Medicine and Health Sciences Commons^™

Implementation Of Upright Treatments For Lung And Head And Neck Cancers, Ming-Jung Hsieh

Dissertations & Theses (Open Access)

There are numerous benefits to treating patients in the upright position such as better patient comfort and increased total lung volume with reduced lung motion. The purpose of this study was to investigate the feasibility of implementing upright treatments for lung and H&N cancers. Several clinical aspects were examined, including radiation shielding for various fixed beams, collision avoidance, retrospective treatment planning, and an end-to-end test with an anthropomorphic lung phantom.

Results from the shielding study indicated that the primary barrier required an additional 10-26 cm of shielding while the secondary barrier in the beam path required an additional 2-12 cm …

The Role Of The C5a Receptor In Host Defense Against Listeria Monocytogenes, Daniel Calame

Dissertations & Theses (Open Access)

Listeria monocytogenes (Lm) is a major cause of mortality resulting from food poisoning in the United States. While the complement component C5 is known to be protective in listeriosis, it is unknown how its cleavage fragment C5a participates. Here we show in a model of systemic Lm infection that the C5a receptor is essential for host defense. C5aR-/- mice have reduced survival and increased bacterial burden in the liver and spleen in comparison to WT mice. Surprisingly, C5aR-/- mice also have a dramatic reduction in splenocyte numbers resulting from elevated cell death as indicated by TUNEL staining and caspase 3 …

Roles For B-Raf Kinase In The Specific Regulation Of Α4Β1 Integrin In T Cells, Wells S. Brown

Dissertations & Theses (Open Access)

The regulation of integrin-mediated adhesion is of vital importance to adaptive and innate immunity. Integrins are versatile proteins and mediate T cell migration and trafficking by binding to ECM or other cells, as well as initiating intracellular signaling cascades promoting survival or activation. The mitogen activated-protein kinase (MAPK) pathway is known to be downstream from integrins and regulate survival, differentiation, and motility. However, secondary roles for canonical MAPK pathway members are being discovered. We show chemical inhibition of RAF by Sorafenib or shRNA-mediated knockdown of B-Raf reduces T cell resistance to shear stress to α4β1 integrin ligands vascular cell adhesion …

Cd56-Specific T Cells: Using Genetically Engineered T Cells To Redirect Specificity To A T Cell Expressed Antigen, Denise L. Crossland

Dissertations & Theses (Open Access)

The CD56 antigen is expressed on several deadly malignancies currently lacking long-term efficacious therapies. Chimeric antigen receptor (CAR) based immunotherapies have shown both safety and efficacy and even a curative ability in clinical trials, laying the foundation for applying CARs to new targets. Using T cells to target a T cell expressed antigen, such as CD56, seems counterintuitive in that the T cells would be susceptible to self-targeting a.k.a. fratricide. However, we expand CD56-specific CAR⁺ T cells that co-express the CD56 antigen. Since other CARs targeting T cell expressed antigens are hypothesized to be undergoing fratricide, such as the …

Association Of Cardiorespiratory Fitness And Adiposity With Inflammatory Biomarkers In Young Adults, Eunduck Park

Dissertations & Theses (Open Access)

Background: Low grade systemic inflammation plays a key role in atherosclerosis, and C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor- alpha (TNF -a), markers of systemic inflammation, are associated with cardiovascular events and adiposity. Cardiorespiratory fitness has shown health benefits by reducing circulating levels of inflammatory markers. However, it remains uncertain whether the negative association between cardiorespiratory fitness and inflammatory biomarkers is due to cardiorespiratory fitness itself or results from lower levels of adiposity. Moreover, the evidence examining the interaction between cardiorespiratory fitness and adiposity in inflammation in young adults is lacking.

