Medicine and Health Sciences Commons^™

Targeting Of Mediator Kinases For Cancer Therapy And Resistance Prevention, Zachary Thomas Mack

Theses and Dissertations

Estrogen receptor (ER)-positive breast cancers make up 70% of all breast cancer incidences in the US. Cell cycle progression of ER-positive breast cancer is highly dependent on cyclin-dependent kinases (CDK) 4 and 6, the G1/S checkpoint kinases. Inhibitors of CDK4/6 have become a major addition to the clinical arsenal against ER-positive breast cancers. CDK4/6 inhibitor palbociclib (IBRANCETM) has been approved for the treatment of ER-positive breast cancers. However, palbociclib treatment eventually fails due to the development of resistance. Laboratory studies revealed several diverse mechanisms of palbociclib resistance, making universal re-sensitization difficult to achieve. However, prevention of the adaptive process that …

Peromyscus Maniculatus Bairdii And Peromyscus Maniculatus Sonoriensis Polymorphisms, Matthew Dixon Lucius

Theses and Dissertations

Sequencing technology has advanced greatly over the past couple of decades. This has led to many studies developing hypotheses based on genomic data. This requires many genomic studies to have up-to-date information on the species’ or subject’s genome being investigated. If a study does not have accurate or up-to-date background information, then they cannot fully develop their theories that are being established. In this study, I utilize outbred Peromyscus maniculatus, deer mice that are genetically diverse, to record the polymorphisms that are found throughout the Peromyscus maniculatus genome. I first explore the differences between the polymorphisms found in Peromyscus …

Genomic Analysis Workflows To Identify Mutational Signatures And Structural Variations In Ovcar8 Cells And Rad51d-Deficient Mouse Embryonic Fibroblasts, Manli Yang

Theses and Dissertations

Specific genomic profiles associated with exposure to DNA damaging agents have been identified in cancer related genes, revealing that mutational patterns can be carcinogen- specific. However, there have been limited efforts to demonstrate similar clear relationships for endogenous mutational processes. One endogenous source of mutations is contamination of the deoxynucleotide pool with damaged bases that, if incorporated into DNA, cause mutations.

The Catalog of Somatic Mutations In Cancer (COSMIC) represents an international effort to characterize mutations in cancer. A mutational signature is the pattern of mutations generated by a mutational process. Each mutational process contains two parts: DNA damage and …

Discovery And Mechanistic Study Of Novel Pbd-Targeted Inhibitors Of Plk1 For Prostate Cancer Treatment, Danda Pani Chapagai

Theses and Dissertations

Polo-like kinase 1 (PLK1) is a central player in regulating entry into and progression through mitosis. Inhibition of sub-cellular localization and kinase activity of PLK1 through the Polo-box domain (PBD) is emerging as a viable alternative to ATP binding site directed drugs for which the development of resistant mutants and inhibition of closely related members of the PLK family (tumor suppressor roles) are primary concerns. I describe related novel non-peptidic PBD binding inhibitors, termed abbapolins, identified through successful application of the REPLACE strategy and demonstrate their potent antiproliferative activity in prostate tumors and other cell lines. Furthermore, the abbapolins show …

Age-Dependent Increase In Tyrosine Level Depletes Tyrosyl-Trna Synthetase And Causes Neuronal Oxidative Dna Damage In Alzheimer’S Disease, Megha Jhanji

Theses and Dissertations

Alzheimer’s disease (AD) is the most common form of dementia, and it currently affects more than 50 million people worldwide. Much of the population develop late-onset AD after 65 and constitute more than 95% of the cases. Currently, there is no definitive cure or way to slow down the progression of this disease that addresses the neurodegeneration and loss of cognitive functions. Although the underlying cause of AD is still unknown, the “amyloid cascade hypothesis” attributed it to the aggregation of amyloid beta (AU+03B2) peptides and has been the focus for targeting most disease-modifying drugs in clinical trials. However, emerging …

