Medicine and Health Sciences Commons^™

Integration Of Biomedical Imaging And Translational Approaches For Management Of Head And Neck Cancer, Abdallah Mohamed, Abdallah Mohamed

Dissertations and Theses (Open Access)

The aim of the clinical component of this work was to determine whether the currently available clinical imaging tools can be integrated with radiotherapy (RT) platforms for monitoring and adaptation of radiation dose, prediction of tumor response and disease outcomes, and characterization of patterns of failure and normal tissue toxicity in head and neck cancer (HNC) patients with potentially curable tumors. In Aim 1, we showed that the currently available clinical imaging modalities can be successfully used to adapt RT dose based-on dynamic tumor response, predict oncologic disease outcomes, characterize RT-induced toxicity, and identify the patterns of disease failure. We …

Innate Lymphoid Cell Characterization And Ilc2s In Neuroinflammation In Aging And Sex Differences, Alexis Mobley, Alexis S. Mobley

Dissertations and Theses (Open Access)

Aging affects immunologic responses by a global immune system suppression, including dysregulation of cytokine mediators, leading to increased inflammation throughout all systems, termed inflammaging. However, understanding healthy aging mechanisms can bypass this effect. Inflammaging also leads to poor outcomes during brain injury, making immune-targeting therapeutics tantamount to overall brain health and longevity. Moreover, sex affects disease etiology and severity through hormonal and chromosomal sex, as the X chromosome contains most immunology-based genes. Androgens have a generally suppressive effect on the immune system. Additionally, when immune responses are mounted, males are better at CD4+ T cell type (Th1) responses, while females …

Assessing The Impact Of Camp Phever On Blood Phenylalanine Levels, Michelle Zelnick

Dissertations and Theses (Open Access)

Phenylketonuria (PKU) is a metabolic disorder that results in accumulation of the amino acid, phenylalanine, throughout the body. This can result in neurocognitive complications if individuals with this disease do not follow a low-protein diet. Camp PHEver is a weeklong summer camp that gives children with PKU an opportunity to obtain skills related to diet compliance, but also enhance their confidence, relationship development, and independence. Through learned skills and the strict diet regimen at camp, campers were found to have a statistically significant drop in phenylalanine (PHE) levels within a single attendance (mean decrease per year range = 2.1 to …

Nanoparticles For Biomedical Applications, Joseph Kim

Dissertations and Theses (Open Access)

This thesis presents development and evaluation of the potential of three new nanoparticles for biomedical applications. With the rapid growth of the field of nanoscience, researchers have explored developing nanoparticles for various biomedical applications, including imaging, therapy, and drug delivery. This thesis demonstrates the development of two C­₆₀ fullerene based nanoparticles and one boron based nanoparticle to answer key questions related to their biological potential.

In the first part of the thesis, we describe synthesis and characterization of a pure boron nanoparticle containing asolectin phospholipid-based liposome construct prepared using a water-in-oil emulsion method, as a novel alternative agent for …

Analysis Of Huntington Disease Caregiver Quality Of Life Using The Enroll-Hd Population, Emilyn Banfield

Dissertations and Theses (Open Access)

Huntington disease (HD) is a neurodegenerative condition inherited in an autosomal dominant manner caused by a CAG triplet repeat expansion within the HTT gene. Thus, HD is unique among neurodegenerative disorders with a caregiver population often burdened by both the caregiver role and concern over transmission to at-risk relatives. This study characterized caregiver quality of life over time using the Enroll-HD study population, an observational cohort with data collected from 171study sites across 20 countries. Self-reported quality of life measures from 3,591 caregiver/patient dyads at the first/baseline Enroll-HD appointment, 192 dyads at the third annual appointment, and 49 dyads at …

Investigating The Attitudes Of The D/Deaf Community To Wards Genetic Counseling And The Utilization Of Genetic Services, Katie Baudoin, Jennifer Czerwinski, Laura Farach, Malorie Jones, Rebecca Lunstroth, Caitlin Mauer, Chelsea Wagner

