Life Sciences Commons^™

The Role Of The Cdk8 Kinase Module In Maintaining Proteostasis, Stephen Willis

Theses and Dissertations

The underlying etiology of numerous disease states results from perturbations in the maintenance of cellular proteostasis. Carcinogenesis relies on these perturbations to foster uncontrolled cell growth and eventual metastases, while neurodegenerative diseases are a consequence of such perturbations. Control of these processes occurs at numerous molecular levels, commonly starting with transcription. A key transcriptional complex that is involved is the CDK8 Kinase Module (CKM). The CKM is conserved from yeast to man, forming a tetrameric complex consisting of MED12, MED13, CDK8, and CCNC. The CKM has not only been implicated in a variety of cancers but also in a spectrum …

Characterizing Stress Granule Regulation By Pas Kinase, Ataxin-2 And Ptc6 And Investigating The Lifespan Of Covid-19 Virus On Currency, Colleen R. Newey

Theses and Dissertations

The protein Ataxin-2 is a known positive regulator of stress granules in humans, mice and yeast (known as yeast PBP1). Due to the role that stress granules play in diseases including Amyotrophic Lateral Sclerosis (ALS) and cancer, this thesis investigates the role of Ataxin-2 and its protein binding partners in stress granule development and its effects on various metabolic phenotypes of the cell. PAS kinase is a sensory protein kinase, conserved from yeast to man, which regulates respiration and lipid biosynthesis. Our lab discovered that PAS kinase phosphorylates and activates Ataxin-2 in yeast, and that PAS kinase overexpression enhances localization …

Comparing Efficiency, Empowerment, And Satisfaction Between Individual And Group Genetic Counseling For Prostate Cancer, Sarah Marie Dickman

Theses and Dissertations

A hereditary cause for prostate cancer can be identified in 5-17% of cases, which can impact treatment and cancer screening recommendations for patients and their families. Increased demand for genetic testing has necessitated consideration of alternative genetic counseling service delivery models to meet needs. Studies have shown that group genetic counseling increases efficiency while maintaining the same patient benefits as individual genetic counseling, but research has mainly focused on patients who were assigned female at birth (AFAB). The purpose of this study was to evaluate the utility of group genetic counseling for prostate cancer by assessing participants’ satisfaction and feelings …

Evaluating Health Awareness In Cancer Genetics Amongst The Black And African American Community In South Carolina, Annika Jaliya Gadson

Theses and Dissertations

Historically minoritized individuals are underrepresented in genomic research which limits the ability to fully understand genetic variation within the population (Sirugo et al., 2019). This creates bias that questions the effectiveness of guidelines for genetic testing, predictive risk values, and medical management. Disparities in cancer genetics may be attributed to historical events that have cultivated mistrust in research and medicine, institutional bias, provider skepticism in patient reporting of medical symptoms, and limited access to genetic testing (Saulsberry et al., 2013). More exploration is needed to better understand how to increase access and awareness of cancer genetic services to Black and …

Protacs – A Novel And Rapidly Developing Field Of Targeted Protein Degradation, Hannah R. Gatley

Theses and Dissertations

There is a continued need for new technology and strategies for tackling cancer and other diseases, and within the current century a novel therapeutic strategy has emerged in the realm of targeted protein degradation called Proteolysis-Targeting Chimeras (PROTACs). This technology specifically targets and degrades disease-causing proteins via the ubiquitin-proteasome system, and has seen an explosion of research and intrigue in both academia and industry over the past two decades. The diversity of PROTAC classes based on the E3 ligase recruiting ligand and the target protein allows for a universal molecular structure that can be customized for a specific target and …

Xenobiotic Exposures On Women’S Reproductive Health, Maria Zubizarreta Mcclam

Theses and Dissertations

Environmental and chemical exposures are continually introduced into our bodies. The female reproductive cycle is complex and particularly sensitive to toxic substances. A recent rise in infertility and reproductive diseases and cancers make reproductive toxicity a public health concern. The overall purpose of this dissertation is to explore how environmental and chemical exposures impact women’s reproductive health and overall wellbeing. To do this, a variety of topics related to women’s reproductive health are explored, including how environmental exposures can impact reproduction, methods for studying reproductive dysfunctions, fertility preservation among cancer patients, and the overall wellbeing of female cancer patients.

