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Oxidative Stress Based Strategies For Enhancing The Efficacy Of Histone Deacetylase Inhibitors (Hdaci), Nilsa Rivera-Del Valle

Dissertations and Theses (Open Access)

Histone deacetylase inhibitors (HDACi) are anti-cancer drugs that primarily act upon acetylation of histones, however they also increase levels of intracellular reactive oxygen species (ROS). We hypothesized that agents that cause oxidative stress might enhance the efficacy of HDACi. To test this hypothesis, we treated acute lymphocytic leukemia cells (ALL) with HDACi and adaphostin (ROS generating agent). The combination of two different HDACi (vorinostat or entinostat) with adaphostin synergistically induced apoptosis in ALL. This synergistic effect was blocked when cells were pre-treated with the caspase-9 inhibitor, LEHD. In addition, we showed that loss of the mitochondrial membrane potential is the …

Molecular And Genomic Based Insights Into The Evolution Of Enterococcus Faecium From Commensal To Hospital-Adapted Pathogen, Jessica R. Galloway-Pena

Dissertations and Theses (Open Access)

The basis for the recent transition of Enterococcus faecium from a primarily commensal organism to one of the leading causes of hospital-acquired infections in the United States is not yet understood. To address this, the first part of my project assessed isolates from early outbreaks in the USA and South America using sequence analysis, colony hybridizations, and minimal inhibitory concentrations (MICs) which showed clinical isolates possess virulence and antibiotic resistance determinants that are less abundant or lacking in community isolates. I also revealed that the level of ampicillin resistance increased over time in clinical strains. By sequencing the pbp5 gene, …

The P63 Isoform ∆Np63Α Inhibits Epithelial – Mesenchymal Transition By Promoting The Expression Of Mir-205 In Human Bladder Cancer Cells, Mai Tran

Dissertations and Theses (Open Access)

p63, a p53 family member, is a transcription factor that has complex roles in cancer. This study focuses on the role of the ∆Np63α isoform in bladder cancer (BC). Epithelial – mesenchymal transition (EMT) is a physiological process that plays an important part in metastasis and drug resistance. At the molecular level, EMT is characterized by the loss of the epithelial marker E-cadherin, and the acquisition of the transcriptional repressors of E-cadherin (ZEB1, ZEB2, TWIST, SNAI1 and SNAI2). Recent publications highlight the role of microRNAs belonging to the miR-200 family and miR-205 in preventing EMT through suppression of ZEB1 and …

Development Of Novel Methods To Minimize The Impact Of Sequencing Errors In The Next-Generation Sequencing Data Analysis, Xiaofeng Zheng

Dissertations and Theses (Open Access)

Next-generation sequencing (NGS) technology has become a prominent tool in biological and biomedical research. However, NGS data analysis, such as de novo assembly, mapping and variants detection is far from maturity, and the high sequencing error-rate is one of the major problems. .

To minimize the impact of sequencing errors, we developed a highly robust and efficient method, MTM, to correct the errors in NGS reads. We demonstrated the effectiveness of MTM on both single-cell data with highly non-uniform coverage and normal data with uniformly high coverage, reflecting that MTM’s performance does not rely on the coverage of the sequencing …

Integrative Biomarker Identification And Classification Using High Throughput Assays, Pan Tong

Dissertations and Theses (Open Access)

It is well accepted that tumorigenesis is a multi-step procedure involving aberrant functioning of genes regulating cell proliferation, differentiation, apoptosis, genome stability, angiogenesis and motility. To obtain a full understanding of tumorigenesis, it is necessary to collect information on all aspects of cell activity. Recent advances in high throughput technologies allow biologists to generate massive amounts of data, more than might have been imagined decades ago. These advances have made it possible to launch comprehensive projects such as (TCGA) and (ICGC) which systematically characterize the molecular fingerprints of cancer cells using gene expression, methylation, copy number, microRNA and SNP microarrays …

The Role Of Nucleolin In B-Cell Lymphomas And Fas-Mediated Apoptotic Signaling, Jillian F. Wise

Dissertations and Theses (Open Access)

