Medicine and Health Sciences Commons^™

Investigating The Roles Of Δnp63 As A Suppressor Of Migration, Invasion, And Metastasis, Ramon E. Flores Gonzalez

Dissertations and Theses (Open Access)

Cancer is one of the leading causes of death and disease in the world. Considerable resources are spent to study and understand cancer, with the hope of developing new treatments and eventually cures that will help millions of people. Efforts to understand cancer are hindered by its inherent complexity and instability. Nonetheless, understanding the basics of tumor development and progression are the key to focused on studying the role of ΔNp63 in cancer, a p53 family member known to be involved in epithelial development, microRNA biogenesis, and stem cell maintenance. Using the strength of in vivo mouse models, we found …

Clinical Significance Of Homologous Recombination Deficiency Score Testing In Endometrial Cancer, Jean M. Hansen

Dissertations and Theses (Open Access)

Objectives: Homologous recombination deficiency (HRD) score is related to chemotherapy response in breast and ovarian cancers. The role of HRD is unknown in endometrial cancer. We examined the relationship between HRD score and survival in a cohort of endometrial cancer patients and with tumor growth using murine orthotopic models.

Methods: TCGA was queried to determine frequency and clinical significance of alterations in the HR pathway in endometrial cancer. 137 formalin-fixed paraffin-embedded endometrioid adenocarcinoma patient samples were tested for HRD score, microsatellite instability (MSI) and high mutation load (HML) using a next generation sequencing assay targeting the coding regions of 43 …

Development Of Rational Combination Therapy With Parp Inhibitors And Kinase Inhibitors In Tnbc, Wen-Hsuan Yu

Dissertations and Theses (Open Access)

Poly (ADP-ribose) polymerase inhibitors (PARPi) emerge as potential targeting drugs for BRCA-deficient cancers including triple negative breast cancer (TNBC). However, it has been reported that a subgroup of patients even with BRCA mutation fails to respond to PARPi in multiple clinical trials. In this study, we identified c-Met, a tyrosine kinase, phosphorylates PARP1 at Y907 and that the phosphorylation increases PARP1 activity, thereby rendering cancer cells resistant to PARPi. The combination of c-Met inhibitors (METi) and PARPi has a synergistic effect for c-Met overexpressed TNBC in vitro and in vivo. In addition to c-Met, through functional analysis, we found …

Development And Implementation Of An Anthropomorphic Head & Neck Phantom For The Assessment Of Proton Therapy Treatment Procedures, Daniela Branco

Dissertations and Theses (Open Access)

Proton therapy has been used to treat cancer for more than 50 years, and over the past decade, its use has grown rapidly. One of the main goals of modern radiation therapy is to deliver a high dose to the planning target volume (PTV) with minimal exposure and damage to the surrounding healthy tissue. Protons offer a unique advantage over photon radiotherapy in that they deposit dose over a finite range, in contrast to the more gradual energy deposition of photon and electron beams. At present, 23 proton centers are in operation in the United States and another 13 centers …

Define The Epigenetic Profiles And Subtype-Specific Genes Of Breast Cancer, Wenqian Li

Dissertations and Theses (Open Access)

Molecular profiling has identified 5 distinct subtypes of breast cancer, luminal A, luminal B, HER2-enriched, basal-like, and claudin-low breast cancer. These 5 subtypes correlate with hormone response, patient prognosis, and response to therapy. Although steady state gene expression patterns have been explored using expression microarrays, very little is known about the initial, disease-driving transcriptional changes in these cancers or epigenetic changes associated with the differential gene expression signatures. Defining these changes may provide new insights into the mechanisms by which these subtypes arise, as well as new avenues for breast cancer prevention, diagnosis, and treatment. Using Chromatin Immunoprecipitation sequencing and …

Interrogating Dux4 Mrna 3′ End Processing, Natoya J. Peart

Dissertations and Theses (Open Access)

Double Homeobox 4, Dux4, is the leading candidate gene for Facioscapulohumeral Dystrophy (FSHD). FSHD is the third most common muscular dystrophy, and is characterized by progressive muscle weakness primarily in the upper body. In individuals diagnosed with FSHD, Dux4 is inappropriately expressed in somatic cells due to two conditions. The first is hypomethylation of the subtelomeric D4Z4 repeats on chromosome 4. Each D4Z4 repeat on chromosome 4 is 3.3kb in length and contains the open reading frame for Dux4. Hypomethylation of the D4Z4 repeats primarily occurs due to contraction of the repeats from 11-100 (typical numbers in the healthy population) …