Purpose: The aims of this study were …

Volumetric Scintillation Dosimetry For Scanned Proton Beams, Daniel G. Robertson

Dissertations & Theses (Open Access)

Scanned beam proton therapy is a promising cancer treatment modality which is becoming more widely available with the increasing number of proton radiotherapy centers. Scanned proton beams can produce complex 3D dose distributions, presenting a challenge for adequate quality assurance testing. Because each scanned beam dose measurement requires the delivery of the entire field, multiple measurements can be time consuming. These quality assurance challenges limit the number of patients who can be treated with this modality. The overall objective of this project is to increase the safety and availability of complex proton therapy treatments by developing a fast volumetric scintillation …

Novel Serum Biomarkers For Lung Cancer Early Diagnosis And Clinical Outcome, Fanmao Zhang

Dissertations & Theses (Open Access)

The five-year survival rate for all stages of lung cancer combined is only 17%, which has changed little over the past 40 years. Despite the tremendous efforts made, serum biomarkers with clinical utility for lung cancer early detection and clinical outcome prediction are still lacking. Metabolic alterations have been recognized as an emerging hallmark of cancer. We aimed to investigate the metabolic changes associated with lung cancer and to identify novel clinically applicable serum biomarkers for lung cancer early diagnosis and clinical outcome.

Serum metabolites are potential biomarkers for lung cancer early detection. We first performed global metabolomic profiling followed …

Notch Signaling Inhibited By Ikaros1 In Human T-Cell Acute Lymphoblastic Leukemia, Camille W. Graham

Dissertations & Theses (Open Access)

The highly conserved Notch signaling pathway regulates cell growth, differentiation, survival and apoptosis. In hematopoiesis, Notch signaling drives commitment to the T-cell fate and promotes differentiation, T-cell receptor signaling and immune function. In T-cells, Notch signaling is oncogenic when constitutively active, promoting proliferation and survival while inhibiting differentiation. The majority of patients with T-cell acute lymphoblastic leukemia (TALL) have activating Notch mutations. Similarly, Notch activation is present in more than 75% of murine T-ALL models. In murine T-ALL, loss of Ikaros, a zinc finger transcriptional regulator, leads to disrupted differentiation and also cooperates with activated Notch signaling to promote T-ALL. …

The Apical Polarity Complex Protein, Pals1, Regulates Cell Fate In The Development Of Cerebellum And Neocortex, Jun Young Park

Dissertations & Theses (Open Access)

Through their biased localization and function within the cell, polarity complex proteins are necessary to establish the cellular asymmetry required for tissue organization. Well-characterized germinal zones, mitogenic signals, and cell types make the cerebellum and neocortex excellent models to address the critical function of polarity complex proteins in the generation and organization of neural tissues. Here we report a focal distribution of Pals1, a central component of the apical complex, in progenitors. Our genetic analyses revealed that Pals1 deletion in the brain developed a remarkably undersized and disrupted layer structure of cerebral cortex and cerebellum. Furthermore we demonstrated that Pals1 …

Potential Roles Of Peroxidases In Caenorhabditis Elegans Innate Immunity, George R. Tiller, George R. Tiller

Dissertations & Theses (Open Access)

The production of ROS (reactive oxygen species) in response to pathogen detection is a rapid, nonspecific response that is evolutionarily conserved from nematodes to humans. ROS serve as direct and indirect effectors of innate and adaptive immunity. In Caenorhabditis elegans, a ROS burst is observed during infection and is mediated by the dual oxidase BLI-3, which produces H₂O₂. RNAi (RNA interference) to reduce the amount of BLI-3 results in a significant increase in susceptibility to pathogens, suggesting BLI-3 has a role in the immune response. However, H₂O₂ by itself is not a …

Targeting The Redox System To Overcome Mechanisms Of Drug Resistance In Chronic Lymphocytic Leukemia, Marcia A. Ogasawara

Dissertations & Theses (Open Access)