Sex Differences And Neuroimmune Effects Of Microglial Response In The Mesolimbic Reward Pathway In Nicotine Substance Use Disorder, Erin Leigh Anderson

Theses and Dissertations

Smoking remains the leading cause of morbidity and mortality in the United States, with less than 5% of smokers attempting to quit succeeding. This is due to the unpleasant withdrawal symptomology, which includes affective symptoms, such as irritability, weight gain, anxiety, and severe craving among others, as well as the cognitive effects, such as difficulty concentrating. This low smoking cessation success rate is also thought to be due to the long-lasting sensitization of nicotinic acetylcholine receptors (nAChRs) leading to long-term neuroadaptations in the brain’s reward system and alterations in synaptic plasticity that occur following chronic nicotine exposure and withdrawal. Glial …

Market Segmentation And Targeted Messaging To Improve Hpv Vaccine Intentions In The College Aged Population, Ashley Caitlin Godwin

Theses and Dissertations

Background: Human Papillomavirus (HPV) is a sexually transmitted infection that can lead to 6 different types of cancer, including cervical, vaginal, vulvar, penile, anal, and oropharyngeal cancer. Every year in the United States, nearly 35,000 cancer cases are estimated to be caused by HPV infection. While catch-up HPV vaccination is recommended through age 26 for those not previously vaccinated, only 21.5% of adults age 18-26 have completed the recommended number of HPV vaccine doses as of 2018. Many interventions have been tested to increase vaccination rates, and one such intervention, framed messaging, has shown promise in increasing intention to vaccinate. …

Design And Synthesis Of Macrocyclic Peptide Braf-Wt Dimerization Inhibitors For The Treatment Of Metastatic Melanoma, Chad Mulloy Beneker

Theses and Dissertations

In cases of metastatic melanoma, BRAF is frequently mutated to the V600E oncoprotein causing uncontrolled cell proliferation driven by the MAPK-ERK pathway. There are several BRAF inhibitors, such as vemurafenib, which are FDA approved, but patients treated with these Type-I kinase inhibitors frequently observe relapse under mutant RAS and BRAF-wt conditions due to paradoxical activation. The mechanism of this resistance occurs through binding of the inhibitor to BRAF-wt initiating conformational changes which leads to BRAF dimerization. Once in the dimerized state, the inhibited monomer induces allosteric transactivation of the second monomer. This drug-induced activation of BRAF in cells with mutant …

Panaxynol’S Pharmacokinetic Properties And Its Mechanism Of Action In Treating Ulcerative Colitis, Hossam Sami Tashkandi

Theses and Dissertations

Panaxynol (PA) is a polyacetylene that was found to be an abundant active ingredient in American ginseng (AG). Pharmacokinetics (PK) studies of PA were conducted to determine how the body reacts to it by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure PA’s concentration. In vitro, PA’s clearance by microsome metabolism is a moderate 48.1 minutes. In vivo, CD-1® mice were treated with PA by intravenous (IV) injection or orally (PO). Concentrations of PA were measured in plasma and tissue using LC-MS/MS. Also, PA has a high bioavailability of 50.4% and a moderate half-life of 5.9 hours. In addition, mice …

Emergent Trends In The Chinese Counterfeit Pharmaceutical Supply Chain And Opportunities For Public-Private Reform, Mary Monk

Senior Theses

This research seeks to identify and analyze emerging trends in the Chinese counterfeit pharmaceutical trade, extending from the supply chain’s point of origin to domestic and overseas retail dispensary. To aid readability, Chapter 1 of this thesis opens with key conclusions and policy recommendations for various Chinese and U.S. stakeholders based on the shortcomings identified in Chapter 5. Chapter 2 begins with a review of international roadblocks to diagnosing the issue, such as lack of consensus on working definitions and cross-border discrepancies in pharmaceutical oversight regulation. This section also provides a general overview of existing factors driving demand for counterfeit …

Early-Onset Colorectal Cancer In Mice, Qi Zhang

Theses and Dissertations

Early-onset colorectal cancer (EOCRC) is the second most common cancer and the third leading cause of cancer mortality in people under 50 years old in the United States. Our hypothesis is that a high-fat diet (HFD), Allura Red AC, and/or psychological stress causes distal and rectal colon inflammation, which are associated with dysbiosis. Furthermore, chronic exposure to one or more of these elements increases the risk of EOCRC. A/J inbred mice were utilized in this study. The results are consistent with our hypothesis.

