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Failed Initial Tumor Necrosis Inhibitor (Tnfi) Therapy – What Next For Rheumatoid Arthritis Patients?, Aliza Matusevich

Dissertations and Theses (Open Access)

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting over 1.3 million Americans with annual societal costs estimated at $39.2 billion, rising faster than medical inflation. Therapy with tumor necrosis factor inhibitors (TNFi) has greatly improved the management of patients with rheumatoid RA; however, substantial numbers of patients do not experience an adequate response to these drugs, necessitating a change in treatment regimen. There are two basic approaches for TNFi failure: cycling (switching to a second TNFi) or swapping (to a drug with another mechanism of action) but the choice is controversial due to questions of comparative …

The Association Between Sleep Duration And Dementia: A Meta-Analysis, Sherri Hong

Dissertations and Theses (Open Access)

In the United States, the current cases of Alzheimer’s disease will double by 2050. Therefore, it is important to study risk factors associated with dementia such as sleep duration. This meta-analysis was conducted to understand the discrepancy in study results since some demonstrated a V shaped association between duration of sleep and dementia while others found no association. If there truly is an association then sleep duration could be targeted to decrease the burdens caused by dementia. A meta-analysis of published studies was conducted to assess the association between sleep duration and the different forms of dementia. The articles were …

A Mendelian Randomization Study Of Circulating Gamma Prime Fibrinogen And Total Fibrinogen Levels On Venous Thromboembolism And Ischemic Stroke Subtypes, Jillian Maners

Dissertations and Theses (Open Access)

Introduction: Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ′) fibrinogen is an isoform of fibrinogen and has anticoagulant properties, including inhibiting thrombin and slowing platelet aggregation, that may affect clot formation.

Methods: Two-sample Mendelian randomization (MR) was applied to estimate the causal effect of total circulating fibrinogen and its isoform, γ′ fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from published genome-wide association studies of fibrinogen, VTE, and ischemic stroke, and an unpublished …

Failed Initial Tumor Necrosis Inhibitor (Tnfi) Therapy – What Next For Rheumatoid Arthritis Patients?, Aliza Matusevich

Dissertations and Theses (Open Access)

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting over 1.3 million Americans with annual societal costs estimated at $39.2 billion, rising faster than medical inflation. Therapy with tumor necrosis factor inhibitors (TNFi) has greatly improved the management of patients with rheumatoid RA; however, substantial numbers of patients do not experience an adequate response to these drugs, necessitating a change in treatment regimen. There are two basic approaches for TNFi failure: cycling (switching to a second TNFi) or swapping (to a drug with another mechanism of action) but the choice is controversial due to questions of comparative …

Big Tobacco. Big Marijuana? Longitudinal Trends And Multi-Directional Tobacco And Marijuana Use Among Youth And Young Adults In Texas, Shannon Rogers

Dissertations and Theses (Open Access)

Due to the pace of legal changes in marijuana policy, shifting trends in marijuana use, and emerging products in the tobacco product marketplace (e.g., ecigarettes), the cycle of risk between marijuana and tobacco use is not currently wellunderstood. I used longitudinal data from two parallel rapid response surveillance studies of youth (aged 12-19 years) and young adults (aged 18-25 years) living in the five counties (Bexar, Dallas, Harris, Tarrant, and Travis) that surround the four largest cities in Texas (Austin, Houston, San Antonio, and Dallas/Fort Worth). I used Generalized Linear Mixed Models (GLMMs) and six-panel cross-lagged regression models to analyze …

Assessing The Relationship Between University Environmental Health And Safety Program Resourcing And Ultimate Outcomes, Jason R. Shyu

Dissertations and Theses (Open Access)

College and university campuses contain a diverse set of potential health and safety risks mixed with a population that is equally varied. Such a combination requires effective risk management programs adapted to address these challenges. Methods currently exist to predict risk financing premiums and institutional risk control resources (inputs), but there are no models addressing relationships to final Environment Health & Safety (EHS) program outcomes (outcomes such as injuries or illnesses). Publicly available data obtained from the University of Texas System Office of Risk Management describing their 14 campuses was combined with publicly available data from the National Science Foundation …

The Use Of Neoadjuvant Brachytherapy In Endometrial Cancer, Alison Yoder

Dissertations and Theses (Open Access)