Chronic Lymphocytic Leukemia (CLL) is the most common form of leukemia diagnosed in Western countries and is characterized by clonal expansion of B cells. The clinical course of CLL is diverse and nearly 50% of patients present with chromosomal abnormalities. Deletion of the short arm on chromosome 17 (del17p) occurs in 5-7% of cases and presents with the shortest median survival time and often respond poorly to therapy. The tumor suppressor gene, TP53 is located on this region and it is well established that the p53 protein regulates multiple functions including: mitochondria biogenesis, response to DNA damage and redox balance. …

Development Of A New Independent Monte Carlo Dose Calculation Quality Assurance Audit Tool For Clinical Trials, Austin M. Faught

Dissertations & Theses (Open Access)

Introduction: Commercially available treatment planning systems (TPS) may use a number of different radiation dose calculation algorithms during the planning process. The Radiological Physics Center (RPC), tasked with ensuring clinically comparable and consistent dose delivery amongst institutions participating in NCI funded multi-institutional clinical trials, has traditionally relied upon measurements to achieve this objective. As a supplement to the tools used by the RPC, an independent dose calculation tool is needed to determine patient dose distributions in three dimensions so as to act as a quality assurance tool for the dose calculations.

Methods: Multiple source models representing the output of Elekta …

The Role Of Traf6 Phosphorylation In Src/Traf6-Mediated Ikk, Jnk, Akt Activation And Tumorigenesis, Yun Seong Jeong

Dissertations & Theses (Open Access)

TRAF6 E3 ligase regulates numerous essential biological processes such as innate immune response, cell survival and osteoclast differentiation. Upon activation, it mediates activation of IKK/NF-κB and JNK signaling in response to engagement of toll-like receptor 4 (TLR4), interleukin-1 receptor (IL-1R), and receptor activator of NF-κB (RANK) to their cognate ligands, including lipopolysaccharide (LPS), IL-1, and RANK ligand (RANKL). Recently, TRAF6 has also been shown to be involved in Akt signaling activation upon activation of insulin-like growth factor-1 receptor (IGF-1R), in turn orchestrating cell survival and tumorigenesis. Therefore, TRAF6 is a key player for the activation of IKK, JNK and Akt …

Pi3k- And Mtor-Dependent Mechanisms Of Lapatinib Resistance And Resulting Therapeutic Opportunities, Samuel Brady

Dissertations & Theses (Open Access)

Breast cancers with HER2 amplification represent 20-25% of breast cancer cases and are frequently responsive to the HER2 kinase inhibitor lapatinib, but generally for only short duration. We aimed to understand how breast cancers with HER2 amplification become resistant to lapatinib, in order to identify potential therapies that can overcome lapatinib resistance. To establish lapatinib resistance models we treated three HER2+ breast cancer cell lines with lapatinib for several months until they became lapatinib-resistant. We then compared lapatinib-sensitive (parental) cells with their lapatinib-resistant (LapR) counterparts to identify changes conferring lapatinib resistance. We found that activation of PI3K, specifically the p110α …

Utilizing Haplotypes For Sensitive Snp Array-Based Discovery Of Somatic Chromosomal Mutations, Selina M. Vattathil

Dissertations & Theses (Open Access)

Somatic copy-number (CN) gains and losses and copy-neutral loss of heterozygosity (CNLOH) frequently occur in tumors and play a major role in the progression of disease by altering gene dosage and unmasking deleterious recessive variants. Characterizing these mutations in an individual tumor sample is therefore critical for research on the relationship of specific mutations to disease outcome and for clinical decision-making based on mutations with known impact. A pervasive hindrance to sensitive detection of these mutations is genetic heterogeneity and high levels of contaminating normal cells in tumor samples, which limit the fraction of cells carrying informative mutations. The method …

Development And Implementation Of An Anthropomorphic Pediatric Spine Phantom For The Assessment Of Craniospinal Irradiation Procedures In Proton Therapy, Dana Lewis

Dissertations & Theses (Open Access)