Tnf Signaling During Tissue Damage-Induced Nociceptive Sensitization In Drosophila, Juyeon Jo

Dissertations and Theses (Open Access)

Tumor necrosis factor (TNF) signaling is required for inflammatory nociceptive sensitization in both Drosophila and vertebrates. In Drosophila larval model of nociceptive sensitization, UV irradiation in results in epidermal apoptosis and thermal allodynia. TNF/Eiger is produced from dying epidermal cells and acts its receptor in nociceptive sensory neurons to induce thermal allodynia. Inhibition of TNF signaling results in attenuation of nociceptive sensitization whereas epidermal apoptosis still occurs in the absence of TNF. Major gaps in this model are the precise relationship between apoptotic cell death and production of TNF/Eiger, downstream signaling mediators for TNFR/Wengen, and target genes that alter nociceptive …

Potentially Inappropriate Medication Use In Older Patient With Breast And Colorectal Cancer, Meghan S. Karuturi

Dissertations and Theses (Open Access)

Our objective was to determine predictors of potentially inappropriate medication (PIM) use and its impact on outcomes (including ER visits, hospitalization, all cause death, and composite of three) in breast and colorectal cancer patients receiving chemotherapy. We used data from the SEER database linked to Medicare claims. Our cohort included patients ≥ 66 years diagnosed with of Stage II/III breast or colorectal cancer between 7/1/2007-12/31/2009. Baseline PIM was defined using the Drugs to Avoid in the Elderly list (DAE) or Beers criteria. Univariate and multivariable logistic regression were used to determine the associations of baseline PIMs with different covariates. Event-free …

An Automated Syringe Pump System For Improving The Reproducibility Of Dynamic Hyperpolarized Mri Phantoms, Harlee G. Harrison

Dissertations and Theses (Open Access)

AN AUTOMATED SYRINGE PUMP SYSTEM FOR IMPROVING THE REPRODUCIBILITY OF DYNAMIC HYPERPOLARIZED MRI PHANTOMS

Harlee Grace Harrison, B.S.

Advisory Professor: James Bankson, Ph.D.

Magnetic Resonance Imaging (MRI) is a powerful tool in the diagnosis of cancer due to its ability to provide good soft tissue contrast and image resolution without the use of ionizing radiation. The use of hyperpolarized pyruvate as a contrast agent for tumor metabolism during MR scans has the potential to provide information about tumor metabolism in vivo that is not available from traditional imaging measurements or any other method. Hyperpolarization is achieved through dynamic nuclear polarization. …

Measurement Of The Electron Return Effect Using Presage Dosimeter, Gye Won Choi

Dissertations and Theses (Open Access)

MR-guided radiation therapy (MRgRT) provides benefits such as superior soft tissue contrast, no imaging dose, and functional imaging capacities, but it also has concerns to be addressed. The electron return effect (ERE) refers to dose enhancement at the interface between different media, caused when radiation is delivered in the magnetic field. The ERE poses clinical concerns in MRgRT because it significantly enhances the dose at interfaces, and the intensity and pattern of the dose enhancement depends on many factors. The ERE results in a complex pattern of dose enhancement over a three-dimensional (3D) volume around tissue interfaces inside the patient …

Epigenetic Modulation In Braf Mutated Metastatic Colorectal Cancer, Van Morris

Dissertations and Theses (Open Access)

Introduction: BRAF V600E mutations are associated with poor clinical outcomes for patients with metastatic colorectal cancer (mCRC). Unlike other tumors with the same mutation, BRAF inhibitors are ineffective as monotherapy. CRC tumors with BRAF V600E mutations are associated with global hypermethylation, which may turn off tumor suppressor gene expression. We studied demethylation in BRAF V600E mCRC to restore sensitivity to BRAF inhibitors.

Methods: Tumor databanks were investigated for genes differentially expressed according to BRAF mutation status to identify genes which may be particularly susceptible to epigenetic influence. Mouse xenograft models of BRAFV600E mCRC were treated with vemurafenib or azacitidine, alone …

The Immune Microenvironment Of Microsatellite Instable Endometrial Cancer, Janelle B. Pakish

Dissertations and Theses (Open Access)

Limited treatment options are available for patients with advanced and recurrent endometrial cancer (EC) should standard chemotherapy fail. Recent studies in other tumor types have shown that tumors with high microsatellite instability (MSI-H) have increased immunogenicity and response to immunotherapy treatments compared to microsatellite stable (MSS) tumors. Patients with MSI-H EC may also benefit from these therapies; however, the tumor immune microenvironment in MSI-H EC has not yet been well described.

