Medicine and Health Sciences Commons^™

Combination Of Oncolytic Adenoviruses, T-Cell Activation, And Blockade Of Ido Metabolic Circuitry For The Treatment Of Glioma, Teresa Nguyen

Dissertations & Theses (Open Access)

Glioblastoma is the most common malignant primary brain tumor in adults; the current aggressive treatment results in a 5% five-year survival rate. More effective therapies should be developed. One promising alternative is oncolytic adenovirus, Delta-24-RGD, which elicits cancer cell lysis and immunogenic cell death. In fact, Delta-24-RGD produced complete responses in 20% of recurrent glioblastoma patients through immune mechanisms that activate anti-tumor cytotoxic properties of T-cells. This cytolytic effect can further be enhanced by adding immune agonists, namely OX40L, which engages the OX40 receptor to co-stimulate activated T cells for enhanced proliferation. Hence, we produced the next generation of Delta-24-RGD, …

Conserved Non-Pocket Interactions Drive The Diversity Of Peptide Presentation By Mhc Class I Molecules, Kyle Jackson

Dissertations & Theses (Open Access)

Cytotoxic T-lymphocytes (CTL) can lyse infected or transformed cells through recognition of peptides presented on human leukocyte antigen (HLA) molecules. A thorough understanding of peptide-HLA interactions is needed for improvement of CTL-based immunotherapies. We observed that aspartic acid (D) and glutamic acid (E) at peptide position 4 are highly prevalent in HLA-I peptide ligands, and discovered that they interact with arginine (R) in position 65 and lysine (L) in position 66 of the α1 helix of the binding groove in HLA-A*0201 and HLA-A*2402. Since this interaction differed from well-characterized peptide-HLA anchor interactions mediated by peptide position 2 and the C-terminus, …

Synthetic Essentiality Of Tdo2 In Apc-Mutated Colorectal Cancer, Rumi Lee

Dissertations & Theses (Open Access)

Inactivation of the adenomatous polyposis coli (APC) tumor suppressor is

common genetic event across many cancers and serves a critical initiating

event in the majority of sporadic colorectal cancers (CRC). The WNT/APC

pathway remains an elusive target for cancer, prompting us to explore

orthogonal strategies to identify specific vulnerabilities for APC-deficient

CRC and other cancers. Using the concept of synthetic essentiality (SE), we

sought to identify essential effectors of APC deficiency with the goal of

expanding targetable vulnerabilities in CRC. We identified Tryptophan 2,3-

dioxygenase 2 (TDO2) as an SE gene for APC-deficient cancers.

Mechanistically, APC loss results in TCF4/b-catenin-mediated …

Investigation Of Trophon® 2 For High Level Disinfection Of Rigid Endorectal Mri Coils, Rebecca Ditusa

Dissertations & Theses (Open Access)

Clinical Magnetic Resonance Imaging is most widely known for anatomical images with good image resolution and superb soft-tissue contrast. However, changes tumor metabolism may precede changes in gross size of the tumor. Newer studies present the use of 13C in MR imaging to interrogate tumor metabolism. With this additional information, not only can the size and makeup of a tumor be obtained, but also information about its metabolic characteristics. An increase in glucose uptake and production of lactate in the presence of oxygen—aerobic glycolysis—identifies abnormal metabolism, and hence a potential increase in tumor aggressiveness. Traditional 1H MRI of the prostate …

Identification And Characterization Of De Novo Germline Tp53 Mutation Carriers In Families With Li-Fraumeni Syndrome, Carlos C. Vera Recio

Dissertations & Theses (Open Access)

Li-Fraumeni syndrome (LFS) is an inherited cancer syndrome caused by a deleterious mutation in TP53. An estimated 48% of LFS patients present due to a de novo mutation (DNM) in TP53. The knowledge of DNM status, DNM or familial mutation (FM), of an LFS patient requires genetic testing of both parents which is often inaccessible, making de novo LFS patients difficult to study. Famdenovo.TP53 is a Mendelian Risk prediction model used to predict DNM status of TP53 mutation carriers based on the cancer-family history and several input genetic parameters, including disease-gene penetrance. The good predictive performance of Famdenovo.TP53 was demonstrated …

Quantitative Magnetic Resonance Imaging For The Early Prediction Of Treatment Response In Triple Negative Breast Cancer, Benjamin C. Musall

Dissertations & Theses (Open Access)

Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer which lacks upregulated hormone receptors. Because of this, it is not vulnerable to clinically available targeted therapies. When treated with standard of care neoadjuvant systemic therapy (NAST), TNBC only shows approximately a 40% rate of pathologic complete response (pCR). A biomarker which could predict TNBC response to NAST early during treatment would be useful, as it would allow for non-responders to be triaged to alternative therapies and potentially allow for the treatment of responders to be de-escalated.