Proton therapy is gaining acceptance as a cancer treatment modality, as it allows for dose deposition to the target volume while sparing the surrounding healthy tissue. This technique is advantageous for craniospinal pediatric patients, as it reduces the radiation side effects that can occur. The purpose of this study is to design an anthropomorphic pediatric spine phantom for use in the evaluation of proton therapy facilities for clinical trial participation by the Imaging and Radiation Oncology Core (IROC) Houston QA Center. It was hypothesized that the designed phantom would evaluate patient simulation, treatment planning and delivery, assuring agreement between the …

Characterization Of The New Xoft Axxent Electronic Brachytherapy Source Using Presage(Tm), Jennifer Sierra Irwin

Dissertations & Theses (Open Access)

With continuing advances in the burgeoning field of electronic brachytherapy, an accurate method of 3D dosimetry is needed to ensure understanding of dose distributions, which can improve patient care. The aim of this study was to characterize the Xoft Axxent electronic brachytherapy source using PRESAGE^TM dosimeters in order to obtain independent confirmation of TG-43U1 dosimetry values, as well as to further add to the literature of both Xoft and PRESAGE.

PRESAGE is a polyurethane-based solid 3D dosimeter doped with a radiochromic leuco dye which produces a linear change in optical density when exposed to radiation. This optical density change …

Genomic Characterization Of Polyps In Familial Adenomatous Polyposis Patients And Identification Of Candidate Chemopreventive Drugs, Francis A. San Lucas

Dissertations & Theses (Open Access)

Familial adenomatous polyposis (FAP) is an autosomal dominant disease characterized by APC germline mutations and the development of hundreds to thousands of premalignant adenomas in the gastrointestinal tract at a young age. If left untreated, these patients inevitably develop colon cancer (CRC) and small bowel tumors. We performed exome sequencing of samples from 12 FAP patients to characterize adenomas and to identify candidate genes of adenoma development that may serve as potential targets for chemoprevention drug development. From each patient, a blood and at least one polyp were sequenced with a total of 25 polyps analyzed. In some cases, normal …

The Role Of Glutamine And Mevalonate Pathway In Affecting The Stemness And Viability Of Glioblastoma Stem Cells, Naima Hammoudi

Dissertations & Theses (Open Access)

Glioblastoma (GBM) remains the deadliest form of brain tumors. The poor prognosis of glioblastoma patients is associated with a high rate of relapse after therapy. It has been suggested that the presence of cancer stem cells, which are relatively resistant to radiation and chemotherapy, may play a significant role in the recurrence of brain tumor. Understanding the biological property of glioblastoma stem cells is important to develop effective therapeutic strategies for glioblastoma. In vitro, glioblastoma stem cells cultured in serum-free medium form self-renewing neurospheres, express the neural stem marker CD133, and are highly tumorigenic. On the other hand, in the …

Role Of The Ang-Tie2 Pathway In The Invasive Recurrence Of Gbm Following Anti-Vegf Therapy, Nahir Cortes Santiago

Dissertations & Theses (Open Access)

Strong pre-clinical and clinical data supporting the effectiveness of bevacizumab, a humanized monoclonal anti-VEGF antibody, for the treatment of gliomas led to its accelerated approval for the treatment of patients with recurrent glioma. However, despite strong anti-tumor effects, upon treatment with bevacizumab, patients will invariably recur with a tumor characterized by enhanced invasiveness and resistance to therapy. This study aims to elucidate the mechanisms leading to this enhanced malignancy with the hope of uncovering new potential therapeutic targets for combined treatment. Using tissue sections from U87-derived glioma bearing mice treated with or without aflibercept (another anti-VEGF antibody) we have gathered …

Dissecting The Roles Of Trim24 In Regulation Of Hepatic Lipid Metabolism And Inflammation, Lindsey C. Minter

Dissertations & Theses (Open Access)

DISSECTING THE ROLES OF TRIM24 IN REGULATION OF HEPATIC LIPID

METABOLISM AND INFLAMMATION

Lindsey Cauthen Minter, B.S., B.A.

