Medicine and Health Sciences Commons^™

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

Dissertations and 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 …

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

Dissertations and 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 and 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 …

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

Dissertations and 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 …

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

Dissertations and 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 …

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

Dissertations and 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 …

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

Dissertations and 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 …

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

Dissertations and 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 …

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

Dissertations and 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 …

Targeting Sequence And Function-Dependence Of Subcellular Localization Of Transient Receptor Potential Mucolipin Channels And Characterization Of Engineered Molecule Probes For Detecting Lysosomal Calcium Release, Jian Xiong

Dissertations and Theses (Open Access)

Both TRPML1 and TRPML3 are members of the mucolipin subfamily of Transient Receptor Potential (TRP) channels. They have been implicated in endolysosomal functions such as divalent cation release, luminal pH regulation, autophagy and vesicle trafficking. Interestingly, whereas TRPML1 is almost extensively localized in lysosomes, TRPML3 is typically found in both lysosomes and the plasma membrane (PM). It has been shown that TRPML3 localization depends on TRPML1, but the mechanism remains unknown. Recently, a number of TRPML1 mutants have been reported to be either retained in the endoplasmic reticulum (ER) or preferentially targeted to the PM. Coexpressing these mutants with either …

Discovery And Elucidation Of The Fgfr3-Tacc3 Recurrent Fusion In Glioblastoma, Brittany C. Parker Kerrigan

Dissertations and Theses (Open Access)

Fusion genes occur due to chromosomal instability where two previously separate genes rearrange and fuse together, forming a hybrid gene. The first fusions were reported in leukemias; however, with the advent of more powerful sequencing technologies, fusions have recently been reported in several solid tumors. Using next-generation deep sequencing approaches, we discovered a fusion gene connecting the fibroblast growth factor receptor 3 (FGFR3) gene to the transforming coiled-coil containing protein 3 (TACC3) gene in glioblastoma multiforme. The fusion occurred in 8.3% of patient samples, but not in low grade or normal samples. FGFR3-TACC3 produced an in-frame …

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

Dissertations and 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 …

Stochastic Data Assimilation Approaches For Magnetic Resonance Temperature Imaging, Joshua P. Yung

Dissertations and Theses (Open Access)

During magnetic resonance (MR)-guided thermal therapies, proton resonance frequency shift (PRFS) based MR temperature imaging can quantitatively monitor tissue temperature changes. It is widely known that the PRFS technique is easily perturbed by tissue motion, tissue susceptibility changes, magnetic field drift, and modality–dependent applicator induced artifacts. Due to recent advances in computational algorithms and hardware, much more powerful statistical analysis methods are becoming realizable in the real-time processing environment. To this end, my dissertation research focused on the development, validation, and implementation of stochastic data-driven processing techniques to increase the robustness of MR temperature monitoring during thermal therapies. MR temperature …

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

Dissertations and 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. …

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

Dissertations and 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 …

Integrating Domain Knowledge To Improve Signal Detection From Electronic Health Records For Pharmacovigilance, Ning Shang

Dissertations and Theses (Open Access)

The intent of this dissertation is to make a contribution to the field of pharmacovigilance. Pharmacovigilance, also known as post-marketing drug surveillance, is the process of continued monitoring for adverse drug reactions (ADRs) after drugs are released into the market. An ADR is a harmful or unpleasant reaction related to the use of a medical product. ADRs were reported to be between the fourth and sixth leading cause of death in the United States in 1994, accounting for 3-7% of medical hospital admissions. On account of the practice of pharmacovigilance, Vioxx (Rofecoxib) and Avandia (Rosiglitazone) are examples of high profile …

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 …

How Do Black Nulliparous Women Cognitively Construct Birth?, Marianne F. Moore

Dissertations and Theses (Open Access)

A focused ethnography was conducted to determine the cognitive constructions about birth described by nulliparous Black women in an urban area of the Southwestern US; also, during postpartum, how do these women reconcile expectations with the actual birth? Semi-structured interviews were conducted before birth and after birth.

Women, 16 or older, 17 - 33 weeks carrying a singleton fetus and without anomalies or problems like pre-gestational diabetes, NYHA Cardiac Class III/IV, cancer, renal failure, or sickle cell anemia that eliminated vaginal birth were sequentially recruited and sampled in an affiliated ultrasound clinic. Women scheduled for an anatomy scan were approached. …

Understanding The "Big Picture": End-Of-Life Decisions In The Picu, Amy J. Howells

Dissertations and Theses (Open Access)

Objective: Describe critical care providers' cognitive constructions or their interpretation of the process of decision-making that influences both the technique of conversations and the recommendations given to parents regarding limitation or withdrawal of life sustaining treatments from terminally ill children in the PICU. Design: Qualitative Medical Ethnography. Setting: Tertiary care children's hospital affiliated with a college of medicine. Participants: Eleven critical care providers in the department of pediatrics (attending physicians, critical care fellows, pediatric nurse practitioners, physician assistants). Interventions: In depth, semi-structured interviews designed to explore the experiences of providers in the participation of end-of-life care decision-making. Measurements and Main …

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 …

Evaluation Of Artifacts In Experimental Cine 4d Ct Acquisition Methods, Sarah Joy

Dissertations and Theses (Open Access)

Four-dimensional computed tomography (4D CT) has increased the accuracy of radiation treatment planning for patients in whom the extent of target motion is large. 4D CT has become a standard of care for radiation treatment simulation, allowing decreased motion artifacts and increased spatiotemporal localization of anatomical structures that move. However, motion artifacts may still remain. These artifacts, or artificial anatomic spatial distributions, add a systematic uncertainty to the treatment process and limit the accuracy of lung function images derived from CT. We proposed to reduce the motion artifacts in cine 4D CT by using three novel investigational 4D CT acquisition …

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 …

Combination Therapy With Aerosol Il-2 And Nk Cells For The Treatment Of Osteosarcoma Lung Metastasis, Sergei R. Guma

Dissertations and Theses (Open Access)

The survival of patients with osteosarcoma lung metastases has not improved in the last 20 years. Novel alternative therapies are needed. The purpose of this investigation was to evaluate the efficacy of combining natural killer [NK] cell therapy with aerosol interleukin-2 [IL-2] for the treatment of osteosarcoma lung metastasis. The expression of NKG2D ligands was analyzed in five different human osteosarcoma cell lines and 103 patient samples (47 from primary tumors and 56 from lung metastases). We discovered that osteosarcoma expresses the ligands for the NKG2D. In vitro studies demonstrated that NK-mediated killing of osteosarcoma cells is dependent on the …

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 …

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 …