Digital Commons Network^™

Evaluating Cancer Rates, Cancer Types, And Variant Hotspots Between Different Races And Ethnicities In Individuals With Li-Fraumeni Syndrome, Hillary Esplen

Dissertations and Theses (Open Access)

Li Fraumeni Syndrome (LFS) is a cancer predisposition syndrome that increases the risk for numerous cancer types in both children and adults. In the general population, incidence rates for various cancer types differ among races and ethnicities. Although a few germline TP53 pathogenic/likely pathogenic (P/LP) variants in those with LFS have been studied and associated with specific populations, such as the South and Southeast Brazil founder variant, p.Arg337His, there still lacks research on the variable expressivity of cancers within the LFS population based on specific variant, race and/or ethnicity. This study aims to describe the specific TP53 germline variants, the …

Relationship Between Processing Body Formation, Epithelial-To-Mesenchymal Transition, And Invasion In Lung Adenocarcinoma, Amanda Warner

Dissertations and Theses (Open Access)

Lung cancer is the leading cause of cancer-related deaths in the United States, largely due to its ability to metastasize. Epithelial-to-mesenchymal transition (EMT) is a process that enhances the ability of cells to lose their cell-cell contacts, invade, and enter the blood stream which are essential during metastasis. Many transcriptional gene programs are altered during EMT such as activation of mesenchymal transcription factors, like ZEB1, and enhanced response to the TGFβ1 cytokine. In oncogenic contexts, TGFβ1 enhances the formation of processing-bodies (P-bodies) where P-body proteins are required for invasion in multiple cancerous cell lines. P-bodies are a type of ribonucleoprotein …

Rod Photoreceptor Regeneration In A Zebrafish Model With Retinitis Pigmentosa, Eyad Shihabeddin

Dissertations and Theses (Open Access)

A cellular hallmark of inherited retinal degenerative diseases is progressive loss of photoreceptors until one is completely blind. Unlike mammalian models, Zebrafish have the ability to naturally regenerate their neurons after injury or disease is detected. We have generated a zebrafish model with the most common autosomal dominant form of the inherited retinal degenerative disease known as Retinitis Pigmentosa. We utilize immunohistochemistry, single-cell RNA sequencing, several analysis tools, behavioral assays and oligonucleotides to characterize our zebrafish model and identify the transcription factors necessary for rod photoreceptor regeneration. We show that our zebrafish model has continuous degeneration and regeneration of rod …

Automated Radiotherapy Treatment Planning For Breast Cancer: A Robust To Ol For Global Deployment, Hana Baroudi

Dissertations and Theses (Open Access)

Breast cancer incidence continues to rise worldwide, particularly in low- and middle-income countries, where limitations in resources already constrain access to timely care. Radiotherapy is a cornerstone of breast cancer management, proven to significantly lower both recurrence and mortality. However, a growing shortage of radiation staff worldwide threatens the prompt delivery of these treatments.This thesis proposes an automated solution to address the limited accessibility of radiotherapy planning in breast cancer management by developing an end-to-end automated treatment planning model and evaluating its performance and limitations across diverse patient populations.

An automated contouring model was trained using data from 104 whole-breast …

Exploring Veto Activity: Dnam-1-Cd155 Axis In Overcoming Nk Cell-Mediated Allo-Rejection And Applications For Car-T Cell Therapy, Wei-Hsin Liu

Dissertations and Theses (Open Access)

As Miller et al. defined veto activity, it enables cells to target host cytotoxic T lymphocyte (CTL) precursors specific to veto cells' antigens, selectively eliminating anti- donor T cell clones without inducing rejection. By leveraging this unique immune property, two key research aims were proposed: “Exploration of the Impact of Veto Activity on Natural Killer (NK) Cell-Mediated Allo-rejection” and “Development of Off-the- shelf Chimeric Antigen Receptor (CAR)-T Therapy: Engineering Anti-Viral Veto CD8+ T Cells”. As demonstrated in our previous research, in a murine model with mild conditioning, anti-third-party central memory CD8+ veto T cells (veto Tcm) can prevent T cell- …

The Gut Microbiome As A Novel Approach For Reversing Long-Term Inflammation And Accelerated Aging Across The Lifespan, Janelle M. Korf

Dissertations and Theses (Open Access)

Introduction: Neonatal hypoxic-ischemic encephalopathy (HIE) arises from disrupted perinatal cerebral oxygenation and perfusion. It is a leading global cause of infant death and disability which disproportionally affects males. Like adult stroke, HIE initiates a rapid influx of inflammatory cells across the blood brain barrier and a loss of microglial homeostasis. Persistent peripheral inflammation in children with a history of HIE is recognized but its ramifications, including accelerated aging, are poorly understood. As this coincides with critical stages of brain development, interventions started months or years post-injury may still improve survivors’ quality of life. One promising intervention is to manipulate the …

