Volumetric, Magnetic Resonance-Visible, And Radiation-Sensitive Detectors For Magnetic Resonance Image-Guided Radiation Therapy, Hannah J. Lee

Dissertations and Theses (Open Access)

VOLUMETRIC, MAGNETIC RESONANCE-VISIBLE, AND RADIATION-SENSITIVE DETECTORS FOR MAGNETIC RESONANCE IMAGE-GUIDED RADIATION THERAPY

Hannah Jungeun Lee

Advisory Professor: Geoffrey S. Ibbott, Ph.D.

Due to the superior soft-tissue contrast of magnetic resonance imaging (MRI) compared to conventional computed tomography (CT) and other on-board imaging techniques, several groups have integrated MRI and radiation treatment machine systems. The advent of MR image-guided radiation therapy (MR-IGRT) using systems, such as the 1.5 MRI – 7 MV linear accelerator (MR-Linac), now allow for improved soft-tissue on-board imaging for patient position and tumor target localization verification and the ability to assess functional biological tissue characteristics with MRI, …

Functional Consequences Of Rna Exosome Complex Alteration By Conformational Changes And Cofactor Binding, Jaeil Han

Dissertations and Theses (Open Access)

The RNA exosome is an essential 3’-5 ribonuclease that processes or degrades a variety of RNA species in eukaryotes. It is composed of nine structural cores and one catalytic subunit, Rrp44. Structural studies captured two different conformations of Rrp44, Rrp44^ch (channel) and Rrp44^da (direct-access). The Rrp44^ch appears to recruit RNA substrates from the central channel formed by the core subunits, while the substrate is directly recruited to Rrp44^da bypassing the central channel. Although in vivo function of the Rrp44^ch-exosome is extensively studied, the function or even the presence of the Rrp44^da-exosome in …

Quantitative Dwi As An Early Imaging Biomarker Of The Response To Chemoradiation In Esophageal Cancer, Benjamin C. Musall

Dissertations and Theses (Open Access)

For patients diagnosed with stages IIa-IIb esophageal cancer, the current standard of care treatment is tri-modality therapy (TMT), where neoadjuvant chemoradiation (nCRT) is followed by surgical resection. Histopathology of resected tumors reveals that pathological complete response (pCR) is achieved in 20-30% of patients through nCRT alone. Because of the high mortality and morbidity associated with esophagectomy, it may be advantageous for patients exhibiting pCR from nCRT alone to be placed under observation rather than completing their TMT. Therefore, a method for predicting response at an early time-point during nCRT is highly desirable. Conventional methods such as endoscopic ultrasound, re-biopsy, and …

Functional Asymmetry Of The Immune Cell Plasma Membrane, Eric Malmberg

Dissertations and Theses (Open Access)

Mammalian cells maintain a distinct disparity in lipid composition between the two leaflets of the bilayer of the plasma membrane. This compositional asymmetry is most prominent for phosphatidylserine (PS), a negatively charged lipid that is found almost exclusively on the cytoplasmic (inner) leaflet of the plasma membrane. This energetically unfavorable asymmetry is maintained by the activity of ATP-dependent transporters called flippases and destroyed by energy-independent lipid channels called scramblases. Although this compositional asymmetry has been known for decades, there has been little investigation of its structural impact on the physical properties of the membrane, nor its functional impact in healthy …

Contrasting Effects Of An Mdm2 Functional Polymorphism On Tumor Phenotypes, Guadalupe J. Ortiz Iv

Dissertations and Theses (Open Access)

Cancer predisposition by the cooperation of genetic variants, such as single nucleotide polymorphisms (SNPs), may be of much greater significance to public health than previously appreciated. Functional polymorphisms are genetic variants that alter gene function. Meta-analyses associate many functional polymorphisms with cancer risk. The MDM2 SNP309G allele is a cancer-associated functional polymorphism positioned in the MDM2 P2 promoter that enhances transcription factor SP1 binding, resulting in elevated levels of MDM2 concomitant with decreased p53 tumor-suppressor activity. Mdm2^SNP309G/G mice are more prone to spontaneous tumor formation than Mdm2^SNP309T/T mice, providing direct evidence for the impact of this SNP on …

Lbpi: A Web Interface For The Identification Of Allosteric Ligand Binding Sites, Nabina Paudyal

Dissertations and Theses (Open Access)