Overall findings are the following: (1) An HFD increased inflammatory scores and polyps’ burden in the distal …

Function Of Gpr68 In Normal Hematopoiesis And Malignant Hematopoietic Diseases, Xiaofei He

Theses and Dissertations

G protein-coupled receptor 68 (GPR68), as a proton-sensing receptor, is involved in numerous physiological processes. However, its specific functions in normal hematopoiesis and malignant hematopoietic diseases were unknown. Using a genetic loss of function approach (i.e. whole-body Gpr68^-/- mouse model), B lymphocytes were reduced under stressed conditions, such as aging and hematopoietic regeneration. However, hematopoietic stem cells (HSC) from Gpr68^-/- mice exhibited comparable function as HSC from wild type mice either under steady-state or upon stress. To determine whether the unaltered HSC function of Gpr68^-/- mice was due to compensatory effects of Gpr68 in nonhematopoietic cells, a …

Treatment With Protease Inhibitor And Development Of Diabetes Among Medicare Beneficiaries With Human Immune Virus/Acquired Immune Deficiency Syndrome (Hiv/Aids), Eric Ejike Chinaeke

Theses and Dissertations

Background: The possibility of an association between the use of protease inhibitors (PI) by HIV/AIDS patients and the occurrence of T2DM mellitus (T2DM) is largely debated. Medicare recipients are disproportionally affected by T2DM. Unfortunately, evidence is unavailable from that particular segment of the population. Clinical management of HIV/AIDS is progressively expanding to include chronic/metabolic complications, which may pose a significant economic burden to both the patients and the Medicare system, which are disproportionally impacted. Objectives: The aims of this project were to (1) examine the association between the use of PIs and the odds of developing T2DM among Medicare beneficiaries …

Influenza Vaccination Coverage In Pediatric Patients With Inflammatory Bowel Disease, Kelly Brown

Senior Theses

Background: Children with chronic health conditions, including inflammatory bowel disease (IBD), are at especially high risk for influenza infection and complications. The Crohn’s & Colitis Foundation and American College of Gastroenterology recommend that IBD patients should receive annual influenza vaccination. The aims of this study were to evaluate influenza vaccination coverage over time and identify predictors of flu vaccination in pediatric IBD and non-IBD patients.

Methods: We utilized longitudinal data (2000 to 2016) from South Carolina Medicaid to conduct a matched cohort study. The primary exposure of interest was IBD diagnosis based upon ICD-9/10 diagnosis codes. Children with IBD were …

Plk1 Pbd Selective Inhibition As A Potential Cancer Therapy, Lauren E. Wilder

Senior Theses

Polo-Like Kinase 1 (PLK1) is a protein that has been found to be overexpressed in a variety of cancers including prostate and colorectal cancers, and it is often an indicator of poor patient prognosis. It has functions in initiating, maintaining, and completing mitosis, so it has an important role in controlling the proliferation of cells. PLK1 contains a highly conserved catalytic kinase domain and a less-conserved Polo Box Domain (PBD). Inhibiting the phospho-ligand binding of the PBD is a potential cancer therapy because it would prevent the cell from properly completing the cell cycle, thus inducing apoptosis. In Dr. McInnes’ …

Analysis Of Hpv16 Variants In The Carolina Women’S Care Study And A Comparison Of Gene Expression Profiles Of Exfoliated Cervical Cells From Women Who Either Clear Or Do Not Clear An Hpv16 Infection, Erica Shirlene Green

