Life Sciences Commons^™

Characterizing The Effects Of Antiandrogens And Senolytics To Enhance The Therapeutic Response To Castration-Resistant Prostate Cancer, Justin M. Silverman

Theses and Dissertations

Prostate cancer is the most frequently diagnosed cancer in males and the second most common cause of cancer deaths. Androgen deprivation therapy, whether through surgical or chemical castration, is the mainstay for treatment of advanced prostate cancer; however, despite an initial response, most patients eventually develop a progressive PSA rise, and castration- sensitive prostate cancer gives rise to castration-resistant prostate cancer. The standard of care therapy includes the antiandrogens such as enzalutamide and abiraterone acetate as well as the microtubule poison, docetaxel, and various immunotherapies; however, while prostate cancer research is progressing, there continues to be a compelling need for …

Development Of New Treatments For Asthma And Neuropathic Pain Based On Ɣ-Aminobutyric Acid A Receptor (Gabaar) Ligands, Nicolas Mark Zahn

Theses and Dissertations

The γ-aminobutyric acid A receptor (GABAAR) is a ligand-gated pentameric chloride channel consisting of several identified subunits: α1-6, β1-3, γ1-3, δ, ε, π, θ, ρ1-3.1-2 Typical arrangement of subunits consists of two α subunits, two β subunits, and one γ subunit.3 GABAARs have two binding sites for the endogenous ligand γ-aminobutyric acid (GABA), between the α and β subunits. GABAARs also have a binding site for positive allosteric modulators, such as benzodiazepines, between the α and γ subunits.4-5 Due to their ability to treat anxiety, epilepsy, insomnia, and muscle relaxation, benzodiazepines are widely prescribed pharmaceuticals.6-7 Still, adverse effects result from …

Targeting Bcl-2 Family Proteins In Therapy Induced Senescent Cancer Cell Models, Wade Cook

Theses and Dissertations

Non-small Cell Lung Cancer (NSCLC) originates from numerous different cell types in the lungs and is among the deadliest of cancers. Head and Neck Squamous Cell Carcinomas (HNSCC) are derived from the mucosal membranes of the oral cavity, pharynx, and larynx. Both NSCLC and HNSCC are predominately caused by tobacco smoke inhalation and as such mutations in the tumor suppressor gene TP53 are common. Since similarities exist in the root cause of NSCLC and HNSCC, they may also share similarities in treatment methods. Cisplatin is a platinum-based DNA damaging agent that has been used as a cancer chemotherapy for decades. …

Theta Burst Brain Stimulation In Painful Diabetic Neuropathy Patients: Investigating Neural Mechanisms, Bhushan Thakkar

Theses and Dissertations

Chronic pain (CP) is a significant contributor to disability and disease burden globally. In 2019, approximately 50.2 million adults (20.4% of the US population) experienced chronic pain, contributing to $560-635 billion in direct medical costs. In addition, the worldwide prevalence of diabetes mellitus has reached epidemic proportions and is set to increase to 629 million by 2045. Almost 50% of patients with diabetes present with diabetic neuropathy (DN), and one in five patients with diabetes presents with painful DN (pDN) which is the most common cause of neuropathic pain (NP) in the US. Symptomatic treatment is the mainstay of management …

Changes In Physical Activity And Relationships To Submaximal Exercise Capacity And Cardiac Function During Breast Cancer Therapy, Moriah P. Bellissimo

Theses and Dissertations

Background: Breast cancer (BC) survivors are at high risk for heart failure due to curative cancer therapies. In non-cancer populations, physical activity is a first line treatment for preventing cardiovascular disease. This study examined whether more physical activity was associated with better submaximal exercise capacity and cardiac function during the first three months of cancer therapy.

Methods: Participants included 223 women with stage I-III BC before therapy and after three months of undergoing treatment and 126 controls. Leisure time physical activity was reported using the Godin Sheppard leisure time exercise questionnaire. Cardiac function was assessed by cardiac magnetic resonance, and …

Nebulizer-Based Systems To Improve Pharmaceutical Aerosol Delivery To The Lungs, Benjamin M. Spence

Theses and Dissertations

Combining vibrating mesh nebulizers with additional new technologies leads to substantial improvements in pharmaceutical aerosol delivery to the lungs across therapeutic administration methods. In this dissertation, streamlined components, aerosol administration synchronization, and/or Excipient Enhanced Growth (EEG) technologies were utilized to develop and test several novel devices and aerosol delivery systems. The first focus of this work was to improve the poor delivery efficiency, e.g., 3.6% of nominal dose (Dugernier et al. 2017), of aerosolized medication administration to adult human subjects concurrent with high flow nasal cannula (HFNC) therapy, a form of continuous-flow non-invasive ventilation (NIV). The developed Low-Volume Mixer-Heater (LVMH) …

