Life Sciences Commons^™

Functional Characterization Of Cancer-Associated Dna Polymerase Ε Variants, Stephanie R. Barbari

Theses & Dissertations

Replicative DNA polymerases ε (Polε) and δ (Polδ) achieve high fidelity DNA synthesis through a precise balance of polymerization and exonucleolytic proofreading. Errors that escape proofreading are corrected by DNA mismatch repair (MMR). Ultramutated human cancers with proficient MMR carry alterations in the exonuclease domain of Polε, which were initially predicted to abolish proofreading. However, functional studies in yeast of the most recurrent Polε-P286R variant suggested defects beyond a loss of exonuclease activity. Indeed, biochemical analysis of the yeast Polε-P286R analog revealed increased polymerization capacity in addition to decreased proofreading, which enables efficient mismatch extension and bypass of replication-blocking non-B …

Differentiating The Mechanistic Role And Chemotherapeutic Potential Of Src And Podoplanin In Oncogenic Transformation, Edward P. Retzbach

Graduate School of Biomedical Sciences Theses and Dissertations

There were an estimated 20 million new cancer cases worldwide in 2020, resulting in nearly 1000 deaths per hour [1]. Oral cancer exemplifies the difficulties of treating cancer patients. The first line for oral cancer treatment is surgery and radiation that can lead to patient disfigurement and decreased quality of life in cancer survivors [2-4]. Though there have been many developments in chemotherapy in the last 30 years, the 50% mortality rate associated with oral cancer has not changed [4, 5]. Longitudinal studies that track survival rates in oral cancer patients demonstrate a 3-fold reduction in patient deaths when patients …

Role Of Sex Differences On Cancer Cachexia Progression And Fibrosis During Cancer Cachexia Development, Wesley Haynie

Graduate Theses and Dissertations

Cancer cachexia is a multifactorial wasting syndrome characterized by losses in bodymass >5% and occurs in approximately 80% of all cancer patients. Chronic inflammation and fibrosis play roles in cancer cachexia and a greater understanding of these contributing pathways to this pathology will pave the way for potential therapeutic avenues. While inflammation and fibrosis have been researched in various models of cancer cachexia, little to no studies have been performed in both sexes as most previous studies focus on males. PURPOSE The purpose of these studies is to investigate the role of fibrosis on cancer cachexia development as well as …

Uncovering A Myc-Driven Tumor-Suppressive Program In Proliferating Lymphocytes, Elena Tonc

Arts & Sciences Electronic Theses and Dissertations

Rapid cell proliferation is a hallmark feature of adaptive immune cells lymphocytes. It is essential for the establishment of diverse antigen receptor repertoires and amplification of antigen-specific immune responses. While such proliferation is beneficial for host protection from infections and cancers, it inevitably elevates the risk of oncogenic transformation. In developing and germinal center B lymphocytes, the risk is further increased by endogenous, genomic insults due to antigen receptor rearrangements and somatic mutations, with which expression of the proto-oncogene c-MYC is closely associated. Nonetheless, frequencies of cancers originated from B lymphocytes are relatively low, suggesting that they are protected from …

Understanding The Pathogenesis Of Renal Medullary Carcinoma, Melinda Soeung

Dissertations & Theses (Open Access)

Renal medullary carcinoma (RMC) is a lethal cancer that predominantly affects young individuals with sickle cell trait (SCT). It is not currently understood why RMC only affects certain individuals with SCT. We found that patients with RMC more frequently participated in high-intensity exercise than matched controls. Using mouse models of SCT, we demonstrated the significant increase of renal hypoxia in the right kidney following high- but not moderate-intensity exercise. We also demonstrated in cell culture studies that SMARCB1 is ubiquitinated for proteasome-mediated degradation in hypoxia, and the re-expression of SMARCB1 leads to compromised proliferation in renal cells specifically in the …

An Assessment Of Inp/Zns As Potential Anti-Cancer Therapy: Quantum Dot Treatment Induces Stress On Hela Cells, Victoria Grace Davenport

MSU Graduate Theses

Indium Phosphide/Zinc Sulfide (InP/ZnS) quantum dots (QDs) are an emerging option in QD technologies for uses of fluorescent imaging as well as targeted drug and anti-cancer therapies based on their customizable properties. In this study we explored effects of InP/ZnS when treated with HeLa cervical cancer cells. We employed XTT viability assays, reactive oxygen species (ROS) analysis, and apoptosis analysis to better understand cytotoxicity extents at different concentrations of InP/ZnS. In addition, we compared the transcriptome profile from the QDtreated HeLa cells with that of untreated HeLa cells to identify changes to the transcriptome in response to the QD. Intracellular …

Targeting Plasma Membrane Phosphatidylserine Content To Inhibit Oncogenic Kras Function, Walaa E. Kattan

Dissertations & Theses (Open Access)

The small GTPase KRAS, which is frequently mutated in human cancers, must be localized to the plasma membrane (PM) for biological activity. We recently showed that the KRAS C-terminal membrane anchor exhibits exquisite lipid-binding specificity for select species of phosphatidylserine (PtdSer). We therefore investigated whether reducing PM PtdSer content is sufficient to abrogate KRAS oncogenesis. Oxysterol-related binding proteins ORP5 and ORP8 exchange PtdSer synthesized in the ER for phosphatidylinositol-4-phosphate (PI4P) synthesized in the PM. We show that depletion of ORP5 or ORP8 reduced PM PtdSer levels, resulting in extensive mislocalization of KRAS from the PM. Concordantly, ORP5 or ORP8 depletion …

A Time-Course Characterization Of Muscle Function And Mitochondrial Markers During Colorectal Cancer-Induced Cachexia In Tumor-Bearing Male Mice, Ana Cabrera Ayuso

Graduate Theses and Dissertations

Cachexia is a multisystemic and multifactorial syndrome prevalent in cancer patients. It is clinically defined by involuntary loss of >5% weight in a six-month window, despite nutritional interventions. A negative energy balance characterizes cancer cachexia (CC), it is associated with weakness and fatigue in skeletal muscle. Impaired muscle function is associated with lower quality of life in cancer patients. Defects in mitochondrial function are strongly associated with muscle wasting. This study explored muscular contractile function and mitochondrial quality control (MQC) markers in soleus, gastrocnemius, and tibialis anterior (TA) muscles of C26-induced male tumor-bearing mice during a 25-day time course. It …

A Forward Genetic Screen To Identify Human Genes Of Interest And Their Roles In Ovarian Cancer, Susan A. Ihejirika

Honors College Theses

Drosophila melanogaster, fruit flies, are very important for modeling and studying human diseases. This study identifies human genes of interest and their contributions to epithelial ovarian carcinogenesis and progression as well as the roles orthologs of these genes play in Drosophila melanogaster. This is important because ovarian cancer is the most common cause of death among the gynecological cancers. This identification of genes was carried out using a forward genetic screen employing the widely used GMR-Gal4 driver/UAS-transgene system. The GMR-Gal4 driver is commonly utilized to express transgenes in the developing eye of the fruit fly. Transgenes that are expressed using …

Comprehensive Characterization Of The Genetic And Neoantigen Landscapes Of Follicular Lymphoma Patients Supports The Feasibility Of Personalized Cancer Vaccine Treatments, Cody Alexander Ramirez

Arts & Sciences Electronic Theses and Dissertations

Follicular lymphoma (FL) is the most common indolent non-Hodgkin’s lymphoma; however, it remains incurable with conventional therapies and is poorly responsive to checkpoint blockade. FL arises from B-lymphocytes and develops slowly (and often asymptomatically). A major research focus has been on how to avoid chemotherapy treatments, to limit the potential development of treatment-related side effects, and the risk of therapy-related second cancers. FL also carries an approximately 30% lifetime risk of transforming from an iNHL to more destructive lymphomas, which are associated with poorer prognosis. The most common transformation results in diffuse large B-cell lymphoma (DLBCL). However, many patients may …

Honokoil Treatment On Glioblastoma Cells, Julianne Weaver

Honors Theses

Glioblastoma is a malignant brain tumor without effective treatment options available because of its resistance to chemotherapy and radiation. This specific type of cancer is difficult to treat because the cancer stem cells that are not actively growing. These cells are dormant, which means they will not react to treatment because they are not dividing, and it is these cells that result in the high prevalence of relapse. Honokiol is a Chinese magnolia species that is known for its anti-inflammatory, anti-proliferative, and proapoptotic effects which make it an optimal candidate for glioma cell treatment. Honokiol was used in this experiment …

Examining The Mechanistic Roles Of Integrin Alpha-6 In Cancer Metastasis., Chase T. Clark

Honors College Theses

Metastasis- the spread of cancer cells from the primary tumor to the surrounding tissues- is responsible for 90% of cancer deaths. Integrin alpha-6 (ITGA6) is a specific transmembrane cell surface protein that functions in cell surface adhesion and signaling. ITGA6 is upregulated in many types of cancers and promotes the migration and invasion of cancer cells to surrounding tissues. It is my objective to determine the mechanism through which ITGA6 facilitates the migration of cancer cells through the extracellular matrix (ECM). These experiments helped to establish the role of ITGA6 in tumor development and provide focus for possible chemotherapeutic treatment. …

Metabolic Reprogramming By Dna Tumour Viruses, Martin Prusinkiewicz

Electronic Thesis and Dissertation Repository

Viruses are the etiological agents of approximately 12% of human cancers. However, only a subset of viral infections eventually progress to cancer. As obligate intracellular parasites, viruses create a host-cell environment that is amenable to virus replication. These changes to host-cell processes during infection are enacted by virally-encoded proteins that act as molecular hubs. When these processes intersect with pathways that encourage the development of cancer, such as the p53 tumour suppressor pathway, these virally-encoded molecular hub proteins function as viral oncoproteins. One major requirement of both virus infected cells and rapidly growing cancer cells is an altered metabolism that …

Anti-Cancer Effects By Interleukin 24, Xuelin Zhong

Dissertations, Theses, and Capstone Projects

Cancers develop as some cells acquire the ability, either by exogenous stimulation or by spontaneous mutation, to keep growing despite normal restraints. Up-regulating translation of oncogenes involved in cell proliferation and tumor development and down-regulating translation of tumor-suppressors that normally suppress tumor development are two most common mechanisms by which cancers develop. Therefore, it is crucial to study how these proteins get either up-regulated or down-regulated at translational level.

The eukaryotic translation initiation factor, which is composed of subunits such as eIF4A, eIF4G and eIF4E, is one of the key factors that contribute to efficient translation initiation. Interleukin 24 (IL-24), …

A New Mathematical Theory For The Dynamics Of Large Tumor Populations, A Potential Mechanism For Cancer Dormancy & Recurrence And Experimental Observation Of Melanoma Progression In Zebrafish, Adeyinka A. Lesi

Dissertations and Theses

Cancer, a family of over a hundred disease varieties, results in 600,000 deaths in the U.S. alone. Yet, improvements in imaging technology to detect disease earlier, pharmaceutical developments to shrink or eliminate tumors, and modeling of biological interactions to guide treatment have prevented millions of deaths. Cancer patients with initially similar disease can experience vastly different outcomes, including sustained recovery, refractory disease or, remarkably, recurrence years after apparently successful treatment. The current understanding of such recurrences is that they depend on the random occurrence of critical mutations. Clearly, these biological changes appear to be sufficient for recurrence, but are they …

Association Between Plasma Genistein And Health-Related Quality Of Life In Breast Cancer Survivors, Tran Pham

Honors Undergraduate Theses

According to the American Cancer Society, breast cancer is the most commonly diagnosed cancer and is the second leading cause of cancer death in American women. Breast cancer screenings and improvement in treatments have resulted in the rising number of survivors in the recent decade. This urged the need for post-diagnosis lifestyle changes to improve breast cancer patients' quality of life. Many studies found soy food, the primary dietary source of phytoestrogens, has a protective effect against breast cancer recurrence and mortality. Dietary phytoestrogens can be classified into two groups: isoflavones and lignans. Daidzein and genistein were identified as the …

Investigating The Antitumor Effects Of A Dsrna-Nanoparticle Complex In An In Vitro Ovarian Cancer Model, Aaron Lewis

Theses and Dissertations (Comprehensive)

An estimated 1 in 70 women will be diagnosed with ovarian cancer in their lifetime. Despite advanced detection and treatment methods, it remains a silent killer with an expected survival rate of 50%. A developing method in cancer treatment is the use of compounds that stimulate the immune system to aid in the body's fight against the disease. This project focused on the use of the potent immune stimulant double-stranded RNA (dsRNA), commercially available as polyinosinic:polycytidylic acid, poly(I:C), to induce cytotoxicity in two ovarian cancer cell lines; SKOV-3 and OVCAR-3. Some challenges exist with the delivery of dsRNA due to …

Cop9 Signalosome Component Csn-5 Promotes Accumulation And Function Of Stem Cell Regulators Fbf-1 And Fbf-2, Emily Osterli

Graduate Student Theses, Dissertations, & Professional Papers

RNA-binding proteins FBF-1 and FBF-2 (FBFs) are required for stem cell maintenance in C. elegans, although the mechanisms by which FBFs protein levels are regulated remain unknown. Using a yeast two-hybrid screen, we identified an interaction between both FBFs and CSN-5, a component of the COP9 (constitutive photomorphogenesis 9) signalosome. This highly conserved COP9 complex can affect protein stability through a range of mechanisms including deneddylation, deubiquitination, and phosphorylation (Wolf et al., 2003). Mapping protein-protein interactions between FBFs and CSN-5 suggested that the MPN (Mpr1/Pad1 N-terminal) metalloprotease domain of CSN-5 interacts with the RNA-binding domain of FBFs at physiologically …