The …

Human Papillomavirus 16 E2 Regulates Host Cell Pathways Important For Cancer Progression And Treatment Sensitivity Which May Contribute To Cancer Outcomes, Christian Fontan

Theses and Dissertations

Human papillomaviruses (HPVs) are causative agents in around 5% of all cancers, including cervical and oropharyngeal. A feature of HPV cancers is their better clinical outcome compared with non-HPV anatomical counterparts. In turn, the presence of E2 predicts a better clinical outcome in HPV-positive cancers; the reason(s) for the better outcome of E2-positive patients is not fully understood.

Previously, we demonstrated that HPV16 E2 regulates host gene transcription that is relevant to the HPV16 lifecycle in N/Tert-1 cells. One of the genes repressed by E2 and the entire HPV16 genome in N/Tert-1 cells is TWIST1. In these studies, we demonstrate …

Changes In Physical Activity And Relationships To Submaximal Exercise Capacity And Cardiac Function During Breast Cancer Therapy, Moriah P. Bellissimo

Theses and Dissertations

Background: Breast cancer (BC) survivors are at high risk for heart failure due to curative cancer therapies. In non-cancer populations, physical activity is a first line treatment for preventing cardiovascular disease. This study examined whether more physical activity was associated with better submaximal exercise capacity and cardiac function during the first three months of cancer therapy.

Methods: Participants included 223 women with stage I-III BC before therapy and after three months of undergoing treatment and 126 controls. Leisure time physical activity was reported using the Godin Sheppard leisure time exercise questionnaire. Cardiac function was assessed by cardiac magnetic resonance, and …

Investigating Bmp7 Expression In Glioblastoma Multiforme, Yajaira Janett Macias

Theses and Dissertations

The PI3K/AKT/mTOR pathway regulates important cell processes such as growth, survival, motility, inflammation, proliferation, and apoptosis. In Glioblastoma multiforme (GBM) the PI3K/AKT/mTOR pathway is aberrant as it is almost always active. This results in the deregulation of downstream molecules and ultimately leads to cancer progression and maintenance in GBM tumors. In this study, we used RNA-sequencing to identify differentially expressed genes (DEGs) in U87MG GBM cells treated with NVP-BEZ235, a dual inhibitory drug targeting PI3K and mTOR. A total of 7,803 differentially expressed genes were identified via RNA-seq. GEPIA2 online tool was used to assess differential gene expression …

Handgrip Strength In Cancer Survivors: 2011-2014 National Health And Nutrition Examination Survey, Ayla Monet Kibler

Theses and Dissertations

Cachexia, or a loss of muscle mass, has been identified as a potential indicator of cancer survival rates. Previous explorations in research have connected muscular strength to muscle loss and cancer survivorship, but nationally generalizable findings are limited. PURPOSE: To investigate handgrip strength in cancer survivors using the National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of US adults. METHODS: The analysis included 368 males and 425 females from the 2011-2014 NHANES dataset. Cancer survivor information (type of cancer and age of diagnosis) was determined by questionnaire. Cancer types were grouped into the following: skin cancers, reproductive …

Assessing The Anticipated Needs Of Transgender Patients In Cancer Genetic Counseling, Jacqueline Baquet

Theses and Dissertations

Most cancers are sporadic, but 5-10% of all cancer is hereditary, or caused by a heritable genetic mutation. A patient’s medical history, family history, genetic test results, intact organs (e.g., ovaries) at an increased risk for developing cancer, and the availability and accessibility of interventions are used to make recommendations for cancer-risk management. In addition to basic medical care, transgender patients have healthcare needs that differ from those of cisgender patients such as expert care related to using hormones or having gender-affirming surgery, as well as unique mental health concerns. Transgender individuals may also experience a greater number of barriers …

Exploration Of Patient Communication Preference Regarding Reclassified Genetic Test Results, Cooper Nicole Hall

Theses and Dissertations

Genetic testing is becoming increasingly used to detect individuals who are predisposed to developing cancer. If genetic testing identifies a variant in an individual’s DNA, the testing laboratory uses available data to classify the variant as either disease-causing or benign. When limited data is available regarding a variant’s pathogenicity and the risk of cancer for an individual is not clear, the variant is classified as a “variant of uncertain significance” (VUS). If new data is discovered, the VUS may be reclassified. There is a gap in current literature regarding desired communication for a reclassified genetic test result. There are no …

Genetic Analysis Of Pi3k And Mtor Inhibition In U87mg Glioblastoma Cell Line, Carl G. Litif