Effect Of Inhibition Of Glycogen Catabolism In Hepatocellular Carcinoma Cells, Shrikant Barot

Theses and Dissertations

Metabolic reprogramming is one of the important features of cancers, and there has been growing interest in targeting metabolic proteins to treat cancer. Glycogen is a polymer of glucose and serves as its storage unit in cells. Glycogen can provide energy to cells during the situations of high energy demand. A number of tumors are known to contain high levels of glycogen than their normal tissue counterparts. The liver plays an essential role in maintaining glucose homeostasis in the body via storing it into glycogen. The significance of glycogen metabolism in patients suffering from hepatocellular carcinoma (HCC) has not been …

Investigation Of Molecular Mechanisms Of Liver Preservation Injury: A Complication Preceding Organ Transplantation, Ria C. Fyffe-Freil

Theses and Dissertations

Of the over 108,000 American awaiting a life-saving organ transplant today, over 12,000 (11%) of those need a new liver (OPTN, 2020). Last year, only 35% of patients on the waiting list for an organ were transplanted. Improving the quality of marginal organs by preventing or reversing preservation injury could vastly increase the number of transplants performed. Washout of circulating blood during liver procurement with cold University of Wisconsin solution flushes out any endogenous pro-survival signaling molecules. We investigated lysophospholipid (LPL) surface receptors (G-protein coupled receptors for lysophosphatidic acid (LPA) and sphingosine- 1-phosphate (S1P)) and their role in protecting hepatocytes …

Functional Characterization Of Lt-Hsc Metabolic Activity Dependent On Ahr Activity, Everett Tate

Theses and Dissertations

The cells of the immune system are descended from multipotent hematopoietic stem cells (HSCs) that emerge during development. Multipotency means that a single progenitor HSC can differentiate into any cell of the immune system. HSCs are required to do this for the lifetime of the organism through a process called self-renewal, and as such, any perturbation during development or in the bone marrow can have a trickle-down effect, affecting the self-renewal capacity or ability to terminally differentiate. The aryl hydrocarbon receptor (AHR) is a known regulator of HSCs. The AHR is a transcription factor required for the detoxification of numerous …

Role Of Regulatory T Cells In The Development And Progression Of Lyme Disease In Balb/C Mice, Kaitlyn Nielsen

Theses and Dissertations

Lyme disease, caused by Borrelia burgdorferi, is an increasingly important public health concern, with tens of thousands of new cases being diagnosed each year, even in previously non-endemic areas. It is known that symptoms of Lyme disease are caused by an inflammatory immune response initiated to aid in clearance of the pathogen. Left unchecked, these inflammatory responses can potentially increase tissue damage, leading to increased disease severity. Mechanisms responsible for the control of the inflammatory response to infection with B. burgdorferi are not entirely understood. Evidence exists that regulatory T (Treg) cells, a population of Foxp3-expressing CD4+ T cells known …

Deciphering The Consequences Of Yolk Testosterone Metabolism In Birds, Nicole A. Campbell

Theses and Dissertations

Maternal steroids transferred to eggs can elicit permanent effects on various aspects of offspring phenotype. Although, testosterone was thought to be a key mediator of maternal effects in birds, we now know that vertebrate embryos actively regulate their exposure to maternal testosterone through steroid metabolism, suggesting testosterone metabolites may elicit the observed phenotypic effects. To address the role steroid metabolism plays in mediating yolk testosterone effects, we used European starling (Sturnus vulgaris) eggs to characterize the timing of testosterone metabolism and determine whether etiocholanolone, a prominent testosterone metabolite in avian embryos, is capable of influencing early embryonic development. Tritiated testosterone …

The Role Of Sphingosine Kinase 2 In Alcoholic Liver Disease, Eric K. Kwong

Theses and Dissertations

Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide characterized by the accumulation of lipids within the liver, inflammation and the possibility of progressing to cirrhosis and liver failure. More importantly, there are currently no effective treatments for ALD and liver transplantation remains the only therapeutic option for end-stage liver disease. Previous studies have shown that ALD is a result of a combination of endoplasmic reticulum (ER) stress, lipid metabolism dysregulation and inflammation. It has been previously reported that alcohol disrupts gut microbiota homeostasis and causes increased endotoxins that contribute to the pathology of ALD. However, …