Advisory Professor: Michelle C. Barton, Ph.D.

In this dissertation, I report the characterization of a new mouse model that recapitulates development of hepatocellular carcinoma (HCC) following spontaneous hepatic lipid accumulation, inflammation, and damage of liver tissue, due to complete loss of Trim24 expression. In human HCC and other cancers, TRIM24 expression is aberrantly high, while deletion of TRIM24 in the mouse has been shown to act as a liver specific tumor suppressor. The hypothesis tested here was that TRIM24, the E3 ubiquitin …

Strategies To Sensitize Bladder Cancer Cells To Small Molecule Inhibitors Targeting The Pi3k Pathway, Giovanni Nitti

Dissertations & Theses (Open Access)

After many years of cancer research, it is well accepted by the scientific community that the future cure for this disease lies in a personalized therapeutic approach. Anticipating therapeutic outcome based on the genetic signature of a tumor has become the new paradigm. The PI3K pathway represents an ideal target for bladder cancer, as many of the key proteins of this pathway are altered or mutated in this particular type of cancer. Several small molecule inhibitors have been developed to target this pathway, but their efficacy has been shown to be heterogeneous among different cell lines and mostly cytostatic but …

Multiple Myeloma And Its Treatment Alter Peripheral Nervous System Structure And Function, Alyssa K. Kosturakis

Dissertations & Theses (Open Access)

MULTIPLE MYELOMA AND ITS TREATMENT ALTER PERIPHERAL NERVOUS SYSTEM STRUCTURE AND FUNCTION

Alyssa Katarina Kosturakis, BA

Supervisory Professor: Patrick M. Dougherty, PhD

Peripheral neuropathy is among the most deleterious side effects of frontline chemotherapeutics used to treat prevalent cancers. Chemotherapy-induced peripheral neuropathy (CIPN) refers to the collection of symptoms (e.g. pain, paresthesias and dysesthesias) that develop in distal, glabrous (non-hairy) skin of 20 to 100% of patients treated with chemotherapy. Peripheral neuropathy negatively impacts quality of life in cancer patients and survivors, is refractory to treatment, and is the impetus for dose-reduction and/or cessation of chemotherapy, thereby limiting treatment. Proteasome …

Mapping The Human Vasculature By In Vivo Phage Display, Julianna Bronk

Dissertations & Theses (Open Access)

In vivo phage display screenings by intravenous injection of a random phage-displayed peptide library allow for the selection of peptides that localize to specific vascular beds. At the University of Texas MD Anderson Cancer Center, we have had the opportunity to perform phage display screenings in cancer patients in order to select for cancer specific targets directly in humans. These targets serve to define biochemical diversity of endothelial cell surfaces and can be validated and explored towards the design of vascular-targeted pharmacology. In the most recent patient screen, samples were recovered from hepatocellular carcinoma (HCC) as well as 26 additional …

Mechanisms Of Astrocyte Contribution To Bortezomib-Induced Peripheral Neuropathy, Caleb R. Robinson

Dissertations & Theses (Open Access)

Bortezomib is a proteasome inhibitor used in the treatment of multiple myeloma and other non-solid malignancies, alone or in combination with other chemotherapy drugs. Like other chemotherapeutic agents, bortezomib treatment is frequently accompanied by chemotherapy-induced peripheral neuropathy (CIPN) that may be dose-limiting, adversely affecting quality of life and prognosis. The mechanisms behind bortezomib-induced peripheral neuropathy (BIPN) and CIPN overall are largely unknown. Recent findings in other pain models have indicated substantial involvement of glial cells in chronic pain. Although injury models have shown activation of both astrocytes and microglia following insult, research in other CIPN models has shown astrocytic activation …