Theses and Dissertations

NVP-BEZ235 is a Glioblastoma Multiform chemotherapeutic dual PI3K/mTOR pathway inhibitor created in 2008 and has since been proven experimentally to induce pluripotentcy in oncological cell populations. The inhibition of PI3K and mTOR has shown to coerce phenotypes associated with stem cell markers, most notably OCT4. It is necessary to understand the genetic composure of how PI3K/mTOR inhibited tumor cells are bypassing the canonical pathway for proliferation and growth and utilizing other parallel sources for tumor invasion into other neural regions. Taking a genetic approach with RNA-sequencing allowed us to gain insight into how glioblastoma interact with cytoskeleton factors MAPK4 and …

Investigating The Localization Of Foxo Transcription Factors In Glioblastoma, Leetoria Hinojosa

Theses and Dissertations

The Phosphatidylinositol 3 Kinase (PI3K) pathway is an essential intracellular signaling pathway that regulates cellular growth, survival, and fate. Canonically, the activation of this pathway removes forkhead box subfamily O transcription factors (FOXO -1, -3, and -4) from the nucleus. However, in cancer cells such as glioblastoma multiforme, FOXO factors are at least in part nuclear despite the activation of the PI3K pathway. Previous research indicated that FOXO3 localization was not affected when the pathway was inhibited in breast cancer cells, which challenged the conventional paradigms for FOXO factor regulation. Therefore, we were interested in investigating the nuclear localization of …

Evidence For P53-Mediated Induction Of Wrap53a In Response To Dna Damage, Anne Shelton Hucks

Theses and Dissertations

p53 is a powerful tumor suppressor mutated in approximately half of all cancers. Its mRNA is stabilized post-transcriptionally via complementary base pairing with the transcript of its antisense gene, WRAP53α; without this interaction, p53 protein cannot accumulate enough to carry out its many functions related to apoptosis, cell cycle arrest, and DNA damage repair. Previous studies have shown that WRAP53α is induced in response to DNA damage. The purpose of this study was to determine which transcription factors might be responsible for this induction. After identifying three putative p53 binding sites on the WRAP53α promoter, we used chromatin immunoprecipitation …

Synthetic Lectins, A Diagnostic And Prognostic Tool For Detecting Glycans In Breast Cancer, Daniel James Gordon

Theses and Dissertations

Cancer diagnostic tools have been pushed to the forefront of medical research because a person’s chance of survival is directly correlated with how early the tumor is identified and treatment is begun. In searching for the subtle differences between healthy and tumor cells, almost every type of cancer has been shown to under, over, or neo express glycans, and these changes in the glycan fingerprint can continue as the disease progresses. This provides a powerful diagnostic opportunity that’s works by screening for glycoproteins and glycosylation patterns that deviate from normal cells.

Boronic acids have a useful and tunable property in …

Exploring Patient Perceptions And Misconceptions: Beliefs Regarding Hereditary Cancer, Margaret Flach

Theses and Dissertations

Many patients who enter a genetic counseling session have preconceived notions about why they or their family members developed a genetic condition. Often these perceptions are deeply rooted in personal, familial, and/ or cultural beliefs; individuals typically have a personal framework, or schema, into which they incorporate new information. There is limited research on what information patients are retaining during a genetic counseling session and how they are assimilating that knowledge into their existing views. We attempted to characterize these patient perceptions with respect to hereditary cancer, in order to assess how patients are adopting the information presented in a …

The Regulation Of Skeletal Muscle Fatigue During The Progression Of Cancer Cachexia, Brandon N. Vanderveen

Theses and Dissertations

Cachexia is the unintentional loss of body weight secondary to chronic disease and is prevalent is roughly 50% of cancer patients. The loss of body weight and skeletal muscle mass is reduced functional capacity associated with reduced life quality. The etiology of cachexia is multimodal and complex; however, cachexia has been linked to several systemic (e.g. chronic inflammation, hypogonadism, anemia, insulin resistance) and behavioral (e.g. anorexia, inactivity) changes that can compound to accelerate muscle mass and body weight loss. While several inflammatory cytokines are associated with cachexia’s disease progression, our laboratory has established that Interleukin-6 (IL-6) is a key regulator …

Investigating The Role Of Nuclear Foxo3 In Pten-Null Glioblastomas, Lilia Sanchez