Differential Migration Of Cd4+ And Cd8+ T Cells During An Immune Response, Jacob Parrott

Theses and Dissertations

ABSTRACT

DIFFERENTIAL MIGRATION OF CD4+ AND CD8+ T CELLS DURING AN IMMUNE RESPONSE

by

Jacob Parrott

The University of Wisconsin-Milwaukee, 2018

Under the Supervision of Professor Douglas Steeber

Lymphocyte migration is critical for recognizing pathogenic challenges in a timely manner and generating effective, rapid immune responses. Lymphocyte numbers in secondary lymphoid tissues such as lymph nodes are rapidly and dramatically increased during an immune response. Lymphocytes use specific adhesion molecules and intracellular signaling cascades to migrate and enter secondary lymphoid tissues under resting conditions. It is not clear if the same migration and/or entry pathways are utilized when secondary lymphoid …

Out Of The Shell: Exploring The Phagocytic Capabilities Of The B Cell And Isolated Lymphoid Follicle-Lie Structures In The Red-Eared Slider, Trachemys Scripta, Marc A. Ashford Jr.

Theses and Dissertations

Management of immunity is crucial for survival in all living organisms. While there is a large amount of research for established model organisms, such as the mouse model, much less is known about reptiles. When compared to immunity in mammals, we discover many differences such as susceptibility to certain pathogens, alteration of immune processes due to environmental temperature, the total absence of certain lymphoid organs contained in mammals, among many others. Despite this, the reptile has shown in many studies that they are worthy systems to study immunity in an evolutionary perspective and recent studies may show that they may …

Markers Of Cardiometabolic Risk And Thyroid Dysfunction In U.S. Adolescents: Nhanes Iii, Jonathan Austin

Theses and Dissertations

The global prevalence of metabolic syndrome (MetS) and its associated components (high fasting glucose, waist circumference, blood pressure, triglycerides, and low HDL) have increased over the past few decades. In addition, abnormal thyroid hormone levels have been found to manifest in a cascade of metabolic dysfunction, which may be linked to MetS in youth. PURPOSE: The purpose of the study is to investigate the association between MetS, its components, and markers of thyroid function in a nationally-representative sample of adolescents. METHODS: The National Health and Nutrition Examination Survey III (1988-1994) collected data on the components of metabolic syndrome and thyroid …

Evaluation And Adaptation Of Live-Cell Interferometry For Applications In Basic, Translational, And Clinical Research, Kevin A. Leslie

Theses and Dissertations

Cell mass is an important indicator of cell health and status. A diverse set of techniques have been developed to precisely measure the masses of single cells, with varying degrees of technical complexity and throughput. Here, the development of a non-invasive, label-free optical technique, termed Live-Cell Interferometry (LCI), is described. Several applications are presented, including an evaluation of LCI’s utility for assessing drug response heterogeneity in patient-derived melanoma lines and the measurement of CD3+ T cell kinetics during hematopoietic stem cell transplantation. The characterization of mast cells during degranulation, the measurement of viral reactivation kinetics in Kaposi’s Sarcoma, and drug …

Influence Of Expectations Of Aging On Older Women’S Use Of Dietary Supplements Using The Health Promotion Theory, Barbara Emily Hekel

Theses and Dissertations

The use of vitamins, minerals and herbal supplements by older adults is increasing and changing. There are concerns about supplement quality, safety, and vitamin D overuse. Little is known about supplement use by nursing home residents and about factors that influence older women to use supplements. The current study describes the supplement use of 247 nursing home residents and 110 independent living women 65 years or older in the Midwestern United States. A secondary analysis of 247 medication administration records describes the prevalence of vitamin, mineral, and herbal supplement use of nursing home residents. Using the health promotion theory, the …

Investigation On Genetic Modifiers Of Age At Onset Of Major Depressive Disorder, Huseyin Gedik

Theses and Dissertations

Major Depressive Disorder (MDD) is a complex multifactorial disorder, which would lead to disability. Environmental and genetic factors are involved in MDD etiology. The aim of this project was to identify loci modifying age at onset (AAO) of MDD using survival models after adjusting for Childhood Sexual Abuse (CSA). To achieve this aim, a dataset was made available by the China Oxford and VCU Experimental Research on Genetic Epidemiology (CONVERGE) consortium. The study population had 5,220 controls and 5,282 cases with MDD. We performed two univariate association analyses using Cox Proportional Hazard (Cox PH) models. These two are Full Sample …