Dissertations and Theses (Open Access)

The Deaf community has previously expressed concerns about the process of genetic counseling/testing and the potential implications it can have for Deaf individuals. Prior studies have explored the motivations of Deaf individuals for pursuing genetic testing related to deafness; however, information regarding the interest and motivations for indications other than deafness is limited. Our study aims to characterize attitudes of individuals within the d/Deaf community towards genetic counseling and testing and to assess interest and motivations to seek genetic counseling for indications other than deafness.

Individuals were recruited through local and national d/Deaf organizations to participate in an anonymous, online …

Tissue-Specific Matrix Control Of Cell Cohesion And Migration Signaling Complexes, Tristen Tellman

Dissertations and Theses (Open Access)

The extracellular matrix (ECM) is a complex, interconnected network of three major constituents: collagens, glycoproteins, and proteoglycans, along with their enzyme modifiers. Within this network and beyond the structural role, each ECM molecule contributes a context-specific signal that influences cellular fate and behavior. Among these behaviors, cellular migration provides an essential function in developing tissues, wound healing, and cancer cell metastasis. Using two glandular organs, the normal salivary gland and the cancerous prostate, this dissertation describes the tissue-specific composition of two ECM signaling complexes (type I hemidesmosomes and the perlecan-semaphorin 3A-plexin A1-neuropilin-1 (PSPN) complex) and translates this knowledge into viable …

The Role And Regulation Of Id2 In Dendritic Cells, Rachel L. Babcock

Dissertations and Theses (Open Access)

Dendritic cells (DCs) are specialized innate immune cells that sense pathogen-associated signals via pattern recognition receptors, including the TLRs, and subsequently stimulate adaptive immune responses to combat infection. The mutual antagonists and transcriptional regulators inhibitor of DNA binding 2 (Id2) and the E protein E2-2 direct type 1 conventional DC (cDC1) and plasmacytoid DC (pDC) development, respectively. Though the requirement of Id2 in cDC1 lineage development during the steady state is well established, roles for Id2 in DC subset or progenitor response to TLR agonists remains unknown. Prior work found Id2 is induced in pDCs upon maturation, suggesting Id2 may …

The Effect Of Cognitive Status And Residency On Oral Health In Patients With Dementia, Nicole Stephens

Dissertations and Theses (Open Access)

Poor oral health is a predictor of cognitive decline in elderly populations and has been shown to precede dementia. As cognitive decline progresses, patients are likely to move from the community into nursing facilities. We hypothesize that severity of dementia and residency type will impact the oral health of patients with dementia. Fifty-two participants of two dementia levels were recruited from the UTHealth Neurocognitive Disorders Center and two Houston-area nursing homes. A standardized oral health assessment, plaque index, and oral bacteria analysis determined participants’ oral health status. Further, data was collected on participants’ medical history, oral hygiene habits, dietary habits, …

Computational Approaches To Understand Chemoresistance & Tumor Evolution Using Longitudinal Clinical Data And Lineage Tracing, Sahil Seth

Dissertations and Theses (Open Access)

Tumors are highly heterogeneous and dynamic, continually adapting and evolving in response to their microenvironment as well as external perturbations. Multi-region (spatial) and single cell sequencing has enabled us to anatomize the heterogeneity further and provide evidence of its association with chemo and drug resistance. To investigate this further we took two different approaches to understand the chemo-resistance, and functional heterogeneity in Triple negative breast cancer (TNBC) and Pancreatic ductal carcinoma in situ (PDAC) from an evolutionary perspective.