In order to evaluate the immune microenvironment of MSI-H EC, multiple approaches were used, including analysis of large publically available datasets and detailed characterization of patient tumor samples. Uterine …

Employing T Cells For Antigen Presentation: Role Of Ny-Eso-1+ T-Apc Vaccine In Multiple Myeloma, Krina K. Patel

Dissertations and Theses (Open Access)

Introduction: Cellular therapy has shown great potential in early phase clinical trials with persistence of effector cells appearing to lead to improved outcomes. Combined immunotherapy with NY-ESO-1⁺ CAR T cells (TCR mimetic) and an NY-ESO-1 specific T-APC vaccine in myeloma patients may lead to enhanced anti-myeloma efficacy due to improved persistence of the CAR T cells.

Materials and Methods: Using the Sleeping Beauty transposon/transposase system, an NY-ESO-1⁺ TCR and CAR were created as effector cells. Vaccine was produced by electroporation of the NY-ESO-1 gene into T cells to make T cell antigen presenting cells (T-APC). Costimulatory …

Understanding The Mechanism And Extent Of Vlse Recombination In Borrelia Burgdorferi Using Next-Generation Sequencing, Surabhi Tyagi

Dissertations and Theses (Open Access)

B. burgdorferi, the causative agent of Lyme disease, have an elaborate antigenic variation system that involves varying the sequence of vlsE. Previous studies have shown that vlsE antigenic variation occurs continuously inside mammalian hosts. Variation has not been shown previously to occur in in vitro or in ticks. We hypothesized that the induction of vlsE recombination requires contact with dense arrays of host tissue cells and/or ECM components. To test this hypothesis, two methods, quantitative PCR and high-throughput sequencing were used determine the extent and nature of vlsE recombination within mouse tissues and in vitro model systems. Using these …

Novel Mechanisms Of Β-Adrenergic Signaling In Prostate Cancer Progression, Mohit Hulsurkar

Dissertations and Theses (Open Access)

Prostate cancer is the second leading cause of cancer death among American men. The American Cancer Society estimates that 180,890 men will be will be diagnosed with prostate cancer in 2016 in the USA. (http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics). Androgen deprivation therapy (ADT) is the standard treatment for early stage prostate cancer. But most patients relapse with aggressive variants of prostate cancer, with survival time between 1-3 years. In order to develop cure for such aggressive variants of prostate cancer, our present understanding of the mechanisms underlying its progression needs to be advanced.

Recently, it has been found that activation of β-adrenergic signaling pathway …

Encapsulated Contrast Agent Markers For Mri-Based Post-Implant Dosimetry, Tze Yee Lim

Dissertations and Theses (Open Access)

Low-dose-rate prostate brachytherapy involves the implantation of tiny radioactive seeds into the prostate to treat prostate cancer. The current standard post-implant imaging modality is computed tomography (CT). On CT images, the radioactive seeds can be distinctively localized but delineation of the prostate and surrounding soft tissue is poor. Magnetic resonance imaging (MRI) provides better prostate and soft tissue delineation, but seed localization is difficult. To aid with seed localization, MRI markers with encapsulated contrast agent that provide positive-contrast on MRI images (Sirius MRI markers; C4 Imaging, Houston, TX) have been proposed to be placed adjacent to the negative-contrast seeds. This …

Implications Of Computational Cognitive Models For Information Retrieval, Joshua Caleb Goodwin

Dissertations and Theses (Open Access)

This dissertation explores the implications of computational cognitive modeling for information retrieval. The parallel between information retrieval and human memory is that the goal of an information retrieval system is to find the set of documents most relevant to the query whereas the goal for the human memory system is to access the relevance of items stored in memory given a memory probe (Steyvers & Griffiths, 2010).

The two major topics of this dissertation are desirability and information scent. Desirability is the context independent probability of an item receiving attention (Recker & Pitkow, 1996). Desirability has been widely utilized in …

Information Processing Speed Impairment After Stroke, A Descriptive Study, Susan Alderman

Dissertations and Theses (Open Access)

Background Information processing speed (IPS) is an elemental cognitive function impacting multiple other functions including memory, attention, and executive function, and academic skills like arithmetic, reading and writing. However, little research has been done on IPS impairment in acute stroke. This article compares the frequency and severity of IPS impairment in mild and moderate stroke and its impact on quality of life.