Quantitative Magnetic Resonance Imaging (MRI) may be used to probe and …

Vascular Disease Pathogenesis In Smooth Muscle Dysfunction Syndrome And Majewski Osteodysplastic Primordial Dwarfism Type Ii, Jamie Wright

Dissertations & Theses (Open Access)

Vascular diseases are a leading cause of morbidity and mortality world-wide. Understanding their pathogenesis is crucial to better diagnosis and management of these life-threatening conditions. Through the study of rare mutations that lead to early onset and severe vascular diseases, we can elucidate underlying mechanisms for vascular disease pathogenesis and develop better treatments to prevent and manage more common causes of vascular diseases. In this study we look at two rare diseases that lead to severe vascular phenotypes, Smooth Muscle Dysfunction Syndrome (SMDS) and Majewski Osteodysplastic Primordial Dwarfism Type II (MOPDII). SMDS is a rare condition due to pathogenic variants …

Development Of Quantitative Molecular Photoacoustic Imaging For Noninvasive Cancer Diagnostics, Cayla Zandbergen

Dissertations & Theses (Open Access)

Traditional diagnostic imaging provides clinicians with anatomical information that guides both diagnosis and treatment planning; however, once a tumor has progressed enough to be visible, it has often reached an advanced stage. Molecular imaging techniques allow for real-time visualization of chemical and biological processes via imaging of specific biomarkers, which can facilitate detection of malignancies before they become visible. One biomarker of interest is blood oxygen saturation (SO₂) due to its correlation with hypoxia, which is associated with increased tumor malignancy; some studies have also established SO₂ as an independent biomarker of disease progression. Additionally, because cancerous …

Virulence And Biofilm Formation In Candida Albicans Are Inhibited By Short Peptide Subunits Of Entv, Shane Cristy

Dissertations & Theses (Open Access)

Candida albicans, the most clinically significant fungal pathogen, commonly causes topical mucosal infections such as oral cavity and urogenital tract infections. It also less frequently causes severe invasive and bloodstream infections. Invasive infections are most prevalent amongst patients with compromised innate immune responses, such as those receiving chemotherapy or recovering from surgery. C. albicans can also form biofilms on implanted medical devices. Fungal infections are difficult to treat due to the paucity of therapeutic options, and this problem is compounded by the resistance properties of biofilm infections.

Candida albicans exists as a member of the commensal flora of the …

The Microsatellite Instability High Endometrial Tumor Microenvironment And Identifying Predictive Biomarkers Of Response To Pembrolizumab, Jeffrey How

Dissertations & Theses (Open Access)

Objective: Half of patients with microsatellite instability high (MSI-H) endometrial cancer are treatment-refractory to pembrolizumab. We sought to evaluate the MSI-H endometrial tumor samples to examine differences in the tumor microenvironment (TME) and identify transcriptomic signatures associated with response/resistance to pembrolizumab. Methods: Archival tumor samples from MSI-H endometrial cancer patients treated at MD Anderson Cancer Center were obtained. Tissue samples originating from patients who did not receive pembrolizumab treatment (“untreated cohort ”; n = 11) were analyzed via RNA sequencing (RNA-seq). Pre-treatment archival tumor samples (“treated cohort”; n = 23) from patients who were later treated with pembrolizumab were collected …

Understanding The Role Of Arglu1 In Interferon Signaling Activation In Breast Cancer, Phuoc Nguyen

Dissertations & Theses (Open Access)

In the U.S., the highest number of new cancer cases belongs to breast cancer in women, and this cancer also bears the second-highest death rate in women. Despite significant progress in breast cancer treatment that has been made in the past several decades, innovative and efficient therapies are still needed to eradicate this deadly disease. Novel cancer immunotherapy with immune checkpoint blockade (ICB) could induce long-lasting responses and improve survival in hard-to-treat malignancies. Regrettably, only a fraction of breast cancer patients respond to this highly promising strategy. To improving ICB therapy in breast cancer treatment, IFN signaling induction is a …

Unveiling Global Roles Of G-Quadruplexes And G4-22 In Human Genetics, Ruth Barros De Paula

Dissertations & Theses (Open Access)

