Medicine and Health Sciences Commons^™

The Thioredoxin Trx-1 Regulates The Major Oxidative Stress Response Transcription Factor, Skn-1, In Caenorhabditis Elegans, Katie C. Mccallum

Dissertations and Theses (Open Access)

The ability to respond to hostile environmental conditions is critical for the survival of an organism. Oxidative stress is an adverse state in which reactive oxygen species (ROS) accumulate to a harmful level and, if left unresolved, can lead to cellular dysfunction and organismal disease. Sophisticated detoxification systems, characterized by a battery of enzymatic antioxidants, are utilized to neutralize ROS thereby reducing stress. However, ROS are also purposefully produced by designated cellular enzymes to facilitate the signaling and regulation of critical physiological processes. Therefore, both the production and neutralization of ROS must be tightly controlled. Indeed, the expression of detoxification …

Factors Influencing Uptake Of Risk-Reducing Salpingo-Oophorectomy By Brca1 And Brca2 Mutation Carriers, Victoria E. Breen

Dissertations and Theses (Open Access)

Germline mutations in the BRCA1 and BRCA2 genes are associated with significantly increased risks for ovarian cancer. The National Comprehensive Cancer Network (NCCN) currently recommends that female BRCA mutation carriers undergo risk-reducing salpingo-oophorectomy (RRSO) after age 35; however, not all women elect this option. The purpose of this study was to prospectively survey women with BRCA mutations currently undergoing ovarian cancer screening about their intention to have an RRSO and the various factors influencing their decision. Of the 26 women who completed our survey, 26 (100%, CI: 86.8-100) plan to undergo an RRSO in their lifetime. The average woman reported …

The Role Of 5-Alpha Reductase 3 In Steroid Metabolism, Zahi Mitri

Dissertations and Theses (Open Access)

Background

The growth and development of prostate cancer is largely driven by androgen mediated signaling. The 5-alpha reductase family of enzymes plays an essential role in the conversion of testosterone to the more potent androgen, 5-alpha dihydrotestosterone (DHT), which is capable of binding the androgen receptor to activate gene targets and downstream signaling. This study aimed to evaluate the role of 5-alpha reductase 3 (SRD5A3), a novel member of the 5-alpha reductase family, in steroid metabolism and prostate carcinogenesis.

Materials and Methods

HEK293 cells were transfected with the SRD5A3 human cDNA ORF Clone from OriGene. Steroid substrates (testosterone, progesterone, androstenedione, …

The Roles Of Malt1 In Nf-Κb Activation And Solid Tumor Progression, Deng Pan

Dissertations and Theses (Open Access)

The transcription factor NF-κB plays a central role in many aspects of biological processes and diseases, such as inflammation and cancer. Although it has been suggested thatNF-κB is critical in tumorigenesis and tumor progression, the molecular mechanism by which NF-κB is activated in solid tumor remains largely unknown. In the current work, we focus on growth factor receptor-induced NF-κB activation and tumor progression, including epidermal growth factor receptor (EGFR)-induced NF-κB in lung cancer and heregulin receptor (HER2)-induced NF-κB in breast cancer. We found that Mucosa-associated lymphoma translocation protein 1 (MALT1), also known as paracaspase, is required for EGFR-induced NF-κB activation …

The Psychosocial Effects Of The Li-Fraumeni Education And Early Detection (Lead) Program On Indivdiuals With Li-Fraumeni Syndrome, Jessica L. Ross

Dissertations and Theses (Open Access)

Li-Fraumeni syndrome (LFS) is a hereditary cancer syndrome that leads to an increased risk of multiple cancers. In the past five years new screening protocols have been developed that provide improved screening options for individuals with LFS. However, very little has been published on the psychosocial impact of these screening protocols. The goals of this study were to determine how participation in screening impacts individuals psychosocially, to examine the benefits and drawbacks of screening, and to evaluate possible barriers to continued screening. This qualitative study consisted of phone interviews with 20 individuals that took part in an LFS screening program …

Attitudes To Wards Prenatal Genetics Among Southeast And East Asian Women: A Qualitative Pilot Study, Ginger J. Tsai

Dissertations and Theses (Open Access)

From 2000-2010, the Asian population in the United States grew five times faster than the overall US population. As Asians become incorporated into the US health care system, it is important to recognize cultural differences that may arise between Asian patients and their health care providers. Prior studies show that cultural values influence genetic perceptions within Asian populations. The reputation of the family unit factors into decisions such as pregnancy termination and disclosure of family medical history, and the non-directive model of American genetic counseling conflicts with the historical Asian model of paternalistic health care. Previous studies also provide conflicting …

