Medicine and Health Sciences Commons^™

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 …

Using Geospatial Analysis To Evaluate Relationships Between Cancer Incidence And Social Factors In Brooklyn, Ny, Sheena Philogene

Theses and Dissertations

This study explored the spatial distribution of cancer incidence in Brooklyn, NY. Using publicly available data, the relationships between cancer incidence and factors linked to cancer were investigated. Furthermore, the study explored the value of using large amounts of data with GIS techniques to quickly analyze geographic trends for cancer.

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 …

A Multilevel And Spatial Analysis Of Oral And Pharyngeal Cancer In South Carolina, Deborah M. Hurley

Theses and Dissertations

Objective: Disparities in the distribution of oral and pharyngeal cancer exist worldwide. This is also true in the United States and in South Carolina. Differences exist in oral and pharyngeal cancer stage and survival by race and sex, with higher incidence rates for Whites but higher proportions of late-stage cancer and lower survival for Blacks. This study was conducted to evaluate whether any differences exist in the spatial distribution of oral and pharyngeal cancer stage at diagnosis and survival, and to evaluate the association of income inequality, material deprivation and other measures of social determinants of health (contextual risk factors) …

Design And Synthesis Of Macrocyclic Peptide Braf-Wt Dimerization Inhibitors For The Treatment Of Metastatic Melanoma, Chad Mulloy Beneker

Theses and Dissertations

In cases of metastatic melanoma, BRAF is frequently mutated to the V600E oncoprotein causing uncontrolled cell proliferation driven by the MAPK-ERK pathway. There are several BRAF inhibitors, such as vemurafenib, which are FDA approved, but patients treated with these Type-I kinase inhibitors frequently observe relapse under mutant RAS and BRAF-wt conditions due to paradoxical activation. The mechanism of this resistance occurs through binding of the inhibitor to BRAF-wt initiating conformational changes which leads to BRAF dimerization. Once in the dimerized state, the inhibited monomer induces allosteric transactivation of the second monomer. This drug-induced activation of BRAF in cells with mutant …

A Multilevel Mixed Methods Examination Of Treatment Nonadherence Among Rural Cancer Survivors, Bonny Morris

Theses and Dissertations

While mortality rates have been decreasing over the last 40 years, cancer remains a leading cause of death in the United States. Over 1.7 million people were diagnosed with cancer in 2019, and there were more than 600,000 cancer deaths. Of the 15 million cancer survivors in the US, nearly 3 million reside in rural areas and experience 3% higher cancer incidence and 10% higher cancer mortality compared to their nonrural counterparts. During 2006-2015, the annual age-adjusted mortality rates for all cancer sites combined decreased at a slower pace in rural areas versus nonrural areas (-1.0% vs -1.6% per year, …

Using The Memorial Sloan Kettering Frailty Index To Identify Patients At High Risk For Postoperative Intensive Care Unit Admission, Specialized Advanced Care Unit Admission, And 30-Day Readmission, Timothy J. Donoghue

Theses and Dissertations

Frailty is roughly defined as an accumulation of physiological, emotional, cognitive, and social deficits that impair a person’s response to stressful events. A frailty diagnosis has been associated with poor outcomes following surgical procedures. Cancer surgical patients aged 65 or older represent a vulnerable population susceptible to being frail and the potential associated complications that can accompany frailty. Measuring frailty is an objective risk assessment that identifies increased risk better than age or American Society of Anesthesiologists Physical Status (ASA-PS) score such that frailty can independently predict poor surgical outcomes.

Frailty is not specifically a result of having cancer, disability, …

An In Silico Study Of Small Molecule Anti-Cancer Agents Targeting Dna G-Quadruplexes, Holli-Joi Sullivan

Theses and Dissertations

Free ligand binding molecular dynamic simulations are a powerful tool used to probe the ligand binding process, mechanism and pathway and the insight gained can help expedite the early stages of drug discovery. Using these methods, we model the binding of two small molecule anti-cancer agents BRACO19 and CX-5461 to a variety of DNA G-quadruplexes (G4s) and a DNA Duplex. The first study focuses on the binding of BRACO19 to three different topological folds (parallel, anti-parallel and hybrid) of the human telomeric G4s. Our detailed analysis identified the most stable binding modes were end stacking and groove binding for the …

The Effects Of Autophagy And Senescence On Sensitivity To Cisplatin In Head And Neck Cancer, Zara H. Siddiqui

Theses and Dissertations

While current treatments in cancer, such as chemotherapy and radiation, can generally be effective in eliminating disease in patients, there also exists the possibility of recurrence of cancer cells over time. In patients diagnosed with locally advanced head and neck carcinoma, about 50-60% develop a loco-regional recurrence within two years, and 20-30% of patients develop metastatic disease at distant sites in the body [5]. On a cellular level, one mechanism for this survival may be that natural mechanisms such as autophagy and senescence play a role in allowing cells to survive after undergoing treatment. One standard of care chemotherapy for …