G-quadruplexes are non-B DNA structures formed by four or more runs of repeated guanines that confer unique features to living organism’s genomes. These sequences are enriched in regulatory regions, such as promoters and 5’ UTRs, and have distinct regulatory roles in both health and disease states. Even though previous studies showed the impact of G4 in gene expression, none of them summarized the location-specific effect of G4. Also, there is no broad understanding about the most common G4 repeat in the human genome, named here as G4-22, and how it links to the evolution of mammals and their biology. In …

Targeting Plasma Membrane Phosphatidylserine Content To Inhibit Oncogenic Kras Function, Walaa E. Kattan

Dissertations & Theses (Open Access)

The small GTPase KRAS, which is frequently mutated in human cancers, must be localized to the plasma membrane (PM) for biological activity. We recently showed that the KRAS C-terminal membrane anchor exhibits exquisite lipid-binding specificity for select species of phosphatidylserine (PtdSer). We therefore investigated whether reducing PM PtdSer content is sufficient to abrogate KRAS oncogenesis. Oxysterol-related binding proteins ORP5 and ORP8 exchange PtdSer synthesized in the ER for phosphatidylinositol-4-phosphate (PI4P) synthesized in the PM. We show that depletion of ORP5 or ORP8 reduced PM PtdSer levels, resulting in extensive mislocalization of KRAS from the PM. Concordantly, ORP5 or ORP8 depletion …

Dissecting The Mechanisms Of Venetoclax Resistance In Myelodysplastic Syndromes, Shuaitong Chen

Dissertations & Theses (Open Access)

Myelodysplastic syndromes (MDS) are a class of heterogeneous clonal hematopoietic disorders. The current standard of care for MDS is the hypomethylating agent (HMA)-based therapy. However, only 50 percent of the patients respond, with transient effects and no approved second-line treatment options after their diseases progress to acute myeloid leukemia (AML). The mechanisms that govern HMA failure are unknown. Recently, we unveiled that MDS are maintained and propagated by two different immunophenotypically distinct hierarchical cellular organizations of MDS hematopoietic stem and progenitor cells (HSPCs) through the upregulation of specific survival pathways. This finding allowed us to potentially stratify MDS patients into …

Standardizing New Diagnostic Tests To Facilitate Rapid Responses To The Covid-19 Pandemic, Xiao Dong

Dissertations & Theses (Open Access)

In order to enhance the data interoperability, an expeditious and accurate standardization solution is highly desirable for naming rapidly emerging novel lab tests, and thus diminishes confusion in early responses to pandemic outbreaks. This is a preliminary study to explore the roles and implementation of medical informatics technology, especially natural language processing and ontology methods, in standardizing information about emerging lab tests during a pandemic, thereby facilitating rapid responses to the pandemic. The ultimate goal of this study is to develop an informatics framework for rapid standardization of lab testing names during a pandemic to better prepare for future public …

Impact Of Intratumor Heterogeneity And The Tumor Microenvironment In Shaping Tumor Evolution And Response To Therapy, Akash Mitra

Dissertations & Theses (Open Access)

Intratumor heterogeneity (ITH) is a crucial challenge in cancer treatment. The genotypic and phenotypic heterogeneity underlying diverse cancer types leads to subclonal variation, which may result in mixed or failed response to therapy. The heterogeneity at the tumor level, along with the tumor microenvironment (TME), often shapes tumor evolution and ultimately clinical outcome. Given that modern treatment paradigms increasingly expose patients with metastatic disease to multiple treatment modalities through the course of their disease, there exists a need to characterize robust and predictive biomarkers of response to therapy. In order to accurately characterize tumor evolution, we need to account for …

Associations Of Perceived Overall Health, Psychological Distress, Functional Impairment, And Alcohol Use Among Older Adults Of Sexual Minority Status And Heterosexual Peers, Carolyn Tran

Dissertations & Theses (Open Access)

Background: Lesbian, gay, and bisexual (LGB) adults, 50 and older, are likely to have experienced mistreatment and discrimination, contributing to poor physical and mental health and risky behaviors, such as alcohol misuse. Few studies have examined the relationships between perceived health, psychological distress, functional impairment, and alcohol use of older LGB adults and heterosexuals.