Patient Perception Of Negative Non-Invasive Prenatal Testing Results, Ann Theresa Wittman

Dissertations and Theses (Open Access)

Non-invasive prenatal testing (NIPT) uses cell-free fetal DNA to assess for fetal aneuploidy during pregnancy. NIPT has higher detection rates and positive predictive values than previous methods; however, NIPT is not diagnostic. Studies suggest patients may underestimate the limitations of prenatal screening. Therefore, we conducted a prospective cross-sectional study of ninety-four women from genetic counseling clinics in Houston, Texas to assess patient understanding of the residual risk for aneuploidy after receiving a negative NIPT. The majority of participants (66%) understood the residual risk for Down syndrome following negative NIPT; however, 34% of participants indicated that negative NIPT completely eliminated the …

Accurate Mutation Annotation And Functional Prediction Enhance The Applicability Of -Omics Data In Precision Medicine, Tenghui Chen

Dissertations and Theses (Open Access)

Clinical sequencing has been recognized as an effective approach for enhancing the accuracy and efficiency of cancer patient management and therefore achieve the goals of personalized therapy. However, the accuracy of large scale sequencing data in clinics has been constrained by many different aspects, such as clinical detection, annotation and interpretation of the variants that are observed in clinical sequencing data. In my Ph.D thesis work, I mainly investigated how to comprehensively and efficiently apply high dimensional -omics data to enhance the capability of precision cancer medicine. Following this motivation, my dissertation has been focused on two important topics in …

Cll Metabolism Is Regulated By Prognostic Factors, Modulated By Stroma And Abrogated By Pi3k Inhibition, Hima Vangapandu

Dissertations and Theses (Open Access)

Metabolism of chronic lymphocytic leukemia (CLL), a disease characterized by the relentless accumulation of mature B cells has been little explored. Bone marrow stromal cells provide a survival benefit to CLL cells, in part through PI3K/AKT pathway. Compared with proliferative B-cell lines, metabolic fluxes of oxygen and lactate were low in quiescent malignant B lymphocytes from CLL patients. Glycolysis (extracellular acidification rate, ECAR) was consistently low in CLL samples, but oxygen consumption (OCR) varied considerably. Higher OCR was associated with poor prognostic factors such as ZAP 70 positivity, unmutated IgVH, high β2M levels, and higher Rai stage. Co-culture with the …

Nipt Results Indicative Of Maternal Neoplasms: Genetic Counselors' Preferences And Attitudes, Meagan E. Giles

Dissertations and Theses (Open Access)

Performing non-invasive prenatal testing (NIPT) on a pregnant woman with a chromosomally abnormal neoplasm may incidentally lead to the diagnosis of cancer due to the coexistence of circulating tumor and placental DNA. Published information regarding NIPT’s accuracy for neoplasm screening is limited, and guidance for patient management is currently lacking. This challenges clinicians’ ability to counsel patients regarding the implications of these results, which often is the responsibility of a genetic counselor. Over three hundred board-eligible/certified genetic counselors were surveyed regarding their awareness, preferences, and attitudes towards NIPT’s ability to indicate maternal neoplasms. Despite 95% of this cohort being aware …

The Role Of Amp-Activated Protein Kinase (Ampk) In Tumorigenesis, Fei Han

Dissertations and Theses (Open Access)

AMPK plays a central role in controlling cellular and whole body energy level. Increasing studies have also discovered the diverse function of AMPK in cancer, such as autophagy and mitochondria biogenesis. However, how AMPK promotes cancer progression is still not clear. Here, we show that AMPK is essential for EGF-induced Akt activation, Glut1 expression, and glucose uptake. AMPK is also required for various stresses induced Akt activation and promote cell survival, including hypoxia and glucose deprivation. In addition, we found glucose deprivation-induced VEGF expression and secretion is also depend on AMPK, which may contribute to angiogenesis of surrounding endothelial cell …

Preeclampsia: The Roles Of Acute Inflammation And Intrauterine Stress, Nicholas Parchim

Dissertations and Theses (Open Access)

Preeclampsia (PE) is a severe, acute disease of pregnancy affecting approximately 8% of pregnant women after week 20 of gestation. PE is characterized by hypertension and renal damage reflected by proteinuria and has significant morbidity to both mother and fetus. Maternal symptoms range from headaches, nausea, edema, to visual changes, but once maternal symptoms present, damage to the fetus has begun. Mothers who progress untreated through the disease can also experience a condition called eclampsia characterized by seizure, coma, and, ultimately, death. PE-affected newborns experience features similar to prematurity—abnormal lung and renal development, intrauterine growth retardation (IUGR), and, possibly, fetal …

