Digital Commons Network^™

Factors Associated With Physical Activity In Kindergarten Children, Carol Hammonds

Dissertations and Theses (Open Access)

Background: Reversing obesity is an urgent public health need for children: worldwide, in 2011 more than 40 million children under the age of five were either overweight or obese. Increasing intensity and duration of physical activity is a strategy to aid in preventing and reducing obesity. A minimum of 60 minutes per day of moderate to vigorous physical activity is recommended for children. School settings, such as full-day kindergarten, where 74% of children in the United States are enrolled, provide opportunities for population-based interventions to increase physical activity, yet little objective data exist on current levels of physical activity in …

Modulated Functions Of The Fanconi Anemia Core Complex, Yaling Huang

Dissertations and Theses (Open Access)

Cells derived from Fanconi anemia (FA) patients are characterized by hypersensitivity to DNA interstrand crosslinks (ICLs), suggesting that FA genes play a role in ICL repair. Fanconi anemia core complex (including A, B, C, E, F, G, L, FAAP20, and FAAP100) activates the Fanconi pathway by providing the essential E3 ligase activity for FANCD2 mono-ubiquitination. Previous studies suggested the existence of three protein-protein interaction groups. However, the functions of most FA core complex protein are still limited to their presence in the complex. How the spatially-defined FANCD2 ubiquitination is accomplished by the core complex remains unknown.

To elucidate the roles …

Investigating The Role Of Exosomal Communication In The Glioma Microenvironment, Javier Figueroa

Dissertations and Theses (Open Access)

Evidence indicates that human cancers are maintained by a population of cells with stem-like properties called cancer stem cells (CSCs). However, the influence of the surrounding stromal cells on the behavior of the CSCs remains poorly understood. We have recently shown that the micro-environment of human gliomas, the most aggressive human brain tumors, contains both glioma stem cells (GSCs) and cells that resemble human bone marrow-derived mesenchymal stem cells (BM-MSCs), called Glioma Associated-MSCs (GA-MSCs). We have also shown that GA-MSCs generate a cytokine-mediated increase in the growth and self-renewal (clonogenicity) of GSCs. However, other paracrine interactions between GA-MSCs and GSCs …

Targeting Breast Cancer With Bacteriophage Associated Silicon Particles, Srimeenakshi Srinivasan

Dissertations and Theses (Open Access)

Nanoparticle based therapeutics have been successfully used in the treatment of breast cancer. Development of nanovectors targeted to cancer cells or elements in the tumor microenvironment has been pursued to improve their site specific accumulation while reducing the non-specific delivery to normal tissues. However, addition of targeting ligands to the surface of nanovectors while maintaining their payload carrying potential is generally challenging. Therefore, there is a critical need to develop surface decoration strategies that allow for effective combination of targeting and payload delivery to the tumor.

In this study, we propose a novel strategy for covering the surface of mesoporous …

Availability Of Dental Anomaly Phenotype In Individuals With Familial Adenomatous Polyposis, Andrea M. Lewis

Dissertations and Theses (Open Access)

Background: Mutations in the APC gene cause familial adenomatous polyposis (FAP), an autosomal dominant colorectal cancer predisposition associated with the development of hundreds to thousands of adenomatous colorectal polyps beginning in childhood or adolescence. Both malignant and non-malignant extracolonic manifestations are associated with APC gene mutations, including approximately 17% of individuals with various dental anomalies. The availability of dental anomaly information in the medical record remains to be evaluated.

Methods: Medical records were reviewed for documentation of dental anomalies. Dental questionnaires were mailed to 271 individuals with FAP at The University of Texas M. D. Anderson Cancer Center (UTMDACC) to …

Natural And Exogenous Genome Editing In Wiskott-Aldrich Syndrome Patient Cells, Tamara J. Laskowski

Dissertations and Theses (Open Access)

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease characterized by thrombocytopenia, recurrent infections and increased autoimmunity. This disease is caused by mutations in the WAS gene (WAS) which encodes for the WAS protein (WASp), exclusively expressed in hematopoietic cells and required for proper platelet production and lymphoid cell function. Approximately 11% of patients with WAS exhibit a phenomenon called Somatic Revertant Mosaicism which is characterized by the presence of lymphocytes which naturally revert back to normal phenotype by restoring WASp expression. To date, the mechanisms of this naturally-occurring gene therapy remains poorly understood, and the full extent …

Functional Analysis Of Cytosolic Hsp70 Nucleotide Exchange Factor Networks In Yeast, Jennifer Lynn Abrams

Dissertations and Theses (Open Access)

