-phosphate disodium (Dex) treatment, monthly intravenous administration of ZSJ-0228 for two months significantly improved the survival of lupus-prone NZB/W F1 mice and was much more effective in normalizing proteinuria, with clear histological evidence …

Dietary Polyunsaturated Fatty Acids Regulate Mammary Tumor Growth And Metastasis By Modulating Tissue Microenvironments, Saraswoti Khadge

Theses & Dissertations

Omega (ω)-6 and ω-3 polyunsaturated fatty acids (PUFAs) are essential fatty acids (FAs) and the precursors of pro- and anti-inflammatory mediators respectively. Epidemiological studies have shown a lower incidence of breast cancer (BC) in the countries where long-chain (LC)-ω-3FAs consumption is higher; however, the role of ω-3FAs in BC growth and metastasis is poorly understood. We used isocaloric, isolipidic ω-6 and ω-3 (contains LC-ω-3FAs) diets and a pair-fed model to evaluate the effects of dietary PUFAs in mammary tumor metastasis. Our studies have resulted in several novel observations including that dietary LC-ω-3FAs modulate mammary gland (MG) microenvironments in non-tumor bearing …

Delivery Of Microrna With Cxcr4-Targeted Nanoparticles In Metastatic Cancer Treatment, Ying Xie

Theses & Dissertations

Metastasis is the main contributor to cancer-associated deaths. Inhibition of CXCR4 emerged as one promising approach in metastatic cancer therapy. MiRNAs represent a new class of therapeutics for cancer treatment through RNA interference-mediated gene silencing. Polymeric CXCR4 antagonist (PCX) is a dual-functional polycation to inhibit CXCR4 and deliver nucleic acids. This dissertation hypothesized that blockade of CXCR4 by PCX combined with delivery of miRNA cooperatively enhances metastatic cancer therapy.

In chapter 1, an overview of CXCR4 inhibition, miRNA delivery and CXCR4 targeted nanomedicine in cancer therapy is given.

Chapter 2 reports that PCX can effectively deliver miR-200c mimic and that …

Health-Related Perception And Responsibility Behavior Among Individuals With And Without Chronic Illness, Danielle Dohrmann

Theses & Dissertations

Few studies have examined perceptions of responsibility attribution and well-being, and health responsibility behaviors in individuals with none, one, and multiple chronic illnesses. Adults (N = 421) in medical clinics completed questionnaires for this cross-sectional descriptive study. The Revised Causal Dimensional Scale measured responsibility attribution whereas sub-sections of the Chronic Disease Self-Management Program evaluation measured well-being perception and the health responsibility behavior of communication associated with a clinic visit. Chi-square, Wilcoxon-Mann-Whitney U, and Kruskal-Wallace tests were used to examine demographic characteristics and group differences. Individuals with multiple morbidities and of advanced age perceived their illnesses as more stable and rated …

Increasing Physical Activity To Improve Health Through Primary Care Clinics In Rural Nebraska, Jill Reed

Theses & Dissertations

Addressing the lack of physical activity (PA) in rural adults is vital because of the role it plays in the risk for many chronic diseases. The purpose of the study was to explore the feasibility of conducting a 12-week intervention to increase PA behavior in inactive rural adults recruited from a primary care clinic. Subjects were randomized to the intervention (n=30) or control (n=29) group and wore a Fitbit to track PA. The intervention group completed action plans and received weekly motivational text messages to improve PA behaviors. Semi-structured interviews were conducted with study participants (n=10) and a focus group …

Essays On The Patient-Centered Medical Home In The United States Military Health System, Glen N. Gilson

Theses & Dissertations

The Patient-Centered Medical Home has been endorsed by the primary care community as the model of the future, with hopes that it will increase quality of care and the patient and provider experience while decreasing costs. Many aspects of the implementation of the Patient-Centered Medical Home model remain unexplored. This dissertation comprises three independent studies examining Patient-Centered Medical Home implementation in the Military Health System, including (1) the effects of environmental correlates on the time to implement the model, (2) the impact of differences in implementation on preventive care quality outcomes, and (3) the effect of differences in implementation on …

Quantification Of Lutein + Zeaxanthin Presence In Human Placenta And Correlations With Blood Levels And Maternal Dietary Intake, Melissa Thoene

Theses & Dissertations

Lutein + zeaxanthin are carotenoids most recognized in eye health, but less is known about their status and transfer during pregnancy. While quantified in maternal and umbilical cord blood, they have never been analyzed in placenta tissue. Therefore, the purpose of this dissertation is to firstly quantify lutein + zeaxanthin concentrations in human placenta and to later correlate with levels in maternal dietary intake, maternal serum, and umbilical cord blood. Proportions of lutein + zeaxanthin will also be compared within diet, placenta, maternal serum, and umbilical cord blood among additionally analyzed carotenoids including lycopene, β-cryptoxanthin, α-carotene, and β-carotene. Lutein + …

Hearing Loss And Hearing Protection Use Among Midwestern Farmers, Josie J. Ehlers

Theses & Dissertations

Many farmers have noise-induced hearing loss, yet few use hearing protection when working around loud noise. A point source intervention (storing hearing protection devices near sources of noise) was implemented to help farmers overcome accessibility barriers related to using hearing protection. Intervention farmers (n=53) received education and the point source intervention; control farmers (n=36) received education only. During each year of the study, all farmers completed a questionnaire about their perceptions of hearing protection and participated in an audiometric test at their farm. Ambient sound pressure levels were taken during tests. The main objectives of this dissertation were to evaluate …

Surveillance, Prevention And Surgical Treatments For Hepatocellular Carcinoma, Kerui Xu

Theses & Dissertations

Liver cancer is the second-leading cause of cancer death, representing roughly 9.1% of all cancer mortality. Of all primary cancers of the liver, hepatocellular carcinoma (HCC) accounts for roughly 85%. HCC has been increasing in the U.S. and other countries. In particular, HCC places a huge burden on the Chinese population, as China alone consists of approximately 50% of the total HCC cases and deaths. In China, chronic hepatitis B virus (HBV) infection is the leading cause for developing HCC. The two challenges in prevention and control of HCC experienced in China are low rates of HCC screening among the …

Towards An In Vitro Model Of Testing Osteoblast Cellular Function In Contact With Various Surfaces, Raheleh Miralami

Theses & Dissertations

Past studies have shown that the success of total joint replacements depends on the biocompatibility of orthopaedic materials, which can be improved by modifying the implant surface. However, the exact roles of these modifications and their effective mechanisms are poorly understood. The objective of this study was to develop and evaluate a model system to investigate the impact of nano-structured surfaces, produced by the ion beam-assisted deposition (IBAD) technique, on biomarkers of osteointegration using an in vitro model. The IBAD technique was employed to deposit zirconium oxide (ZrO₂), Titanium oxide (TiO₂), and Titanium (Ti) nano-films on …

Functional And Mechanical Role Of Splice Variant Of Mucin4 (Muc4/X) And Trefoil Factors In Pancreatic Cancer Pathogenesis, Rahat Jahan

Theses & Dissertations

Pancreatic Cancer (PC) is one of the vicious cancers as it ranks third in the race of leading cause of cancer-related death. Lack of early diagnostic marker, poor understanding of molecular mechanism of the disease and failure to conventional chemotherapy makes this disease dreadful.

Mucin 4 (MUC4), a high molecular weight glycoprotein is one of the top differentially expressed molecules in PC while not expressed in normal pancreas. Accumulating evidence from our lab suggested its tumorigenic role in PC by increasing cell proliferation, invasion, chemotherapy resistance, tumor growth, and metastasis. Previously, our lab and other has identified 24 different splice …