The Novel Regulation Of Histone Modification In Cancer Development, Xian Zhang

Dissertations and Theses (Open Access)

Dynamic changes in histone acetylation by various physiological cues play important roles in gene transcription and cancer. However, the cellular signaling underlying this regulation is not well understood. Here, we show that, in a glucose dependent manner, E3 ubiquitin ligase NEDD4 ubiquitinates histone H3 on previously unstudied lysine (K) 23/36/37 residues, which specifically recruits histone acetyltransferase (HAT) GCN5 for subsequent H3 acetylation. Genome-wide analysis of chromatin immunoprecipitation followed by sequencing (ChIP-seq) data sets reveals that NEDD4 regulates glucose-induced H3K9 acetylation at transcription starting site (TSS) and enhancer regions. Integrative analysis of ChIP-seq and microarray data sets also reveals a consistent …

The Notch Target Hes4 Promotes Osteosarcoma Tumor Growth And Metastasis By Inhibiting Osteogenic Differentiation, And Has Potential As A Prognostic Biomarker For Newly Diagnosed Patients With High Grade Osteosarcoma., Madonna Mcmanus

Dissertations and Theses (Open Access)

Currently, there are no well-established prognostic biomarkers for osteosarcoma (OS) at the time of diagnosis. Although response to preoperative chemotherapy correlates with metastasis risk and overall survival, this information is obtained 3-4 months after the initial diagnosis. The major purpose of this study is to identify clinically relevant biomarkers that will allow for the stratification of patients into good or poor responders to chemotherapy at diagnosis. We also aim to understand the biology of these markers in OS pathogenesis. Because the development of OS is caused by genetic disruptions of osteogenic differentiation, we sought to identify pathways that are involved …

Gsk3Beta-Mediated Ezh2 Phosphorylation Suppresses Methylation Of H3k27 And Ezh2’S Oncogenic Functions, How-Wen Ko

Dissertations and Theses (Open Access)

During the process of tumorigenesis, inactivation of tumor suppressors is a critical step. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and the enzymatic core subunit of polycomb repressive complex 2 (PRC2), promotes cell growth and migration through catalyzing trimethylation of histone H3 at Lys 27 (H3K27me3) and plays an important role in tumorigenesis. Its expression can be controlled by phosphorylation. However, the regulation of EZH2 activity by tumor suppressor kinase is not well understood. Glycogen synthase kinase 3 beta (GSK3b), a multifunctional serine/threonine kinase, is involved in many cellular processes. GSK3b also participates in neoplastic transformation, tumor development …

In Vivo Kinome Screen Reveals Non-Canonical Cdk-Driven Metabolic Adaptation In Brain Metastasis, Frank J. Lowery Iii

Dissertations and Theses (Open Access)

Brain metastasis, which frequently arises from breast cancer, lung cancer, melanoma, and colorectal cancer, remains a severely unmet medical need and its incidence continues to rise while treatment options remain palliative. To better understand the biology underlying its aggressive, incurable nature, I performed an unbiased in vivo kinome screen to identify potential driver kinases of experimental brain metastasis in a nude xenograft model using the human breast cancer cell line MDA-MB-231. Several of the kinase pools led to decreased brain metastasis-specific survival in nude mice, shortening survival time by up to 50% relative to controls. Targeted next-generation sequencing (NGS) was …

Clinical And Demographic Variables Associated With Cognitive Deficits, Symptom Severity, And Duration After Concussive Injury In Adolescents: A Retrospective Study, Seema S. Aggarwal

Dissertations and Theses (Open Access)

Background: Concussions in adolescents are a public health concern with the growing popularity of high school sports. Recent legislation mandates that athletes who are suspected of a concussion be cleared to return-to-play by a clinician. More research is needed to develop a concussion predictive model to identify populations at risk for more severe and prolonged symptoms and long-term neurologic deficits.

Aims: The aims of this study were to (1) examine the effect of race and gender on neurocognitive and symptom scores and (2) determine which clinical (e.g., number of concussions, migraine history, learning disabilities/ attention deficit disorders) and demographic factors …

Process Mining Of Medication Revisions In Electronic Health Records, Deevakar Rogith

Dissertations and Theses (Open Access)

Objective: The objective of this work is to develop process mining techniques for analysing Electronic Health Record (EHR) events in order to uncover factors contributing to the event, and understanding deviations in the process. We have outlined a method for combining data mining with expert review to model the EHR process and develop automated algorithms that can be used to detect potential deviations for a defined process.