Methods The longitudinal study of patients with mild stroke (NIHSS

Results Using linear mixed model regression, similar frequency and severity of IPS and memory impairments were noted, regardless of stroke severity, in the sample of 30 patients (60% …

Psychometric Performance Of The Arabic Versions Of The Cancer Behavior Inventory‐Brief And The Functional Assessment Of Cancer Therapy‐Breast In Saudi Arabia, Maaidah M. Algamdi Msn

Dissertations and Theses (Open Access)

Background: Arabic is the mother tongue of 26 countries, including Saudi Arabia where cancer is the fourth leading cause of death. Cancer is a sensitive issue in the Arabic population and a clear understanding of patients’ perceptions of self-efficacy for coping with cancer and quality of life helps assess interventions designed to facilitate optimal patient outcomes. In preliminary studies, the Cancer Behavior Inventory-Brief (CBI-B) was translated and back translated between English and Arabic, and reviewed for translational validity by an expert panel. The Arabic version of the CBI-B (CBI-BA) had acceptable evidence of translational validity with an overall translational validity …

Regulation Of The Escrt Function Of Alix, Sheng Sun

Dissertations and Theses (Open Access)

The ESCRT (endosomal sorting complex required for transport) is an evolutionary conserved membrane remodeling machinery that performs membrane invagination and abscission. ALIX is a widely expressed adaptor protein that is critically involved in three classical ESCRT-mediated processes, including MVB (multivesicular body) sorting, cytokinetic abscission and retroviral budding. Previous studies have demonstrated that ALIX involvement in these ESCRT-mediated processes requires ALIX interaction with the ESCRT-III component CHMP4 as well as a cargo protein. However, the native form of ALIX contains a default intramolecular interaction between N-terminal Bro1 domain and C-terminal PRD (proline-rich domain), leading to a closed conformation of ALIX that …

Ethnic Identity And Teratogenic Risk Perceptions, Katie M. Chan

Dissertations and Theses (Open Access)

Elevated perceptions of teratogenic risk can cause anxiety and confusion among pregnant women. To assess whether ethnic identity and demographic factors can influence teratogenic risk perceptions, 194 pregnant women in Houston were surveyed using the Multigroup Ethnic Identity Measure (MEIM) and visual analog scales to quantify perceptions of teratogenic risk for common exposures during pregnancy. Overall, participants estimated an elevated baseline risk of 25% for birth defects among the general population. In addition, participants overestimated birth defect risks for specific exposures, such as alcohol and marijuana. Based on the MEIM scores, ethnic identity was not significantly associated with teratogenic risk …

Effect Of Photographs Of Visible Genetic Conditions On Quality Of Life Perceptions, Christina Falugi

Dissertations and Theses (Open Access)

Historically, medical photographs are used to demonstrate dysmorphic features and characteristic presentations of genetic conditions. Traditional, pictorial depictions of genetic conditions typically involve nude subjects against walls to emphasize their features. These stark, black and white photographs may negatively influence students’ perceptions of the depicted individual. Natural photographs which include individuals in non-clinical environments may impact perceptions. To assess the influence of photographs on a viewer’s perception, 649 students from medical, nursing, genetic counseling and dental programs were surveyed in a cross-over study. Students were randomized to view a traditional or a natural photograph of three distinct genetic conditions followed …

Integration Of Multi-Platform High-Dimensional Omic Data, Xuebei An

Dissertations and Theses (Open Access)

The development of high-throughput biotechnologies have made data accessible from different platforms, including RNA sequencing, copy number variation, DNA methylation, protein lysate arrays, etc. The high-dimensional omic data derived from different technological platforms have been extensively used to facilitate comprehensive understanding of disease mechanisms and to determine personalized health treatments. Although vital to the progress of clinical research, the high dimensional multi-platform data impose new challenges for data analysis. Numerous studies have been proposed to integrate multi-platform omic data; however, few have efficiently and simultaneously addressed the problems that arise from high dimensionality and complex correlations.

In my dissertation, I …

Genomic Drivers Of Cutaneous Squamous Cell Carcinoma Development, Vida Chitsazzadeh

Dissertations and Theses (Open Access)

Skin cancer is the most common malignancy in humans. Annually, in U.S. there are over 3 million cases with an estimated overall economic impact of $2 billion. Cutaneous Squamous Cell Carcinoma (cuSCC) comprises 15-20% of all skin cancers. cuSCC has the best-defined progression from a distinct precancerous lesion, the Actinic Keratosis (AK), to invasive cuSCC. Destructive therapies for AK treatment must be used repetitively, causing significant morbidity. There is a tremendous need for targeted diagnostics and therapy for AKs, representing an important opportunity for secondary skin cancer prevention. Our knowledge of the molecular and cellular events that lead to the …

