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

Dissertations & 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 …

The Role Of Dual Specificity Phosphatase -11 In Innate And Adaptive Immune Responses, Kalyan Chakravarthy Nallaparaju

Dissertations & Theses (Open Access)

THE ROLE OF DUAL SPECIFICITY PHOSPHATASE -11 IN INNATE AND ADAPTIVE IMMUNE RESPONSES

Kalyan Chakravarthy Nallaparaju, M.S.

Supervisory Professor: Chen Dong, Ph.D.

Dual-specificity phosphatases (DUSPs) constitute a subfamily of protein tyrosine phosphatases characterized by their ability to dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues within a substrate, typically among members of the MAP kinase family. DUSPs have been shown to play a critical role in the regulation of various cellular processes including signal transduction, cell cycle regulation and cellular proliferation via modulation of MAP kinase activities. Also, many members of this family have been demonstrated to be potent immune regulators. …

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

Dissertations & 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 …

The Role Of Mir-34a In Inhibition Of Prostate Tumor Growth In The Bone And Induction Of Autophagy, Sanchaika Gaur

Dissertations & Theses (Open Access)

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in the United States, with most deaths occurring from bone metastasis. Several new therapies have been FDA approved for bone-metastatic PCa, but patient survival has only marginally improved due to therapy resistance, which often arises from constitutive activation of compensatory signaling pathways. This dissertation work focused on a mechanistic understanding of how cross talk between tyrosine kinase receptors contributes to therapy resistance, and how this may be overcome by downregulating expression of these receptors. In PCa cell lines and xenograft models, I demonstrated that activation of IGF-1R …

Mdm2-Mediated Degradation Of Sirt6 Phosphorylated By Akt1 Promotes Tumorigenesis And Trastuzumab Resistance In Breast Cancer, Umadevi Thirumurthi

Dissertations & Theses (Open Access)

Sirtuin6 (SIRT6) is one of the members of the Sirtuin family and functions as a longevity assurance gene by promoting genomic stability. It also regulates various cancer-associated pathways and was recently established as a bonafide tumor suppressor in colon cancer. This suggests that SIRT6 is an attractive target for pharmacological activation in cancer treatment, and hence, identification of potential regulators of SIRT6 would be an important and critical contribution towards cancer treatment. Here, we show that AKT1 phosphorylates SIRT6 at Ser³³⁸ and induces MDM2-SIRT6 interaction, priming SIRT6 for degradation via the MDM2-dependent ubiquitin-proteasome pathway. Blocking SIRT6 Ser³³⁸ phosphorylation …

Identification Of Cell Signaling Pathway Regulated By Micrornas In Cancer Cells Using A Systems Biological Approach, Sangbae Kim

Dissertations & Theses (Open Access)

MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules that regulate gene expression via imperfect binding of the miRNA to specific sites in the 3' untranslated region of the mRNAs. Because prediction of miRNA targets is an essential step for understanding the functional roles of miRNAs, many computational approaches have been developed to identify miRNA targets. However, identifying targets remains challenging due to the inherent limitation of current prediction approaches based on imperfect complementarity between miRNA and its target mRNAs. To overcome these current limitations, we developed a novel correlation-based approach that is sequence independence to predict functional targets of miRNAs by …

Named Entity Recognition In Chinese Clinical Text, Jianbo Lei

Dissertations & Theses (Open Access)

Objective: Named entity recognition (NER) is one of the fundamental tasks in natural language processing (NLP). In the medical domain, there have been a number of studies on NER in English clinical notes; however, very limited NER research has been done on clinical notes written in Chinese. The goal of this study is to develop corpora, methods, and systems for NER in Chinese clinical text.

Materials and methods: To study entities in Chinese clinical text, we started with building annotated clinical corpora in Chinese. We developed an NER annotation guideline in Chinese by extending the one used in the 2010 …

Swarna Ramaswamy_Thesis, Swarna S. Ramaswamy

Dissertations & Theses (Open Access)

STRUCTURAL INVESTIGATIONS OF LIGAND GATED ION CHANNELS

Swarna Ramaswamy, B.S

Advisor: Vasanthi Jayaraman, Ph.D.