Uterine cancer is the most common gynecologic malignancy in the United States with almost 62,000 cases expected in 2019. In general, treatment consists of primary surgery possibly followed by adjuvant radiation and/or chemotherapy. However, in cases with cervical involvement or when the patient is a non-surgical candidate, neoadjuvant treatment can be employed; specifically, neoadjuvant radiation with or without brachytherapy and/or chemotherapy. There have not been any large-scale studies looking at the addition of brachytherapy to external beam radiation in the neoadjuvant setting and whether or not its addition improves outcomes. In order to analyze this, the National Cancer Database was …

The Relationship Between Social Media Use And Depression In College Students: A Scoping Review, Susan Wu

Dissertations and Theses (Open Access)

Background: In 2017, 17.3 million adults in the U.S. (7.1% of all U.S. adults) have had at least one major depressive episode, with individuals ages 18-25 having the highest prevalence of major depression at 13.1%. Studies have looked at the association between social media (SM) use and depression with mixed findings. The goal of this research is to conduct a scoping review of existing evidence for the relationship between SM use and depression among college students.

Methods: Searches for articles published in the scientific literature were performed on PubMed, Embase and Scopus. Articles selected followed an inclusion criteria: studied SM …

Long-Term Outcomes After Endovascular Stent Placement For Long-Segment Superficial Femoral Artery Lesions, Nader Zamani

Dissertations and Theses (Open Access)

Objective: Endovascular intervention is commonly pursued as first-line management of symptomatic, long-segment superficial femoral artery (SFA) disease. The relative effectiveness and comparative long-term outcomes among bare metal stents (BMSs), covered stents (CSs), and drug-eluting stents (DESs) for long-segment SFA lesions remain uncertain.

Methods: A retrospective cohort study identified patients with symptomatic SFA lesions measuring at least 15cm who successfully received an endovascular stent (BMS, CS, or DES). The outcomes were patency, patient presentation upon stent occlusion, amputation free survival (AFS), and all-cause mortality. Proportional hazards regressions and a multinomial logistic regression model were used to control for significant confounders.

Results: …

Lymphocyte-Specific Tyrosine Kinase Expression In Ovarian Cancer: A Valuable Prognostic Indicator, Emily Moss Hinchcliff

Dissertations and Theses (Open Access)

Cellular immune response, specifically tumor infiltrating lymphocytes (TILs), has been correlated to survival in epithelial ovarian cancer; however, specific gene expression patterns for this response remain poorly understood. The objective of this research was to investigate the prognostic and biologic significance of immune-related gene expression in high grade serous ovarian cancer (HGSOC). To do so, a panel of immune related gene expression was evaluated in HGSOC utilizing The Cancer Genome Atlas (TCGA) and validated in an independent cohort of ovarian tumors. Based on the strong association with survival, the cohort was grouped into LCK (lymphocyte specific tyrosine kinase) high and …

Clinical Diagnostic Whole Exome Sequencing For Infants In Intensive Care Settings: Outcomes Analysis And Economic Evaluation, Hadley Stevens Smith

Dissertations and Theses (Open Access)

Whole exome sequencing (ES) is an extensive form of genetic testing and increasingly used as a diagnostic tool. Clinical uptake of genome-scale sequencing occurred without clear guidelines for application or robust information regarding potential impact on patient health outcomes or cost of care. For infants in intensive care with suspected genetic conditions, ES can be especially powerful to identify a specific diagnosis and inform crucial decisions about medical care. However, little is known about the cost-effectiveness of ES compared to other diagnostic strategies. This project first assessed the literature on pediatric clinical ES. Then, using electronic medical record, diagnostic laboratory, …

An Oxanthroquinone Derivative Disrupts Ras Plasma Membrane Localization And Function By Inhibition Of Acylpeptide Hydrolase And Perturbation Of Sphingomyelin Metabolism, Lingxiao Tan

Dissertations and Theses (Open Access)

Oncogenic RAS proteins are commonly expressed in human cancer. To be functional, RAS proteins must undergo post-translational modification and localize to the plasma membrane (PM). Therefore, compounds that prevent RAS PM targeting have potential as putative RAS inhibitors. Here we examined the mechanism of action of oxanthroquinone G01 (G01), a recently described inhibitor of KRAS PM localization. We show that G01 mislocalized HRAS and KRAS from the PM with similar potency and disrupted the spatial organization of RAS proteins remaining on the PM. G01 also inhibited recycling of epidermal growth factor receptor and transferrin receptor, but did not impair internalization …

Platiscity Of C. Elegans Germline Stem Cells Under Nutritional And Metabolic Stress, Kenneth Trimmer

Dissertations and Theses (Open Access)

