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Functions Of The Homeobox Gene Dlx4 In Controlling Inflammatory Signaling And Metastasis Of Epithelial Ovarian Cancer, Dhwani Haria

Dissertations and Theses (Open Access)

Epithelial ovarian cancer (EOC) accounts for the most number of deaths among women with gynecological malignancies in the United States. Approximately 80% of EOC patients are diagnosed with disease that has disseminated beyond the confines of the ovaries. The five year survival rate for patients with advanced stage EOC is less than 30% and the recurrence of chemoresistant disease is high. Identifying the mechanisms that control peritoneal metastasis of EOC is therefore critical for improving treatment of advanced stage disease. The homeobox gene DLX4 encodes a transcription factor that is absent from most normal adult tissues. Previous studies from our …

Differential Pax5 Levels Promote Mcl Dispersal And Progression And Predict A Poor Prognosis In Advanced Mcl Patients, Albert Teo

Dissertations and Theses (Open Access)

Although PAX5 conditional silencing in mice models led to aggressive lymphoma formation, there has been a lack of understanding in the precise functions of PAX5 in human B cell cancers. PAX5 expression is used to diagnose different B cell lymphoma in the clinic including mantle cell lymphoma (MCL), which is one of the most aggressive B cell cancers. PAX5 levels in MCL patients were significantly repressed compared to normal B cells. Surprisingly, we found there were quantitative differences in PAX5 expression levels within MCL patient tissues, which prompted us to silence PAX5 in MCL cell lines to characterize PAX5 functions …

Nprl2/Tusc4 Functions As A Tumor Suppressor By Regulating Brca1’S Stability Via The E3 Ubiquitination Pathway, Yang Peng

Dissertations and Theses (Open Access)

Expression of the tumor suppressor protein BRCA1 is frequently lost in breast cancer patients, and the loss of its expression is associated with disruption of various critical functions in cells and cancer development. In the present study, we demonstrate through microarray analysis that cells with tumor suppressor candidate 4 (NPRL2/TUSC4) knockdown show critical changes to cell cycle, cell death pathways and a global impact on cancer development. More importantly, we observed a clear cluster pattern of NPRL2/TUSC4-knockdown gene profiles with established homologous recombination (HR) repair defect signature. Additionally, NPRL2/TUSC4 protein physically interacts with the E3 ligase HERC2 and prevents ubiquitin …

Jab1 Negatively Regulates Pten And Promotes Resistance To Trastuzumab In Her2-Positive Breast Cancer, Thuy T. Vu

Dissertations and Theses (Open Access)

HER2-positive breast cancer, which is characterized by the over-expression of the HER2 onco-protein, accounts for approximately 20% of all breast cancer cases. Trastuzumab (Herceptin), the first targeted therapy approved for HER2-positive disease, potently prevents the activation of signaling pathways downstream of HER2 and significantly improves patients’ outcomes. However, resistance to trastuzumab is inevitable; such resistance can occur through reduced expression of PTEN protein.

Jab1 is over-expressed in 50% of primary cancers and 90% of metastatic tumors. Our lab previously showed that depletion of Jab1 in combination with trastuzumab treatment up-regulated PTEN in mouse xenografts refractory to trastuzumab. PTEN was not …

Epidermal Growth Factor Receptor Induces Fyn Expression Via Up-Regulation Of P47phox In Glioblastoma Multiforme, Blake P. Johnson

Dissertations and Theses (Open Access)

Src family kinases (SFKs) are commonly over-expressed and/or activated in glioblastoma multiforme (GBM), where they serve as key mediators of GBM cell proliferation, survival, invasion and angiogenesis. Mechanisms of allosteric SFK activation are well described; however, the SFK Fyn is commonly up-regulated at the mRNA level in multiple human cancers, including GBM, where the mode of increased expression is poorly understood. Since activating mutations in the epidermal growth factor receptor (EGFR) are commonly occurring in GBM, we examined whether EGFR could induce Fyn expression. Here, we found that wild-type EGFR, and to a greater extent hyper-activating EGFR mutants, EGFRΔIII and …

Targeting Cox-2 And Rank In Aggressive Breast Cancers: Inflammatory Breast Cancer And Triple-Negative Breast Cancer, Monica Elizabeth Reyes

Dissertations and Theses (Open Access)

Inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) are two highly aggressive breast cancer subtypes associated with a poor outcome. Despite sensitivity to current treatment, these breast cancers subtypes have a high recurrence rate and proclivity to metastasize early. The aggressiveness of IBC and TNBC have been linked to CSCs and epithelial to mesenchymal transition (EMT), which are critical features of breast cancer progression and metastasis. The clinical challenge faced in the treatment of IBC and TNBC is finding a treatment strategy to target the cancer stem-like (CSC) population to block metastasis. Cyclooxygenase-2 (COX-2) and receptor activator of nuclear …