Theses and Dissertations

The PI3K pathway activates AKT, leading to inactivation of FOXO transcription factors. Loss of PTEN results in constitutive inactivation of tumor suppressor FOXO. There is increasing evidence that FOXO resides and promotes transcriptional activity in the nucleus despite high PI3K output within certain advanced cancers and embryonic stem cells. Here, we investigate the regulation and roles of FOXO transcription factors in glioblastoma and basal breast cancer. First, we built and published genetic models to investigate the roles of FOXO transcription factors in cancer cell lines for glioblastoma (U87MG). We examined the function of FOXO transcription factors using these genetic models …

Metabolic Dysregulation: An Investigation Of The Role Of Foxo3 In Gluconeogensis In Pten-Null Glioblastomas, Victor Fanniel

Theses and Dissertations

Many processes are regulated by the Phosphatidylinositol 3 kinase (PI3K) pathway in the cell including cell survival, metabolism, and apoptosis. Increased activation of the PI3K pathway is a hallmark of many cancers which can be oftentimes attributed to the mutation of PTEN, which encodes an enzyme that performs the reverse reaction of PI3K. When PTEN is null-mutated, this creates a constitutively active PI3K pathway and constitutively active AKT. Since AKT phosphorylates conserved residues on FOXO transcription factors to mark them for nuclear export, this renders FOXO inactive. However, new research has provided evidence that FOXO is still present in …

The Role Of Mdm2 In Dna Damage Signaling, Stanley Tam

Theses and Dissertations

The overexpression of the oncogene MDM2 is common in a variety of human cancers. MDM2 overexpression is known to increase genome instability in cells by delaying DNA double strand break repair and γH2AX levels. This study explores the knockdown of MDM2 and how it may affect DNA damage signaling.

Evaluation And Adaptation Of Live-Cell Interferometry For Applications In Basic, Translational, And Clinical Research, Kevin A. Leslie

Theses and Dissertations

Cell mass is an important indicator of cell health and status. A diverse set of techniques have been developed to precisely measure the masses of single cells, with varying degrees of technical complexity and throughput. Here, the development of a non-invasive, label-free optical technique, termed Live-Cell Interferometry (LCI), is described. Several applications are presented, including an evaluation of LCI’s utility for assessing drug response heterogeneity in patient-derived melanoma lines and the measurement of CD3+ T cell kinetics during hematopoietic stem cell transplantation. The characterization of mast cells during degranulation, the measurement of viral reactivation kinetics in Kaposi’s Sarcoma, and drug …

Novel Insights Into The Contribution Of Cellular Senescence To Cancer Therapy: Reversibility, Dormancy And Senolysis., Tareq Saleh

Theses and Dissertations

Cellular senescence a specialized form of growth arrest that contributes to the pathogenesis of several aging-related disorders including cancer. While by definition tumor cells are considered immortalized, they can undergo senescence when exposed to conventional and targeted cancer therapy. Therapy-Induced Senescence (TIS) represents a fundamental response to therapy and impacts its outcomes. However, TIS has been considered a positive therapeutic goal since senescent tumor cells are expected to enter a state of permanent growth abrogation. In this work we examined the hypothesis that a subpopulation of senescent cells can re-acquire proliferative potential after a state of senescent dormancy, indicating that …

Histone Deacetylase Inhibition Induces Apoptosis And Cell Cycle Dysregulation In Human And Murine Cancer Cell Lines, Joseph Skurski

Theses and Dissertations

Carcinogenesis is a complex multistep process that requires tumor cells to grow rapidly while overcoming growth inhibitory signals and sustained challenges from the host immune response. Mutations within promoter or enhancer regions, along with epigenetic changes, can induce aberrant expression of genes that regulate differentiation, cell cycle, and apoptosis, all of which enhance potential for cellular transformation. In recent years, our understanding of the biological processes that influence the activation and repression of transcription have evolved to highlight the role of chromatin architecture, and how chromatin remodeling may be utilized for the potential therapeutic benefit of genetic disease. Histone deacetylase …

Characterization Of Staphylococcal Nuclease And Tudor Domain Containing Protein 1 (Snd1) As A Molecular Target In Hepatocellular Carcinoma And Non-Alcoholic Steatohepatitis, Nidhi H. Jariwala

Theses and Dissertations

CHARACTERIZATION OF STAPHYLOCOCCAL NUCLEASE AND TUDOR DOMAIN CONTAINING PROTEIN 1 (SND1) AS A MOLECULAR TARGET IN HEPATOCELLULAR CARCINOMA AND NON-ALCOHOLIC STEATOHEPATITIS

Nidhi Jariwala, PhD

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Integrative Life Sciences

Virginia Commonwealth University, 2017

Devanand Sarkar, M.B.B.S., PhD.