The Hsp70 class of molecular chaperones play critical roles in protein homeostasis via an ATP-dependent folding cycle. Cytosolic Hsp70s in the budding yeast Saccharomyces cerevisiae, Ssa and Ssb, interact with up to three distinct nucleotide exchange factors (NEFs) homologous to human counterparts; Sse1/Sse2/HSP110, Fes1/HspBP1, and Snl1/Bag1. In an effort to understand the differential functional contributions of the cytosolic NEFs to protein homeostasis (“proteostasis”), I carried out comparative genetic, biochemical and cell biological analyses. For these studies, I developed protocols to monitor protein disaggregation and reactivation in a near real-time coupled assay that revealed the importance of aggregate dynamics in the …

Tethered Il-15 To Augment The Therapeutic Potential Of T Cells Expressing Chimeric Antigen Receptor: Maintaining Memory Potential, Persistence, And Antitumor Activity, Lenka Hurton

Dissertations and Theses (Open Access)

Tethered IL-15 to augment the therapeutic potential of T cells expressing chimeric antigen receptor: Maintaining memory potential, persistence, and antitumor activity

Adoptive immunotherapy can retarget T cells to CD19, a tumor-associated antigen (TAA) expressed on B-cell malignancies, by the expression of a chimeric antigen receptor (CAR). Infusion of CAR-modified T cells for the treatment B-cell malignancies has demonstrated promise in preclinical and clinical trials. These data highlight the ability of infused CD19-specific T cells to be synchronously activated by large burdens of CD19⁺ leukemia and lymphoma. This can lead to dramatic antitumor effects, but also exposes the recipient to …

Differential Regulation Of Iress In The Aurora A Mrna By Bfgf Through The Mtor Complex To Rc2 Modulates Aurora A Kinase Expression, Roy L. Voice Iii

Dissertations and Theses (Open Access)

Identifying the mechanisms that contribute to tumorigenesis is a major area of focus in our fight against cancer. Epithelial malignant tumors, such as breast, colon, ovarian and pancreatic cancers have been shown to overexpress proteins that control cell mitosis, growth, and proliferation. One of those proteins is the Aurora A kinase. Aurora A kinase is a member of a small family of kinases that contribute to mitotic events such as centrosome duplication, separation, and maturation. Aurora A overexpression leads to genomic instability, which can contribute to tumorigenesis, on the other hand, inhibiting Aurora A expression leads to apoptosis, making it …

Competition Between Grb2 And Plcγ1 For Binding To Fgfr2 Regulates Phospholipase And Pten Activity, Leading To Cell Invasion And Proliferation, Zahra Timsah

Dissertations and Theses (Open Access)

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Fluctuations in the relative concentrations of proteins in non-stimulated cells can lead to aberrant signaling. In a novel interaction, the SH3 domain of Plcγ1 competes with the SH3 domain of Grb2 for binding to FGFR2 in a concentration-dependent manner. Consequently, reduction of cellular concentrations of Grb2 lead to receptor-dependent recruitment of unphosphorylated Plcγ1. Bringing of the phospholipase to the membrane in this way …

Mechanisms Underlying Distinct Egfr Versus Fgfr-3 And -1 Dependency In Human Bladder Cancer Cells, Tiewei Cheng

Dissertations and Theses (Open Access)

The epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) are activated by gene amplification, mutation and overexpression in bladder cancer, which drives tumor development and progression. Both EGFR and FGFR inhibitors are currently being tested in clinical trials. However, bladder cancer (BC) cells show remarkably heterogeneous sensitivities to both inhibitors, and the molecular determinants of this heterogeneity are presently unclear. Therefore, in this study, using selective EGFR and FGFR inhibitors in BC cells, we demonstrated that FGFR3 and FGFR1 play largely non-overlapping roles in mediating proliferation and invasion in the distinct “epithelial” and “mesenchymal” subsets of human …

Gain-Of-Function Mouse Models To Investigate Biological Roles Of Prmt6, Alessandra Di Lorenzo

Dissertations and Theses (Open Access)

Gain-of-function Mouse Models to Investigate Biological Roles of PRMT6

Alessandra Di Lorenzo, Ph.D. Candidate

Mentor: Dr. Mark T. Bedford

Protein Arginine Methyltransferase 6 (PRMT6) is the histone tail writer that methylates the H3R2 (arginine 2 of histone H3) residue, which counteracts the activating H3K4me3 mark. PRMT6 has been shown to behave both as transcriptional co-repressor (i.e. trhrombospondin-1, p21, p53), and co-activator (nuclear receptors). The co-repressor function of PRMT6 is likely the result of H3K4me3 antagonism, while the mechanism by which PRMT6 exerts its co-activator function has yet to be elucidated. PRMT6 is over-expressed in several types of tumors including small …