Dual Assembly Nanoparticles Achieve Sustained Silencing Of Znf304: A Novel Transcription Factor For Β1 Integrin, Burcu Aslan

Dissertations and Theses (Open Access)

Ovarian cancer (OC) is a highly metastatic disease, but no effective strategies to this process currently are known. Here, an integrated computational analysis of The Cancer Genome Atlas ovarian cancer dataset coupled with experimental validation identified a novel zinc finger transcriptional factor 304 (ZNF304) as one of the key factors for ovarian cancer metastasis. High tumoral ZNF304 expression was associated with poor overall survival in ovarian cancer patients. Through reverse phase protein array analysis, we demonstrated that ZNF304 promotes multiple proto-oncogenic pathways important for cell survival, migration, and invasion. ZNF304 transcriptionally regulates β1 integrin, which subsequently regulates Src/focal adhesion kinase …

Targeting Cox-2 And Rank In Aggressive Breast Cancers: Inflammatory Breast Cancer And Triple-Negative Breast Cancer, Monica E. Reyes

Dissertations and Theses (Open Access)

Inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) are two highly aggressive breast cancer subtypes associated with a poor outcome. Despite sensitivity to current treatment, these breast cancers subtypes have a high recurrence rate and proclivity to metastasize early. The aggressiveness of IBC and TNBC have been linked to CSCs and epithelial to mesenchymal transition (EMT), which are critical features of breast cancer progression and metastasis. The clinical challenge faced in the treatment of IBC and TNBC is finding a treatment strategy to target the cancer stem-like (CSC) population to block metastasis. Cyclooxygenase-2 (COX-2) and receptor activator of nuclear …

Gsbs News, Fall 2014, Graduate School Of Biomedical Sciences, University Of Texas Health Science Center At Houston/M.D. Anderson Cancer Center

GSBS News

No abstract provided.

Selective Elimination Of Malignant Melanoma Using The Novel Anti-Tumor Agents, Osw-1 And Peitc, Kausar Begam Riaz Ahmed

Dissertations and Theses (Open Access)

Metastatic melanoma is amongst the most refractory of cancers. Drug resistance and lack of therapeutic selectivity are two main challenges to successful melanoma therapy. Herein, we investigated the mechanims of anticancer activity and therapeutic selectivity of two novel agents, 3β, 16β, 17α-trihydroxycholest-5-en-22-one 16-O-[2-O-4-methoxybenzoyl-β-D-xylopyranosyl]- [1→3]-2-O-acetyl-α-l-arabinopyranoside (OSW-1) and β-Phenylethyl Isothiocyanate (PEITC) in melanoma.

OSW-1 inhibited melanoma cell viability at nanomolar concentrations with minimal toxicity to normal melanocytes. Mechanistic studies revealed that OSW-1 suppressed Disialoganglioside 3 Synthase (GD3S) gene expression in melanoma cells, leading to inhibition of gangliosides GD3 and GD2. GD3 is an abundantly expressed melanoma …

Large-Scale Identification Of Chemically Induced Mutations In Drosophila Melanogaster, Nele A Haelterman, Lichun Jiang, Yumei Li, Vafa Bayat, Hector Sandoval, Berrak Ugur, Kai Li Tan, Ke Zhang, Danqing Bei, Bo Xiong, Wu-Lin Charng, Theodore Busby, Adeel Jawaid, Gabriela David, Manish Jaiswal, Koen J T Venken, Shinya Yamamoto, Rui Chen, Hugo J Bellen

Faculty, Staff and Students Publications

Forward genetic screens using chemical mutagens have been successful in defining the function of thousands of genes in eukaryotic model organisms. The main drawback of this strategy is the time-consuming identification of the molecular lesions causative of the phenotypes of interest. With whole-genome sequencing (WGS), it is now possible to sequence hundreds of strains, but determining which mutations are causative among thousands of polymorphisms remains challenging. We have sequenced 394 mutant strains, generated in a chemical mutagenesis screen, for essential genes on the Drosophila X chromosome and describe strategies to reduce the number of candidate mutations from an average of …

Inflammation And C-Reactive Protein In Atrial Fibrillation: Cause Or Effect?, Roberto Galea, Maria Teresa Cardillo, Annalisa Caroli, Maria Giulia Marini, Chiara Sonnino, Maria L Narducci, Luigi M Biasucci

The Texas Heart Institute Journal

Atrial fibrillation is associated with substantial morbidity and mortality rates. The incompletely understood pathogenesis of this cardiac dysrhythmia makes it difficult to improve approaches to primary and secondary prevention. Evidence has accumulated in regard to a relationship between inflammation and atrial fibrillation. Investigators have correlated the dysrhythmia with myocarditis, pericardiotomy, and C-reactive protein levels, suggesting that inflammation causes atrial fibrillation or participates in its onset and continuation. Conversely, other investigators suggest that atrial fibrillation induces an inflammatory response. In this review, we summarize and critically discuss the nature and clinical role of inflammation and C-reactive protein in atrial fibrillation.

