Medicine and Health Sciences Commons^™

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 …

Forecasting Longitudinal Changes In Oropharyngeal Tumor Volume, Position, And Morphology During Image-Guided Radiation Therapy, Adam D. Yock

Dissertations and Theses (Open Access)

The purpose of this work was to generate, evaluate, and compare models that predict longitudinal changes in oropharyngeal tumor volume, position, and morphology during radiation therapy.

One volume, one position, and two morphology (size, shape, and position) feature vectors were used to describe 35 oropharyngeal gross tumor volumes (GTVs) during radiation therapy. The two morphology feature vectors comprised the coordinates of the GTV centroids and one of two shape descriptors. One shape descriptor was based on radial distances between the GTV centroid and 614 surface landmarks. The other was based on a spherical harmonic decomposition of these distances. For a …

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 …

Activating The 4-1bb Pathway For The Expansion Of Tumor-Infiltrating Lymphocytes For Adoptive T-Cell Therapy For Metastatic Melanoma Patients, Jessica Ann Chacon

Dissertations and Theses (Open Access)

This dissertation project focused on improving the quality of the tumor-infiltrating lymphocytes (TIL) used in Adoptive T-cell therapy by understanding the role of 4-1BB/CD137 co-stimulation during the expansion of the tumor-infiltrating lymphocytes (TIL). Adoptive T-cell therapy using TIL is a promising therapy for late stage melanoma patients, resulting in a 50% response rate and durable long-term survival in over 20% of patients. Current research is aiming at improving the quality of the expanded cells and their persistence in vivo after adoptive transfer to further boost response rates. The specific focus of this dissertation project is the testing of agonistic anti-4-1BB …

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 …

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 …

Performance Evaluation Of Material Decomposition Using Rapid Kvp-Switching Dual-Energy Ct For Assessing Bone Mineral Density, John M. Wait

Dissertations and Theses (Open Access)

Osteoporosis is diagnosed by assessing the bone mineral density (BMD) of the trabecular bone, and has previously been characterized with dual-energy x-ray absorptiometry (DXA) or single-energy computed tomography (SECT). Dual-energy computed tomography (DECT) is able to create two three-dimensional sets of images representing the densities of two materials in a given basis pair. DECT is theoretically capable of providing a true density measurement of trabecular bone material with the proper material basis pair.

Using the rapid kVp-switching GE HD750 scanner, the concentrations of various solutes were assessed in two-material syringe-phantoms in different experimental conditions with DECT material density images, SECT …

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 …

Support Desired By Women Following Termination Of Pregnancy For A Fetal Anomaly, Aarti Ramdaney

Dissertations and Theses (Open Access)

With the rapidly evolving field of prenatal testing, there is a growing need to provide support for women pursuing a termination of pregnancy following the discovery of a fetal anomaly. Previous studies have documented that women in this situation often feel unsupported after the procedure, but the type of resources desired by this population remains undetermined. A longitudinal study was performed in 51 women terminating for a fetal anomaly at a private clinic at the time of the procedure, at 6 weeks, and at 3 months following the event. Surveys were kept anonymous and investigated the awareness and utilization of …

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 …

Diabetes And Obesity Induce Transcriptomic And Metabolomic Changes Enhancing Pancreatic Cancer Aggressiveness, Guermarie Velázquez Torres

Dissertations and Theses (Open Access)

Pancreatic cancer is one of the most aggressive types of cancer, with poor prognosis that lacks effective diagnostic markers and therapies. It is expected that in 2014 the incidence and the mortality of pancreatic cancer in the United States will be 46,420 and 39,590 respectively. Diabetes and obesity are modifiable risk factors associated with accelerated pancreatic carcinogenesis and tumor progression, but the biological mechanisms are not completely understood. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating these epidemiologic phenomena. Our hypothesis is that obesity and diabetes mellitus type 2 (DM2) accelerate pancreatic cancer and …

Evaluation Of Current Clinical Criteria For Li-Fraumeni Syndrome In A Diverse Sample Of Tp53 Mutation Carriers, Emily A. Parham

Dissertations and Theses (Open Access)

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by heterozyogous germline mutations in the TP53 gene and characterized by an excess of early-onset cancers, high lifetime risk of cancer, and a wide range of tumor types. Recent studies suggesting a benefit in comprehensive screening protocols for both children and adults make the timely identification of individuals with LFS increasingly important.

A number of criteria have been proposed to identify patients with LFS. The National Comprehensive Cancer Network (NCCN) combines several in its Clinical Practice Guidelines for TP53 genetic testing. Prior studies have shown that the cumulative sensitivity of …

Car-Modified T Cells Capable Of Distinguishing Normal Cells From Malignant Cells, Hillary G. Caruso

Dissertations and Theses (Open Access)

T cells can be redirected to target tumor-associated antigen (TAA) by genetic modification to express a chimeric antigen receptor (CAR), which fuses the specificity derived from an antibody to T-cell activation domains to result in lysis of TAA-expressing cells. Due to the potential for on-target, off-tissue toxicity, CAR⁺ T-cell therapy is currently limited to unique or lineage-restricted TAAs. Glioblastoma, a grade IV brain malignancy, overexpresses epidermal growth factor receptor (EGFR) in 40-50% of patients. EGFR also has widespread normal tissue expression. To target EGFR on glioblastoma while reducing the potential for normal tissue toxicity, EGFR-specific CAR generated from cetuximab, …

