Medicine and Health Sciences Commons^™

Axon Initial Segment Integrity In Aging And Traumatic Brain Injury, Mazen M. Gouda

Theses and Dissertations

According to the Center for Disease Control’s (CDC) report to the Congress, there are 2.2 million emergency department visits; 80,000 hospitalizations; and 50,000 deaths each year due to traumatic brain injury. Adults 65 years and older account substantially for the majority of the hospitalization and deaths. Over 70% of the traumatic brain injuries of the older adults are classified as mild to moderate; however, even with these milder injuries, older adults present with a significantly higher morbidity and mortality compared to all other age groups (LeBlanc et al., 2006). With that in mind, it seems essential to develop a deeper …

Modulation Of Autophagy And Senescence To Enhance The Response To Therapy In Triple Negative Breast Cancer, Liliya Tyutyunyk-Massey

Theses and Dissertations

Abstract

Although great strides have been made over the decades in development and optimization of anti-cancer therapies, even highly effective drugs often fail to completely eliminate tumors. Residual tumor cells can enter into a state of dormancy for prolonged periods of time but eventually are able to regain proliferative capacity and reemerge as chemotherapy-resistant disease. Because recurrent disease is a leading contributor to patient’s mortality, it is paramount to identify strategies for effectively destroying residual tumor cells.

Cytotoxic drugs and ionizing radiation are used as standard therapies in a variety of cancers. These modalities induce apoptosis, autophagy and senescence. Senescence …

The Role Of Tumor And Tumor Microenvironment On Breast Cancer-Associated Adipocyte Plasticity, Janina V. Pearce

Theses and Dissertations

Cancer-associated cachexia is a condition defined by a sustained net-negative energy imbalance. Although the different types of adipose tissue – white, beige, and brown – have been implicated in contributing to cancer-associated cachexia, the mechanisms of these maladaptive changes and their impact on whole-body energy expenditure have not been fully elucidated. Using breast cancer as our model, we demonstrate white adipose tissue browning in murine and human breast cancer; furthermore, we demonstrate that this effect is extremely localized and takes place early in tumor progression. We utilized in vitro cell culture techniques and demonstrate that cancer secreted factors and cross-talk …

Embryonic Stem Cell-Derived Exosomes Increase The Antiproliferative Activity Of Doxorubicin In Breast Cancer, Alexander M. Hirsch

Theses and Dissertations

The field of cancer research has grown immensely in recent decades and has led to a better understanding of the causes of the disease, as well as greatly improved treatment for various types of cancers, especially breast cancer. One of the most effective treatments involves the chemotherapeutic drug doxorubicin (DOX). DOX is an effective tool against all types of breast cancer, especially against triple negative breast cancer. However, DOX causes adverse side effects that include damage to the heart and skeletal muscle, particularly above specific cumulative doses. Recent evidence suggests that embryonic stem cell-derived (ES) exosomes, nanoscale extracellular vesicles that …

Characterization Of The Novel Interaction Between Neisseria Gonorrhoeae Tdfj And Its Human Ligand S100a7, Stavros Maurakis

Theses and Dissertations

Neisseria gonorrhoeae is an obligate human pathogen that causes the common STI gonorrhea, which presents a growing threat to global health. The WHO estimated 78 million new cases of gonorrhea worldwide in 2017, with estimates of 820,000 new cases in the United States alone according to the CDC. High-frequency phase and antigenic variation inherent in N. gonorrhoeae, coupled with its natural ability to rapidly acquire and stably integrate antimicrobial resistance factors into its genome, have culminated in an infection against which there is no effective vaccine, and for which the list of viable therapeutic options is quickly shrinking. Moreover, no …

Diuretic, Natriuretic, And Vasodepressor Activity Of A Lipid Fraction Enhanced In Medium Of Cultured Mouse Medullary Interstitial Cells By A Selective Faah Inhibitor, Zdravka P. Daneva

Theses and Dissertations

The relationship between the endocannabinoid system in the renal medulla and the long-term regulation of blood pressure is not well understood. To investigate the possible role of the endocannabinoid system in renomedullary interstitial cells, mouse medullary interstitial cells (MMICs) were obtained, cultured and characterized for their responses to treatment with a selective inhibitor of fatty acid amide hydrolase (FAAH), PF-3845. Treatment of MMICs with PF-3845 increased cytoplasmic lipid granules detected by Sudan Black B staining and multilamellar bodies identified by transmission electron microscopy. HPLC analyses of lipid extracts of MMIC culture medium revealed a 205nm-absorbing peak that showed responsiveness to …