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

Dissertations and 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 …

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

Dissertations and 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 …

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

Dissertations and 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 …

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

Dissertations and 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 …

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

Dissertations and 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 …

Characterization Of The Vascular Pathology In The Acta2 R258c Mouse Model And Cerebrovascular Characterization Of The Acta2 Null Mouse, Carlos A. Villamizar

Dissertations and Theses (Open Access)

Mutations in ACTA2, the gene encoding for smooth muscle α-actin, predispose patients to a wide range of vascular diseases and is most commonly associated with thoracic aortic aneurysms (TAAD) and dissections (TAAD) and strokes. TAAD in patients is characterized by aortic media degeneration and loss in contractile force generation followed by aortic enlargement and subsequent rupture. Most stroke cases associated with ACTA2 are described as moyamoya-like cerebrovascular incidents characterized by distal occlusion of the internal carotid artery, stenosis of arteries in the Circle of Willis, and straightening of cerebral arteries. Patient samples are scarcely available for analysis, and the few …

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

Dissertations and 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 …

Reactive Oxygen Species And P21 Waf1/Cip1 Are Both Essential For, Alison Fitzgerald

Dissertations and Theses (Open Access)

Treatment of Head and Neck Squamous Cell Carcinoma, HNSCC, often requires multimodal therapy, including radiation therapy. The efficacy of radiotherapy in controlling locoregional recurrence, the most frequent cause of death from HNSCC, is critically important for patient survival. One potential biomarker to determine radioresistance is TP53, whose alterations are predictive of poor radiation response. The following work shows that the p53 transcriptional target, p21, is crucial in initiating and maintaining senescence in HNSCC, through its ability to regulate reactive oxygen species (ROS). With the use of a novel system to evaluate the impact of the TP53 missense mutations, we …

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

Dissertations and 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 …

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 …

The Kras/Mapk Pathway And Ligand Independent Activation Of Erα: Implications For The Treatment Of Endometrial Cancer, Kari Ring

Dissertations and Theses (Open Access)

Hormonal therapy remains a first line option for the treatment of recurrent endometrial cancer (EC), however, many tumors demonstrate de novo or acquired resistance. Member kinases of the PI3K/AKT and Ras/MAPK pathways activate estrogen receptor α (ERα) independent of estrogen, however, few studies have evaluated the role of the Ras/MAPK pathway in predicting response to hormonal therapy in EC. The aims of this project were to evaluate the role of ligand independent activation of ERα in EC and to explore therapeutic implications for the treatment of recurrent EC.

A xenograft model for recurrent EC was used to evaluate the effect …

Role Of Macrophages In Adaptive Resistance To Anti-Vegf Therapy, Heather Dalton

Dissertations and Theses (Open Access)

Background: The clinical implementation of therapies targeting the VEGF pathway in cancer has been limited by acquired resistance; yet, the mechanisms by which this occurs is unclear. We investigated the role of macrophages in the development of acquired resistance to anti-VEGF antibody (AVA) therapy.

Materials and Methods: We first established a murine ovarian cancer model of resistance to anti-VEGF therapy. Using this model we investigated changes in macrophage infiltration during AVA sensitive and resistant phases. We also investigated the in vivo effects of macrophage depletion at the emergence of anti-VEGF resistance and in upfront combination with AVA therapy. In vitro …

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

Dissertations and 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 and 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 and 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. …

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

Dissertations and 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 …

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

Dissertations and 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 …

Genetic Predictors Of Metabolic Side Effects Of Diuretic Therapy, Jorge L. Del Aguila

Dissertations and Theses (Open Access)

Thiazide diuretics are a recommended first-line monotherapy for hypertension (i.e.SBP>140 mmHg or DBP>90 mmHg). Even so, diuretics are associated with adverse metabolic side effects, such as hyperlipidemia, hyperglycemia and hypokalemia which increase the risk of developing type II diabetes. This thesis used three analytical strategies to identify and quantify genetic factors that contribute to the development of adverse metabolic effects due to thiazide diuretic treatment. I performed a genome-wide association study (GWAS) and meta-analysis of the change in fasting plasma glucose and triglycerides in response to HCTZ from two different clinical trials: the Pharmacogenomic Evaluation of Antihypertensive Responses …