Ion channels form an integral part of membrane proteins. In the nervous system including the central and the peripheral nervous system, ligand gated ion channels form a very important part of intercellular communications. They receive chemical signals and convert them to electrical signal, mainly by allowing ion passage across the cell membrane. Ion passage also translates into downstream signaling events. Faithful translation of these signals and transmittance is crucial for several physiological functions, implying that irregular ion channel function could lead to serious consequences.

This thesis …

In Vivo Dosimetry Using Plastic Scintillation Detectors For External Beam Radiation Therapy, Landon S. Wootton

Dissertations & Theses (Open Access)

In vivo dosimetry, the direct measurement of dose delivered to patients during radiation therapy, has significant potential in ensuring safe and effective treatment in radiation therapy. It can serve as point-of-delivery, patient specific quality assurance and direct verification of treatment. Despite evidence that in vivo dosimetry can detect errors in patient treatment that would otherwise go undetected, it is not commonly practiced. This is due in part to a lack of available detectors ideally suited to perform in vivo dosimetry. Plastic scintillation detectors (PSDs) possess a number of dosimetric characteristics advantageous for in vivo dosimetry including water equivalence, real-time capability, …

Hypoxia Mediated Downregulation Of Mirna Biogenesis Leads To Increased Tumor Progression, Rajesha Rupaimoole

Dissertations & Theses (Open Access)

In recent years, there has been a growing recognition of the importance of tumor associated microenvironment in the initiation and progression of tumors. However, a mechanistic understanding of the complicated biological interplay between the stromal framework and malignant regions of the tumor remains incompletely understood. In this study, we address mechanisms by which hypoxia in the tumor microenvironment leads to attenuation of miRNA biogenesis by downregulation of two key enzymes, Drosha and Dicer in cancer cells. Previous data from our laboratory had shown the clinical relevance of downregulated Dicer and Drosha in ovarian and other cancer types, but a clear …

Effects Of Oxytocin On Human Aggression, Joseph L. Alcorn Iii

Dissertations & Theses (Open Access)

EFFECTS OF OXYTOCIN ON HUMAN AGGRESSION

Joseph Louis Alcorn III, B.S.

Advisory Professor: Scott D. Lane, Ph.D.

Human interaction is comprised of common, yet complex, behaviors and the outcomes of these social behaviors can beneficially or detrimentally impact individual and public health. One social behavior that can have profound detrimental outcomes is aggression. Aggression is a class of social behavior that is particularly prevalent in individuals with antisocial personality disorder (ASPD) and comorbid substance use disorder (SUD). Aggression in these individuals can manifest at maladaptive levels that place considerable burdens on public health and communities. Therefore, understanding the neurobehavioral underpinnings …

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

Dissertations & 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 …

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

Dissertations & 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 …

Regulation Of Functional Expression Of Mechanosensitive Trpv4 Channel In The Distal Nephron By Dietary Potassium And Sodium Intake, Nabila Boukelmoune

Dissertations & Theses (Open Access)

The Ca²⁺-permeable TRPV4 channel is predominantly expressed in the distal nephron (DN) and its activity is essential for [Ca²⁺]_i elevations in response to increased tubular flow. Here, I probed the physiological mechanisms controlling TRPV4 function and expression in the DN. I found that renal TRPV4 expression and mRNA levels were significantly increased by high K⁺ diet (5%) and decreased by dietary K⁺ restriction (0.003%). In contrast, variations in Na⁺ regimen had no apparent effect on TRPV4 expression and mRNA levels. Regulation of TRPV4 protein expression by K⁺ diet was independent of …

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

Dissertations & 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 …

Sustained Adrenergic Signaling Promotes Cervical Cancer Progression, Nouara C. Sadaoui

Dissertations & Theses (Open Access)

Background: Chronic stress and sustained adrenergic signaling are known to promote tumor progression. The underlying mechanisms behind this process are not well understood. We examined the effects of sustained adrenergic signaling on cervical cancer progression through increased expression of HPV oncogenes, E6 and E7.