Conjugated Bile Acid And Sphingosine 1-Phosophate Prompt Cholangiocarcinoma Cell Growth Via Releasing Exosomes, Waad A. Alruwaili

Theses and Dissertations

Cholangiocarcinoma (CCA) is a fatal primary malignancy that is formed in the bile ducts. Cancer-associated myofibroblasts play a crucial role in CCA proliferation and invasion. Furthermore, there is a growing interest in the role of the exosome in the interaction between the cancer-associated myofibroblasts and cholangiocarcinoma which lead to CCA growth. However how cholangiocarcinoma-derived exosome affect the cancer-associated myofibroblasts in the tumor microenvironment remain unknown. In this study, we examined whether exosome produced by cholangiocarcinoma could involve in the prompt of CCA cells growth by regulation of myofibroblast. We found that cholangiocarcinoma-derived exosome could prompt elevated α-smooth muscle actin and …

Pharmacodynamics Of Monoamine Transporter Releasing Agents And Reuptake Inhibitors, Alexa Holloway

Theses and Dissertations

Ligands of the human monoamine transporters encompass a wide range of both illicit and therapeutic drugs that act upon neural circuitry related to reward, motivation, and the processing of salient stimuli. The present study utilizes two methods for analyzing transporter substrates and inhibitors in order to characterize activity and assess potency. The first measures transient changes in intracellular calcium as a surrogate for transporter activity by harnessing the electrical coupling of monoamine transporters and L-type calcium channels. This is used to analyze novel chimera of the strong hDAT inhibitors methylphenidate and ��-PPP in order to assess the contribution of specific …

Advances In Dual-Energy Computed Tomography Imaging Of Radiological Properties, Dong Han

Theses and Dissertations

Dual-energy computed tomography (DECT) has shown great potential in the reduction of uncertainties of proton ranges and low energy photon cross section estimation used in radiation therapy planning. The work presented herein investigated three contributions for advancing DECT applications. 1) A linear and separable two-parameter DECT, the basis vector model (BVM) was used to estimate proton stopping power. Compared to other nonlinear two-parameter models in the literature, the BVM model shows a comparable accuracy achieved for typical human tissues. This model outperforms other nonlinear models in estimations of linear attenuation coefficients. This is the first study to clearly illustrate the …

Age-Dependent Changes In Oxygen Supply And Demand Of Rat Spinotrapezius Muscle, Sami C. Dodhy

Theses and Dissertations

Because of the aerobic nature of cellular metabolism in mammalian organisms, a continuous supply of oxygen is necessary to maintain normal physiological function. As organisms age, their metabolic rates generally decline and there are accompanying alterations in the structure and function of the microcirculation, as this part of the cardiovascular system is especially important for oxygen exchange. The overall Oxygen Transport System can be considered as being composed of two complementary components: one for Oxygen Demand and one for Oxygen Supply. The purpose of the current work is to describe the age-dependent changes in both oxygen demand and oxygen supply …

Glycosaminoglycan Lyases In The Preparation Of Oligosaccharides, Alhumaidi B. Alabbas

Theses and Dissertations

Glycosaminoglycans are heterogeneous polysaccharides that mediate important biological functions. There has been considerable interest in deciphering the precise GAG sequences that are responsible for protein interactions. In fact, several GAG oligosaccharides have been discovered to date as targeting proteins with higher level of specificity. Yet, it has been difficult to develop GAG oligosaccharides as drugs. One of the key reasons for this state of art is that GAG synthesis is extremely challenging and is highly structure-specific. Thus, much of the biology and pharmacology of GAG remains unknown and unexploited to date.

An alternative approach is to prepare GAG oligosaccharides using …

Gastrointestinal Microbiota Modulate Antinociceptive Tolerance Development In Mice With Chronic Morphine Exposure, Ryan A. Mischel

Theses and Dissertations

In October 2017, the United States government declared a state of public health emergency in response to the burgeoning prescription opioid epidemic. Opioid analgesics are the gold standard of therapy for moderate to severe pain, but their clinical utility is greatly limited by analgesic tolerance – a primary driver of diminished pain control and opioid dose escalations. Integral in this process are primary afferent sensory neurons in dorsal root ganglia (DRG), the first-order components of nociceptive sensation. With surmounting evidence that morphine and other narcotics can alter gut microbial composition and promote bacterial translocation to other tissues, a question arises …