The death receptor Fas has a key role in mediating homeostasis, elimination of defective cells and more recently implicated in cancer promotion. Many effective anti-cancer therapies depend on Fas-mediated apoptosis to eradicate tumor cells and ineffective Fas-apoptotic signaling is a basis for primary as well as acquired resistance to chemotherapy. We hypothesized that Fas is subjected to direct regulation by inhibitory proteins attained by cancer cells. To screen for potential binding modulators of Fas, we analyzed lymphoma cells for Fas binding proteins. This purification scheme identified high scoring peptides derived from nucleolin, a nuclear protein known to be overexpressed in …

Genome-Wide Profiling Unveils Criticial Functions Of P53 In Human Embryonic Stem Cells, Kadir C. Akdemir

Dissertations and Theses (Open Access)

Embryonic stem cells (ESCs) possess two unique characteristics: infinite self-renewal and the potential to differentiate into almost every cell type (pluripotency). Recently, global expression analyses of metastatic breast and lung cancers revealed an ESC-like expression program or signature, specifically for cancers that are mutant for p53 function. Surprisingly, although p53 is widely recognized as the guardian of the genome, due to its roles in cell cycle checkpoints, programmed cell death or senescence, relatively little is known about p53 functions in normal cells, especially in ESCs. My hypothesis is that p53 has specific transcription regulatory functions in human ESCs (hESCs) that …

The Natural And Orthogonal Interaction (Noia) Models For Quantitative Traits (Qts) And Complex Diseases, Feifei Xiao

Dissertations and Theses (Open Access)

My dissertation focuses on developing methods for gene-gene/environment interactions and imprinting effect detections for human complex diseases and quantitative traits. It includes three sections: (1) generalizing the Natural and Orthogonal interaction (NOIA) model for the coding technique originally developed for gene-gene (GxG) interaction and also to reduced models; (2) developing a novel statistical approach that allows for modeling gene-environment (GxE) interactions influencing disease risk, and (3) developing a statistical approach for modeling genetic variants displaying parent-of-origin effects (POEs), such as imprinting.

In the past decade, genetic researchers have identified a large number of causal variants for human genetic diseases and …

The Role Of Il-8-Mediated Src Family Kinase Activation In Tumor-Tumor And Tumor-Stromal Interactions In Metastasis Of Prostate Cancer, Lynnelle Thorpe

Dissertations and Theses (Open Access)

Men with localized prostate cancer (PCa) have a 100% five-year survival rate, but this rate drops to 33% for men with metastatic disease. A better understanding of the metastatic process is needed to develop better therapies for PCa. Aberrant activation of protein tyrosine kinases, including Src Family Kinases (SFKs) contribute to metastasis through numerous functions, one of which leads to increased expression of cytokines, such as IL-8. However, the relationship between Src activity and IL-8 regulation is not completely understood. In cell line models, I determined that IL-8 activates Src and in turn Src activates IL-8 demonstrating a feed forward …

Galectin-3 Enhances The Malignant Melanoma Phenotype By Regulating Autotaxin, Russell R. Braeuer

Dissertations and Theses (Open Access)

In melanoma patient specimens and cell lines, the over expression of galectin-3 is associated with disease progression and metastatic potential. Herein, we have sought out to determine whether galectin-3 affects the malignant melanoma phenotype by regulating downstream target genes. To that end, galectin-3 was stably silenced by utilizing the lentivirus-incorporated small hairpin RNA in two metastatic melanoma cell lines, WM2664 and A375SM, and subjected to gene expression microarray analysis. We identified and validated the lysophospholipase D enzyme, autotaxin, a promoter of migration, invasion, and tumorigenesis, to be down regulated after silencing galectin-3. Silencing galectin-3 significantly reduced the promoter activity of …

Novel Therapeutic Targets Identified By High-Throughput Technologies For Triple-Negative Breast Cancer, Christine Shiang

Dissertations and Theses (Open Access)

Triple-negative breast cancers (TNBC) are characterized by the lack of or reduced expression of the estrogen and progesterone receptors, and normal expression of the human epidermal growth factor receptor 2. The lack of a well-characterized target for treatment leaves only systemic chemotherapy as the mainstay of treatment. Approximately 60-70% of patients are chemosensitive, while the remaining majority does not respond. Targeted therapies that take advantage of the unique molecular perturbations found in triple-negative breast cancer are needed. The genes that are frequently amplified or overexpressed represent potential therapeutic targets for triple-negative breast cancer. The purpose of this study was to …

Pim Kinase Inhibition: Single Agent And Combination Approaches In B-Cell Lymphoma, Qingshan Yang

Dissertations and Theses (Open Access)

Proviral integration site for Moloney murine leukemia virus (Pim) kinases are Ser/Thr/Tyr kinases. They modulate B-cell development but become oncoproteins and promote cancer development once overexpressed. Containing three isoforms, Pim-1, -2 and -3 are known to phosphorylate various substrates that regulate transcription, translation, cell cycle, and survival pathways in both hematological and solid tumors.