Associate Professor, Department of Human and Molecular Genetics

Virginia Commonwealth University

Richmond, Virginia

SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). Oncoprotein SND1 regulates gene expression at a post-transcriptional level in multiple cancers including hepatocellular carcinoma (HCC). …

The Role Of Viral Interleukin-6 In Tumor Development Of Kaposi's Sarcoma-Associated Herpesvirus Lymphomas, Rebecca A. Fullwood

Theses and Dissertations

Kaposi's sarcoma herpesvirus (KSHV) is a cancer-causing virus, primarily affecting AIDS patients. KSHV is found in 3-10% of the U.S. population and can cause a range of cancers in the highly immunosuppressed; these cancers include Kaposi's sarcoma, pleural effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). The current techniques for treating these cancers are relatively ineffective, largely due to their inefficiency at targeting tumors formed by the infection. One protein produced by KSHV, the viral homolog of interleukin-6 (vIL-6), is thought to play a major role in tumor development post-infection. Here a novel animal model is implemented to study the …

Re-Contacting Cancer Genetic Counseling Patients: Expectations Of Patients And Physicians, Zoe Elizabeth Siegel

Theses and Dissertations

The landscape of cancer genetic counseling and testing is rapidly evolving. Genetic testing technology is improving, management guidelines are evolving, and genetic testing options are expanding. These frequent updates to the components of cancer genetics have increased the complexity of managing patient care over time. In particular, this raises questions on the duty to re-contact patients as new information becomes available. This study explored healthcare providers’ duty to re-contact through the interests and expectations of patients, including which circumstances warrant re-contacting, which healthcare provider is responsible for re-contacting the patient, and the preferred method of re-contacting. Physicians’ opinions on whether …

Nitric Oxide Synthase Activity And Its Modulation In The Treatment Of Colorectal Cancer, Asim Alam

Theses and Dissertations

The American Cancer Society estimates more than 141,000 new cases of and about 50,000 deaths from colorectal cancer every year. Treatment options include surgery, radiation therapy and targeted therapies such as anti-angiogenics. However, no therapies address the key driving factor of colorectal cancer: inflammation. It is well known that chronic inflammatory conditions such as Crohn’s Disease, ulcerative colitis, diabetes, obesity and cigarette smoking all elevate the risk of developing colorectal cancer. One of the hallmarks of chronic inflammation is the elevated levels of reactive oxygen/nitrogen species (ROS/RNS). A primary source of these ROS/RNS is uncoupled Nitric Oxide Synthase (NOS). Under …

Interaction Between Atm Kinase And P53 In Determining Glioma Radiosensitivity, Syed F. Ahmad

Theses and Dissertations

Glioblastoma multiforme (GBM) is the most common primary brain tumor. Studies have shown that targeting the DNA damage response can sensitize cancer cells to DNA damaging agents. Ataxia telangiectasia mutated (ATM) is involved in signaling DNA double strand breaks. Our group has previously shown that ATM inhibitors (ATMi) sensitize GBM cells and tumors to ionizing radiation. This effect is greater when the tumor suppressor p53 is mutated.

The goals of this work include validation of a new ATM inhibitor, AZ32, and elucidation of how ATMi and p53 status interact to promote cell death after radiation. We propose that ATMi and …

Novel Drug 2-Benzoyl-3-Phenyl 6,7-Dichloroquinoxaline 1,4-Dioxide Induces Colon Cancer Cell Apoptosis Through Hif-1Α Pathway, Alexander-Jacques Theodore Sougiannis

Theses and Dissertations

Recent developments in the field of cancer genomics have shown transcription factor HIF-1α as a major player in the survival and proliferation of colorectal tumors. Hypoxia targeted drug engineering has led to significant advancements in cancer treatments as a method of directly utilizing the hypoxic regions against the tumor. Novel drug DCQ (2-benzoyl-3-phenyl 6,7-dichloroquinoxaline 1,4-dioxide) has shown promising anti-tumor results in-vitro and in-vivo. The purpose of this study was to utilize a tumor xenograft and genetic mouse model of colorectal cancer to investigate the safety, clinical effectiveness, and mechanism of action of DCQ. Methods: 10 week old Balb/c mice were …