Stem cells are integral for tissue maintenance and fertility. Therefore, understanding how stem cells are regulated under stress is imperative. When confronted with acute starvation, stem cells must conserve energy and metabolites to cope with the lack of an external source. Caenorhabditis elegans germline stem cells (GSCs) are an excellent model for studying stem cell properties and regulation as they can divide throughout the life of the organism. While GSCs are an adult stem cell population, their cell cycle structure more closely mimics mouse and human embryonic stem cells with short G1 and long S phases. In this thesis, I …

Multimodality Somatostatin Analog For Fluorescence-Guided Surgery In Cancer, Servando Hernandez Vargas

Dissertations and Theses (Open Access)

Cancer surgery remains the primary curative treatment for most solid cancers and has major therapeutic implications for patients with neuroendocrine tumors (NETs). Anatomical and functional imaging technologies are widely used during the pre- and postoperative stages, but intraoperative disease recognition relies on direct visual inspection and the hands of surgeons. The limited number of clinical tools for real-time intraoperative visual feedback restricts the ability to remove the complete cancer source and is partially responsible for the high rate of disease recurrence in patients. Intraoperative imaging with fluorescent contrast agents has the potential to improve the ability of surgeons to detect …

Thiol-Based Misfolding: Linking Redox Balance To Cytosolic Proteostasis, Ford Amy

Dissertations and Theses (Open Access)

The eukaryotic cytosolic proteome is vulnerable to changes in proteostatic and redox balance caused by temperature, pH, oxidants and xenobiotics. Cysteine-containing proteins are especially at risk as the thiol side chain is subject to oxidation, adduction and chelation by thiol-reactive compounds. All of these thiol-modifiers have been demonstrated to induce the heat shock response and recruit protein chaperones to sites of presumed protein aggregation in the budding yeast Saccharomyces cerevisiae. However, endogenous targets of thiol stress toxicity responsible for these outcomes are largely unknown. Furthermore, I hypothesize proteins identified as redox-active are prone to misfolding and aggregation by thiol-specific …

Higher Order Chromosome Organization And Recombination Dynamics Of Meiotic Prophase I In Mouse Spermatocytes, Rhea Kang

Dissertations and Theses (Open Access)

Meiotic recombination is required for parental chromosomes to find each other (pairing/synapsis) and to exchange genetic information thus allowing faithful segregation of chromosomes and the production of haploid gametes. At the start of meiotic prophase I, meiotic chromosomes organize into loop arrays that extrude out of the chromosome axis. Then, a large number of programmed double-strand breaks (DSBs) are formed at specific chromosomal locations or “hotspots” on parental chromosomes, which are repaired by homologous recombination (HR). HR produces either crossovers, which result in the exchange of flanking markers between homologs, or noncrossovers, which are short regions ofgene conversion to the …

Metabolic Control, Quality Of Life, And Body Image In Patients With Glycogen Storage Disease Type Ia, Alexa Bream

Dissertations and Theses (Open Access)

Glycogen storage disease is a group of inborn errors of metabolism, with type Ia being the most common form of the disorder. Glycogen storage disease type Ia (GSDIa) is a multisystemic condition in which individuals have various complications secondary to an inability to properly break down glycogen and to perform gluconeogenesis. Complex management is then necessary for patients and includes dietary modification, frequent cornstarch usage, and evaluation for additional complications such as hepatic adenomas, hypertriglyceridemia, and kidney disease. Previous studies have found lower scores in quality of life and body image in GSDIa patients; however, the specific factors influencing this …

Hypoglycemia In Mitochondrial Disorders, Allison Moats

Dissertations and Theses (Open Access)

INTRODUCTION: The electron transport chain (ETC) in mitochondria functions to produce energy in the form of adenosine triphosphate (ATP). Defects in the mitochondrial or nuclear DNA that codes for components of the ETC lead to mitochondrial disorders (MTDs). MTDs are multi-system conditions affecting the heart, muscles, and especially brain. The endocrine system is commonly affected in MTDs, and diabetes and hyperglycemia are established secondary diagnoses. Rates of non-iatrogenic hypoglycemia have not been studied in individuals with MTDs. This study aims to investigate the frequency of hypoglycemia in patients with MTDs.

