Digital Commons Network^™

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

Dissertations and 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 To Ol For Clinical Trials, Austin M. Faught

Dissertations and 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 …

Development Of Chimeric Type Iv Secretion Systems For Transfer Of Heterologous Substrates Across The Gram-Negative Cell Envelope, Trista M. Berry

Dissertations and Theses (Open Access)

Many bacteria use Type IV Secretion Systems (T4SSs) to aid in pathogenesis by translocating virulence factors across the cell envelope and into eukaryotic cells. These systems are structurally and functionally diverse, but are often compared to the archetypal VirB/VirD4 T4SS of Agrobacterium tumefaciens. This system is composed of the VirD4 type IV coupling protein (T4CP) and 11 VirB subunits (VirB1-11) that assemble as the secretion channel and an extracellular pilus. The T4CP is an inner membrane ATPase that interacts with T4SS substrates and the secretion channel, and is thought to link substrates with the secretion channel and possibly energize …

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

Dissertations and 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 …

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

Dissertations and 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, …

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

Dissertations and 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 …

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’ …

Egfr Modulates Microrna Maturation In Response To Hypoxia Through Phosphorylation Of Argonaute2, Jia Shen

Dissertations and Theses (Open Access)

MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at posttranscriptional level. Deregulation of miRNAs has been linked to diverse pathological processes, including cancer. Recent studies have also implicated miRNAs in regulatory roles to cope with a spectrum of stresses, such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumor. However, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the question of how tumor cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here, we show that EGFR, …

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 …

Brit1/Mcph1 Mediates The Dna Damage Response By Inducing P53 Stability And Promoting Atr Signaling, Edward Wang

Dissertations and Theses (Open Access)

The BRCT-repeat inhibitor of hTERT (BRIT1)/MCPH1 protein promotes the process of homologous recombination (HR) to repair DNA double strand breaks (DSBs). In response to DSBs, BRIT1 foci form at damaged sites, and recruits downstream repair proteins including 53BP1, MDC1, NBS1, and the SWI/SNF complex to the DSB region to promote DNA repair. BRIT1 copy number deficiency correlates with increased genomic instability in ovarian cancer specimens and breast cancer cell lines. Here, we propose that additional functions of BRIT1 include a direct interaction with the p53 tumor suppressor protein to promote p53 stability, and binding and recruitment of TopBP1 to sites …

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 …

Nuclear Translocation Of Met Via Internet Mechanism, Mei-Kuang Chen

Dissertations and Theses (Open Access)

MET is one of the receptor tyrosine kinases (RTKs) that are overexpressed in malignant cancer types, including breast cancer. While RTKs are traditionally known for their roles in signaling transduction from the cell surface, recent studies have provided evidence demonstrating that most of RTKs can translocate into nucleus to regulate cellular processes in response to both ligand and stress stimulation. Oxidative stress is a common stress in cancer cells due to alteration of metabolism, and constitutive oxidative stress related to reactive oxygen species (ROS) has been observed in breast cancer cells. Here, we show that hepatocyte growth factor (HGF) as …

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 …

Angiomotin Is A Novel Cadherin-11 Interacting Protein That Mediates Migration In Prostate Cancer Cells, Angelica Ortiz

Dissertations and Theses (Open Access)

Prostate cancer (PCa), the second leading cause of cancer-related deaths among men in the United States, has the proclivity to metastasize to bone resulting in sclerotic lesions. These cancer induced bone growths cause bone pain and fractures. Therefore, understanding the molecular mechanisms contributing to PCa bone metastasis is required in order to find better prognostic tools and suitable targets for metastasis treatment and/ or prevention. Previous work in our laboratory showed increased expression of cadherin-11 (Cad11), a mesenchymal cadherin, during PCa progression. Furthermore, Cad11 expression endows PCa cells with increased migratory potential and metastasis to bone. Deletion of the Cad11 …

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 …

Energy Stress Causes Chaperones To Assemble Into Cytoplasmic Complexes, Kimberly J. Cope

Dissertations and Theses (Open Access)

The majority of proteins require molecular chaperones to assist their folding into tertiary and quaternary structures. Certain stresses can compromise the weak hydrophobic forces responsible for these structures and lead to protein unfolding, misfolding, and aggregation. Aggregates of proteins are hallmarks of devastating diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. Fortunately, bacteria, plants, and fungi have a potent disaggregase, named Hsp104 in Saccharomyces cerevisiae. Recently, heat-induced aggregates, termed Q-bodies, were found to contain three molecular chaperones: Hsp70, Hsp104, and Hsp42. Their coalescence from small puncta into larger inclusions required Hsp104. During glucose deprivation, a stress that isn’t known to …

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 …

Use Of Oversized Injectable Valves In Growing Children For Total Repair Of Right Ventricular Outflow Tract Anomalies (Preliminary Results), Luca Deorsola, Pietro Angelo Abbruzzese

The Texas Heart Institute Journal

Right ventricular outflow tract surgery was originally confined to transannular patching, in the belief that pulmonary regurgitation was well tolerated. Because follow-up evaluations revealed the deleterious effects of pulmonary regurgitation, surgery today aims to spare or replace the valve. Available replacement devices have short lifetimes, considering growth mismatch in children. We hypothesize that oversizing the right infundibulum anticipates growth and that a squeezed prosthesis can complete the expansion process.

The No-React® Injectable BioPulmonic Valve is designed for right infundibular surgery in adults, and hundreds of implants have shown promising results. We used this device for surgery in babies, with the …

Nontyphoidal Cardiac Salmonellosis: Two Case Reports And A Review Of The Literature, Daniel Ortiz, Eric M Siegal, Christopher Kramer, Bijoy K Khandheria, Ernesto Brauer

The Texas Heart Institute Journal

Nontyphoidal Salmonella, especially Salmonella enterica, is a rare cause of endocarditis and pericarditis that carries a high mortality rate. Proposed predisposing conditions include immunodeficiency states, congenital heart defects, and cardiac valve diseases. We present 2 cases of cardiovascular salmonellosis. The first case is that of a 73-year-old woman with mechanical mitral and bioprosthetic aortic valves who died from sequelae of nontyphoidal Salmonella mitral valve vegetation, aortic valve abscess, and sepsis. The second case is that of a 62-year-old man with a recent systemic lupus erythematosus exacerbation treated with oral steroids, who presented with obstructive features of tamponade and sepsis secondary …

Right Ventricular Outflow Tract Obstruction Caused By Double-Chambered Right Ventricle Presenting In Adulthood, John Kokotsakis, Efthymia G Rouska, Leanne Harling, Hutan Ashrafian, Vania Anagnostakou, Christos Charitos, Thanos Athanasiou

The Texas Heart Institute Journal

Congenital heart diseases that cause obstruction of the right ventricular outflow tract are often difficult to diagnose. We report the case of a 49-year-old man who presented with long-standing shortness of breath on exertion. Imaging revealed right ventricular outflow tract obstruction caused by a double-chambered right ventricle, and he was referred for surgical correction. This case emphasizes both the detailed perioperative evaluation that is needed when diagnosing adults who present with manifestations of congenital heart disease and a method of successful surgical correction that resulted in symptom resolution.

The In-Hospital Consultation Today: Whom Does It Best Serve?, Herbert L Fred

The Texas Heart Institute Journal

No abstract provided.