Specific Aims: The specific aims were: (1) to determine if perceived overall health status is associated with psychological distress and functional impairment in sexual minority older adults compared to heterosexual older adults, and (2) to determine if sexual minority status moderates the relationship between psychological distress …

Dermatological Concerns For Women And Girls With Turner Syndrome, Meaghan Mones, Siddharth K. Prakash, Kate Mowrey, Michelle Rivera-Davila, Melissa B. Aldrich, David F. Rodriguez-Buritica

Dissertations & Theses (Open Access)

Turner syndrome (TS) is associated with distinct manifestations in women and girls involving many mesoderm-derived body systems, including endocrine, cardiovascular, lymphatic, and renal. Many TS signs and symptoms may go undetected until teenage years or later. Non-mesoderm-derived manifestations of dermatological nature, which are just as common as other features of TS, but often present either at birth or soon after, can aid in earlier detection and impact clinical management. The main objective of this study was to determine self-reported prevalence of various dermatological manifestations in a sample of women and girls with TS. We created a six-part questionnaire that included …

Disability Awareness Education And Implications For Genetic Counselor Training, Lauren Douglas, Chelsea Wagner, Jennifer Czerwinski, Myla Ashfaq, Rebecca Lunstroth, Rose Vukoic

Dissertations & Theses (Open Access)

The genetic counseling (GC) community has faced criticism concerning the duality of promoting patient autonomy while advocating for individuals with disabilities. Research suggests that focusing on the education of GC students could ensure GCs feel prepared to have conversations about disability, as well as strengthen the relationship with the disability community. This study aimed to evaluate the landscape of GC disability awareness education to identify gaps and strengths. The study also aimed to assess attitudes and perspectives of GCs and the disability community to identify content that should be included in GC student’s disability awareness curriculum. GCs and members of …

Endogenous Mechanisms Regulating Myeloid Cell Mediated Inflammation During Acute Lung Injuries, Nathaniel Berg

Dissertations & Theses (Open Access)

Acute lung injuries (ALI) can result from both direct insults (e.g. pneumonia or inhalation injury), or systemic conditions such as sepsis or trauma. Current treatment options for patients are limited to supportive care and novel approaches are urgently needed. Appreciating the role of excessive inflammation that underlies the pathophysiology of ALI, we sought to identify endogenous mechanisms that dampen inflammation. Here we investigated two pathways that worked to limit excessive pulmonary inflammation in myeloid cells using a mouse model of sepsis-associated ALI. In the first approach we screened for microRNAs during the recovery phase of ALI that could potentially regulate …

Imaging Based Prediction Of Pathology In Adult Diffuse Glioma With Applications To Therapy And Prognosis, Evan Gates

Dissertations & Theses (Open Access)

The overall aggressiveness of a glioma is measured by histologic and molecular analysis of tissue samples. However, the well-known spatial heterogeneity in gliomas limits the ability for clinicians to use that information to make spatially specific treatment decisions. Magnetic resonance imaging (MRI) visualizes and assesses the tumor. But, the exact degree to which MRI correlates with the actual underlying tissue characteristics is not known.

In this work, we derive quantitative relationships between imaging and underlying pathology. These relations increase the value of MRI by allowing it to be a better surrogate for underlying pathology and they allow evaluation of the …

Functions Of Dcp2 And Ski7 In Mrna Degradation, Minseon Kim, Ambro Van Hoof

Dissertations & Theses (Open Access)

Posttranscriptional gene regulation is essential to maintain gene expression fidelity. This is partially achieved by mRNA decay. When no longer required, mRNA is degraded by two alternative pathways. The decapping enzyme Dcp2 removes the 5` <sup>m7</sup>G cap of mRNAs, allowing Xrn1 to degrade the mRNA from the 5` end. Alternatively, mRNA is degraded from the 3` end by the RNA exosome.

While decapping by Dcp2 is a critical step in mRNA decay, its physiological function has been unclear. Null mutations of Saccharomyces cerevisiae DCP2 have been reported to be lethal in some studies but slow-growing in others. In this …

Genetics In The Nicu: Nurses’ Perceived Knowledge And Desired Education, Kathleen Shields

Dissertations & Theses (Open Access)

A large proportion of infants admitted to neonatal intensive care units (NICUs) have genetic conditions. NICU nurses play an important role in providing comprehensive care to these patients and their families. Previous research has demonstrated gaps exist in the genetics knowledge of nurses and that they lack comfort applying genetics information to clinical practice, but no research has been done assessing the knowledge of or comfort with genetics of NICU nurses specifically. NICU nurses (n=122) completed an online survey assessing their perceived knowledge of genetics, comfort with clinical scenarios involving genetics, and desired genetics education. Participants reported the highest levels …

The Impact Of Synchrony On Neuronal Coding And Behavior, Natasha Kharas

Dissertations & Theses (Open Access)