Theses and Dissertations

Human papillomavirus (HPV) is the etiologic agent for cervical cancer with HPV type 16 (HPV16) being found in about 50% of cervical cancers worldwide. HPVs vary in genomic (DNA) sequence not only between types, but also within types, known as variants. Variants of a particular HPV type may differ by up to 2% in nucleotide sequence in the coding region and up to 5% in the noncoding region. Variants within HPV16 have been identified and grouped into six distinct phylogenetic branches, which segregate geographically: European (E), Asian-American (As.A), African-1 (Af-1), African-2 (Af- 2), Asian (As), and North American (NA). However, …

Susceptibility To Metabolic Disease And Individual Variations In Unfolded Protein Response In Deer Mice (Peromyscus Maniculatus), Amanda Rose Havighorst

Theses and Dissertations

The endoplasmic reticulum is the site where integral membrane and secreted proteins are synthesized and folded, and is also the site of synthesis of steroids, lipids, and other macromolecules. While ER is found in most cell types, hepatocytes in particular contain large amounts of both rough and smooth ER to facilitate their tasks, which include lipoprotein assembly and secretion, cholesterol biosynthesis, and lipid metabolism. As such, stress in the ER – and the cells’ ability to respond to it – plays a key role in disease pathogenesis. In particular, hepatic steatosis, or fatty liver, is linked to ER stress. However, …

Effects Of Human Dopamine Transporter (Dat) Mutations And Novel Allosteric Modulatory Compounds In Disrupting Hiv-1 Tat-Dat Protein Interaction, Pamela Marie P. Quizon

Theses and Dissertations

More than 37 million people are living with HIV worldwide. Despite the widespread use of antiretroviral therapy (ART), up to 70% of HIV-positive individuals suffer from cognitive and behavioral deficits collectively known as HIV-associated neurocognitive disorders (HAND). HIV-mediated damage to the dopaminergic system is a mediating factor in HAND. Dopamine (DA) transporter (DAT)-mediated reuptake is essential for maintaining DA homeostasis. Because most ART cannot efficiently cross the blood-brain barrier (BBB), the brain serves as a viral reservoir that facilitates the spread of infection to microglia and astrocytes. Infected cells shed viral proteins such as Tat, which plays a critical role …

Investigating The Neural Correlates Of Nicotine Withdrawal Phenotypes In Mice: Involvement Of Creb-Dependent Nrg3-Erbb4 Signaling In Mediating Anxiety-Like Behavior, Miranda Fisher

Theses and Dissertations

Addiction to nicotine and the ability to quit smoking are influenced by genetic factors. Therefore, it is important to understand how genes and drugs of abuse mechanistically impact each other. One well-characterized protein responsible for regulating both response to drugs and gene expression is the transcription factor cAMP response element-binding protein (CREB). Work from our lab indicates that hippocampal specific alterations in CREB signaling and synaptic plasticity underlie certain nicotine withdrawal (WD) phenotypes in a region-specific manner. We found that CREB deletion in the ventral hippocampus (VH), a region known for regulation of mood and emotion, results in amelioration of …

Glia Responsivity In Nicotine Dependence, Adewale Oluwamuyiwa Adeluyi

Theses and Dissertations

Neurons are the primary research target in the exploration and development of novel smoking cessation pharmacotherapies over the years. These research efforts have led to the discovery and development of three FDA-approved smoking cessation aids – nicotine replacement therapy, varenicline, and bupropion, each of which have quantifiable success as smoking cessation aids. However, relapse is still very common and smoking cessation is successful in less than 5% of quit attempts, making paramount the development of novel therapeutics. One untapped therapeutic target are glia, particularly, astrocytes and microglia, which are active participants in the neuroplastic events underlying drug addiction.

