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Effect Of Anchoring On Perceived Amniocentesis Related Miscarriage Risk Within A Latina Population, Laura E. Panos

Dissertations and Theses (Open Access)

Most recognized pregnancies are completed without difficulty, yet there is always a 3-5% background risk to have a child with a birth defect. Amniocentesis, the most common type of prenatal diagnostic test, is used to detect chromosomal abnormalities, such as Down syndrome. Amniocentesis is associated with a risk of complications that can lead to a miscarriage, which is typically quoted to be between 1 in 300 and 1 in 500. Amniocentesis uptake rates are typically lowest within the Latina community, and although the factors related to this have been studied before, no specific conclusions have been reached.

The general population …

Delineating The Mechanism(S) Of Bdnf/Trkb Mediated Proliferation In Neuroblastoma, Timothy C. Graham

Dissertations and Theses (Open Access)

Delineating the mechanism(s) of BDNF/TrkB mediated proliferation in Neuroblastoma

Timothy Christopher Graham, B.S.

Supervisory Professor: Patrick Zweidler-McKay, MD/PhD

Neuroblastoma is the most common extra-cranial solid tumor in children, arising from neural crest precursor cells.  The neurotrophin receptors (TrkA/B/C) have been implicated as important prognostic markers, linking the biology of the tumor to patient outcome.  High expression of TrkA and TrkC receptors have been linked to favorable biological features and high patient survival, while TrkB is expressed in unfavorable, aggressive tumors.  Several studies suggest that high levels and activation of TrkB by its ligand brain-derived neurotrophic factor (BDNF) stimulates tumor cell …

Mechanisms Regulating The P120-Catenin/Kaiso Pathway, Ji Yeon Hong

Dissertations and Theses (Open Access)

The Wnt pathways contribute to many processes in cancer and developmental biology, with β-catenin being a key canonical component. P120-catenin, which is structurally similar to β-catenin, regulates the expression of certain Wnt target genes, relieving repression conferred by the POZ/ zinc-finger transcription factor Kaiso. In my first project, employing Xenopus embryos and mammalian cell lines, I found that the degradation machinery of the canonical Wnt pathway modulates p120-catenin protein stability, especially p120 isoform-1, through mechanisms shared with b-catenin. Exogenous expression of destruction-complex components such as GSK3b or Axin promotes p120-catenin degradation, and consequently, is able to rescue developmental phenotypes resulting …

Δnp63 Regulates A Complex Network Of Target Genes In Limb And Epidermal Development, Min Soon Cho

Dissertations and Theses (Open Access)

The skin is composed of two major compartments, the dermis and epidermis. The epidermis forms a barrier to protect the body. The stratified epithelium has self-renewing capacity throughout life, and continuous turnover is mediated by stem cells in the basal layer. p63 is structurally and functionally related to p53. In spite of their structural similarities, p63 is critical for the development and maintenance of stratified epithelial tissues, unlike p53. p63 is highly expressed in the epidermis and previously has been shown to play a critical role in the development and maintenance of the epidermis. The study of p63 has been …

Atm Signaling To Tsc2: Mechanisms And Implications For Cancer Therapy, Angela Alexander

Dissertations and Theses (Open Access)

Ataxia telangiectasia mutated (ATM) is a critical component of the cellular response to DNA damage, where it acts as a damage sensor, and signals to a large network of proteins which execute the important tasks involved in responding to the damage, namely inducing cell cycle checkpoints, inducing DNA repair, modulating transcriptional responses, and regulating cell death pathways if the damage cannot be repaired faithfully. We have now discovered that an additional novel component of this ATM-dependent damage response involves induction of autophagy in response to oxidative stress. In contrast to DNA damage-induced ATM activation however, oxidative stress induced ATM, occurs …

Role Of Synapsin In Long-Term Synaptic Facilitation In Aplysia, Anne Hart

Dissertations and Theses (Open Access)

Enhanced expression of the presynaptic protein synapsin has been correlated with certain forms of long-term plasticity and learning and memory. However, the regulation and requirement for enhanced synapsin expression in long-term memory remains unknown. In the present study the technical advantages of the marine mollusc Aplysia were exploited in order to address this issue. In Aplysia, learning-induced enhancement in synaptic strength is modulated by serotonin (5-HT) and treatment with 5-HT in vitro of the sensorimotor synapse induces long-term facilitation (LTF) of synaptic transmission, which lasts for days, as well as the formation of new connections between the sensory and …

Cocaine Dependence: The Role Of Serotonin Genes In, Lorena Maili

Dissertations and Theses (Open Access)