Dietary Advanced Glycation End-Products (Ages) And Breast Cancer Risk And Survival, Omonefe Opeyemi Omofuma

Theses and Dissertations

Introduction: Advanced glycation end-products (AGEs) are implicated in the pathogenesis of chronic diseases including cancer. AGEs are produced endogenously and are also consumed from foods. High amounts of AGEs are found in animal products and processed foods, and AGE formation is accelerated during cooking at high temperatures. Using data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), we assigned and quantified NƐ-carboxymethyl-lysine (CML)-AGE content in food and investigated the association between dietary AGE intake and breast cancer (BrCa) risk. We assessed whether the risk was modified by race/ethnicity, obesity status, fruit and vegetable intake, BrCa invasiveness …

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 …

Psychometric Evaluation Of Lung Cancer Stigma Among Lung Cancer Survivors In South Carolina, Lisa A. Webb

Theses and Dissertations

Background: Despite the improved screening and treatment modalities, lung cancer is the second leading cause of cancer and accounts for 27% of all cancer deaths in the United States. Survivors of lung cancer experience physical, social, and particularly psychological challenges. Lung cancer stigma is a formidable challenge for survivors of lung cancer that complicates their physical, psychological and social well-being.

The Cataldo Lung Cancer Stigma Scale is the first instrument adapted to measure lung cancer stigma. This instrument was adapted from Berger’s HIV Stigma Scale. HIV stigma and lung cancer stigma share similarities. These health-related stigmas reflect behaviors that …

Examining Sleep And Family Functioning In Pediatric Craniopharyngioma Using Ecological Momentary Assessment, Nour Al Ghriwati

Theses and Dissertations

Craniopharyngiomas are among the most common brain tumors in children and are associated with greater rates of sleep problems compared to other pediatric cancers. However, research examining sleep among youth with craniopharyngioma has been limited by a reliance on retrospective reports or sleep studies. Families also play a crucial role in children’s adjustment following a pediatric cancer diagnosis, yet remarkably little is known about transactional associations between family functioning and sleep in pediatric cancer. This study examined cross-sectional and daily associations among family functioning, affect, and sleep difficulties for youth with pediatric craniopharyngioma using retrospective reports and ecological momentary assessment …

Modulation Of Autophagy And Senescence To Enhance The Response To Therapy In Triple Negative Breast Cancer, Liliya Tyutyunyk-Massey

Theses and Dissertations

Abstract

Although great strides have been made over the decades in development and optimization of anti-cancer therapies, even highly effective drugs often fail to completely eliminate tumors. Residual tumor cells can enter into a state of dormancy for prolonged periods of time but eventually are able to regain proliferative capacity and reemerge as chemotherapy-resistant disease. Because recurrent disease is a leading contributor to patient’s mortality, it is paramount to identify strategies for effectively destroying residual tumor cells.

Cytotoxic drugs and ionizing radiation are used as standard therapies in a variety of cancers. These modalities induce apoptosis, autophagy and senescence. Senescence …

The Role Of Cdk8 In Metastatic Growth Of Colon Cancer, Jiaxin Liang

Theses and Dissertations

Unresectable hepatic metastases of colon cancer poorly respond to existing therapies and are a major cause of colon cancer lethality. Transcription- regulating Mediator kinase CDK8, an early clinical stage drug target, is amplified or overexpressed in many colon cancers and CDK8 expression correlates with shorter patient survival. Here we show that CDK8 inhibition does not generally suppress proliferation of CDK8-overexpressing colon cancer cells but nevertheless CDK8 knockdown by shRNA or CDK8 kinase inhibition by a selective small-molecule drug candidate suppresses metastatic growth of mouse and human colon cancer cells in the liver. This effect is due at least in part …

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 …

Spiritual Care In Cancer Genetic Counseling: Patient Perceptions Of Methods, Christopher Michael Spencer

Theses and Dissertations

The integration of spirituality into medical care is a growing area of debate among professionals, involving a delicate balance between serving patients who may benefit from this without alienating those who would not. To date, little research has targeted spirituality in cancer genetic counseling, particularly concerning the various methods a genetic counselor can use to address spirituality with their patients. A paper questionnaire was created and distributed to patients following their cancer genetic counseling appointments to gain insight on their perception of these methods. Fifty-two participants completed this questionnaire. The eight different spiritual integration methods presented each showed positive responses …

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 …

Investigating The Role Of Nicotinic Acetylcholine Receptor Agonists In Lung Cancer Progression And Chemosensitivity In The Context Of Treating Chemotherapy-Induced Peripheral Neuropathy, Sarah L. Kyte

Theses and Dissertations

While cancer chemotherapy continues to significantly contribute to the number of cancer survivors, exposure to these drugs can often result in chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration. CIPN is characterized by sensory symptoms in the hands and feet, such as numbness, burning, and allodynia, resulting in an overall decrease in quality of life. Paclitaxel (Taxol), a microtubule poison that is commonly used to treat breast, lung, and ovarian cancers, has been found to cause CIPN in 59-78% of cancer patients. There is currently no effective preventative or therapeutic treatment for this side effect, …

Role Of The Pediatric Dental Provider In Human Papillomavirus (Hpv) Education, Meredith L. Dugoni

Theses and Dissertations

Purpose: This study investigates knowledge about HPV and examines if pediatric dental providers should include HPV education for guardians of patients 10-18 years.