The first approach was to leverage tumor profiling from an ongoing randomized clinical trial in triple-negative breast cancer (ARTEMIS) to assess mechanisms …

Non-Invasive Prenatal Screening (Nips) Testing Motivations And Informed Decision Making In The Low-Risk Population, Jenna Lea

Dissertations and Theses (Open Access)

Non-Invasive Prenatal Screening (NIPS) provides a risk assessment for aneuploidies by utilizing cell-free DNA (cfDNA). Recently, it was recommended that NIPS be offered to all pregnant people regardless of a priori risk for aneuploidy. In the absence of an increased risk, alternative motives for electing NIPS, such as for fetal sex disclosure, may arise and result in a less informed decision about proceeding with NIPS. Therefore, our study aimed to characterize low-risk patients’ motivations for NIPS election, compare motivations between informed and uninformed decision makers, and determine whether electing NIPS for fetal sex disclosure had any bearing on informed decision …

The Tca Cycle As A Nexus Of Metabolic Vulnerabilities In Cancer, Sunada Khadka

Dissertations and Theses (Open Access)

Uncontrolled proliferation of cancer cells necessitates rewiring of metabolic pathways to meet biosynthetic and bioenergetic demands of proliferation and fortify redox homeostasis. An increasing body of literature suggests that mitochondrial metabolism (tricarboxylic acid cycle (TCA) and oxidative phosphorylation) is imperative for cancer cell growth and proliferation. The scope of the works presented in this dissertation is to explore the importance of mitochondrial metabolism, and primarily the TCA cycle—the anabolic factory of cancer cells and leverage it as a targetable vulnerability in cancer. Cancer cells consume anabolic nutrients that are used to generate biosynthetic precursors in the TCA cycle. Continuous efflux …

Mechanism Of Rare Variant In Acta2, P.Arg149cys, Driving Diverse Vascular Disease, Kaveeta Kaw

Dissertations and Theses (Open Access)

Heterozygous variants in ACTA2 (smooth muscle (SM) α-actin) predispose to thoracic aortic aneurysms and dissections (TAAD) and early-onset coronary artery disease (CAD). The most common ACTA2 mutation is a genetic alteration of arginine 149 to a cysteine, ACTA2 p.Arg149Cys, which accounts for disease in 24% of all ACTA2 mutation carriers.(1) ACTA2 p.Arg149Cys mutation carriers present with either TAAD or CAD but rarely have both diseases. To identify the molecular mechanisms dictating whether an individual with ACTA2 p.Arg149Cys develops TAAD or CAD, CRISPR/Cas9 technology was used to generate the mutant mouse, Acta2^R149C/+, in a C57BL6 background. Acta2^R149C/+ mice …

Hepatocellular Carcinoma Image-Guided Intervention: Quantitative Characterization Of Reagents For Thermochemical Ablation, Emily A. Thompson

Dissertations and Theses (Open Access)

Thermochemical ablation (TCA) is a minimally invasive therapy under development for hepatocellular carcinoma, a leading cause of cancer death worldwide. TCA utilizes acid-base chemistry delivered simultaneously to induce local ablation when administered. When delivered via a mixing catheter placed directly into the tumor, acid (e.g., AcOH) and base (e.g., NaOH) react to completion at the catheter tip, producing the acetate salt, water, and releasing heat (Δ>50°C) in sufficient quantities to induce lethal osmotic and thermal stress in tumor cells. However, these two reagents are not distinguishable from tissues with noninvasive imaging modalities, which makes monitoring the delivery of TCA …

Modeling Of Cns Cancer With A Focus On The Immune Component, Daniel Zamler

Dissertations and Theses (Open Access)

The knowledge surrounding cancers of the central nervous system remains poorly developed, in particular with regard to the immune component. The works contained in this thesis look at craniopharyngioma, glioblastoma, and several forms of brain metastasis. While some attention is given to the tumor cells themselves, as well as the patient setting which these studies model, the immune component of disease progression and treatment plays a strong role in each and is the primary focus of the works contained.