Animal studies have shown that behavioral responses to cocaine-related cues are altered by serotonergic medications. The effects of pharmacological agents on serotonin receptors 2a (5-HT2A) and 2c (5-HT2C), have yielded results suggesting that selective 5-HT2A antagonists and 5-HT2C agonists promote the disruption of cocaine-associated memories. One measure of cocaine related cues in humans is attentional bias, in which cocaine dependent individuals show greater response latency for cocaine related words than neutral words. Data from our laboratory shows that cocaine dependent subjects have altered attentional bias compared to controls. The purpose of this thesis was to investigate the role of the …

Defining The Role Of Egfr Acetylation In Cellular Processes: Clinical Implications, Hui Song

Dissertations and Theses (Open Access)

Epidermal growth factor receptor (EGFR) is a cell membrane tyrosine kinase receptor and plays a pivotal role in regulating cell growth, differentiation, cell cycle, and tumorigenesis.  Deregulation of EGFR causes many diseases including cancers.  Intensive investigation of EGFR alteration in human cancers has led to profound progress in developing drugs to target EGFR-mediated cancers.  While exploring possible synergistic enhancement of therapeutic efficacy by combining EGFR tyrosine kinase inhibitors (TKI) with other anti-cancer agents, we observed that suberoylanilide hydroxamic acid (SAHA, a deacetylase inhibitor) enhanced TKI-induced cancer cell death, which further led us to question whether SAHA-mediated sensitization to TKI was …

Modification And Implementation Of The Rpc Heterogeneous Thorax Phantom For Verification Of Proton Therapy Treatment Procedures, Anthony Blatnica

Dissertations and Theses (Open Access)

The Radiological Physics Center (RPC) provides heterogeneous phantoms that are used to evaluate radiation treatment procedures as part of a comprehensive quality assurance program for institutions participating in clinical trials. It was hypothesized that the existing RPC heterogeneous thorax phantom can be modified to assess lung tumor proton beam therapy procedures involving patient simulation, treatment planning, and treatment delivery, and could confirm agreement between the measured dose and calculated dose within 5%/3mm with a reproducibility of 5%. The Hounsfield Units (HU) for lung equivalent materials (balsa wood and cork) was measured using a CT scanner. The relative linear stopping power …

Cop 9 Signalosome Subunit 6 Stabilizes Cop1, A Novel E3 Ubiquitin Ligase For 14-3-3Σ, Hyun Ho Choi

Dissertations and Theses (Open Access)

14-3-3σ, a gene upregulated by p53 in response to DNA damage, exists as part of a positive-feedback loop which activates p53 and is a human cancer epithelial marker downregulated in various cancer types. 14-3-3σ levels are critical for maintaining p53 activity in response to DNA damage and regulating signal mediator such as Akt. Here, we identify Mammalian Constitutive Photomorphogenic 1 (COP1) as a novel E3 ubiquitin ligase for targeting 14-3-3σ through proteasome degradation. We show for the first time that COP9 signalosome subunit 6 (CSN6) associates with COP1 and is involved in 14-3-3σ ubiquitin-mediated degradation. Mechanistic studies show that CSN6 …

Role Of Gsh Metabolism In Mediating Stromal-Leukemia Interaction And Promoting Cell Survival And Drug Resistance In Chronic Lymphocytic Leukemia, Wan Zhang

Dissertations and Theses (Open Access)

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western countries. The interaction between CLL cells and the bone marrow stromal environment is thought to play a major role in promoting the leukemia cell survival and drug resistance. My dissertation works proved a novel biochemical mechanism by which the bone marrow stromal cells exert a profound influence on the redox status of primary CLL cells and enhance their ability to sustain oxidative stress and drug treatment. Fresh leukemia cells isolated from the peripheral blood of CLL patients exhibited two major redox alterations when they were cultured alone: …

Developmental And Cellular Functions Of Delta-Catenin, Dongmin Gu

Dissertations and Theses (Open Access)

Catenins have diverse and powerful roles in embryogenesis, homeostasis or disease progression, as best exemplified by the well-known beta-catenin. The less studied delta-catenin likewise contains a central Armadillo-domain. In common with other p120 sub-class members, it acts in a variety of intracellular compartments and modulates cadherin stability, small GTPase activities and gene transcription. In mammals, delta-catenin exhibits neural specific expression, with its knock-out in mice correspondingly producing cognitive defects and synaptic dysfunctions.