Materials and Methods: ADRβ expression levels were examined in patient-derived cervical cancer samples. We used an orthotopic model of cervical cancer to investigate the effects of restraint stress on tumor growth and metastasis. We evaluated the in vivo effects of a β-blocker, propranolol, and HPV E6/E7 siRNA. In vitro, ADRβ positive cervical cancer cells were …

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

Dissertations & 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 …

Lkb1 Deficient Non-Small Cell Lung Cancer Cells Are Vulnerable To Energy Stress Induced By Atp Depletion, Chao Yang

Dissertations & Theses (Open Access)

Lung cancer is the second most frequent cancer in United States, which represents about 13.5% of new cancer cases every year. It accounts for about 27.2% of all cancer related deaths, which is more than the sum of deaths caused by prancretic, breast and colorectal. On average, only about 16% of lung cancer patients survive beyond 5 years. LKB1 is the third most mutated gene in lung cancer. It has been shown that LKB1 is mutated in at least 15% to 30% of NSCLC. Tumor with LKB1 mutation is associated with poor differentiation, high metastasis and worse response to chemotherapy. …

Investigating Checkpoint Kinases 1/2 As Novel Therapeutic Targets In Head And Neck Squamous Cell Carcinoma, Mayur Arvind Gadhikar

Dissertations & Theses (Open Access)

Cisplatin, despite being the cornerstone chemotherapy for the treatment of head and neck squamous cell carcinoma (HNSCC), provides clinical benefits in just a subset of patients. This together with the lack of biomarkers predicting therapeutic responses, have led to unacceptably high rate of treatment failures in HNSCC. TP53 is the most frequently mutated gene in HNSCC, and the effect of p53 loss or mutation on cisplatin responses in HNSCC is poorly understood. In the current study, we hypothesized that HNSCC cells respond to cisplatin in a p53 dependent manner and unambiguously show that presence of wild-type TP53 (wtp53) confers sensitivity …

A Novel Tablet Based System To Measure The Effect Of Subconcussive Blows On Sensorimotor And Cognitive Functioning, Stuart D. Red

Dissertations & Theses (Open Access)

Concussions have become a major societal concern with studies showing detrimental short and long-term effects on cognitive and sensory functioning. More recently, research has begun to focus on “subconcussive” blows to the head. Subconcussive blows, which are common in many sports (soccer, boxing, football, etc), do not result in the more obvious symptoms of a concussion but have the potential to cause severe brain injury. In our lab and others, eye movements have been used as a sensitive marker of cognitive and sensory changes related to specific diseases and treatments. We have developed a novel measure based on eye movement …

Sox2-Dependent Transcriptional Control Of Airway Differentiation In The Mouse Lung, Belinda J. Hernandez

Dissertations & Theses (Open Access)

The lung is a highly branched tree-like tubular system that results from more than 20 generations of the conducting airways and consists of 300 million alveoli for gas exchange. Airway branches form via branching morphogenesis and then mature into conducting airways, in which the number and distribution of different cell types need to be precisely controlled. The conducting airways contain four lung cell types: club cells, ciliated cells, basal cells, and neuroendocrine cells.SOX2 is a well-known conducting airway marker. SOX2 is a transcription factor that is known to be important in embryonic development and induction of pluripotent stem cells. We …

P120-Catenin Regulates Rest And Corest, And Modulates Mouse Embryonic Stem Cell Differentiation, Moonsup Lee

Dissertations & Theses (Open Access)

The canonical-Wnt pathway and beta-catenin have been extensively studied to determine their contributions to stem cell biology, but less is known about p120-catenin in the nuclear compartment. P120 is developmentally required as a consequence of its biochemical and functional interactions with cadherins, small-GTPases and transcriptional regulators. We report here that p120-catenin binds to and negatively regulates REST and CoREST, that others have indicated form a repressive complex having diverse key roles in developmental and pathologic gene regulation. We thus provide the first evidence for a direct upstream modulator of REST/CoREST function. Using mouse embryonic stem cells (mESCs), mammalian cell lines, …