Craniopharyngioma is a relatively rare tumor in adults. Although histologically benign, it can be locally aggressive and may require additional therapeutic …

Computer-Aided Diagnosis For Melanoma Using Ontology And Deep Learning Approaches, Xinyuan Zhang

Dissertations and Theses (Open Access)

The emergence of deep-learning algorithms provides great potential to enhance the prediction performance of computer-aided supporting diagnosis systems. Recent research efforts indicated that well-trained algorithms could achieve the accuracy level of experienced senior clinicians in the Dermatology field. However, the lack of interpretability and transparency hinders the algorithms’ utility in real-life. Physicians and patients require a certain level of interpretability for them to accept and trust the results. Another limitation of AI algorithms is the lack of consideration of other information related to the disease diagnosis, for example some typical dermoscopic features and diagnostic guidelines. Clinical guidelines for skin disease …

Clinical Impact Of A Highly Sensitive Next-Generation Sequencing Measurable Residual Disease Assay In Patients With Acute Lymphoblastic Leukemia, Nicholas Short

Dissertations and Theses (Open Access)

Measurable residual disease (MRD) is highly prognostic for relapse and overall survival (OS) in acute lymphoblastic leukemia (ALL), although many patients with apparent “MRD negativity” by standard assays still relapse. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay in 74 adults with ALL undergoing frontline therapy. Among remission samples that were MRD negative by multiparameter flow cytometry (MFC), 46% were MRD positive by the NGS assay. At the time of complete remission (CR), MRD negativity by MFC at a sensitivity of 1x10^-4 and NGS at a sensitivity of 1x10^-6 was achieved in …

Understanding Young Adult Tobacco And Marijuana Use, Shazia Rangwala

Dissertations and Theses (Open Access)

In 2015, young adults in the United States (U.S.) reported co-use of tobacco and marijuana at a much higher rate than exclusive use of marijuana. While there is some qualitative research specific to using tobacco and marijuana separately, there is a lack of qualitative research studying poly/dual or co-use of these products and to understand the complex interactions between the varied modes of delivery for tobacco and marijuana. Qualitative research in this area is important especially due to the major developmental shifts that occur as youth transition into young adulthood. The proposed study is a descriptive analysis of qualitative data …

4d Ex Vivo Crispr/Cas9 Whole-Genome Screen To Identify Genes Regulating Lung Cancer Metastasis, Alexandria Plumer

Dissertations and Theses (Open Access)

Metastatic lung cancer has a 5-year survival rate of 5%. Lung cancers tend to be asymptomatic until late stages, and almost 90% are not diagnosed until they are advanced. Metastases are very rare events, often initiated by a single cell from a primary tumor into a new niche at a distant location. Investigation of the early metastatic process is of urgent need for the development of early diagnostics and targeted therapeutics. We performed a proof-of-concept CRISPR/Cas9 whole genome knockout screen in the A549 lung adenocarcinoma cell line and utilized a novel ex vivo 4D lung metastasis model to find gene …

The Src- And Abl- Dependent Regulation Of Net1a In Breast Cancer, Ashabari Sprenger

Dissertations and Theses (Open Access)

The neuroepithelial cell transforming gene 1 (Net1) is a RhoA guanine nucleotide exchange factor that promotes cancer cell motility and metastasis. Two isoforms of Net1 exist, Net1 and Net1A, both of which are which sequestered in the nucleus in quiescent cells to prevent aberrant RhoA activation. Many cell motility stimuli drive cytosolic relocalization of Net1A, but mechanisms controlling this event are not fully understood. Here we demonstrate that EGF stimulates Src- and Abl1-dependent phosphorylation of Net1A to promote its cytosolic localization. We find that Abl1 efficiently phosphorylates Net1A on Y373, and that phenylalanine substitution of Y373 prevents Net1A cytosolic localization. …

Lgr5 Regulation Of Stat3 Signaling And Drug Resistance In Colorectal Cancer, Tressie Posey, Tressie Alexandra Posey

Dissertations and Theses (Open Access)

LGR5 Regulation of STAT3 Signaling and Drug Resistance in Colorectal Cancer

Tressie Alexandra Capri Posey B.S.