Cancers Associated With Brca1 And Brca2 Mutations Other Than Breast And Ovarian, Jacqueline Mersch

Dissertations and Theses (Open Access)

Mutations in BRCA1 and BRCA2 cause tumor development in Hereditary Breast and Ovarian Cancer syndrome (HBOC) through accumulation of unrepaired DNA damage. Extensive research of BRCA1 and BRCA2 mutations has led to well-defined breast and ovarian cancer risks in individuals with HBOC. Previous studies have reported additional cancers associated with BRCA mutations; however, the type of cancer, magnitude of risk, and differences between sexes remains to be clarified. Ultimately, a consensus of additional cancer risks can aid in better recommendations for genetic testing and more effective screening and prevention guidelines.

A retrospective chart review of MD Anderson Cancer Center patients …

The Regulation Of Microrna Biogenesis By Ribosome-Interacting Proteins, Brian Pickering

Dissertations and Theses (Open Access)

MicroRNA (miRNA) are small, non-coding RNAs that affect gene expression through degradation of complementary mRNA targets or inhibition of translation. As they affect approximately 50% of all cellular processes, miRNA are tightly regulated by the cell through transcriptional and post-transcriptional mechanisms. Transcribed miRNA are capped and polyadenylated (referred to as pri-miRNA) which are cleaved by Drosha and DGCR8 to generate 60-90 nucleotide precursor miRNA. The precursors are cleaved again by Dicer and loaded into the RNA-induced silencing complex (RISC) of which Argonaute 2 is the functional component. Many of the proteins involved in miRNA biogenesis share a common role in …

Proteasome Inhibition Enhances The Effect Of Bikdd Gene Therapy, Ye Sun

Dissertations and Theses (Open Access)

BikDD is a phosphorylation mimic mutant form of pro-apoptotic protein Bik, and possesses a stronger apoptosis induction capability. By constructing into a highly amplified “VISA” (VP16-GAL4-WPRE integrated systemic amplifier) system under the control of a cancer specific promoter, previous studies have verified the specific killing effect of BikDD in cancer cells both in in vitro and in vivo models. C-VISA-BikDD delivered by liposome has been approved by FDA for clinical trial in advanced pancreatic cancer. In this study, we proposed proteasome inhibition as a combinational therapy strategy with BikDD gene therapy to enhance the clinical benefits. Proteasome inhibition stabilized exogenously …

No-Independent Modulation Of Soluble Guanylyl Cyclase (Sgc) Activity And Function, George L. Britton Jr

Dissertations and Theses (Open Access)

Soluble guanylyl cyclase (sGC) plays a key role in the nitric oxide (NO) signaling pathway, where it functions as an NO receptor and generator of a secondary intracellular messenger, cGMP. In addition to NO, investigators have identified a number of proteins that interact with sGC and modulate its function. For example, the interaction of sGC with ADP-ribosylation factor GTPase activating protein 1 (AGAP1) governs sGC’s intracellular distribution and therefore mediates localized production of cGMP. Interactions of sGC with heat-shock protein 90 (HSP90) or HSP70 promote the extent of sGC activation upon NO stimulation, while interaction of sGC with the η …

Latinas And The Traditional Genetic Counseling Model: A Qualitative Study, Stephanie Thompson

Dissertations and Theses (Open Access)

The traditional genetic counseling model reflects an individualized counseling session that includes the presentation of information about genes, chromosomes, personalized risk assessment, and genetic testing and screening options. Counselors are challenged to balance providing educational information with discussion of implications of this information in an allotted amount of time. The aim of this study was to explore the perceptions of pregnant Latinas on the benefits and limitations of the traditional prenatal genetic counseling model and to determine the specific preferences for receiving prenatal genetic counseling. Data were collected through focus groups and one-on-one, semi-structured interviews of twenty-five Spanish speaking Latinas …

Regulation Of Mammary Gland Development And Tumorigenesis By 14-3-3 Zeta, Sumaiyah Rehman

Dissertations and Theses (Open Access)

Signaling pathways that play critical roles in organ development are often aberrantly regulated during cancer initiation and progression. 14-3-3z is overexpressed in more than 40% of breast cancers and is associated with poor patient prognosis. Therefore, the function of 14-3-3z in cancer and normal mammary gland development was investigated utilizing multiple in vivo and in vitro approaches. 14-3-3z is a chaperone protein that interacts with a multitude of oncogenes and tumor suppressor genes, thereby functioning as a critical node in multiple oncogenic signaling networks. Mammary gland-specific 14-3-3z transgenic mouse models showed that 14-3-3z overexpression was sufficient to induce mammary tumorigenesis. …

Contribution Of Interleukin 6 Trans Signaling In Pulmonary Fibrosis, Thuy T. Le

Dissertations and Theses (Open Access)

Idiopathic Pulmonary Fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2-3 years of diagnosis. IPF incidence and prevalence rates are increasing annually, and because the pathogenesis is unknown, there are no effective treatments available. Inhibition of interleukin 6 (IL-6) results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6 receptor alpha (mIL-6Rα), or trans signaling, mediated by soluble IL-6Rα (sIL-6Rα). Our study assessed the role of sL-6Rα in IPF. We demonstrated elevations of sIL-6Rα in IPF patients and in mice …