Insights Into Determinants That Contribute To Colonization, Virulence And Antibiotic Resistance In Enterococci, Maria Camila Montealegre

Dissertations and Theses (Open Access)

Enterococcus faecalis and Enterococcus faecium are increasingly common as causative agents of human infections, many of which are very difficult to treat due to multi-drug resistance. The work presented in the first part of this dissertation elucidates a mechanism for the regulation of pilus expression. I showed that ATT is the initiation codon of ebpA, the first gene of an operon that codes for the endocarditis and biofilm-associated pili (Ebp), a recognized virulence factor in E. faecalis. The presence of this rare start codon downregulates EbpA translation and protein levels, diminishing biofilm and binding abilities of …

Developing And Using Methyl-Specific Antibodies To Study The Biological Roles Of Arginine Methylation, Vidyasiri Vemulapalli

Dissertations and Theses (Open Access)

Arginine residues can be modified in three different ways to produce asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and monomethylarginine (MMA). These modifications are catalyzed by a family of nine protein arginine methyltransferases (PRMT1-9), which are of three types (I, II, and III). The majority of Type I enzymes asymmetrically dimethylate Glycine- and Arginine-rich (GAR) motifs, except for PRMT4, which methylates Proline-, Glycine-, and Methionine-rich (PGM) motifs. The same substrates (GAR or PGM motifs) can also be dimethylated by PRMT5 in a symmetric fashion. However, it is not clear whether there are dedicated residues within these motifs for ADMA and SDMA, …

Network Dynamics Of Visual Object Recognition, Mehmet C. Kadipasaoglu

Dissertations and Theses (Open Access)

Visual object recognition is the principal mechanism by which humans and many animals interpret their surroundings. Despite the complexity of neural computation required, object recognition is achieved with such rapidity and accuracy that it appears to us almost effortless. Extensive human and non-human primate research has identified putative category-selective regions within higher-level visual cortex, which are thought to mediate object recognition. Despite decades of study, however, the functional organization and network dynamics within these regions remain poorly understood, due to a lack of appropriate animal models as well as the spatiotemporal limitations of current non-invasive human neuroimaging techniques (e.g. fMRI, …

Poly (Adp) Ribose Polymerase Inhibitors For The Treatment Of Malignant Peripheral Nerve Sheath Tumor, Christine M. Kivlin

Dissertations and Theses (Open Access)

Malignant peripheral nerve sheath tumor (MPNST) is a rare subtype of soft tissue sarcoma. Surgical excision has remained the standard of care for this highly aggressive malignancy for over a decade. Conventional chemotherapy and radiotherapy have shown limited efficacy in MPNST; therefore, it is imperative that targeted treatment be identified to improve the outcome for MPNST patients. Poly (ADP) ribose polymerase (PARP) inhibitors were first reported over a decade ago to have substantial anti-tumorigenic effects in malignancies with defective DNA repair, specifically those with BRCA1/2 (breast cancer, early onset 1/2) mutations. Further evaluation of these inhibitors has shown multiple mechanisms …

Characterization Of Stem Cell Turnover In A Living Epithelial Bilayer, Elizabeth Sumner

Dissertations and Theses (Open Access)

Homeostatic maintenance of epithelia requires the renewal and replacement of old or dying cells while sustaining a functional barrier. Imbalance between cell production and elimination are hypothesized to underlie many pathological conditions. However, our knowledge of cell turnover within living tissues remains largely restricted to static images due to the limited ability to study epithelia in their native context. Here we report that clearance of damaged basal stem cells promotes compensatory proliferation of neighboring stem cells to maintain overall population numbers in a bilayered epithelium. Time-lapse imaging and electron microscopy experiments reveal that dying cells are rapidly cleared as nearby …

No Difference In Health Related Quality Of Life Between Therapeutic Options For Type 1 Gaucher Disease, Victoria Wagner

Dissertations and Theses (Open Access)

Type 1 Gaucher disease (GD) is the most common lysosomal storage disorder. Previously, treatment for GD was limited to intravenous enzyme replacement therapy (ERT). ERT reduces symptoms and increases health­related quality of life (HRQoL) in people with this condition. In 2014, oral substrate reduction therapy (SRT) was approved for type 1 GD treatment. Although both therapies alleviate disease symptoms, effects of SRT on HRQoL and preferences for therapy are not well established. Electronic surveys were administered to adults with type 1 GD. HRQoL was scored with the Short Form­36 Version 2 ® Health Survey and descriptive statistics were used to …