Development Of Lineal Energy Spectrum-Based Biological Effects Models For Protons, Joseph M. Decunha, Fada Guan, David Grosshans, Zhongxing Liao, Dragan Mirkovic, Oleg Vassiliev, Radhe Mohan

Dissertations and Theses (Open Access)

In this dissertation, methods are developed and described to allow for the rapid calculation of microdosimetric spectra (specifically, lineal energy) for protons. SuperTrack, a GPU-accelerated tool for calculation of microdosimetric spectra was developed and is capable of computing lineal energy spectra up to 5000x faster than using Geant4 directly. Proton lineal energy spectra generated by SuperTrack are indistinguishable from those generated by Geant4. With SuperTrack, large libraries of lineal energy spectra for monoenergetic protons spanning 0-300 MeV have been developed. The proton lineal energy spectra calculated by SuperTrack have been compared to experimental measurements made by a tissue equivalent proportional …

Novel Statistical Methods For Mediation Analysis With High-Dimensional Omics Mediators, Zhichao Xu

Dissertations and Theses (Open Access)

Mediation analysis is a widely used statistical method for examining how molecular traits, such as gene or protein expression, act as intermediaries linking an exposure to a health outcome. For example, it can help explain how smoking affects disease risk through molecular changes. The rapid progress in high-throughput omics profiling technologies and large-scale epidemiology consortia, such as the Trans-Omics for Precision Medicine (TOPMed) program from the National Heart, Lung and Blood Institute (NHLBI) and UK Biobank, now has resulted in an extensive accumulation of genomic data for biomedical research and analysis. At the same time, it poses significant methodological challenges, …

Overcoming Resistance To Cdk4/6-Targeted Therapy Using Jak2/Stat3 Inhibitor In Triple-Negative Breast Cancer, Chuling Zhuang

Dissertations and Theses (Open Access)

Breast cancer is the most common type of cancer diagnosed in women, with nearly 30% of cases becoming metastatic accounting for over 90% of breast cancer-related deaths. Among different breast cancer subtypes, triple-negative breast cancer (TNBC) has the worst prognosis and the highest propensity to metastasize. However, TNBC patients have limited treatment options due to their lack of actionable drug targets while therapeutic resistances result in high rates of recurrence and metastasis. Cyclin-dependent kinase 4 and 6 (CDK4/6) are major cell cycle regulators that control G1 to S phase transition and aberrant hyperactivation of the CDK4/6 pathway results in uncontrolled …

Elucidating The Multi-Omics Of Early-Onset Colorectal Cancer, Jumanah Alshenaifi

Dissertations and Theses (Open Access)

The incidence and mortality rates of sporadic early-onset colorectal cancer have increased in recent decades, but there is no clear etiological basis for this trend. EOCRC is commonly defined as colon and rectal cancers diagnosed before the age of 50 years. The rising incidence of EOCRC has made it the second most common cancer and the third leading cause of cancer death in this age group. The rising incidence of EOCRC is also documented internationally in more than 20 countries across different continents. Clinically, EOCRC has a distinct, more aggressive clinical profile than LOCRC. While approximately 15% of EOCRC cases …

Combined Inhibition Of Lysine-Specific Demethylase 1 And Kinase Signaling As A Preclinical Treatment Strategy In Glioblastoma, Lea Stitzlein

Dissertations and Theses (Open Access)

Glioblastoma is the most common primary malignant brain tumor in adults, with limited treatment options resulting in a poor prognosis. Lysine-specific demethylase 1 (LSD1) is overexpressed in glioblastoma and contributes to tumor growth and treatment resistance. Inhibitors of LSD1 have shown preclinical promise but have had limited clinical development for glioblastoma. Given the frequent kinase pathway alterations in glioblastoma, the interplay between LSD1 inhibition and kinase signaling pathways was investigated to identify vulnerabilities that could be exploited through rationally designed combination therapies. We hypothesized that LSD1 inhibitors would activate kinase signaling pathways, such as MAPK, and the addition of kinase …

Impact Of Personal And Family History Of Huntington's Disease On The Decision And Ability To Obtain Life, Long-Term Care, And Disability Insurance, Karli Livingston

Dissertations and Theses (Open Access)