First, we …

Cellular Localization Of Rad51d Mutant Proteins And The Application Of Art To Increase Scientific Literacy In America, Claire L. Chabot

Senior Theses

Ovarian cancers are the leading cause of death from cancer of the female reproductive system. Approximately 50% of ovarian cancers have defects in the homologous recombination (HR) DNA repair pathway that is required for the repair of DNA double-stranded breaks. The status of HR genes, such as BRCA1, BRCA2, and the RAD51 family, contributes to ovarian cancer development as well as treatment decisions regarding chemotherapy, radiation, and immunotherapy. The overarching goal of this project is to identify new insights into HR that can integrate with Precision Medicine Initiatives and align with the goals of the Cancer Moonshot 2020 Program. I …

The Pharmabiotic For Phenylketonuria: Development Of A Novel Therapeutic, Chloé Elizabeth Lebegue

Senior Theses

Phenylketonuria, now known as phenylalanine hydroxylase (PAH) deficiency, is a genetic disorder of metabolism affecting approximately one in every 15,000 infants born in the United States. Patients have nonfunctional PAH enzyme secondary to one or more genetic mutations. The enzyme deficit results in destructive supraphysiologic blood phenylalanine levels upon consumption of the essential dietary amino acid phenylalanine. Current standards of care mitigate signs and symptoms of the disorder, but do not approach a cure. The methods for creating a prototype pharmabiotic as an innovative treatment strategy for PAH deficiency are described herein.

DNA molecular cloning techniques were utilized to engineer …

The Role Of Cdk8 In Metastatic Growth Of Colon Cancer, Jiaxin Liang

Theses and Dissertations

Unresectable hepatic metastases of colon cancer poorly respond to existing therapies and are a major cause of colon cancer lethality. Transcription- regulating Mediator kinase CDK8, an early clinical stage drug target, is amplified or overexpressed in many colon cancers and CDK8 expression correlates with shorter patient survival. Here we show that CDK8 inhibition does not generally suppress proliferation of CDK8-overexpressing colon cancer cells but nevertheless CDK8 knockdown by shRNA or CDK8 kinase inhibition by a selective small-molecule drug candidate suppresses metastatic growth of mouse and human colon cancer cells in the liver. This effect is due at least in part …

Evaluation Of Pharmacy Students’ Tendency To Self-Medicate, Rebekah Lee Crandall, Danielle O'Neal

Senior Theses

Objective: To investigate whether the tendency to self-medicate increases as students progress though the pharmacy curriculum.

Design: An online survey was administered through Survey Monkey by a link sent to the email addresses of students who attended the South Carolina College of Pharmacy/ University of South Carolina College of Pharmacy (SCCP/USC-COP) during the 2017-2018 school year.

Methods: Self-medication was defined as the use of over-the-counter (OTC) medications, medications prescribed to another person, and recreational (i.e. alcohol, tobacco) or illicit substances for therapeutic purposes. The primary outcome was the likelihood of each class of pharmacy students to self-medicate based on a …

Kv7 Channels Of The Urinary Bladder Smooth Muscle: Functional Roles And Therapeutic Potential, Aaron Provence

Theses and Dissertations

Overactive bladder (OAB) is a pervasive and debilitating condition for which effective therapeutic modalities are lacking. As potential novel pharmacological targets for lower urinary tract dysfunction, our recent studies have demonstrated voltage-gated KV7 channels (KV7.1-KV7.5) to be functionally expressed in detrusor smooth muscle (DSM) of the urinary bladder. Nonetheless, the specific roles of individual KV7 channel subtypes remains poorly understood. Using Western blot, immunocytochemistry, isometric DSM tension recordings, ratiometric fluorescence Ca2+ imaging, and patch-clamp electrophysiology, we demonstrated expression and key physiologic roles for the KV7.2/KV7.3 channels in guinea pig DSM using the novel and selective KV7.2/KV7.3 channel opener N-(2-Chloro-5-pyrimidinyl)-3,4-difluorobenzamide (ICA-069673). …

Mechanisms Of Rad51d-Dependent Repair Of Dna And Telomere Damage Induced By Interstrand Crosslinking Agents And Thiopurines, Nicole M. Reilly