Effects Of Chemotherapy On Motivated Behavior And Opioid Reward In Rats, Luke P. Legakis

Theses and Dissertations

Paclitaxel, vincristine, oxaliplatin, and bortezomib are cancer chemotherapy drugs with adverse effects that include chemotherapy-induced neuropathic pain (CINP) as well as depression of behavior and mood. In the clinical setting, opioids are often used concurrently with or following chemotherapy to treat pain related to the cancer or CINP, but repeated opioid exposure can also increase the risk of opioid abuse. This dissertation evaluated the effect of chemotherapy treatment on motivated behaviors and opioid reward in rats. The main findings of this evaluation are as follows: (1) Chemotherapy, at doses that produce robust and sustained mechanical hypersensitivity produce only weak or …

Metabotropic Glutamate Receptor 2 Activation: Computational Predictions And Experimental Validation, Amr Ellaithy

Theses and Dissertations

G protein-coupled receptors (GPCRs) are the largest family of signaling proteins in animals and represent the largest family of druggable targets in the human genome. Therefore, it is of no surprise that the molecular mechanisms of GPCR activation and signal transduction have attracted close attention for the past few decades. Several stabilizing interactions within the GPCR transmembrane (TM) domain helices regulate receptor activation. An example is a salt bridge between 2 highly conserved amino acids at the bottom of TM3 and TM6 that has been characterized for a large number of GPCRs. Through structural modeling and molecular dynamics (MD) simulations, …

The Contribution Of Sarm1 To Axonal Degeneration In Cns Inflammatory Disorders, Daniel C. Njoku

Theses and Dissertations

BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) that results in demyelination and axonal loss. Efficiently targeting mechanisms of axonal degeneration in MS has the potential to reduce disability but remains an unmet need. Prior research has identified the protein sterile alpha and TIR motif containing 1 (SARM1) as a critical factor that promotes axonal destruction in the program of axonal degeneration known as Wallerian degeneration. SARM1 inactivation reduces axonal degeneration in a variety of contexts including traumatic and toxic injury, but it remains unknown to what extent SARM1 is involved in axonal degeneration …

Usefulness Of The Captia Syphilis Igg Eia Test Method And Reverse Algorithm For Detection Of Syphilis Infection In A Public Health Setting, Patricia Armour

Theses and Dissertations

Syphilis, a systemic sexually transmitted disease, is on the rise in the US, with infection rates the highest recorded since 1994 according to the CDC. Useful laboratory testing is an important diagnostic tool for determining individual syphilis infection and preventing community-wide disease spread.

The purpose of this study was to determine the usefulness of a specific automated treponemal test method, the Captia^TM Syphilis IgG EIA, and the syphilis reverse algorithm interpretation for detecting syphilis infection among patients seeking care in a public health clinic. The study employed a retrospective, nonexperimental descriptive correlational design with data collected between 2012-2013 from …

Investigating The Role Of Nicotinic Acetylcholine Receptors (Nachrs) In The Development And Maintenance Of Chemotherpy-Induced Peripheral Neuropathy In Mice, Wisam B. Toma

Theses and Dissertations

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a major dose-limiting side effect of several anticancer drugs. The prevalence of CIPN ranges from one-third to two-thirds of cancer patients. CIPN can persist for months to years after completion of chemotherapy. Despite the efficacious use of paclitaxel in the treatment of tumors, it can induce many sensory symptoms, such as paresthesia, numbness, tingling and burning pain, and mechanical and cold allodynia, which typically are present in the hands and feet. Similar to other types of chronic pain, paclitaxel-induced CIPN is comorbid with depression and anxiety in cancer survivors, and paclitaxel induces changes in affect-like …

Novel Insights Into The Contribution Of Cellular Senescence To Cancer Therapy: Reversibility, Dormancy And Senolysis., Tareq Saleh

Theses and Dissertations

Cellular senescence a specialized form of growth arrest that contributes to the pathogenesis of several aging-related disorders including cancer. While by definition tumor cells are considered immortalized, they can undergo senescence when exposed to conventional and targeted cancer therapy. Therapy-Induced Senescence (TIS) represents a fundamental response to therapy and impacts its outcomes. However, TIS has been considered a positive therapeutic goal since senescent tumor cells are expected to enter a state of permanent growth abrogation. In this work we examined the hypothesis that a subpopulation of senescent cells can re-acquire proliferative potential after a state of senescent dormancy, indicating that …