Epigenetic Editing To Validate Findings From Methylome-Wide Association Studies Of Neuropsychiatric Disorders, Robin F. Chan

Theses and Dissertations

DNA methylation is necessary for learning, memory consolidation and has been implicated in a number of neuropsychiatric disorders. Obtaining high quality and comprehensive data for the three common forms of methylation in brain is challenging for methylome-wide association studies (MWAS). To address this we optimized a panel of enrichment methods for screening the brain methylome. Results show that these enrichment techniques approach the coverage and fidelity of the current gold standard bisulfite based techniques. Our MBD-based method can also be used with low amounts of genomic material from limited human biomaterials. Psychiatric disorders have high prevalence and are often chronic …

Type 2 Immune Responses In The Context Of Helminth Infection, Asthma, Dendritic Cells, And Myeloid Derived Suppressor Cell Function, Sheela Ruby Damle

Theses and Dissertations

Type 2 (T_H2) immune responses evolved to respond to helminth parasite infections by the production of T_H2 cytokines, which stimulate anti-helminth immunity. Macrophage migration inhibitor factor (MIF) is a pleiotropic cytokine, which is produced by many cell types. We demonstrate that mice deficient in MIF have enhanced clearance of a helminth parasite. MIF deficiency in CD4⁺ T cells was found to be the most important for mediating parasite clearance. We mimicked MIF deficiency by administering an inhibitor of the MIF tautomerase activity, sulforaphane, and this also increased parasite clearance (Section I).

T_H2 immune …

Tissue Factor Expression, Regulation, And Signaling In Human Airway Cells, Michael D. Davis

Theses and Dissertations

Rationale: Tissue Factor (TF) is a transmembrane glycoprotein that canonically functions as the initiator of the coagulation cascade. Increased levels of TF have been associated with inflammatory airway diseases. Since lipopolysaccharide (LPS) is known to elicit and inflammatory response in airway epithelium, we hypothesized that airway epithelial cells release TF when exposed to LPS. Since TF aids in local wound healing, we also hypothesized that inhibition of TF would decrease NHBE growth. The specific aim of this work was to evaluate the effects of LPS exposure on TF production and release from airway epithelia and determine the signaling pathways involved. …

Regulatory Mechanisms In Borrelia Burgdorferi-Induced Arthritis, Emily Siebers Hansen

Theses and Dissertations

Lyme arthritis is a common symptom of Lyme borreliosis that involves inflammation of the synovial joints. Elucidating the immune events involved in Lyme arthritis is complicated by the fact that not all individuals infected with B. burgdorferi develop arthritis. Additionally, Lyme arthritis manifests in different severities between affected individuals. It is known that an inflammatory response is initiated by B. burgdorferi infection and that inflammatory T cells contribute to the development of arthritis. However, the anti-inflammatory mechanisms that regulate the pathogenic T cells’ response are not entirely understood. Here, the hypothesis that a dysregulated immune response results in an excessive …

Age-Associated B Cell And T Helper Cell Dysfunction In Rhesus Macaques, Evan Knox Stalvig

Theses and Dissertations

The immune system undergoes drastic changes as we age, known as immunosenescence. An example of this is the dysfunction and subpopulation distribution changes of immune cells. Due to immunosenescence, the elderly have a higher risk of complications and rapid progression of new challenges to the immune system, including human immunodeficiency virus (HIV). In an effort to determine the mechanism of dysfunction of humoral immunity due to age, I compared B cell and T cell responses to non-specific, mitogenic stimuli between aged and young adult rhesus macaque peripheral blood mononuclear cells (PBMCs). Analysis by flow cytometry revealed several differences in B …

Effects Of Drift, Selection And Gene Flow On Immune Genes In Prairie Grouse, Zachary Bateson

Theses and Dissertations

Fragmentation of natural habitats is related to population decline in many species. The resulting small and isolated populations are expected to lose genetic variation at a rapid rate, which reduces the ability to adapt to environmental change. One concern is that small populations are more susceptible to emerging pathogens due to the loss of variation at immune genes. My dissertation examined the relative effects of gene flow, genetic drift and selection on immune genes in prairie-chickens (Tympanuchus cupido), a species that has undergone drastic population declines across their range. In the first chapter, I examined how artificial gene flow through …