Cortical columns represent the elementary functional and computational module of the neocortex. Although much is known about its laminar structure and synaptic connectivity, how patterns of spiking activity propagate within columnar circuits when the state of the brain changes remains poorly understood. We used multi-electrode laminar arrays to reveal that brain state modulates the propagation of neural activity across the layers of early and mid-level visual cortex (areas V1 and V4). We found a high prevalence of neuronal synchrony (vigorous (On) and weak (Off) spiking) in rest but low prevalence of synchrony during wakefulness. We next tested whether propagation of …

A Novel Role For Dyrk1a In Kidney Development, Alexandria Blackburn

Dissertations & Theses (Open Access)

Congenital anomalies of the kidney and urinary tract (CAKUT) are a leading cause of pediatric kidney failure and encompass a wide range of structural malformations resulting from defects in morphogenesis. CAKUT occur in ∼1/500 live births and with an average wait time of 3-5 years for a kidney transplant, the need is high for the development of new strategies aimed at reducing the incidence of CAKUT and preserving renal function. Approximately 14% of CAKUT cases have a known genetic component. This low causality suggests that CAKUT is complex and that there are underlying genes and mechanisms which lead to CAKUT …

Exploring Motivational Factors To Pursue Genetic Counseling And Testing In Adolescent And Young Adult Cancer Patients, Megan Morand

Dissertations & Theses (Open Access)

Adolescent and young adult (AYA) cancer patients face a unique set of challenges when navigating cancer treatment and survivorship. For many patient populations, motivational factors to pursue genetic counseling/testing have been described, but these motivational factors in AYA cancer patients have yet to be explored. The goal of this study was to describe AYA cancer patients’ decision-making process, including motivational factors and barriers as it relates to genetic counseling/testing. We conducted a qualitative study consisting of semi-structured interviews with 30 individuals from the AYA Program at MD Anderson Cancer Center who attended or were referred to a genetic counseling appointment. …

Molecular Drivers Of Bladder Cancer Motility, Bryan Wehrenberg

Dissertations & Theses (Open Access)

Bladder cancer (BC) progression is measured by the degree of tumor cell invasion into the bladder wall and dissemination to distant sites. The study of BC cell motility will both enable development of anti-invasion therapeutics to limit progression of early-stage disease and improve our understanding of the metastatic process which drives patient mortality in BC. BCs display a great deal of intertumoral heterogeneity, and can be divided into basal and luminal subtypes, which are biologically and clinically distinct entities. Here, I examine the invasion phenotypes of BC as a function of both subtype and epithelial to mesenchymal transition (EMT) status. …

Biases And Blind-Spots In Genome-Wide Crispr-Cas9 Knockout Screens, Merve Dede

Dissertations & Theses (Open Access)

Adaptation of the bacterial CRISPR-Cas9 system to mammalian cells revolutionized the field of functional genomics, enabling genome-scale genetic perturbations to study essential genes, whose loss of function results in a severe fitness defect. There are two types of essential genes in a cell. Core essential genes are absolutely required for growth and proliferation in every cell type. On the other hand, context-dependent essential genes become essential in an environmental or genetic context. The concept of context-dependent gene essentiality is particularly important in cancer, since killing cancer cells selectively without harming surrounding healthy tissue remains a major challenge. The toxicity of …

Breast Cancer Risk For Female Relatives Of Male Breast Cancer Patients With Negative Brca1/2 Testing, Emily Martin

Dissertations & Theses (Open Access)

Risk models exist to estimate a female’s lifetime risk of breast cancer in the absence of a hereditary predisposition to cancer, namely Hereditary Breast and Ovarian Cancer syndrome. These risk models consider various factors such as reproductive history and family history, but few models take a family history of male breast cancer into account. This study aims to evaluate if prevalence of breast cancer among female relatives is higher when there is a family history of male breast cancer in the context of uninformative BRCA1 and BRCA2 testing. This information may aid in the process of risk assessments for patients …

A Fully-Automated, Deep Learning-Based Framework For Ct-Based Localization, Segmentation, Verification And Planning Of Metastatic Vertebrae, Tucker Netherton, Tucker James Netherton

Dissertations & Theses (Open Access)

Palliative radiotherapy is an effective treatment for the palliation of symptoms caused by vertebral metastases. Visible evidence of disease is localized on medical images as part of the treatment planning process. However, complicating factors such as time pressures, anatomic variants in the spine, and similarities in adjacent vertebrae are associated with wrong level treatments of the spine. In addition, erroneous manual contouring of anatomic structures is a major failure mode in radiotherapy treatment planning.

The purpose of this study is to mitigate the challenges associated with treatment planning of the spine by automating the treatment planning process for three-dimensional conformal …