METHODS: Individuals diagnosed with a ‘definite’ or ‘probable’ …

Il-6/Jak1 Drives Pd-L1 Phosphorylation And Glycosylation To Promote Cancer Immune Evasion, Li-Chuan Chan

Dissertations and Theses (Open Access)

Glycosylation of immune receptors and ligands, such as T-cell receptor (TCR), major histocompatibility complex (MHC), and co-inhibitory molecules, regulates immune signaling activation, antigen presentation, and immune surveillance. Recent studies revealed that the glycan structures of co-inhibitory molecules are required for receptor-ligand interaction, a critical feature for activating cancer immune evasion. However, it is unclear how oncogenic signaling initiates glycosylation of co-inhibitory molecules to induce immunosuppression. Here we show interleukin (IL)-6-activated Janus kinase 1 (JAK1) phosphorylates programmed death-ligand 1 (PD-L1)-Tyr112, leading to the recruitment of endoplasmic reticulum (ER)-associated N-glycosyltransferase, STT3A, which catalyzes the glycosylation of PD-L1, contributing to its stability. A …

Genetic Counselor Utilization And Interpretation Of Somatic Tumor Testing In Evaluation For Lynch Syndrome, Danielle Williams

Dissertations and Theses (Open Access)

Lynch syndrome (LS) is a hereditary cancer predisposition syndrome characterized by increased risk for colorectal and uterine cancers. Individuals with pathogenic variants in the mismatch repair (MMR) genes (MLH1, MSH2/EPCAM, MSH6, PMS2) are diagnosed with LS and subsequently recommended to proceed with high risk screening protocols to increase prevention and early detection of LS-related cancers. Various tumor studies can help identify those at high risk for LS, but sometimes create uncertainty with discordant screening and germline results, leading to unexplained mismatch repair deficiency (UMMRD). Somatic testing of the MMR genes has created opportunities for resolving …

Investigating The Role Of The P63 Isoform Δnp63 In Lung Stem Cell Populations And Lung Cancer, Sarah J. Wu

Dissertations and Theses (Open Access)

Cell of origin studies have determined separate populations of lung progenitor cells that give rise to lung adenocarcinoma and squamous cell carcinoma. ΔNp63 is known to regulate lung development but its role in lung cancer progression remains unclear. We utilized a ΔNp63-specific conditional knockout mouse model to determine ΔNp63’s role in lung progenitor cells and lung cancer. In vivo and in vitro experiments revealed a role for ΔNp63 in maintaining lung progenitor cells. ChIP-seq results indicate that deletion of ΔNp63 results in robust loss of enhancer histone marks at cell identity genes for lung progenitor populations of basal cells and …

Exploring Experiences & Expectations Of Prenatal Healthcare And Genetic Counseling/Testing In Immigrant Latinas, Georgiann Garza

Dissertations and Theses (Open Access)

In recent years, the Latino population of the United States has continued to increase, but the specific needs of Latinos in the genetic counseling setting have yet to be explored. Genetic counselors tailor sessions to the needs of the patient, and more information regarding general attitudes of a population can assist in building rapport. We aimed to investigate the relationship between acculturation, prenatal care, genetic testing experiences, and expectations for their prenatal care in an immigrant Latino population. A total of 20 Spanish-speaking, pregnant Latinas from various Latin American countries were interviewed after completing a prenatal genetic counseling session. The …

Hsp70-Mediated Regulation Of Hsf1 Transcriptional Activity In Saccharomyces Cerevisiae, Sara Peffer

Dissertations and Theses (Open Access)

In eukaryotic cells, protein homeostasis and cellular fitness is promoted by the transcription factor heat shock factor 1 (HSF1) during exposure to proteotoxic stress. HSF1 controls the basal and stress-induced expression of molecular chaperones and other protective targets. Dynamic regulation of HSF1 involves the major heat shock proteins Hsp70 and Hsp90. Recent advances in the understanding of this regulatory circuit in Saccharomyces cerevisiae have shown that the Hsp70 Ssa1 acts as a sensor for some proteotoxic stresses and is capable of a direct interaction with Hsf1. This work continues to explore the complex regulatory interaction between Hsf1 and Ssa1. I …

The Role Of Gene Expression Noise In Mammalian Cell Survival, Kevin Farquhar

Dissertations and Theses (Open Access)

Drug resistance and metastasis remain obstacles to effective cancer treatment. A major challenge contributing to this problem is cellular heterogeneity. Even in the same environment, cells with identical genomes can display cell-to-cell differences in gene expression, also known as gene expression noise. Gene expression noise can vary in magnitude in a population or in fluctuation time scales, which is influenced by gene regulatory networks.