Advisory Professor: Kendra Carmon, Ph.D.

The greatest difficulty in treating colorectal cancer (CRC) is the development of drug resistance which leads to relapse after treatment and progression to metastasis. Cancer stem cells (CSCs) are believed to drive relapse because of their capacity to self-renew, acquire resistance mechanisms, and differentiate promoting tumor growth and heterogeneity. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), is a bona-fide marker of CSCs and has been considered a viable target for CSC specific therapeutic development. While we showed targeting LGR5 …

Investigating Therapeutic Strategies To Target Metabolic Vulnerabilities Of Nsclc Tumors With Mutant Keap1 Gene, Pranavi Koppula

Dissertations and Theses (Open Access)

The metabolic vulnerability of cancers has long been envisaged as an attractive window to develop novel therapeutic strategies. Metabolic flexibility at the cellular level encompasses the efficient rerouting of anabolic and catabolic pathways in response to varying environmental stimuli to maintain cellular homeostasis and sustain proliferation. The primary objective of this study is to identify metabolic vulnerabilities bestowed by KEAP1/NRF2 signaling axis through SLC7A11. SLC7A11 is a transcriptional target of NRF2, an essential regulator of cellular anti-oxidant response. Under unstressed basal conditions, NRF2 interacts with KEAP1, a tumor suppressor gene and a substrate adaptor protein of the Cullin3-dependent ubiquitin ligase …

Modulation Of The Receptor Gating Mechanism And Allosteric Communication In Ionotropic Glutamate Receptors, Nabina Paudyal, Nabina Paudyal

Dissertations and Theses (Open Access)

Ionotropic glutamate receptors (iGluRs) found in mammalian brain are primarily known to mediate excitatory synaptic transmission crucial for learning and memory formation. The family of iGluRs consists of AMPA receptors, NMDA receptors and kainate receptors with each member having distinct physiological role. In the recent years, significant progress has been made in understanding the biophysical, and functional properties of iGluRs. The development of Cryo-EM and X-Ray crystallography techniques have further facilitated in the structural understanding of these receptors. However, the multidomain nature, large size of the protein, complex gating mechanism and inadequate knowledge regarding the conformational dynamics of the receptors …

Mutant Kras Alters Extracellular Vesicle Microrna Sorting In Pancreatic Cystic Neoplasms, Rachel L. Dittmar

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers by organ site with a 5-year survival rate of just 10.8%. This is largely because most patients do not experience symptoms until the disease has already metastasized. The best hope to cure PDAC is surgery, which can only be done with a curative intent at an early stage when the disease is localized. There are no reliable circulating, body-fluid-based biomarkers to detect early stage PDAC or its precursor lesions in a timely manner for effective surgical intervention. When potential PDAC precursor lesions, such as mucinous pancreatic cysts are found, there are …

Enhancing Adoptive Cell Therapy By Augmenting Fitness And Anti-Tumor Function Of Tumor-Infiltrating Lymphocytes, Parin Shah

Dissertations and Theses (Open Access)

The success of immune checkpoint inhibitors (ICIs) has established the importance of cancer immunotherapy in solid cancers, where it has been adopted as one of the standards of care for advanced melanoma and lung cancer. It is currently being investigated to treat other solid cancers. However, a large fraction of patients do not respond to ICIs and relapse. ICI therapy offers an in vivo approach to activate tumor-specific T cells, albeit in some cases, this modality does not create a sufficiently robust anti-tumor response. Thus, ex vivo approaches employing manipulation of immune cells, such as Adoptive Cell Therapy (ACT) using …

Cross-Seeding Potential Of Misfolded Amyloid-Beta Strains On Tau Protein: Examining The Puzzle Pieces Of Alzheimer's Disease, Sara Kelley

Dissertations and Theses (Open Access)

Alzheimer’s disease (AD) is a neurodegenerative disorder that will progressively impair cognitive function. AD is the leading source of dementia, and affects one third of the senior citizens in the United States. Aging is the primary risk factor for AD and due to the expected rise in human lifespan worldwide, the occurrence rate of AD diagnosis is projected to increase. This observation is increasingly alarming when considering there is no treatment for reversal or prevention of AD yet.