Alternative Splicing Of Cytoplasmic Polyadenylation Element Binding Protein 2 Is Modulated Via Serine Arginine Splicing Factor 3 In Cancer Metastasis, James T. Deligio, James Thomas Deligio

Theses and Dissertations

Our laboratory delineated a role for alternative pre-mRNA splicing (AS) in triple negative breast cancer (TNBC). We found the translational regulator cytosolic polyadenylation element binding protein 2 (CPEB2) which has two isoforms, CPEB2A and CPEB2B, is alternatively spliced during acquisition of anoikis resistance (AnR) and metastasis. The splicing event which determines the CPEB2 isoform is via inclusion/ exclusion of exon four in the mature mRNA transcript. The loss of CPEB2A with a concomitant increase in CPEB2B is required for TNBC cells to metastasize in vivo. We examined RNAseq profiles of TNBC cells which had CPEB2 isoforms specifically downregulated to …

Effects Of The Na-Cl Co-Transporter (Ncc) In Western Diet Induced Metabolic And Cardiac Dysfunction, Zachary S. Cutter

Theses and Dissertations

Interleukin-18 (IL-18) is a pro-inflammatory cytokine known to be involved in maintaining metabolic homeostasis; however, also capable of inducing cardiac dysfunction. Additionally, IL-18, has been shown to bind to a novel receptor, the Na-Cl Co-transporter (NCC). We hypothesized that NCC mediates IL-18 metabolic and cardiac signaling in mice. Using male C57BL/6J mice, we compared the metabolic and cardiac function changes after at least 8 weeks of high-saturated fat high sugar diet (Western Diet) in NCC knockout (NCCKO), IL-18 knockout (IL-18KO), and wild-type mice. We show that NCCKO mice have significantly increased body weight gain from baseline, no difference in fasting …

Development And Validation Of A Semi-Physiological Pharmacokinetic (Pbpk) Model To Predict Systemic And Pulmonary Exposures After Intravenous, Oral Administration And Pulmonary Inhalation Of Selected Drugs, Budesonide, Tobramycin And Ciprofloxacin, In Humans, Bishoy Hanna

Theses and Dissertations

Using a semi-PBPK modeling/quantitative meta-analysis approach, this project investigated what factors affect pulmonary and systemic exposures of Budesonide (BUD), Tobramycin (TOB), and Ciprofloxacin (CIP) after inhalation:

Three structurally different pulmonary disposition models were developed for each drug, including pulmonary absorption (all three), excretion (TOB and CIP) and sequestration (TOB) in a peripheral and central lung compartment. Systemic disposition parameters were estimated using available human mean plasma (c_p(t)) and sputum (c_s(t)) concentration profiles after IV administration, and GI absorption parameters were estimated from these profiles after oral administration. Pulmonary disposition parameters were estimated from c_p(t) …

Branched Short Chain Fatty Acid Isovaleric Acid Causes Smooth Muscle Relaxation Via Camp/Pka Pathway, Inhibits Gastrointestinal Motility, And Disrupts Peristaltic Movement, Bryan Adam Blakeney

Theses and Dissertations

Isovaleric Acid (IVA) is a 5-carbon branched chain fatty acid present in fermented foods and produced by the fermentation of leucine by colonic bacteria. IVA activates G-protein coupled receptors such as FFAR2, FFAR3, and OR51E1 known to be expressed on enteric neurons and enteroendocrine cells. We previously reported that the shorter, straight chain fatty acids acetate, propionate and butyrate, differentially affect colonic propulsion; however, the effect of branched chain fatty acids on gastrointestinal motility is unknown. We hypothesize that IVA relaxes smooth muscle in a cAMP/PKA dependent manner by direct action on smooth muscle cells. IVA will also decrease peristalsis …

Investigating The Role Of Nicotinic Acetylcholine Receptor Agonists In Lung Cancer Progression And Chemosensitivity In The Context Of Treating Chemotherapy-Induced Peripheral Neuropathy, Sarah L. Kyte

Theses and Dissertations

While cancer chemotherapy continues to significantly contribute to the number of cancer survivors, exposure to these drugs can often result in chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration. CIPN is characterized by sensory symptoms in the hands and feet, such as numbness, burning, and allodynia, resulting in an overall decrease in quality of life. Paclitaxel (Taxol), a microtubule poison that is commonly used to treat breast, lung, and ovarian cancers, has been found to cause CIPN in 59-78% of cancer patients. There is currently no effective preventative or therapeutic treatment for this side effect, …