Theses and Dissertations

Mutations in homologous recombination (HR) genes increase genomic instability, an enabling characteristic of cancer. However, the status of these same genes can also determine chemotherapy outcomes. RAD51D is a breast and ovarian cancer susceptibility gene that is an important component of HR. Mammalian cells defective for RAD51D have extensive chromosomal aberrations and are more sensitive to the interstrand crosslink-inducing agent mitomycin C (MMC) and the thiopurine 6-thioguanine (6TG). Previously, the RNF138 E3 ubiquitin ligase was identified to promote RAD51D ubiquitination, and loss of RNF138 also increased cellular sensitivity to MMC. Ubiquitination assays were used to show that a 3-ubiquitin modification …

The Effects Of Stand-Alone Prescription Drug Plans On Health Care Utilizations, Expenditures And Medication Adherence Among Elderly Medicare Beneficiaries, Jing Yuan

Theses and Dissertations

Since the implementation of Medicare Part D in 2006, a growing body of evidence has shown that Medicare Part D might offset the total healthcare spending by improving the use of prescription drugs. However, little is known about the impact of different types of Part D plans – Stand-alone Prescription Drug Plan (PDPs) and Medicare Advantage Prescription Drug Plan (MA-PDs) – on health care utilizations and expenditures. This dissertation examined the association between the effect in PDPs on health care utilizations as well as expenditures, and medication adherence among elderly Medicare beneficiaries, compared to MA-PDs. Data was pooled from 2006-2010 …

Mechanism Of Action Of American Ginseng And Its Components In The Treatment Of Ulcerative Colitis, Anusha Chaparala

Theses and Dissertations

Inflammatory bowel diseases (IBD), mainly ulcerative colitis (UC), Crohn’s disease (CD), are chronic, idiopathic, inflammatory diseases of the gastrointestinal tract affecting millions of people worldwide. The incidence of IBD is steadily increasing in the modern world due to changes in dietary habits and other environmental influences that originated from industrialization. The etiology is poorly understood but is believed to be a combination of genetic predisposition, environmental factors, and overactive immune system. UC is characterized by inflammation and ulceration of colonic mucosa and rectum and has a higher incidence than CD. Aside from severely affecting the quality of life of the …

Impact Of Medicare Reimbursement Policy Change On The Utilization, Risks, And Costs Associated With Erythropoiesis-Stimulating Agents In Cancer Patients With Chemotherapy-Induced Anemia, Minghui Li

Theses and Dissertations

Background: Erythropoiesis-stimulating agents (ESAs) are biological drugs used to stimulate the production of red blood cells. ESAs are commonly prescribed for cancer patients with chemotherapy-induced anemia and chronic kidney disease (CKD) patients with low levels of hemoglobin. Due to the increasing safety concerns, Centers for Medicare and Medicaid Services (CMS) issued a Medicare reimbursement policy change for ESAs in cancer patients to regulate the utilization of ESAs. For chemotherapy-induced anemia, when patients had solid tumors, multiple myeloma, lymphoma, or lymphocytic leukemia, ESA treatment is reimbursable by CMS only when the hemoglobin level is < 10g/dL.

Objectives: The objectives of this study were …

Impact Of Prenatal Exposure To Antidepressants On Adverse Birth Outcomes, Sudeepti Pahuja

Theses and Dissertations

BACKGROUND: There has been an increase in the diagnosis of depression and the use of antidepressants, especially in women of childbearing age, in the past decade. This has drawn attention to the potential impact of depression and antidepressants on pregnancy and fetal development.

OBJECTIVE: (i) To determine the impact of prenatal exposure to antidepressant on the risk of adverse birth outcomes. (ii) To assess the effect of type of antidepressants on the risk of adverse birth outcomes using selective serotonin reuptake inhibitors as the referent group. (iii) To assess the effect of duration and time of prenatal exposure …