Quantitative Analysis And Imaging-Based Insights Into The Characteristics And Mechanisms Of Yeast Pattern Formation, Lin Chen

Dissertations & Theses (Open Access)

Biofilm formation is a common lifestyle adapted by bacteria and fungi in response to various environmental stresses. Bacterial and fungal biofilms adhering to medical devices convey resistance to antibiotics or biocides, causing high rates of clinical infections. Microorganisms are protected from harsh environmental conditions by reduced stress penetration through the complex biofilm architecture with distinct patterns. Although the molecular regulations of surface patterning have been well characterized in bacteria, the mechanisms underlying the complex pattern formation in eukaryotic biofilms remain unclear.

This dissertation aims to investigate the salient features of robust colony expansion in yeast biofilms and the processes driving …

Role Of Phosphorylation Of Focal Adhesion Kinase At Tyrosine 861 In Prostate Cancer Metastasis, Tanushree Chatterji

Dissertations & Theses (Open Access)

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that mediates interactions between the extracellular matrix and intracellular signaling pathways critical in promoting numerous cellular functions including adhesion, proliferation, survival and migration. Most FAK functions result from phosphorylation by Src family kinases, which trigger numerous signaling cascades. Overexpression of FAK is associated with metastasis in many solid tumors, including prostate cancer. Hence, understanding the mechanisms by which FAK is regulated in prostate cancer will better elucidate its role in prostate cancer metastasis. Work in this dissertation tested the hypothesis that altered phosphorylation of FAK is critical for cell migration and …

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

Dissertations & 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 …

Novel Posttranslational Modification In Lkb1 Activation And Function, Szu-Wei Lee

Dissertations & Theses (Open Access)

Cancer cells display dramatic alterations in cellular metabolism to meet their needs of increased growth and proliferation. In the last decade, cancer research has brought these pathways into focus, and one emerging issue that has come to attention is that many oncogenes and tumor-suppressors are intimately linked to metabolic regulation (Jones and Thompson, 2009). One of the key tumor-suppressors involved in metabolism is Liver Kinase B1 (LKB1). LKB1 is the major upstream kinase of the evolutionarily conserved metabolic sensor—AMP-activated protein kinase (AMPK). Activation of the LKB1/AMPK pathway provides a survival advantage for cells under energy stress. LKB1 forms a heterotrimeric …

Change Detection In Rhesus Monkeys And Humans, Deepna T. Devkar, Deepna T. Devkar

Dissertations & Theses (Open Access)

Visual working memory (VWM) is the temporary retention of visual information and a key component of cognitive processing. The classical paradigm for studying VWM and its encoding limitations has been change detection. Early work focused on how many items could be stored in VWM, leading to the popular theory that humans could remember no more than 4±1 items. More recently, proposals have suggested that VWM is a noisy, continuous resource distributed across virtually all items in the visual field, resulting in diminished memory quality rather than limited quantity. This debate about the nature of VWM has predominantly been studied with …

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

Dissertations & 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 …

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

Dissertations & 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 …

Masculinity, Male Empowerment, And Hiv/Aids Risk In Caprivi, Namibia, Mark Perry

Dissertations & Theses (Open Access)

Namibia has a generalized HIV epidemic, with 13% of adults being infected. Its East Caprivi Region has the highest prenatal HIV prevalence in the country, 21%, among girls and women aged 15-24 years. In recent years, researchers have pointed to men who express their masculinity through high-risk sex as driving the epidemic in East Caprivi. This exploratory study examined the role that men and their masculinity concepts played in transmission, how those concepts were evolving over time, what was influencing the change, and in which directions. Employing grounded theory methods and guided by Robert Connell's theoretical framework on masculinities, the …