Currently, it is unclear how gene expression noise from gene regulatory networks contributes to drug survival outcomes in mammalian cells. An isogenic cell line with a noise-modulating genetic system tuned to the same mean is required. …

Development Of A High-Throughput System For Screening Of Anti-Prion Molecules, Katherine Do

Dissertations and Theses (Open Access)

The misfolded prion protein causes and transmits disease in both humans and animals. As other infectious agents, prions display strain variation, which can generate different pathological outcomes in affected individuals. Unfortunately, there are no known therapies for these diseases, which at present are invariably fatal. In this work, the Protein Misfolding Cyclic Amplification technology (PMCA, an in vitro test that replicates minimum quantities of infectious prions) has been modified to screen for small molecules inhibiting prion protein misfolding in a strain-specific manner. In order to approach a high-throughput PMCA system, technical aspects in PMCA has been optimized for application of …

The Characterization Of T-Cell Manufacturing For Adoptive T-Cell Therapies, Amir Alpert

Dissertations and Theses (Open Access)

Adoptive T-cell therapy using genetically modified T cells has emerged as a potential therapeutic option for several malignancies. Central to the production of the cellular therapy is the manufacturing using a stimulation, genetic engineering, and expansion methodology. Within this framework, there is a delicate balance between expansion of the cells to a therapeutically relevant dosage and the need to retain the proliferative potential of the ‘living drug’. I show that as T-cells are expanded for elongated periods of time, they lose their proliferative potential and become functionally senescent despite the presence of multiple proliferative cytokines. In addition, I show that …

Cross-Presentation Is A Source Of Tumor Antigens For Multiple Myeloma Immunotherapy, Alexander A. Perakis

Dissertations and Theses (Open Access)

Cross-presentation is an essential bridge between the innate and adaptive arms of the immune system where antigen presenting cells (APCs) prime cytotoxic T cell responses. We have recently identified cross-presentation as a mechanism by which solid tumors present exogenous antigens. We therefore hypothesized that multiple myeloma would be capable of cross-presentation as these cells are derived from B cells, known APCs. We explored the capacity of multiple myeloma to cross-present PR1, a human leukocyte antigen (HLA)-A2 nonameric peptide that is derived from neutrophil elastase (NE) and proteinase 3 (P3), and the ability to treat multiple myeloma using PR1-targeting immunotherapies. Here …

Computational Genomic Models For Spatio-Temporal Investigation Of Early Lung Cancer Pathology, Smruthy Sivakumar

Dissertations and Theses (Open Access)

Lung cancer, of which non-small cell lung cancer (NSCLC) is the most common form, is the second most prevalent cancer and the leading cause of cancer-related deaths. NSCLCs primarily comprise adenocarcinomas (LUAD) and squamous cell carcinomas (LUSC). Advances in early detection and prevention have been limited by the lack of early-stage biomarkers and targets. A comprehensive molecular characterization of premalignant lesions and tumor-adjacent normal tissue can aid in better understanding NSCLC pathogenesis. However, these investigations are further challenged by limited tissue availability and low cellular fractions of detectable somatic mutations.

Therefore, there is a dearth of knowledge about the pathogenesis …

Systemic Antibiotic Therapy Reduces Circulating Inflammatory Dendritic Cells And Treg-Th17 Plasticity In Periodontitis, Mythilypriya Rajendran, Stephen Looney, Nagendra Singh, Mahmoud Elashiry, Mohamed M Meghil, Ahmed R El-Awady, Omnia Tawfik, Cristiano Susin, Roger M Arce, Christopher W Cutler

Faculty, Staff and Student Publications

Periodontitis (PD) is a common dysbiotic inflammatory disease that leads to local bone deterioration and tooth loss. PD patients experience low-grade bacteremias with oral microbes implicated in the risk of heart disease, cancer, and kidney failure. Although Th17 effectors are vital to fighting infection, functional imbalance of Th17 effectors and regulatory T cells (Tregs) promote inflammatory diseases. In this study, we investigated, in a small pilot randomized clinical trial, whether expansion of inflammatory blood myeloid dendritic cells (DCs) and conversion of Tregs to Th17 cells could be modulated with antibiotics (AB) as part of initial therapy in PD patients. PD …

Spatial Analysis Of Exposure To Soil Heavy Metals, Oral Bioaccessibility And Risk Assessment In Houston, Texas, Tsai Shu Chu

Dissertations and Theses (Open Access)

Chronic exposure to heavy metals could lead to adverse health effects such as cancer, neurological development diseases and immunological diseases. The ingestion pathway has been considered the major exposure route for heavy metal contaminated soils. Heavy metals may be proportionally bioaccessible for the human body to absorb. There are no risk assessment studies done in Houston to evaluate health risks from exposure to heavy metals and no spatial analysis done yet. The aims of this dissertation are (1) to characterize 13 heavy metals: magnesium (Mg), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc …