Life 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 …

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 …

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 …

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 …

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 …

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 …