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma. Elevated Pim kinase levels are common in MCL, and it negatively correlates with patient outcome. SGI-1776 is a small molecule inhibitor selective for Pim-1/-3. We hypothesize that SGI-1776 treatment in MCL will inhibit Pim kinase function, and …

Interaction Between Brk And Her2 In Breast Cancer, Midan Ai

Dissertations and Theses (Open Access)

INTERACTION BETWEEN BRK AND HER2 IN BREAST CANCER

Midan Ai, Ph.D.

Supervisory Professor: Zhen Fan, M.D.

Breast tumor kinase (Brk) is a nonreceptor protein-tyrosine kinase that is highly expressed in approximately two thirds of breast cancers but is not detectable or is expressed at very low levels in normal mammary epithelium. Brk plays important roles in promoting proliferation, survival, invasion, and metastasis of breast cancer cells, but the mechanism(s) of which remain largely unknown. Recent studies showed that Brk is frequently co-overexpressed with human epidermal growth factor receptor-2 (HER2) and is physically associated with HER2 in breast cancer. The mechanism …

Design, Synthesis And Development Of Transporter Targeting Agents For Image-Guided Therapy And Drug Delivery, Ning Tsao

Dissertations and Theses (Open Access)

The purpose of this study was to design, synthesize and develop novel transporter targeting agents for image-guided therapy and drug delivery. Two novel agents, N4-guanine (N4amG) and glycopeptide (GP) were synthesized for tumor cell proliferation assessment and cancer theranostic platform, respectively. N4amG and GP were synthesized and radiolabeled with ^99mTc and ⁶⁸Ga. The chemical and radiochemical purities as well as radiochemical stabilities of radiolabeled N4amG and GP were tested. In vitro stability assessment showed both ^99mTc-N4amG and ^99mTc-GP were stable up to 6 hours, whereas ⁶⁸Ga-GP was stable up to 2 hours. Cell culture studies …

Attitudes To Ward And Utilization Of Non-Invasive Prenatal Testing For Chromosome Aneuploidy Among Ob/Gyns, Jessica Davis

Dissertations and Theses (Open Access)

Prenatal diagnosis is traditionally made via invasive procedures such as amniocentesis and chorionic villus sampling (CVS). However, both procedures carry a risk of complications, including miscarriage. Many groups have spent years searching for a way to diagnose a chromosome aneuploidy without putting the fetus or the mother at risk for complications. Non-invasive prenatal testing (NIPT) for chromosome aneuploidy became commercially available in the fall of 2011, with detection rates similar to those of invasive procedures for the common autosomal aneuploidies (Palomaki et al., 2011; Ashoor et al. 2012; Bianchi et al. 2012). Eventually NIPT may become the diagnostic standard of …

Trpv1 Channels Contribute To Behavioral Hypersensitivity And Spontaneous Activity In Nociceptors After Spinal Cord Injury, Zizhen Wu

Dissertations and Theses (Open Access)

A majority of persons who have sustained spinal cord injury (SCI) develop chronic pain. While most investigators have assumed that the critical mechanisms underlying neuropathic pain after SCI are restricted to the central nervous system (CNS), recent studies showed that contusive SCI results in a large increase in spontaneous activity in primary nociceptors, which is correlated significantly with mechanical allodynia and thermal hyperalgesia. Upregulation of ion channel transient receptor vanilloid 1 (TRPV1) has been observed in the dorsal horn of the spinal cord after SCI, and reduction of SCI-induced hyperalgesia by a TRPV1 antagonist has been claimed. However, the possibility …

Knowledge And Expectations Of Support People In Prenatal Genetic Counseling Sessions, Michelle A. Mcdougle

Dissertations and Theses (Open Access)

Prenatal genetic counseling patients have the ability to choose from a myriad of screening and diagnostic testing options, each with intricacies and caveats regarding accuracy and timing. Decisions regarding such testing can be difficult and are often made on the same day that testing is performed. Therefore, it is reasonable to consider that the support people brought to an appointment may have a role in the decision-making process. We aimed to better define this potential role by examining the incoming knowledge and expectations of support people who attended prenatal genetic counseling appointments.