Introduction: To analyse EHR events meaningfully, process mining can be applied to distil structured process description from a set of real executions. Process mining can be applied for 1) Discovery, 2) Conformance, and …

Community-Based Participatory Research To Improve Early Detection And Treatment Of Hypertension In A Suburban Community In Thailand, Chuncharaporn Sinsiri

Dissertations and Theses (Open Access)

Communities have a significant role in working with health personnel to detect new and previously diagnosed cases of high blood pressure during community BP screening programs. In Thailand there are many people with elevated BP who do not access care. The purpose of this Community-Based Participatory Research (CBPR) was to build a community partnership following the CBPR approach to develop a health program to improve early detection and treatment of hypertension. Three specific aims were: Aim 1. Using CBPR principles, describe the process of building a community partnership to develop a community health program to improve early detection and treatment …

Trim28 Interacts With Ezh2 To Regulate Its Activity, Jing Li, Jing Li

Dissertations and Theses (Open Access)

In this dissertation, I discovered that TRIM28 interacts with EZH2 and regulates its activity in breast cancer cells. EZH2, the major H3K27 tri-methyltransferase, is over expressed in multiple subtypes of breast cancer; however, whether EZH2 plays an active role in breast cancer progression or treatment resistance is unknown. Here, we determined EZH2-interacting proteins in MCF7 cells by immunoprecipitation/mass spectrometry and detected TRIM28 with a high confidence score. TRIM28 is a transcription co-regulator with an N-terminal tri-partite RING finger, B-boxes and a coiled-coil domain (RBCC) and a C-terminal PHD/Bromo domain. Domain mapping revealed that the RBCC domain of TRIM28 interacts with …

Targeting Oncogenic Mirnas With Small Molecules For Breast Cancer Therapy, Paloma Del C. Monroig

Dissertations and Theses (Open Access)

The crucial role of microRNAs (miRNAs) in cancer pathobiology has driven the introduction of new drug development approaches such as miRNA inhibition. In order to advance miRNA-therapeutics, there is a need to develop screening strategies that can target tumors in a specific way. Small molecule inhibitors represent an attractive approach to pursue this. However, the absence of molecular structures for most of the miRNAs makes it very difficult to predict which inhibitors can bind to them. Herein we designed a strategy to screen for small molecules by assesing whether they could directly bind/ interact with miR-10b/miR-21. As part of our …

Investigation Of Quatitative Image Features From Pretreatment Ct And Fdg-Pet Scans In Stage Iii Nsclc Patients Undergoing Defintive Radiation Therapy, David Fried

Dissertations and Theses (Open Access)

The purpose of this work was to determine if quantitative image features (QIFs) extracted from computed tomography (CT) and flourodeoxyglucose (FDG) positron emission tomography (PET) could provide prognostic information to improve outcome models. Our goal for this work was to determine if it may one day be feasible to incorporate QIFs into personalized cancer care. QIFs were used to quantitatively characterize patient disease as seen on imaging. A leave-one-out cross-validation procedure was used to assess the prognostic ability of QIFs extracted from CT and PET in addition to conventional prognostic factors (CPFs). QIFs were found to improve model fit for …

Identifying Protein Kinase Tbk1 As A Novel Inhibitor Of Intestinal Tumorigenesis, Amber L. Mathews

Dissertations and Theses (Open Access)

Colorectal cancer (CRC) is the third most common cancer diagnosed in women and men， causing almost 600,000 annual deaths worldwide. There is a clear need to understand how CRC forms and progresses in order to improve the strategies of CRC prevention and therapy. A major factor that drives the development of CRC is genetic mutations that lead to activation of oncogenes and inactivation of tumor suppressor genes in intestinal epithelial cells (IECs). In addition, the initiation and progression of CRC involve environmental and immunological factors. In particular, chronic inflammatory conditions are known as an important risk factor for CRC. Intestinal …

The Role Of Dna Methylation And Hydroxymethylation In Smooth Muscle Cell Phenotypic Change During Atherogenesis, Jason Williams

Dissertations and Theses (Open Access)

Atherosclerosis is a chronic arterial disease which impacts systemically the function of organs and tissues by causing inflammation and disruption of blood supply. During atherogenesis, lipid deposits, inflammation, and cells accumulate within the walls of arteries, ultimately leading to a buildup of fatty plaques and occlusion of the arterial lumen. In a multifactorial disease like atherosclerosis there are complex interplays between environmental, genetic and epigenetic risk factors. The epigenetics of atherosclerosis involving DNA methylation has been progressing from single gene to genome wide analyses. Although these epistudies have provided evidence that DNA methylation exists within certain genes during atherogenesis, the …

Prediction Of Laser Ablation In Brain: Sensitivity, Calibration, And Validation, Samuel J. Fahrenholtz

Dissertations and Theses (Open Access)

The surgical planning of MR-guided laser induced thermal therapy (MRgLITT) stands to benefit from predictive computational modeling. The dearth of physical model parameter data leads to modeling uncertainty. This work implements a well-accepted framework with three key steps for model-building: model-parameter sensitivity analysis, model calibration, and model validation.