The Association Between The Il-1 Pathway, Isaac C. Wun

Dissertations and Theses (Open Access)

Cutaneous malignant melanoma (CMM) is a potentially lethal malignancy that warrants attention and further research, as it is known to that there is an increasing rate of incidence in theUnited States, and it is also known that exposure to UV light is its most crucial risk factor, and family history of melanoma is also an important risk factor. Melanoma is an aggressive and lethal cancer in humans. There are an estimated new 132,000 melanoma cases annually worldwide, and the trend has doubled in the past 20 years. However, attempts to treat melanoma have encountered considerable resistance and remained ineffective. The …

Development Of A Multi-Purpose Automated Synthesis Module For Production Of Novel Pet Radiopharmaceuticals, I Hong Shih

Dissertations and Theses (Open Access)

Among radiopharmaceuticals of positron emission tomography (PET), ¹⁸F-Fluorodeoxyglucose (¹⁸F-FDG) made from commercialized automated synthesis module is the most frequently used in tumor diagnoses. But the false positive findings, such as infectious tissues and post-operative surgical conditions, show strong uptake of ¹⁸F-FDG in PET scans which requires extra clinical procedures to confirm the results. Moreover, the false negative findings, such as low glycolytic activity tumors, reduce the accuracy of PET scans. Therefore, there will be new PET radiopharmaceuticals to redeem the defects of ¹⁸FDG-PET applications.

Current commercialized automated synthesis modules are suitable for clinical use, but …

Systematic Methodology For The Identification Of A Novel Autosomal Dominant Retinitis Pigmentosa Disease-Causing Gene, Jennifer D. Churchill

Dissertations and Theses (Open Access)

Retinitis pigmentosa (RP) is an inherited retinal disease that leads to degeneration of the retina through loss of rod and cone photoreceptor cells and subsequent loss of vision. RP affects approximately 1.5 million people world-wide. Mutations causing autosomal dominant retinitis pigmentosa (adRP) have been identified in 23 different genes. However, these mutations only account for approximately 70% of known adRP cases in Caucasians of Western-European origin and for an even smaller percentage of cases in other ethnicities. My research aims to increase the number of known genes associated with adRP by using an array of advanced genetic techniques to search …

The Novel Upstream Regulator Of Fbxw7, Ji-Hyun Shin

Dissertations and Theses (Open Access)

SCF^FBXW7 is a tumor suppressor E3 ligase protein that targets numerous oncoproteins such as Cyclin E, c-Myc, c-Jun and MCL1. The deregulation of these proteins often leads to the proliferation of cancer cells. Thus, intracellular stability and functional activity of FBXW7 is critical for regulating cancer. However, there is a gap of knowledge about the intracellular signaling pathway or if there is another ubiquitin ligase that regulates FBXW7 stability. Here, I identify a novel mechanism of FBXW7 stability regulation which involves constitutive photomorphogenic 1 (COP1), AKT and CSN6 (i.e. the COP9 signalosome 6).

COP1 is an E3 ubiquitin ligase …

Use Of Positron Emission To Mography For Proton Therapy Verification, Jongmin Cho

Dissertations and Theses (Open Access)

Positron emission tomography (PET), a tool commonly used for cancer staging and response monitoring, has recently been used for proton therapy verification. By imaging tissue activation following proton treatment, attempts have been made to verify proton dose and range. In this dissertation, two novel approaches were developed and tested for the purpose of help improve the proton dose and range estimation as well as verification.

Although there are still some challenges, attempts for proton dose verification using PET has been made by comparing Monte Carlo dose and PET simulations with treatment planned dose and measured PET. In this approach, …

Imbalance Between Neutrophil Elastase And Elafin Promotes Breast Cancer Growth And Progression, Joseph Anthony Caruso

Dissertations and Theses (Open Access)

Elafin, an endogenous serine protease inhibitor, is a critical component of the epithelial barrier against neutrophil elastase (NE) activity. The central hypothesis examined in this dissertation was that elafin has tumor suppressive properties in breast cancer. In support of this hypothesis, immunohistochemical (IHC) analysis revealed that elafin was downregulated in the majority of invasive breast tumors and a subset of pre-invasive ductal carcinoma in situ (DCIS) compared to elafin expression in the normal mammary epithelium. To understand the role of elafin in the mammary epithelium and the impetus for its downregulation during breast tumorigenesis, primary and immortalized human mammary epithelial …