Penalized Mixed-Effects Ordinal Response Models For High-Dimensional Genomic Data In Twins And Families, Amanda E. Gentry

Theses and Dissertations

The Brisbane Longitudinal Twin Study (BLTS) was being conducted in Australia and was funded by the US National Institute on Drug Abuse (NIDA). Adolescent twins were sampled as a part of this study and surveyed about their substance use as part of the Pathways to Cannabis Use, Abuse and Dependence project. The methods developed in this dissertation were designed for the purpose of analyzing a subset of the Pathways data that includes demographics, cannabis use metrics, personality measures, and imputed genotypes (SNPs) for 493 complete twin pairs (986 subjects.) The primary goal was to determine what combination of SNPs and …

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 …

Understanding The Role Of Phosphoinositide 3-Kinase And Its Function As A Driving Force Behind The Er Stress Response In Fibrostenotic Crohn’S Disease-Affected Ileal Smooth Muscle Cells, Prashant Yadav

Theses and Dissertations

Crohn’s disease (CD) affects about 780,000 people in the United States alone, and it is estimated that 6-15 per 100,000 persons will receive a diagnosis of this disease each year. There currently is no cure for Crohn’s disease, and available medical therapies simply serve to alleviate the inflammation. This does not help treat fibrostenosis that Crohn’s disease patients may develop, which can only be treated surgically. Finding alternatives to treat CD requires an understanding of mechanisms at the biochemical level. In this thesis, we attempted to gain a better understanding of certain pathways found to be active in Crohn’s disease-affected …

Impaired Cardiorespiratory Fitness Following Thoracic Radiotherapy, Justin M. Canada

Theses and Dissertations

Cancer (CA) is the second leading cause of death in the United States preceded only by cardiovascular disease (CVD). Over the past 30 years, the 5-year survival rate for all cancers combined has increased by more than 20%. This improved survival rate is due to early diagnosis and advances in treatment involving a multimodality treatment approach that includes radiotherapy [RT] with about half of all CA patients receiving some type of RT sometime during the course of their treatment. Cardiotoxicity is one of the most important adverse reactions of RT and leads to a meaningful risk of CVD-related morbidity and …

The Role Of Adam10 And Adam17 In Humoral And Type 2 Immunity, Joseph C. Lownik

Theses and Dissertations

The proper regulation of inducible costimulator (ICOS) and its ligand (ICOSL) have been shown to be essential for maintaining immune homeostasis. Loss of either protein results in defective humoral immunity, and overexpression of ICOS results in aberrant antibody production resembling lupus. How ICOSL is regulated in response to ICOS interaction is still unclear. We demonstrate that ADAM10 is the primary physiological sheddase of ICOSL in both mouse and human. Using an in vivo system in which ADAM10 is deleted only on B cells (ADAM10^B-/-), elevated levels of ICOSL were seen. This increase is also seen when ADAM10 is …

Heme Oxygenase 1 Expression After Traumatic Brain Injury And Effect Of Pharmacological Manipulation On Functional Recovery., Nicholas H. Russell

Theses and Dissertations

Traumatic Brain Injury (TBI) is an increasingly diagnosed constellation of injuries derived from acute mechanical trauma to the brain. With the rise of advanced neuroimaging techniques recent focus has oriented primarily towards the mild-moderate range of TBI which previously was missed diagnostically. Characteristically, these advances have shown increasing areas of micro-hemorrhage in susceptible areas of the brain and to date there are no treatment modalities targeting micro-hemorrhages or their sequelae. This dissertation explores the effects of the resulting heme processing response in the days following injury with a particular focus on inducing early heme clearance from the parenchyma using a …

Sleep Disturbances And Depression: The Role Of Genes And Trauma, Mackenzie J. Lind

Theses and Dissertations

Sleep disturbances and insomnia are prevalent, with around 33% of adults indicating that they experience at least one main symptom of insomnia, and bidirectional relationships exist with common psychopathology, particularly major depressive disorder (MDD). However, genetic and environmental (e.g., traumatic event exposure) contributions to the etiology of these phenotypes are not yet well understood. A genetically informative sample of approximately 12,000 Han Chinese women aged 30-60 (50% with recurrent MDD) was used to address several gaps within the sleep literature. Sleep disturbances were assessed in all individuals using a general item addressing sleeplessness (GS). A sleep within depression sum score …