Huntington’s disease (HD) is an inherited, neurodegenerative condition characterized by a clinical triad of motor, cognitive, and psychiatric symptoms. Individuals diagnosed with HD manifest characteristic symptoms of the disease including motor and cognitive changes, and they may or may not have undergone genetic testing to confirm the diagnosis. Individuals at-risk for HD are those who have not yet undergone genetic testing for HD, but have a first- or second- degree relative diagnosed with the disease. Genetic testing for HD is categorized into two forms: predictive and confirmatory. However, many individuals choose not to pursue testing due to a fear of …

The Influence Of Scientific, Genetic, And Health Literacy On Carrier Screening Decision-Making, Brenna D. Albracht

Dissertations and Theses (Open Access)

For those wishing to assess their reproductive risks and make informed decisions in their reproductive planning, carrier screening for autosomal recessive and X-linked conditions, as well as cell-free DNA (cfDNA) screening for aneuploidy, are recommended during pregnancy. Despite similarities in purpose, sample requirements, insurance coverage, and safety, a lower percentage of individuals elect carrier screening than cfDNA screening, suggesting there may be a disconnect in what patients perceive as valuable information for their pregnancy. Previous studies have attempted to explain the factors associated with carrier screening uptake or decline; however, no models have yet accounted for a patient’s literacy level …

Identifying And Characterizing Transition Cells In Developmental Processes From Scrna-Seq Data, Yuanxin Wang

Dissertations and Theses (Open Access)

During the development of multicellular organisms, individual cells make distinct decisions about their cell types and states. Understanding the molecular mechanisms underlying cellular state transitions at different developmental stages provides deep insights into physiology, morphology and the etiology of diseases. Single-cell RNA-sequencing (scRNA-seq), which is widely used to study complex cell states and dynamic gene expression patterns, enables us to investigate molecular mechanisms of cellular state transitions. Currently, however, computational tools available for identifying cellular states and state transitions remain limited.

Although trajectory-based methods such as Monocle and Slingshot assume that state transitions generate continuous expression profiles, they cannot distinguish …

Harnessing The Immunomodulatory Potential Of Radiofrequency Ablation To Improve Therapeutic Outcomes In Pancreatic Ductal Adenocarcinoma, Bhumi Maniyar

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) continues to rank among the most lethal cancers with poor prognosis. PDAC is characterized by a thick desmoplastic stroma, severe immunological suppression, and resistance tostandard treatments. The need for innovative therapeutic approaches is highlighted by the tumor microenvironment's (TME) critical role in promoting disease development and reducing the effectiveness oftreatment. A promising locoregional treatment that can induce tumor necrosis and modify the TME is endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA). However, there is still minimal understanding around its wider impact on stromal remodeling and immunological activation. This study investigates the immunomodulatory effects of RFA combined with neoadjuvant …

Achieving The Practice-Based Competencies: Are More Than 50 Cases Needed?, Farren Lopez

Dissertations and Theses (Open Access)

Genetic counseling graduate programs are required to provide didactic coursework and fieldwork experiences to foster development of the practice-based competencies (PBCs) in trainees. Currently, every graduating trainee must log a minimum of 50 participatory encounters to demonstrate readiness for entry-level practice of the PBCs. Previous studies have noted that many trainees exceed the 50-case standard, raising the question of whether this minimum satisfies the training needs of every student. To assess the perceived number of encounters needed for graduates to independently perform the PBCs, a survey was administered to 2023 and 2024 graduates of North American genetic counseling training programs. …

Role Of Mir-4732-3p In Breast Cancer Brain Metastasis And Brain Metastatic Tumor Microenvironment, Munazza Samar Khan

Dissertations and Theses (Open Access)

In this study, we aimed to identify microRNAs (miRNAs) that may play important roles in breast cancer brain metastasis (BCBM). To this end, we conducted miRNA-sequencing of extracellular vesicles isolated from the serum samples of 6 BCBM patients and 8 Stage I/II/III breast cancer patients, and identified 49 circulating miRNAs that were upregulated in BCBM patients compared to Stage I/II/III breast cancer. Upon further analysis, we identified miR-4732-3p to be upregulated in brain-tropic triple-negative breast cancer (TNBC) cell lines, compared to parental lines. MiR-4732-3p overexpression increased metastatic properties of TNBC cells, including proliferation, migration, invasion, and maintenance of a mesenchymal …

Uncovering A Fundamental Mechanism Underlying Female Oocyte Quality And Rasopathies Using C. Elegans As A Model System, Han Bit Baek

Dissertations and Theses (Open Access)