Structure Based Prediction Of Drug-Protein Interactions At Allosteric Sites: To Wards Direct Inhibition Of The Ras Oncogene, Harrison Hocker

Dissertations and Theses (Open Access)

Ras is a monomeric G-protein that mediates multiple signaling pathways. When bound to GTP, Ras binds to and activates effectors and when bound to GDP it does not. Somatic mutations occur in ~15% of all human cancers and cause Ras to be predominantly bound to GTP. Recently, several studies revealed that Ras exists in an ensemble of at least two states when bound to GTP. In the state 1 conformation, Ras is unable to properly bind effectors but holds potential for binding ligands. Conversely, at allosteric sites, state 2 conformations readily bind effectors but not ligands.

To incorporate the flexibility …

Anti-Gd2 Etoposide-Loaded Immunoliposomes For The Treatment Of Gd2 Positive Tumors, Brandon S. Brown

Dissertations and Theses (Open Access)

Systemic chemotherapeutics remain the standard of care for most malignancies even though they frequently suffer from narrow therapeutic index, poor serum solubility, and off-target effects. Monoclonal antibodies that specifically bind antigens overexpressed on many tumors such as the ganglioside, GD2, can be conjugated to drug-loaded liposomes to create a targeted drug delivery system. In this study, we have encapsulated etoposide, a topoisomerase inhibitor effective against a wide range of cancers, in surface modified liposomes decorated with anti-GD2 antibodies. We characterized the properties of the liposomes using a variety of methods including dynamic light scattering, electron microscopy, and Fourier transformed infrared …

Image-Guided Proton Therapy For Online Dose-Evaluation And Adaptive Planning, Joey P. Cheung

Dissertations and Theses (Open Access)

The main advantage for using protons in radiotherapy is their finite range in patients, allowing for potential improved sparing of normal tissues. However, this comes at a cost of increased sensitivity to range uncertainties. Density changes along the beam path will affect the proton range and the resultant dose distribution, making it difficult to estimate the impact of visible anatomic changes to the patient dose distribution. In order to better understand the effect of anatomy change on proton dose, some form of treatment-time verification is required and methods to correct for observed changes would be beneficial. Therefore, this project aims …

Bioactivity And Cell-Mediated Targeting Of Multistage Nanoporous Silicon Particles, Jonathan O. Martinez

Dissertations and Theses (Open Access)

Progress in drug delivery approaches have not adequately translated into clinical advances in the diagnosis or treatment of inflammatory disorders (e.g., cancer). This disconnect is rooted in the inefficient delivery of imaging and therapeutic agents to the inflamed site upon systemic delivery. A multitude of biological barriers pose insurmountable obstacles limiting the ability of the agent to effectively reach and accumulate at the target site. Nanoparticles (NP) surfaced as potential vectors to encapsulate and deliver biological agents. However, even after surface decoration, NP have failed to evade biological barriers (i.e., MPS) and to accumulate at the tumor site at therapeutic …

Methodological Development Of A Multi-Parametric Quantitative Imaging Biomarker Framework For Assessing Treatment Response With Mri, Ryan J. Bosca

Dissertations and Theses (Open Access)

Quantitative imaging biomarkers (QIBs) are increasingly being incorporated into early phase clinical trials as a means of non-invasively assessing the spatially heterogeneous treatment response to anticancer therapies, particularly as indicators for early response. MR QIBs are derived from the analysis of in vivo imaging data, such as that acquired via dynamic contrast enhanced (DCE), dynamic susceptibility enhanced (DSC), and diffusion tensor imaging (DTI). To date, preclinical and clinical applications of such QIBs have provided strong evidence for potential efficacy, but efforts to create meaningful estimates of localized treatment response using multiple QIBs have been stifled by the need for rigorous …

Eye-Tracking Measures Of Attentional Bias In Cocaine Dependent Subjects, Nadeeka Dias

Dissertations and Theses (Open Access)

Cocaine-dependent (CD) subjects show evidence of attentional bias toward cocaine-related cues, and this measure of cue-reactivity is predictive of craving and relapse. In previous work, cue-reactivity and attentional bias have been assessed by models that present drug-relevant stimuli (e.g., cocaine-specific Stroop task) and measure physiological and behavioral reactivity (e.g., heart rate, reaction times). Studies have indicated competition between the higher-order cortical processes (frontal eye-fields, DLPFC) in voluntary eye control (i.e., anti-saccades) and more reflexive saccades driven by involuntary midbrain (superior colliculus) perceptual input (i.e., pro-saccades). In addition, neuroimaging studies in patients with cocaine dependence have shown activation in frontal regions …