The sensitivity study is via generalized polynomial chaos (gPC) paired with a transient finite element (FEM) model. Uniform probability distribution functions (PDFs) capture the plausible range of values suggested by the literature for five model parameters. The five PDFs are input separately into the FEM model to gain a probabilistic sensitivity response …

Characterization Of Erbb4 Expression In Osteosarcoma, Nupur Lala

Dissertations and Theses (Open Access)

ERBB4 (Her-4) is a member of the ERBB family of Class I receptor tyrosine kinases. ERBB4 is unique within the ERBB family for alternate splicing in its juxtamembrane and cytoplasmic regions, which produces four juxtamembrane isoforms and two cytoplasmic isoforms. The cleavable juxtamembrane isoforms, Jm-a and Jm-d, can undergo proteolytic cleavage and produce an 80-kDa cytoplasmic fragment referred to as “p80,” which has been demonstrated to enhance cellular survival and malignant behavior in many solid tumors [44]. ERBB4 was almost exclusively 80 kDa in size and localized to the nucleus in primary tumors and metastases in studies characterizing ERBB4 expression …

Regulation Of The Oxidative Stress Response By Arid1a, Suet Yan Kwan

Dissertations and Theses (Open Access)

SWI/SNF is mutated in about 20% of all human cancers; in particular ARID1A is the most frequently mutated SWI/SNF subunit. ARID1A is a tumor suppressor gene, inactivating mutations in ARID1A are most frequently found in ovarian and endometrial cancers, specifically uterine corpus endometrioid carcinomas (UCEC), ovarian clear cell carcinomas (OCCC) and ovarian endometrioid carcinomas (OEC). The functional roles of ARID1A are not completely understood and there are limited therapeutic strategies that specifically target ARID1A-mutant cancers. Given that ARID1A expression is lost in cancer, ARID1A mutations cannot be targeted directly and novel therapeutic strategies are required to target ARID1A-mutant …

In Vivo Functional Significance Of Ccat2 Long Non-Coding Rna In Myelodysplastic Syndrome, Maitri Y. Shah

Dissertations and Theses (Open Access)

Long non-coding RNAs form the largest part of the mammalian non-coding transcriptome and control gene expression at various levels including chromatin modification, transcriptional and post-transcriptional processing. Although the underlying molecular mechanisms are not yet entirely understood, lncRNAs are implicated in initiation and progression of several cancers. CCAT2 is a lncRNA that spans the highly conserved 8q24 region associated with increased risk for various cancers. CCAT2 has been shown to play an important role in inducing chromosomal instability and supporting cell proliferation and cell cycle arrest. However, a causal role of CCAT2 in initiation of tumorigenesis and the importance of G/T …

Role Of Stat3 In Human Nk Cell Functions, Prasad V. Phatarpekar

Dissertations and Theses (Open Access)

Natural Killer (NK) cells are cytotoxic lymphocytes, which play a critical role in the immune response against malignant cells and microbial infections. NK cells are equipped with activating receptors, which upon detecting ligands expressed on stressed cells induce cytolytic activity of NK cells. Stimulation of NK cell proliferation and priming of NK cytolytic capability are accomplished by cytokines, which mediate their signals mainly through JAK-STAT signaling pathway. Previously, we found that K562 cells genetically modified to express membrane bound IL-21 (mbIL-21), which predominantly activates STAT3, induce robust expansion and activation of human NK cells. Further investigations revealed role of STAT3 …

Mobilization Of Adipose Stromal Cells In Obesity And Cancer By Sparc And Its Proteolytic Isoforms, Chieh Tseng

Dissertations and Theses (Open Access)

Obesity increases cancer risk and progression as shown by epidemiologic studies. However, the underlying pathophysiology remained unclear. Adipose stromal cells (ASC) are adipose tissue-derived mesenchymal progenitors, abundant in white adipose tissue (WAT). In this study, we show that the ASC pool is expanded in obesity and is associated with promoted tumor growth. Next, by using a chimeric GFP-RFP bone marrow transplant model, we observed higher tumor infiltrating cells with ASC phenotype in obese mice compared to lean. Consistently, systemic circulating ASC frequency is six fold higher in tumor-bearing obese mice compared to lean. The tumor infiltrating cells with ASC phenotype …