Signaling pathways are molecular networks that allow cells to communicate between and within themselves. They are crucial for the coordination of diverse cellular processes and are the molecular mechanism in which cells sense and respond to their environment. RAS (Rat Sarcoma) is a small GTPase that transmits extracellular growth factor signals through a downstream kinase cascade and ERK (Extracellular-signal regulated kinase) is the terminal kinase, and it controls cellular processes such as proliferation, differentiation, and survival by phosphorylating its downstream effectors. This post translational modification regulates the effector by modulating its activity, levels, and/or interaction with other molecules. Given the …

"Magic Computer In The Sky" - Participant Perspectives On Control And The Genetic Counseling Admissions Match, Jessica Clark

Dissertations and Theses (Open Access)

Since the 2018 admissions cycle, genetic counseling graduate programs in North America have utilized the Genetic Counseling Admissions Match (GCAM), a Match algorithm to place applicants. While a study prior to implementation found that most students were uninterested in a Match due to concerns of control, there has been no investigation into matched applicants’ experiences since its inception. A mixed-methods study explored the experiences and perceptions of control of genetic counselors and genetic counseling (GC) students who entered a program following the GCAM. An anonymous survey documenting GCAM experience and a validated measure for locus of control (LOC) was disseminated …

Exploring The Immunologic Consequences Of Atrx Deficiency In Glioma, Benjamin Whitfield

Dissertations and Theses (Open Access)

ATRX is a key chromatin regulator that is frequently mutated across multiple cancer types. One of the most common ATRX-mutated tumor types is the adult-type glioma, IDH-mutant, Astrocytoma. It is known that ATRX mutation leads to increases in DNA damage, replication stress, and global epigenetic regulation at a cell level; however, less is known about the impact of ATRX mutation on immune signaling. Furthermore, little is known about the interaction of ATRX loss with gain-of-function mutations in IDH. In this paper we set out to explore the impact of ATRX loss on immune signaling in gliomas, both in the context …

Investigating Prefrontal Cortex Neuronal Signatures Of Opioid-Induced Risk-Taking Behavior, Cana Quave

Dissertations and Theses (Open Access)

Opioid use disorder occurs alongside impaired risk-related decision-making, but the underlying neural correlates are unclear. We developed an approach-avoidance conflict task using a modified conditioned place preference procedure to study neural signals of risky opioid seeking in the prefrontal cortex, a region implicated in executive decision-making. Following morphine conditioned place preference, rats underwent a conflict test in which fear-inducing cat odor was introduced in the previously drug-paired side of the apparatus. While the saline-exposed control group avoided cat odor, the morphine group included two subsets of rats that either maintained a preference for the paired side despite the presence of …

Stat3, Nf-Κb, And Estrogen Receptor Beta: The Balance Of Inflammation In K-Ras Mutant Lung Adenocarcinoma, Michael J. Clowers

Dissertations and Theses (Open Access)

K-ras mutant lung adenocarcinoma (KM-LUAD) is a difficult-to-treat cancer subtype in which chronic inflammation pervades the tumor immune microenvironment (TIME). Pro-inflammatory pathways dampen the response to treatments, including immune checkpoint inhibitors, necessitating therapies that target this inflammatory signaling network in the TIME. This network is underpinned by interaction and coordination of two inflammatory pathways: signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB). The balance of these transcription factors determines the degree of anti- vs. pro-tumor immunity, and a skewing towards STAT3 is known to promote tumor development and a pro-tumor TIME. It is also …

Mhc Class I Tyrosine Phosphorylation Site Y320 Augments Cd8+ T Cell Priming, Effector Function, And Memory Response, Yimo Sun, Gregory A Lizee, Yitao Tang, Priscilla Ortiz, R Eric Davis

Dissertations and Theses (Open Access)

The cytoplasmic domain of MHC class I (MHC-I) molecules contains a single, highly conserved tyrosine residue (Y320). In previous work, we found that mice expressing a Y320F-mutated form of H-2K^b had reduced capacity to generate K^b-restricted cytotoxic T lymphocyte (CTL) responses following viral infection, due (at least in part) to defects in endolysosomal trafficking of H-2K^b and antigen cross-presentation by dendritic cells (DCs). In this study, we investigated whether there are additional, post-presentation dependencies on Y320 for T-cell priming. We engineered both human- and mouse-derived antigen-presenting cells (APCs) to express either wild-type MHC-I or variants of …

Automated To Ols For Contour Review In Radiotherapy, Barbara Marquez

Dissertations and Theses (Open Access)

Peer review of organ-at-risk and target volume delineation is essential for patient safety and optimization of treatment outcomes. Peer review makes a substantial impact on patient outcomes, reporting notable rates of plan changes when reviewed and worse survival when patient cases are not reviewed. In around half of revised cases, target volume change is the required cause for modification (related to tumor control); in one in ten cases, it is normal tissue sparing (related to treatment toxicity). Essentially all North American institutions with accredited residency training programs hold peer review to some capacity. However, accessibility to practicing routine peer review …