My work instead employed the amphibian, Xenopus laevis, to explore delta-catenin’s physiological functions in a distinct vertebrate system. Initial isolation and characterization indicated delta-catenin’s expression in Xenopus. Unlike …

Risk Of Second Malignant Neoplasms Following Proton Arc Therapy And Volumetric Modulated Arc Therapy For Prostate Cancer, Laura A. Rechner

Dissertations and Theses (Open Access)

The risk of second malignant neoplasms (SMNs) following prostate radiotherapy is a concern due to the large population of survivors and decreasing age at diagnosis. It is known that parallel-opposed beam proton therapy carries a lower risk than photon IMRT. However, a comparison of SMN risk following proton and photon arc therapies has not previously been reported. The purpose of this study was to predict the ratio of excess relative risk (RRR) of SMN incidence following proton arc therapy to that after volumetric modulated arc therapy (VMAT). Additionally, we investigated the impact of margin size and the effect …

Altered Responses To Endoplasmic Reticulum Stress In Pancreatic Cancer, Jennifer H. Choe

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) represents the fourth most common cause of cancer-associated death in the United States. Little progress has been made in understanding how proteotoxic stress affects rapidly proliferating pancreatic tumor cells. Endoplasmic reticulum (ER) stress occurs when protein homeostasis in the ER lumen is perturbed. ER stress activates the unfolded protein response (UPR) to reduce the protein load in the ER. Under conditions of moderate ER stress, the UPR promotes cell cycle arrest which allows time for successful protein load reduction and enables cell survival. However, under conditions of high levels of ER stress the UPR induces cellular …

Investigating The Effects Of Silencing Epha2 In Metastatic Breast Cancer Cells, Stephanie Erzinger

Dissertations and Theses (Open Access)

EphA2, also known as ECK (epithelial cell kinase), is a transmembrane receptor tyrosine kinase that is commonly over-expressed in cancers such as those of the prostate, colon, lung, and breast. For breast cancers, EphA2 overexpression is most prominent in the ER-negative subtype, and is associated with a higher rate of lung metastasis. Studies conducted to demonstrate the role of EphA2 in a non-cancerous environment have shown that it is very important in developmental processes, but not in normal adult tissues. These results make EphA2 a prospective therapeutic target since new therapies are needed for the more aggressive ER-negative breast cancers. …

The Neural Substrates Of Multisensory Speech Perception, Audrey R. Nath

Dissertations and Theses (Open Access)

Comprehending speech is one of the most important human behaviors, but we are only beginning to understand how the brain accomplishes this difficult task. One key to speech perception seems to be that the brain integrates the independent sources of information available in the auditory and visual modalities in a process known as multisensory integration. This allows speech perception to be accurate, even in environments in which one modality or the other is ambiguous in the context of noise. Previous electrophysiological and functional magnetic resonance imaging (fMRI) experiments have implicated the posterior superior temporal sulcus (STS) in auditory-visual integration of …

Stromal Derived Growth Factor Alpha (Sdf-1Α) Induces The Differentiation Of Bone Marrow Progenitor Cells (Bmcs) Into Pericytes By Regulating Platelet Derived Growth Factor B (Pdgf-B) Transcription, Randala Hamdan

Dissertations and Theses (Open Access)

We previously demonstrated that bone marrow cells (BMCs) migrate to TC71 and A4573 Ewing’s sarcoma tumors where they can differentiate into endothelial cells (ECs) and pericytes and, participate in the tumor vascular development. This process of neo-vascularization, known as vasculogenesis, is essential for Ewing’s sarcoma growth with the soluble vascular endothelial growth factor, VEGF₁₆₅, being the chemotactic factor for BMC migration to the tumor site. Inhibiting VEGF₁₆₅ in TC71 tumors (TC/siVEGF_7-1) inhibited BMC infiltration to the tumor site and tumor growth. Introducing the stromal-derived growth factor (SDF-1α) into the TC/siVEGF_7-1 tumors partially restored vasculogenesis …

The Role And Mechanism Of The Homeobox Gene Dlx4 In Transforming Growth Factor-B Resistance In Cancer, Bon Q. Trinh

Dissertations and Theses (Open Access)

Transforming growth factor-b (TGF-b) is a cytokine that plays essential roles in regulating embryonic development and tissue homeostasis. In normal cells, TGF-b exerts an anti-proliferative effect. TGF-b inhibits cell growth by controlling a cytostatic program that includes activation of the cyclin-dependent kinase inhibitors p15^Ink4B and p21^WAF1/Cip1 and repression of c-myc. In contrast to normal cells, many tumors are resistant to the anti-proliferative effect of TGF-b. In several types of tumors, particularly those of gastrointestinal origin, resistance to the anti-proliferative effect of TGF-b has been attributed to TGF-b receptor or Smad mutations. However, these mutations are absent from many …