The development of efficient tools for allosteric ligand binding site identification in potential drug targets is an important step for computational drug design. Ligand binding specificity analysis (LIBSA) is one of the protocols that utilize filtering algorithms to assess the propensity of a site on a target structure or structures to bind a ligand. However, LIBSA requires expert skills to be properly executed. Thus, a Web interface, LBPI (Ligand Binding Pocket Identification) has been developed using Django, a Python-based web framework. A Python Wrapper has also been developed to streamline pre-existing algorithms of LIBSA. The Wrapper helps in the …

Novel Bayesian Adaptive Clinical Trial Designs In Early Phases, Haitao Pan

Dissertations and Theses (Open Access)

Early phase, or phase I and phase II, trials are the first step in testing new medicines that have been developed in the lab. The main goal of phase I clinical trials is to establish the recommended dose of new drugs for phase II trials. For the cytotoxic drugs, the goal is to find maximum tolerated dose (MTD). The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Therefore, dose escalation methods, especially Bayesian designs, are recommended to be used in phase I …

Improving Nk Cell Therapy For Osteosarcoma, Jennifer Foltz

Dissertations and Theses (Open Access)

Osteosarcoma (OS) is the most common primary bone tumor. Despite new treatment options, 5-year survival for metastatic OS has remained at only 30% for the last 30 years. Adoptive transfer of Natural Killer (NK) cells holds promise for a new, non-toxic therapy for OS. NK cells are part of the innate immune system and readily kill metastatic and chemotherapy-resistant OS in vitro and in murine models. However, there is little data regarding their efficacy in animal models with an intact immune system. In addition, the OS tumor microenvironment is highly suppressive, producing TGFβ which impedes NK cell killing of solid …

Image Registration To Map Endoscopic Video To Computed To Mography For Head And Neck Radiotherapy Patients, William S. Ingram

Dissertations and Theses (Open Access)

The purpose of this work was to explore the feasibility of registering endoscopic video to radiotherapy treatment plans for patients with head and neck cancer without physical tracking of the endoscope during the examination. Endoscopy-CT registration would provide a clinical tool that could be used to enhance the treatment planning process and would allow for new methods to study the incidence of radiation-related toxicity.

Endoscopic video frames were registered to CT by optimizing virtual endoscope placement to maximize the similarity between the frame and the virtual image. Virtual endoscopic images were rendered using a polygonal mesh created by segmenting the …

Preclinical Development Of Therapeutic Strategies Against Triple-Negative And Inflammatory Breast Cancer, Angie M. Torres-Adorno

Dissertations and Theses (Open Access)

Triple-negative (TNBC) and inflammatory (IBC) breast cancer are the most aggressive forms of breast cancer, accounting for 20% and 10% of cancer-related deaths, respectively. Among IBC cases, 30% are additionally classified with TNBC molecular pathology, a diagnosis that significantly worsens patient’s prognosis. The current lack of TNBC and IBC molecular understanding prevents the development of effective therapeutic strategies. To identify effective treatments, we explored aberrant apoptosis pathways and cell membrane fluidity as novel therapeutic targets.

We first identified an effective therapeutic strategy against TNBC and IBC by pro-apoptotic protein NOXA-mediated inhibition of the anti-apoptotic protein MCL1 following inhibition of histone …

Investigating The Role Of Prmt1 And Arginine Methylation Of Hsp70 In Human Pancreatic Cancer, Liang Wang

Dissertations and Theses (Open Access)

Protein arginine methyltransferase 1 (PRMT1) is the major arginine methyltransferase, which catalyzes the addition of one or two methyl groups to the arginine residues of its substrate proteins. The best-known substrate for PRMT1 is histone, while more and more non-histone proteins are now found to be methylated by PRMT1. Dysregulation of PRMT1 is reported in several human cancer types. However, its biological roles in human pancreatic cancer initiation and development are still unclear. In the first part of this study, I found that the expression level of PRMT1 was elevated in both human and mouse pancreatic cancer tissues in immunohistochemistry …

A Tail-Based Test For Differential Expression Analysis And Pathway Analysis In Rna-Sequencing Data, Jiong Chen

Dissertations and Theses (Open Access)

RNA sequencing data have been abundantly generated in biomedical research for biomarker discovery and pathway analysis. Such data at the exon-level are usually heavily tailed and correlated. Conventional statistical tests based on the mean or median difference for differential expression likely suffer from low power when the between-group difference occurs mostly in the upper or lower tail of the distribution of gene expression. We propose a tail-based test to make comparisons between groups in terms of a specific distribution area rather than a single location. The proposed test, which is derived from quantile regression, adjusts for covariates and accounts for …

Structural And Functional Effect Of Phosphorylation On Ampa Receptors, Caitlin E. Nurik

Dissertations and Theses (Open Access)

Structural and Functional Effect of Phosphorylation on AMPA Receptors

Cailtin Edmunds show you, BA

Advisory Professor: Vasanthi Jayaraman, Ph. D.