Role Of Talin1 Phosphorylation In Beta1 Integrin Activation And Prostate Cancer Metastasis, Jung-Kang Jin

Dissertations and Theses (Open Access)

Talins are adaptor proteins that regulate focal adhesion signaling by conjugating integrins to the cytoskeleton. Talins directly bind and activate integrins but the mechanism by which this occurs is unknown. As integrin activation and overexpression of talins promote prostate cancer metastasis, understanding the mechanism by which talins activate integrins will better elucidate their roles in Prostate cancer metastasis. Phosphorylation of talins on serine 425 has been associated with β1 integrin functions. Work in this dissertation tested the hypothesis that increased talin1 S425 phosphorylation was required for β1 integrin activation and promotion of prostate cancer metastasis.

I first used shRNA to …

Metadherin Functions As A Laminin Receptor That Is Essential For Metastasis And Is Associated With Poor Survival In Osteosarcoma, Limin Zhu

Dissertations and Theses (Open Access)

Osteosarcoma is a highly invasive bone malignancy in which metastasis accounts for the vast majority of death and morbidity in patients. Understanding the mechanisms controlling metastasis is essential for improving patient survival in this disease. In order to improve the clinical outcomes for patients with poor prognosis, it is urgent to find new therapeutic targets to block metastasis in this disease. Recent studies have shown that Metadherin (MTDH) plays an essential role in mediating tumorigenesis and metastasis in a variety of human cancers. Our study assessed the role of MTDH in osteosarcoma metastasis and elucidated the mechanisms underlying its metastasis-promoting …

Anti-Insulin Resistance Treatments Suppress Her2+ Breast Cancer Growth Via Altering Metabolism, Ping-Chieh Chou

Dissertations and Theses (Open Access)

Epidemiological studies have identified that type 2 diabetes mellitus (DM2) is a significant risk factor for carcinogenesis and cancer death, including breast cancer. Our previous finding in patients showed that anti-insulin resistance treatments are associated with improved HER2⁺ breast cancer survival of diabetic women. However, there were no transgenic mouse models to study the correlation and explain the detailed mechanism. We generated a mouse model of HER2⁺ breast cancer with DM2 by crossing leptin receptor point mutation (Lepr ^db/+) and MMTV-ErbB2 (neu) mice. The MMTV-ErbB2/Lepr ^db/db mice had a poor survival rate compared …

Phage Display Library Screening For Psa-/Lo Prostate Cancer Cell-Binding Peptides, John R. Moore

Dissertations and Theses (Open Access)

Prostate cancer (PCa) is one of the leading malignancies affecting men worldwide. Our lab focuses on understanding the molecular mechanisms underlying prostate carcinogenesis and developing therapeutics that target the cells responsible for driving PCa and mediating therapy resistance. My master thesis research employs a phage display library screening technology aiming to identify peptides that preferentially home in to undifferentiated PCa cells, which our lab has previously demonstrated to be intrinsically resistant to castration.

There is now evidence that a population of cells in PCa possesses characteristics associated with stem cells; these cells are referred to as cancer stem cells (CSCs). …

Characterization Of Ftsa-Ftsn Interaction During Escherichia Coli Cell Division, [email protected] K. Busiek

Dissertations and Theses (Open Access)

Division of a bacterial cell into two equal daughter cells requires precise assembly and constriction of the division machinery, or divisome. The Escherichia coli divisome includes nearly a dozen essential cell division proteins that assemble at midcell between segregating sister chromosomes. FtsZ, a homolog of eukaryotic tubulin, is the first essential cell division protein to localize at midcell where it polymerizes into a ring-shaped scaffold (Z ring). Establishment of the Z ring is required for recruitment of downstream cell division proteins including FtsA, a cytoplasmic protein that tethers the Z ring to the inner membrane. Following localization of FtsA and …

Cancer Diagnosis During Pregnancy: Evaluating The Challenges Faced By Oncologists, Shannon Kaye Mulligan

Dissertations and Theses (Open Access)

Cancer during pregnancy is occurring more often than in the past, and it is estimated that cancer is diagnosed in approximately 1/1000 pregnancies. A consensus exists that management of these patients should prioritize survival of the mother and minimize teratogenic effects to the fetus, and utilize a multidisciplinary approach, involving medical oncology, surgical oncology, radiation oncology, radiology, and a maternal fetal medicine specialist. In spite of this consensus, there is not a standardized approach for treating cancer in women diagnosed during pregnancy. Due to the relative infrequency of this situation in the oncologic setting, the aims of this study were …