Knowledge And Perception Of The Role Of Targeted Ultrasound In Detecting Down Syndrome Among A High Risk Population, Ashley M. Henriksen

Dissertations and Theses (Open Access)

The purpose of this study was to determine the perception and knowledge of targeted ultrasound in women who screen positive for Down syndrome in the first or second trimester, and to assess the perceived detection rate of Down syndrome by targeted ultrasound in this population.  While several studies have reported patient perceptions’ of routine ultrasound, no study has specifically examined knowledge regarding the targeted ultrasound and its role in detecting Down syndrome.  A targeted ultrasound is a special ultrasound during the second trimester offered to women who may be at a higher-than-average risk of having a baby with some type …

The Effects Of Curcumin On Body Composition Of Patients With Advanced Pancreatic Cancer, Henrique A. Parsons Md

Dissertations and Theses (Open Access)

Cachexia is very common among patients with advanced pancreatic cancer and is a marker of poor prognosis. Weight loss in cachexia is due to both adipose and muscle compartments, and sarcopenia (severe muscle depletion) is associated with worse outcomes. Curcumin has shown a myriad of biological effects, including anti-cancer and anti-inflammatory. The ability of curcumin to attenuate cachexia and muscle loss has been tested in animal models, with conflicting results so far. The hypothesis of this study was that patients with advanced pancreatic cancer treated with curcumin for two months have less fat and muscle loss as compared to matched …

Cell Cycle Regulatory Roles Of Estrogen Receptor Alpha (Erα) In Breast Cancer Cells, Sonia Javanmoghaddam

Dissertations and Theses (Open Access)

Previous studies have shown that Estrogen Receptor alpha (ERα) is an important indicator for diagnosis, prognosis and treatment of breast cancers. However, the question remains as to the role of ERα in the cell in the presence versus absence of 17-β estradiol  In this dissertation the role of ERα in both its unliganded and liganded state, with respect to the cell cycle will be explored.  The cell line models used in this project are ER-positive MCF-7 cells with and without siRNA to ERα and ER-positive MDA-MB-231 cells that have been engineered to express ERα. Cells were synchronized and the cell …

Physician Perceptions Of Risk Regarding Mood Disorders And Pharmacological Management During Pregnancy: What Is Current Practice?, Laura G. Hendon

Dissertations and Theses (Open Access)

Mood disorders are the most common form of mental illness and one of the leading causes of morbidity worldwide.  Major depressive disorder and bipolar disorder have a lifetime prevalence of 16.2% and 4.4%, respectively.  Women comprise a substantial proportion of this population, and an estimated 500,000 pregnancies each year involve women with a psychiatric condition.  Management with psychotropic medications is considered standard of care for most patients with mood disorders.  However, many of these medications are known human teratogens.  Because pregnant women with mood disorders face a high risk of relapse if unmanaged, the obstetrician faces a unique challenge in …

Cell Polarity Regulates Organ Growth Through The Hippo Pathway, Chiao-Lin Chen

Dissertations and Theses (Open Access)

Defects in apical-basal cell polarity and abnormal expression of cell polarity determinants are linked to human cancer. Loss of polarity is highly correlated with malignancy. In Drosophila, perturbation of apical-basal polarity, including overexpressing the apical determinant Crumbs, can lead to uncontrolled tissue growth. Cells mutant for the basolateral determinant scribble overproliferate and can form neoplastic tumors. Interestingly, scribble mutant clones that arise in wild-type tissues are eliminated and therefore do not manifest their tumorigenic potential. However, the mechanisms by which cell polarity coordinates with growth control pathways in developing organs to achieve appropriate organ size remain obscure.

To investigate …

Role Of Vitamin-D3 And Retinoic Acid In A Human Thp-1 Macrophage Model Of Mycobacterium Tuberculosis Infection, Jaymie L. Estrella

Dissertations and Theses (Open Access)

Mycobacterium tuberculosis (Mtb) replicates within the human macrophages and we investigated the activating effects of retinoic acid (RA) and vitamin D3 (VD) on macrophages in relation to the viability of Mtb. A combination of these vitamins (RAVD) enhanced the receptors on THP-1 macrophage (Mannose receptor and DC-SIGN) that increased mycobacterial uptake but inhibited the
subsequent intracellular growth of Mtb by inducing reactive oxygen species (ROS) and autophagy. RAVD also enhanced antigen presenting and homing receptors in THPs that suggested an activated phenotype for THPs following RAVD treatment. RAVD mediated activation was also associated with a marked phenotypic change in Mtb …