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is the primary contributor to neuronal fast excitatory transmission, and plays a key role in learning and memory. Previous studies have established that residues S818, S831, and T840 in the C-terminal segment of GluA1 homomeric AMPA receptor are phosphorylated by PKC, and phosphorylation at these sites leads to an increase in receptor conductance. We show that the domain inclusive of those sites alters its secondary structure due to phosphorylation (using glutamate substitution as a mimic) …

Improvements In Four-Dimensional And Dual Energy Computed To Mography, Rachael M. Martin

Dissertations and Theses (Open Access)

Dual energy and 4D computed tomography (CT) seek to address some of the limitations in traditional CT imaging. Dual energy CT, among other purposes, allows for the quantification and improved visualization of contrast materials, and 4D CT is often used in radiation therapy applications as it allows for the visualization and quantification of object motion. While much research has been done with these technologies, areas remain for potential improvement, both in preclinical and clinical settings, which will be explored in this dissertation. Preclinical dual energy cone-beam CT (CBCT) can benefit from wider separation between the peak energy of the two …

Hsp27 And Chemotherapy-Induced Autophagy As Biomarkers In Osteosarcoma, John Andrew Livingston

Dissertations and Theses (Open Access)

Survival for patients with osteosarcoma has not improved for > 30 years. Despite aggressive multi-agent chemotherapy combined with surgical resection, a significant fraction of patients with localized disease relapse after optimal treatment. We evaluated the occurrence of cytoplasmic LC3B (light chain 3B)-positive puncta (a marker of autophagy) and presence of HSP27 (heat shock protein 27) in cancer cells within pre-treatment biopsy, post-treatment surgical resection, and metastatic osteosarcoma specimens by immunohistochemistry in 260 patients. LCB3+ puncta expression was seen in 34% of pre-treatment. 50% of resection, and 67% of metastasis samples. Sixty-six percent of all specimens were scored positive for HSP27 (85% …

Mechanisms Underlying The Sensitivity And Resistance Of Gastric Cancer Cells To Met Inhibitors, Rebecca Schroeder

Dissertations and Theses (Open Access)

MET amplification has been clinically credentialed as a therapeutic target in gastric cancer, but the molecular mechanisms underlying sensitivity and resistance to MET inhibitors are still not well understood. Using whole-genome mRNA expression profiling, we identified autophagy as a top molecular pathway that was activated by the MET inhibitor crizotinib in drug-sensitive human gastric cancer cells, and functional studies confirmed that crizotinib increased autophagy levels in the drug sensitive cells in a concentration-dependent manner. We then used chemical and molecular approaches to inhibit autophagy in order to define its role in cell death. The clinically available inhibitor of autophagy, chloroquine, …

Modification Of Aplysia Feeding Network By L-Dopa And Dopamine-Dependent Learning, Curtis Neveu, Curtis L. Neveu

Dissertations and Theses (Open Access)

Dopamine (DA) is a ubiquitous neuromodulator of neuronal networks in the animal kingdom and has a well-established role in modulating motor behavior and encoding reward information. Although the effects of DA and DA-dependent learning at the behavioral and molecular levels are well-understood, many questions still remain concerning the effects of DA at the network level. DA-dependent learning effects on a neuronal circuit were examined by measuring the biophysical properties before and after in vitro operant conditioning (OC) of the feeding circuit of Aplysia. OC reduced the excitability of B4 and the B4-to-B51 synaptic connection, with a trend towards an …

Pharmacologic And Genetic Manipulations Of Angiotensin Signaling In Thoracic Aortic Disease Models, Andrew M. Peters

Dissertations and Theses (Open Access)

Thoracic aortic aneurysms and dissections (TAAD) are a major cause of morbidity and mortality in patients. Many different risk factors have been associated TAAD, but hypertension is the largest risk factor. Subsets of TAAD patients have identifiable syndromic genetic diseases, yet a number of genetic non-syndromic patients have been identified. Infusion of angiotensin II into mouse models causes aortic disease through inflammation and fibrosis. An angiotensin type I receptor (AT1R) blocker (ARB) or an angiotensin converting enzyme (ACE) inhibitor (ACEi) can reverse aortic pathology in some mouse models. I set out to better understand the relationship between angiotensin and TAAD …

Eliminating Mental And Physical Health Disparities Through Culturally And Linguistically Centered Integrated Healthcare, Octavio N. Martinez Jr.