Support people were asked to complete a survey …

Comparison Of Tumor Shrinkage And Cumulative Dose Distribution For Lung Cancers, Yi Pei Chen

Dissertations and Theses (Open Access)

Background: The physical characteristic of protons is that they deliver most of their radiation dose to the target volume and deliver no dose to the normal tissue distal to the tumor. Previously, numerous studies have shown unique advantages of proton therapy over intensity-modulated radiation therapy (IMRT) in conforming dose to the tumor and sparing dose to the surrounding normal tissues and the critical structures in many clinical sites. However, proton therapy is known to be more sensitive to treatment uncertainties such as inter- and intra-fractional variations in patient anatomy. To date, no study has clearly demonstrated the effectiveness of proton …

Mismatch Repair Deficient Tumors Lacking Known Sporadic Causes: Are They All Due To Lynch Syndrome?, Katherine M. Dempsey

Dissertations and Theses (Open Access)

BACKGROUND: Mismatch repair deficient (MMRD) colorectal (CRC) or endometrial (EC) cancers in the absence of MLH1 promoter hypermethylation and BRAF mutations are suggestive of Lynch syndrome (LS). Positive germline genetic test results confirm LS. It is unclear if individuals with MMRD tumors but no identified germline mutation or sporadic cause (MMRD+/germline-) have LS.

HYPOTHESIS: Since LS is hereditary, individuals with LS should have a stronger family history of LS-related cancers than individuals with sporadic tumors. We hypothesized that MMRD+/germline- CRC and/or EC patients would have less suggestive family histories than LS CRC and/or EC patients.

METHODS: 253 individuals with an …

An Assessment Of Knowledge And Attitudes Of Genetic Counseling Services In U.S. Htcs, Brad Rolf, Deborah Brown, Miguel Escobar, Syed Hashmi M.D., Ph.D, Aroub Ayham Khleif, Sarah Noblin, Marianna Raia

Dissertations and Theses (Open Access)

Hemophilia is a hereditary bleeding disorder which requires lifelong specialized care. A network of Hemophilia Treatment Centers (HTCs) exists to meet the medical needs of patients affected by hemophilia. Genetic counseling services are an integral part of the HTC model of care; however, many HTCs do not have genetic counselors on staff. As a result, the duty to provide these services must fall to other healthcare providers within the HTC. To assess the knowledge and attitudes of these providers we developed a 49 question survey that was distributed electronically to hematologists and nurses at U.S. HTCs. The survey consisted of …

Stimulation Through Tlr4 Increases Fviii Inhibitor Formation In A Mouse Model Of Hemophilia A, Claire K. Holley

Dissertations and Theses (Open Access)

Hemophilia A is a clotting disorder caused by functional factor VIII (FVIII) deficiency. About 25% of patients treated with therapeutic recombinant FVIII develop antibodies (inhibitors) that render subsequent FVIII treatments ineffective. The immune mechanisms of inhibitor formation are not entirely understood, but circumstantial evidence indicates a role for increased inflammatory response, possibly via stimulation of Toll-like receptors (TLRs), at the time of FVIII immunization. I hypothesized that stimulation through TLR4 in conjunction with FVIII treatments would increase the formation of FVIII inhibitors. To test this hypothesis, FVIII K.O. mice were injected with recombinant human FVIII with or without concomitant doses …

Attitudes And Practices Of Genetic Counselors In Providing Predictive Testing To Minors At Risk For Li-Fraumeni Syndrome, Allison Copeland

Dissertations and Theses (Open Access)

Li- Fraumeni Syndrome (LFS) is a rare autosomal dominant hereditary cancer syndrome caused by mutations in the TP53 gene that predisposes individuals to a wide variety of cancers, including breast cancer, soft tissue sarcomas, osteosarcomas, brain tumors, and adrenocortical carcinomas. Individuals found to carry germline mutations in TP53 have a 90% lifetime cancer risk, with a 20% chance to develop cancer under the age of 20. Despite the significant risk of childhood cancer, predictive testing for unaffected minors at risk for LFS historically has not been recommended, largely due to the lack of available and effective screening for the types …