Multiple Posttranscriptional Regulatory Features Control Expression Of Ethanolamine Utilization Genes In Enterococcus Faecalis, Kristina A. Fox

Dissertations and Theses (Open Access)

Enterococcus faecalis is a Gram-positive bacterium that lives as a commensal organism in the mammalian gastrointestinal tract, but can behave as an opportunistic pathogen.  Our lab discovered that mutation of the eutK gene attenuates virulence of E. faecalis in the C. elegans model host.  eutK is part of the ethanolamine metabolic pathway which was previously unknown in E. faecalis.  I discovered the presence of two unique posttranscriptional regulatory features that control expression of eut locus genes.  The first feature I found is an AdoCBL riboswitch, a cis-acting RNA regulatory element that acts as a positive regulator of gene …

Gene Discovery In Nonsyndromic Cleft Lip With Or Without Cleft Palate, Brett T. Chiquet

Dissertations and Theses (Open Access)

Nonsyndromic cleft lip with or without cleft palate (NSCLP), a common, complex orofacial birth defect that affects approximately 4,000 newborns each year in the United States, is caused by both genetic and environmental factors. Orofacial clefts affect the mouth and nose, causing severe deformity of the face, which require medical, dental and speech therapies. Despite having substantial genetic liability, less than 25% of the genetic contribute to NSCLP has been identified. The studies described in this thesis were performed to identify genes that contribute to NSCLP and to demonstrate the role of these genes in normal craniofacial development. Using genome …

A Novel Function For Aurora B Kinase In The Regulation Of P53 By Phosphorylation, Chris P. Gully

Dissertations and Theses (Open Access)

The mitotic kinase Aurora B plays a pivotal role in mitosis and cytokinesis and governs the spindle assembly checkpoint which ensures correct chromosome segregation and normal progression through mitosis.  Aurora B is overexpressed in breast and other cancers and may be an important molecular target for chemotherapy.  Tumor suppressor p53 is the guardian of the genome and an important negative regulator of the cell cycle. Previously, it was unknown whether Aurora B and p53 had mutual regulation during the cell cycle.  A small molecule specific inhibitor of Aurora B, AZD1152, gave us an indication that Aurora B negatively impacted p53 …

Patient Characteristics And Outcomes Of Gastrointestinal Stromal Tumor Patients Undergoing Imatinib Plasma Level Testing, Laura Nolden

Dissertations and Theses (Open Access)

Although gastrointestinal stromal tumor (GIST) is effectively treated with imatinib, there are a number of clinical challenges in the optimal treatment of these patients. The plasma steady-state trough level of imatinib has been proposed to correlate with clinical outcome. Plasma imatinib level may be affected by a number of patient characteristics. Additionally, the ideal plasma trough concentration of imatinib is likely to vary based on the KIT genotype (genotype determines imatinib binding affinity) of the individual patient. Patients’ genotype or plasma imatinib level may influence the type and duration of response that is appreciable by clinical evaluation.

The objectives of …

Regulation Of Set1-Mediated Methylation Of Dam1, John A. Latham

Dissertations and Theses (Open Access)

Eukaryotic genomes exist within a dynamic structure named chromatin in which DNA is wrapped around an octamer of histones forming the nucleosome. Histones are modified by a range of posttranslational modifications including methylation, phosphorylation, and ubiquitination, which are integral to a range of DNA-templated processes including transcriptional regulation. A hallmark for transcriptional activity is methylation of histone H3 on lysine (K) 4 within active gene promoters. In S. cerevisiae, H3K4 methylation is mediated by Set1 within the COMPASS complex. Methylation requires prior ubiquitination of histone H2BK123 by the E2-E3 ligases Rad6 and Bre1, as well as the Paf1 transcriptional …

The Role Of Il-6 In Adenosine-Mediated Pulmonary Fibrosis, Mesias Pedroza

Dissertations and Theses (Open Access)

Adenosine is a purinergic signaling molecule that regulates various aspects of inflammation and has been implicated in the pathogenesis of chronic lung diseases. Previous studies have demonstrated that adenosine up-regulates IL-6 production through the engagement of the A_2B adenosine receptor in various cell types, including alveolar macrophages. IL-6 is elevated in mouse models and humans with chronic lung disease, suggesting a potential role in disease progression. Furthermore, chronic elevation of adenosine in the lungs of adenosine deaminase deficient (Ada^-/-) mice leads to the development of pulmonary inflammation, alveolar destruction, and fibrosis, in conjunction with IL-6 elevation. …