Methods: Legal guardians of 10-18 year-old patients of the Virginia Commonwealth University Pediatric Dental Clinic were enrolled in this prospective cohort study. Participants completed a baseline survey, were provided HPV education, completed an initial follow-up survey, and then completed a 6-month follow-up survey.

Results: A total of 54 participants completed the baseline and initial follow-up surveys and 17 completed the 6-month follow-up survey. The average number of correct responses was 3.4 of 6 knowledge questions, which significantly …

Association Between Diabetes And Cancer In Indian And Us Populations Using Longitudinal Study Design, Shraddha S. Vyas

Theses and Dissertations

Background: There is growing evidence of association between diabetes and cancer. No studies have been conducted in India evaluating this association. With the current epidemiologic, nutritional and economic transition in India, it becomes extremely important to examine this association in an Indian population. Additionally, difference in association exists based on different cancer subtypes. Research has shown that diabetes is associated with an increased risk of colorectal cancer. However most of these studies suggest detection bias to be one of the probable reasons for this association. Additionally, the common risk factors shared by both these conditions are considered to one of …

Effects Of A Mindfulness Based Intervention On Diurnal Cortisol In Cancer Survivors, Susannah Small

Theses and Dissertations

Background. There are approximately 15.5 million individuals alive today in the U.S. with a personal history of cancer. For this large and growing population, ill effects associated with cancer diagnosis and treatment include both physical and psychosocial symptoms adversely affecting quality of life. One low-risk alternative to conventional pharmaceutical use in treating these symptoms is mindfulness practice. Research on self-reported measures provides strong evidence that this type of intervention improves quality of life for cancer survivors, but evidence of impact on objective measures is limited. Cortisol, the body’s primary stress hormone, is one relatively easy to measure indicator that …

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). …

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 …

Federal Policies And Prescription Drugs, Ali Bonakdar Tehrani

Theses and Dissertations

This dissertation comprises three discrete empirical papers, with an introductory essay that evaluates the impact of different federal policies on prescription drug prices, utilization, and spending. Two main databases are used: (a) Medicaid State Drug Utilization Data and (b) the Medical Expenditure Panel Survey (MEPS) data. These two databases are designed to track Medicaid drug utilization and overall medical use and expenditures, respectively. The variables of interest in this dissertation are prescription drug price, prescription drug use and spending, and overall drug expenditures.

The objective of the first paper (Chapter 2) is to examine whether oncology drug prices have significantly …

Stimuli Responsive Nanoparticle For Cancer Targeted Therapy, Huacheng He

Theses and Dissertations

Nanoparticle is the particle with a size in the range from several nanometers to hundreds of nanometers. It has been extensively used for cancer diagnosis and therapy. However, it is still a great challenge to fabricate nanoparticles with spatiotemporally controllable delivery of anticancer drugs to tumors and with high therapeutic efficacy. This thesis mainly focuses on the development of stimuli responsive nanoparticles for cancer targeted therapy. These nanoparticles either response to internal stimuli such as pH and redox potential or external stimuli like temperature and light could effectively target tumors and control the release of anticancer drugs there to improve …

Testing A Low-Intensity And Accessible Cognitive Behavioral Therapy For Insomnia (Cbt-I) Intervention In Individuals Newly Diagnosed With Cancer, Amma Agyemang

Theses and Dissertations

Insomnia is defined as difficulty initiating or maintaining sleep, or nonrestorative sleep that lasts for at least one month and is accompanied by significant impairment in daytime functioning including fatigue, irritability, and/or difficulty concentrating. It is one of the most common complaints reported by individuals with cancer, especially around the time of cancer diagnosis and treatment. Yet it is often unrecognized and untreated, leading to adverse health consequences and increased healthcare costs. Cognitive Behavioral Therapy for Insomnia (CBT-I) has been recommended as the gold standard for treating insomnia among individuals with cancer. Multiple studies have tested and proven the efficacy …

Multifunctional Nanocarriers For Cancer Therapy, Bei Cheng

Theses and Dissertations

Cancer is one of the leading causes of human mortality and mortality in all diseases. There has been a boost in developing nanocarrier-based therapies for treating cancer or other diseases during the past decade. One of the major advantages about nanocarrier (with the size range from 1-1000 nm) lies in its ability to specifically target tumor and maximize drug accumulation in tumor foci through the enhanced permeability and retention effect. Advancement in nanotechnology has opened a new paradigm in pharmaceutical field. But new challenges have to be overcome in order to fully exploit the technology and improve safety in clinical …