Turnover Rate Of The Neuronal Connexin Cx36 In Hela Cells, Yanran Wang

Dissertations and Theses (Open Access)

Electrical synapses formed of the gap junction protein Cx36 show a great deal of functional plasticity, much dependent on changes in phosphorylation state of the connexin. However, gap junction turnover may also be important for regulating cell-cell communication, and turnover rates of Cx36 have not been studied. Connexins have relatively fast turnover rates, with short half-lives measured to be 1.5 to 3.5 hours in pulse-chase analyses of connexins (Cx26 and Cx43) in tissue culture cells and whole organs. We utilized HaloTag technology to study the turnover rate of Cx36 in transiently transfected HeLa cells. The HaloTag protein forms irreversible covalent …

Inflammatory Breast Cancer: The Immune Perspective, Evan N. Cohen

Dissertations and Theses (Open Access)

Inflammatory breast cancer (IBC) is the most insidious form of locally advanced disease. Although rare and less than 2% of all breast cancer, IBC is responsible for up to 10% of all breast cancer deaths. Despite the name, very little is known about the role of inflammation or immune mediators in IBC. Therefore, we analyzed blood samples from IBC patients and non-IBC patients, as well as healthy donor controls to establish an IBC-specific profile of peripheral blood leukocyte phenotype and function of T cells and dendritic cells and serum inflammatory cytokines.

Emerging evidence suggests that host factors in the microenviromement …

Delayed Thrombus Resolution And Fibroproliferative Vascular Wound Healing From Deficiency Of Type Iii Collagen: A Paradoxical Mechanism For Tissue Fragility, Amy J. Reid

Dissertations and Theses (Open Access)

Vascular Ehlers-Danlos syndrome is a heritable disease of connective tissue caused by mutations in COL3A1, conferring a tissue deficiency of type III collagen. Cutaneous wounds heal poorly in these patients, and they are susceptible to spontaneous and catastrophic rupture of expansible hollow organs like the gut, uterus, and medium-sized to large arteries, which leads to premature death. Although the predisposition for organ rupture is often attributed to inherent tissue fragility, investigation of arteries from a haploinsufficient Col3a1 mouse model (Col3a1^+/-) demonstrates that mutant arteries withstand even supraphysiologic pressures comparably to wild-type vessels. We hypothesize that injury …

Investigating The Roles Of The P63 Isoforms In The Microrna Biogenesis Pathway, Deepavali Chakravarti

Dissertations and Theses (Open Access)

MicroRNAs play roles in various biological processes like development, tumorigenesis, metastasis and pluripotency. My thesis work has demonstrated roles for p63, a p53 family member, in the upstream regulation of microRNA biogenesis. The p63 gene has a complex gene structure and has multiple isoforms. The TAp63 isoforms contain an acidic transcription activation domain. The ΔNp63 isoforms, lack the TA domain, but have a proline rich region critical for gene transactivation. To understand the functions of these isoforms, the Flores lab generated TAp63 and ΔNp63 conditional knock out mice. Using these mice and tissues and cells from these mice we have …

The Role Of Type I Insulin-Like Growth Factor Receptor Signaling In Breast Cancer Brain Metastasis, Sandra M. Saldana

Dissertations and Theses (Open Access)

Brain metastasis is a common cause of mortality in cancer patients. Approximately 20-30% of breast cancer patients acquire brain metastasis, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF- IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that the IGF-IR signaling axis is constitutively active in brain-seeking sublines of breast cancer cells, driving an increase in in vitro metastatic properties. We demonstrate that IGF-IR signaling is activated in an autocrine manner …

Connecting Public Libraries With Community Emergency Responders, Michelle Malizia, Karen Vargas, Rebecca Hamilton, Deborah Littrell, Cynthia Olney

Library Staff Publications

No abstract provided.

Ms 015 Guide To Joseph Melnick, Phd Papers (1943-1989), Joseph Melnick (1914-2001)

Manuscript Finding Aids

Joseph Melnick, PhD papers contains correspondence and reprints that document the career of Dr. Melnick, who was a leading epidemiologist, best known for his research on polio. See more at MS 015.

New Vaccines: How And Why Acip Makes Vaccine Recommendations; National Library Week At The Tmc Library; Basics Of Evidence-Based Practice, Vol 11. (4), Texas Medical Center Library

Insider Express (2003-2013)

No abstract provided.