Journal of Family Strengths

Since the U.S. Surgeon General’s report on mental health (1999) declared mind and body to be inseparable, integrated healthcare, bringing the body and mind back together, has been gaining significant momentum across the nation as a preferred approach to care for people with co-morbid physical health and mental health conditions. Primary care settings often are the gateway to healthcare for racial and ethnic minority populations and individuals with limited English proficiency (LEP) and, as such, it has become the portal for identifying undiagnosed or untreated behavioral health disorders. An integrated holistic philosophical approach to behavioral healthcare provides an opportunity to …

Education Program Using Non-Pharmacologic Support During Benzodiazepine Reduction In Patients With Anxiety Disorders, Kelly D. Kearney Dnp, Rn, Pmhnp-Bc, Diane Wardell Phd, Whnp-Bc

Journal of Nursing & Interprofessional Leadership in Quality & Safety

A private mental health clinic developed an initiative to aid patients with anxiety disorders to taper their use of benzodiazepines. Based on best practices, a treatment protocol was developed in which patients attended 4 sessions (1 per month) in which they combined instruction in non-pharmaceutical anti-anxiety techniques (guided imagery, mindfulness meditation, deep breathing, progressive muscle relaxation, exercise, emotional freedom) with cognitive behavioral therapy and use of selective serotonin re uptake inhibitors. Participants experienced a reduction in benzodiazepine use. This small scale initiative showed that the holistic approach to anxiety management was an effective plan to decrease the use of benzodiazepines …

Transcatheter Tricuspid Valve-In-Valve Replacement With An Edwards Sapien 3 Valve, Pranav Loyalka, Angelo Nascimbene, Benjamin Metz, Igor D Gregoric, Ajay Sundara Raman, Biswajit Kar

The Texas Heart Institute Journal

A few case reports and case series have documented the outcomes in patients with tricuspid bioprosthetic valvular degeneration who underwent transcatheter implantation of the Medtronic Melody and the Edwards Sapien XT and Sapien 3 valves. In this report, we describe the case of a 49-year-old woman with severe bioprosthetic tricuspid valvular stenosis and multiple comorbidities who underwent transcatheter tricuspid valve replacement with a Sapien 3 valve.

Unproven Stem Cell-Based Interventions: Advancing Policy Through Stakeholder Collaboration, Kirstin R W Matthews, Ana S Iltis

The Texas Heart Institute Journal

No abstract provided.

Taking What We Have And Making What We Need: Utilizing Natural Helping Support Networks To Decrease Self Directed Violence Among Adolescents Of Color., Ladrea Ingram, Vanessa Drew-Branch

Journal of Family Strengths

Previous research has linked family and community connectedness with decreased risk of self-directed violence among adolescents. Despite the strong correlation between social connectedness and lowered risk of self-directed violence, very few interventions use social connections as mediators. This article identifies the risk and protective factors associated with self-directed violence among adolescents of color. In alignment with Healthy People 2020, this paper highlights the social determinants of self-directed violence including factors associated with individual’s social and physical environments. The authors provide an interdisciplinary review of current trends and historical data on self-directed violence in adolescents of color. The researchers suggest, the …

Predictors Of Obesity In African American College Students, Christiana Chinenye Osuagwu

Journal of Family Strengths

Abstract

Introduction: Obesity is the second highest cause of death in the United States due to its numerous co-morbidities, and data reveal that African Americans are at greatest risk for this disease. The study explored the multiple factors that predict obesity in the African American college students.

Method: Using a hybrid of the PRECEDE-PROCEED and the vital renewal models, a mixed methods study design that included 142 male and female African American college students was conducted. A Likert-scaled survey for the quantitative phase and a focus group interview for the qualitative arm were utilized. Constructs of attitude, culture, environment, …

A Novel Bioinformatic Approach To Understanding Addiction, Latifa F. Jackson

Journal of Family Strengths

Finding the genetic markers that influence complex, multigenic substance addiction phenotypes has been an area of significant medical study. Understanding complex disease traits like addiction has been hampered by the lack of functional insights into novel variants to the human genome. We hypothesized that gene location plays a role in functional genomic neighborhoods.