The Effects Of 830nm Light On Inflammation In Retinitis Pigmentosa, Krystal Marie Bach

Theses and Dissertations

Purpose: Retinitis Pigmentosa (RP) is an inherited retinal degenerative disease and the most common cause of blindness in developed countries, affecting approximately 1 in 4,000 people. RP is characterized by photoreceptor cell death and recent studies suggest that chronic inflammation may play a key role in the pathogenesis of RP. Currently, there are no known treatments or preventive measures to delay or halt the loss of photoreceptor cells. Photobiomodulation (PBM) by light in the far-red or near-infrared (NIR) range of the light spectrum has been documented to help promote cell survival and reduce inflammation in several disease states. Recent studies …

Bacterially-Based Immune Challenges And Trauma Elicit Terminal Investment In Male Aedes Aegypti, Molly K. Schumacher

Theses and Dissertations

Investment in life history traits such as immune function and reproduction is constrained by finite available resources. A cost-of-immunity trade-off may occur in response to infection when resources are diverted away from reproductive effort and into an immune response. Alternatively, an infected individual may enhance reproductive effort to maximize terminal reproductive success in response to the survival threat inherent to infection (terminal investment). We measured male Aedes aegypti reproductive behavior following inoculations with: living bacteria; killed bacteria as an immune elicitor; and a sham control. Mating competitiveness relative to naïve males was also determined through a binary mate choice experiment …

Effects Of 670 Nm And 830 Nm Light On The Immune Response To Borrelia Burgdorferi, Felice Chen

Theses and Dissertations

ABSTRACT

EFFECTS OF 670 NM AND 830 NM LIGHT ON THE IMMUNE RESPONSE TO BORRELIA BURGDORFERI

by

Felice Chen

The University of Wisconsin-Milwaukee, 2015

Under the Supervision of Dean T. Nardelli, Ph.D. and Janis T. Eells, Ph.D.

Lyme arthritis is a debilitating joint disorder that arises from Lyme disease, which is a result of infection by the spirochete Borrelia burgdorferi. Antibiotics are the traditional treatment for Lyme disease, but chronic arthritis may persist in some patients despite antibiotic treatment. Therefore, other forms of treatment for Lyme arthritis are needed. Photobiomodulation (PBM) using red or near-infrared light, with wavelengths between 630 …

The Characterization Of A Putative Virulence Factor Expressed By Sneathia Amnii, Amy Sanford

Theses and Dissertations

Preterm birth, defined at birth before 37 weeks gestation, affects millions of newborns worldwide every year. Preterm birth is a leading cause of infant morbidity and mortality. One major cause of preterm birth is preterm premature rupture of membranes (PPROM), which can be triggered by bacterial infection and inflammation. A bacterial species that has been implicated in preterm birth and other obstetric complications is Sneathia amnii. The goals of this study were to observe cytopathogenic effects caused by S. amnii strain Sn35 and identify putative virulence factors causing those effects. Sn35 was able to adhere to, invade, and damage/kill …

Impact Of Gestational Exposure To 2,3,7,8-Tetrachlorodibenzo-P-Dioxin On T Lymphocyte Development, Lori S. Ahrenhoerster

Theses and Dissertations

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant and the best characterized agonist of the arylhydrocarbon receptor (AHR), a transcription factor crucial to the detoxification of numerous xenobiotics. Studies in animals show that TCDD is immunosuppressive in adult exposures, and epidemiological studies have found an association between TCDD exposure and hematologic cancers. Additionally, developmental exposure to TCDD has been shown to increase the likelihood of autoimmunity and to impair immune response to later-life infections. The cells of the immune system are all descended from multipotent hematopoietic stem cells (HSCs) that originate in the fetus. This multipotency, defined as the ability to …

Th17 Cell-Associated Response To Borrelia Burgdorferi Outer Surface Protein A, Megan Elizabeth Johnson

Theses and Dissertations

Arthritis is a common symptom of Lyme disease, a debilitating condition resulting from infection with Borrelia burgdorferi. A protein found on the surface of B. burgdorferi, outer surface protein A (OspA), is known to elicit an inflammatory immune response involving T helper cells. T helper 17 (Th17) cells are associated with the inflammatory cytokines interleukin-17 (IL-17) and interleukin-23 (IL-23) and have been implicated in the development of Lyme arthritis. The objective of this thesis is to provide further characterization of the immune response to B. burgdorferi OspA. The central hypothesis of this thesis is: Vaccination with OspA will predispose mice …