The Oncogenic Map Kinase Signaling Pathway Modulates Mhc-I Surface Expression In Melanoma, Sherille Denae Bradley

Dissertations & Theses (Open Access)

The mitogen-activated protein kinase (MAPK) pathway is a cascade of serine-threonine kinases involved in cell growth, proliferation, and apoptosis; it is one of the most well-known pathways associated with melanoma progression. The MAPK pathway is constitutively activated in melanomas due to mutations in the signaling components, particularly the proto-oncogene BRAF ^V600E that accounts for (40-50%) of these cases. Metastatic melanoma is one of the deadliest and most aggressive forms of cancer, with a 3-year survival rate of less than 15%. Immunotherapies that utilize cytotoxic T lymphocytes (CTLs) have proven to be very effective at inducing regressions of large, bulky tumors, …

Pancreatic Ribonuclease Functions As An Epidermal Growth Factor Receptor Ligand Independently Of Its Enzyme Activity And Contributes To Cetuximab Resistance, Heng-Huan Lee

Dissertations & Theses (Open Access)

Ribonuclease (RNase) with its catalytic enzyme activity to degrade RNAs has been shown as a diagnostic serum marker for pancreatic cancer and has also been suspected to have an unidentified cell surface receptor. Epidermal growth factor receptor (EGFR), a well-characterized receptor tyrosine kinase is an effective therapeutic target in multiple cancer types. However, clinical trials targeting EGFR have not demonstrated improved therapeutic efficacy in pancreatic cancer. Here, we show that both bovine pancreatic RNase A (bRNaseA) and human RNase 5 (hRNase5) act as EGFR ligands and directly activate EGFR to promote epithelial-mesenchymal transition. This ligand-like activity is independent of RNases’ …

Targeting The Mdm2-P53 Axis For The Treatment Of Dedifferentiated Liposarcoma, Katelynn Bill

Dissertations & Theses (Open Access)

Dedifferentiated liposarcoma (DDLPS) is an aggressive malignancy characterized by a high rate of recurrence and dismal patient outcome. Minimal improvement in patient survival has been made in the last several decades, highlighting the crucial need for improved therapeutic strategies. A better understanding of the molecular deregulations underlying DDLPS would facilitate the discovery of improved therapeutic approaches. MDM2 is a well characterized oncoprotein and the most known negative regulator of p53. MDM2 amplification is considered the “hallmark” of DDLPS. Additionally, these tumors are known to harbor wild-type p53. We sought to take advantage of this knowledge and evaluate the role of …

Development Of A Molecular Gram-Stain Assay For The Diagnosis Of Blood Stream Infections Associated With Sepsis, Douglas Bryan Litwin

Dissertations & Theses (Open Access)

Sepsis is a serious medical condition resulting from the severe dysregulation of the immune response that is generally triggered by infection. It affects more than 1.1 million Americans, has an average mortality rate of 30%, and is estimated to cost $24.3 billion annually. Currently, blood culture followed by Gram-stain analysis is the gold standard for diagnosing bacterial infections associated with sepsis. This method generates a high rate of false negative results and, in general, requires 20 to 48 hr to provide results. Both of these problems are related to the requirement that the bacterial pathogens grow under defined laboratory conditions. …

Regulators Of Bacterial Cell Division: Investigations Of Min Oscillation And Ftsa Activity, Jennifer R. Herricks

Dissertations & Theses (Open Access)

Cytokinesis is a fundamental process that is essential for bacterial proliferation. The cytokinetic machinery in bacteria is termed the “divisome”. The divisome is a complex of proteins that forms a ring at midcell over dividing nucleoids. In order for daughter cells to form, the divisome must constrict. As constriction occurs, two new cell poles are formed, one for each daughter cell. The first step in divisome formation is the assembly of FtsZ into a Z ring. The work presented in this dissertation focuses on two proteins that regulate the Z ring: MinD, which is a part of the Min system …