To test whether there is a relationship between opiate, dopamine, and GABA disease and population allele frequencies, we used genes obtained from addiction literature curated by the National Center for Biotechnology Information (NCBI). These addiction and metabolism focused search terms generated opiate, dopamine, and GABA addiction results …

Geospatial Distribution And Population Substructure Of Subgroups Of Us Ethnic Minorities: Implications For Perpetuation Of Health Disparities And Paucity Of Precision Medicine, Hasan Jackson, Fatimah L.C. Jackson

Journal of Family Strengths

Substructure due to familial-associated divisions exists in all large populations. Geographical heterogeneity in US ethnic minorities is a function of historical, social, political, and economic factors overlaying regional geographical biodiversity. Using geospatial, historical, demographic, genetic, and epidemiological databases, we identify 40 US microethnic isolates across the US, the “minorities within ethnic minorities” and locate their geospatial distributions within the US. Key components of the environment relevant to health disparities are identified and elaborated in terms of their impact on genomics. US ethnic minority microethnic isolates often have distinct genetic and social histories from the US ethnic majority that put these …

Cyclin B1 Mediates The Effect Of Uchl1 In Promoting Cell Cycle Progression In Uterine Papillary Serous Carcinoma, Suet Ying Kwan

Dissertations and Theses (Open Access)

Uterine papillary serous carcinoma (UPSC) is an aggressive form of endometrial cancer with poor survival rates and a high risk of recurrence. The rarity of UPSC poses challenges to the discovery of novel targeted therapies. Therefore, the purpose of this dissertation was to identify novel therapeutic targets that could aid in the management of UPSC. To do so, we began with the relatively large cohort of UPSC cases in the TCGA data set, which was used to identify differentially expressed genes between UPSC and low-grade endometrioid endometrial carcinoma (EEC) and normal tissue.

We identified Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1 …

Phopsphorylation And Ubiquitin Modification At Dna Damage Sites In Response To Double-Strand Breaks, Atanu Paul

Dissertations and Theses (Open Access)

Genomes of all organisms are continuously damaged by numerous exogenous and endogenous sources leading to different kinds of DNA lesions, which if not repaired efficiently may trigger wide-scale genomic instability, a hallmark of cancer development. To overcome this, cells have evolved a sophisticated sensory network called the DNA damage response (DDR) comprised of a large number of distinct protein complexes categorized as sensor, mediator, transducer and effector proteins that amplify the DNA damage signal and activate cell cycle checkpoint to initiate DNA repair or trigger apoptosis where the defect is beyond repair. This intricate signaling pathway is tightly regulated by …

Visualizing The Dynamics Of Immune Surveillance In Brain Tumors By Intravital Multiphoton Microscopy, Felix Nwajei

Dissertations and Theses (Open Access)

Visualizing the dynamics of immune surveillance in brain tumors by intravital multiphoton microscopy

By

Felix I. Nwajei, MD

Supervisory Professor: Tomasz Zal, Ph.D.

Brain tumors (BTs) generally have a bad prognosis despite conventional treatment strategies. Immunotherapy is a relatively novel treatment approach that has shown benefit for durable treatment of melanoma, and is a promising candidate for different tumor types including BTs. Immunotherapeutic strategies work by exploiting and/or enhancing natural anti-tumor immune response, a process that is critically dependent on adaptive immunity, T cell infiltration and surveillance of tumor. However, little is known about the dynamics and regulation of T …

Parp Inhibitor Upregulates Pd-L1 Expression And Enhances Cancer-Associated Immunosuppression, Shiping Jiao

Dissertations and Theses (Open Access)

With recent approvals for therapeutic antibodies that block CTLA4, PD-1 and PD-L1, immune checkpoints have emerged as new targets in cancer therapy. In addition, there is accumulating evidence highlighting the role of cancer-associated immunity in patient response to cytotoxic anticancer agents. Inhibitors of poly (ADP-ribose) polymerase (PARP) have shown substantial cytotoxic effects against tumors with defects in DNA damage responses. However, whether a crosstalk between PARP inhibition and immune checkpoints exists remains unclear. Here, it has been shown that PARP inhibitors (PARPis) upregulate PD-L1 expression in multiple cancer cell lines, human xenograft tumors, and syngeneic mouse tumors. Mechanistically, PARPi inactivates …