An Investigation Into The Potential Of Cell Therapies For Acute Myeloid Leukemia (Aml) Treatment, Amanda Eckstrom

Dissertations and Theses (Open Access)

Despite recent advances in acute myeloid leukemia (AML) treatment, curative rates remain poor with high rates of relapse and many patients are unable to tolerate the intensive chemotherapy standard of care regimen. Cell therapies have shown great success against hematologic malignancies but face several challenges including treatment-related toxicities and human-leukocyte antigen (HLA) matching. Natural killer (NK) cells and gamma delta (γδ) T cells offer alternative effector cell options for cell therapies that do not require HLA-matching and have shown low toxicity in previous studies. In this project, we sought to evaluate FT538 induced pluripotent stem cell-derived NK (iPSC-NK) and donor-derived …

Evaluating Triage To Genetic Counseling Using An Online Reproductive Genetics Module, Grace Ra

Dissertations and Theses (Open Access)

The American College of Obstetricians and Gynecologists recommends genetic screening for all pregnant women. As clinical recommendations broaden and demand for prenatal screening increases, obstetric practitioners report time constraints and lack of genetics knowledge as challenges to providing sufficient pretest education. These challenges in offering routine screening are further compounded by the inequities in access to genetic counseling and testing. Thus, alternative education and service delivery models have emerged to meet the demands for prenatal genetics education and help mitigate challenges surrounding access. At UTHealth Houston, an online triage and education module, the Prenatal Genetics Education Program (PGEP), was created …

Denial Of Inpatient Genetic Testing: A Study On Outpatient Yield And Outcomes, Cindy Y. Canales

Dissertations and Theses (Open Access)

This study investigates the difference in diagnostic yield between patients approved for inpatient genetic testing compared to those denied inpatient testing and the effect of an earlier diagnosis on outcomes and medical/clinical care. In the literature, research has explored the impact of a diagnostic delay for patients with genetics conditions, assessed the utility of genetic testing in the inpatient setting, and described the impact to care of an earlier diagnosis. However, gaps remain on research exploring the diagnostic yields of inpatient versus outpatient settings and the potential impact to care an inpatient genetic testing request denial may pose. This is …

Neural Activity Within And Between Visual And Executive Areas Is Modulated Post-Locomotion In Rhesus Macaques, Sergey Egranov

Dissertations and Theses (Open Access)

Physical activity has been shown to benefit cognitive and mental health by improving cerebrovascular perfusion and regulating hormone-mediated processes on a systemic level. However, the acute effects of physical activity, such as locomotion, on the neuronal circuits underlying cognitive processes have yet to be fully characterized. This body of work seeks to rectify this gap in knowledge through analysis of how both behavioral performance and neuronal activity signatures in visual and executive brain regions are modulated post-locomotion in rhesus macaques.

To this end, we performed high-yield electrophysiological recordings simultaneously from area V4, a mid-tier visual cortical region, and the dorsolateral …

Investigating Metabolic And Mitochondrial Adaptations Triggered By Blood Flow During The Endothelial-To-Hematopoietic Transition, Paulina Horton

Dissertations and Theses (Open Access)

Hematopoietic stem cell (HSC) transplant is the standard of care for many hematologic diseases. However, many patients cannot benefit from this potentially curative treatment because they cannot find a suitable donor, contributing to a high level of unmet need. Recently, bona fide HSCs capable of robust engraftment and differentiation have been generated from iPSCs utilizing wall shear stress (WSS) to help promote HSC generation. However, the mechanisms through which WSS regulates hematopoiesis remain poorly understood. Scientists, therefore, continue to look for the mechanotransduction pathways that promote hematopoiesis, and key answers may lie in examining the role of extrinsic factors that …

Differential Progression Of Pancreatic Premalignancy In Geographically Distant Murine Transgenic Cohorts Uncovers Key Role Of Microbial Metabolites, Rian M. Howell

Dissertations and Theses (Open Access)

Cancer is a leading cause of death worldwide. Despite recent advances in diagnostic and therapeutic modalities, pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that remains highly lethal. Efforts have been made to increase the understanding of the underlying mechanisms driving early stages of tumor development, when the cancer is most susceptible to intervention. To this end, genetically engineered mouse models (GEMMs) have been developed with the mutations most commonly seen in the patient population. Expression of these mutations in select cellular compartments has resulted in the ability to recapitulate characteristics of human pancreatic cancer such as the development of …