AD is characterized by gross pathological hallmarks in the brain. These include the extracellular accumulation of misfolded amyloid-beta (Aβ) and the intraneuronal …

Deciphering The Role Of Hsp110 Chaperones In Diseases Of Protein Misfolding, Unekwu M. Yakubu

Dissertations and Theses (Open Access)

Molecular chaperones maintain protein homeostasis (proteostasis) by ensuring the proper folding of polypeptides. Loss of proteostasis has been linked to the onset of numerous neurodegenerative disorders including Alzheimer’s, Parkinson’s, and Huntington’s disease. Hsp110 is a member of the Hsp70 class of molecular chaperones and acts as a nucleotide exchange factor (NEF) for Hsp70, the preeminent Hsp70-family protein folding chaperone. Hsp110 promotes rapid cycling of ADP for ATP, allowing Hsp70 to properly fold nascent or unfolded polypeptides in iterative cycles. In addition to its NEF activity, Hsp110 possesses an Hsp70-like substrate binding domain (SBD) whose biological roles are undefined. Previous work …

Agonist-Induced Conformational Changes In The Nmda Receptor, Ryan Durham, Ryan Durham

Dissertations and Theses (Open Access)

NMDA receptors are ligand-gated ion channels that mediate a number of physiological and pathological phenomena within the mammalian central nervous system. Under the typical course of activation, these receptors bind to glycine and glutamate molecules and undergo a series of conformational changes that results in the opening of a cation-permeable pore in the neuronal plasma membrane. Various aspects of NMDA receptor function are not fully understood, including the phenomenon of negative cooperativity between the glycine- and glutamate-binding sites of the receptor and the mechanism controlling partial agonism. Past studies utilizing static structural snapshots of the receptor or isolated domains of …

Mitochondrial Unfolded Protein Response Regulator Atf5 In Mitochondrial Targeted Therapies In Aml, Ran Zhao

Dissertations and Theses (Open Access)

Mitochondrial unfolded protein response (UPR^mt) is an adaptive transcriptional response induced by damaged proteins accumulated in mitochondria. UPR^mt signaling involves induction of mitochondrial specific chaperones and proteases such as HSP60, LonP1 and ClpP, aiding in the restoration of mitochondrial protein pool homeostasis. However, the cell-protective roles of UPR^mt in the context of mitochondrial stress-induced cell death in AML has not been well explored. We demonstrate that AML cells are susceptible to mitochondrial targeted agents such as ONC201, an agonist of the mitochondrial protease ClpP, and gamitrinib, an inhibitor of mitochondrial chaperone TRAP1, however, these agents also …

Atrx Inactivation And Idh1-R132h Drive Preferential Sensitivity To Proton Vs. X-Ray Radiotherapy In Glioma Stem Cells, Ángel Adrián Garcés

Dissertations and Theses (Open Access)

Background: Glioma Stem Cells (GSCs) are self-renewable, treatment resistant cells in the glioma tumor mass known to promote tumor development. In contrast to traditional photon-based radiation therapy (XRT), proton radiation therapy (PRT) may induce more complex DNA damage and therefore might have the potential to eliminate GSCs. Although previous studies have individually linked IDH mutations, specifically IDH1^R132H, and ATRX inactivating mutations to improved patient outcomes and suppressed DNA damage repair compared to their respective wild-types, the mechanisms by which these two genetic alterations interact in GSCs treated with PRT compared to XRT are currently unknown. We hypothesize that …