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The Splice Is Not Right: Splice-Site-Creating Mutations In Cancer Genomes, Reyka Glencora Jayasinghe

Arts & Sciences Electronic Theses and Dissertations

Accurate interpretation of cancer mutations in individual tumors is a prerequisite for precision medicine. Large-scale sequencing studies, such as The Cancer Genome Atlas (TCGA) project, have worked to address the functional consequences of genomic mutations, with the larger goal of determining the underlying mechanisms of cancer initiation and progression. Many studies have focused on characterizing non-synonymous somatic mutations that alter amino acid sequence, as well as splice disrupting mutations at splice donors and acceptors. Current annotation methods typically classify mutations as disruptors of splicing if they fall on the consensus intronic dinucleotide splice donor, GT, the splice acceptor, AG. Splice …

Regulation Of Canonical And Non-Canonical Hippo Pathway Components In Mitosis And Cancer, Seth Stauffer

Theses & Dissertations

The Hippo pathway is conserved regulator of organ size through control of proliferation, apoptosis, and stem-cell self-renewal. In addition to this important function, many of the canonical signaling members have also been shown to be regulated during mitosis. Importantly, Hippo pathway components are frequently dysregulated in cancers and have attracted attention as possible targets for improved cancer therapeutics. Further exploration of Hippo-YAP (yes-associated protein) signaling has revealed new regulators and effectors outside the canonical signaling network and has revealed a larger non-canonical network of signaling proteins in which canonical Hippo pathway components crosstalk with important cellular homeostasis and apoptosis signaling …

In Silico Development Of An Rna Aptamer Library To Be Use For The Selection Of Rna Aptamer That Target Biomolecules, Nehad Nawfawi

Electronic Theses & Dissertations

The systematic evolution of ligands by exponential enrichment (SELEX) is a powerful method for the development of high affinity RNA ligands toward and infinite array of target molecules. SELEX is based upon the generation of a randomized population of RNA or DNA molecules followed by a target molecule that selects high affinity ligands from the randomized population followed by the subsequent amplification of the selected molecules. The procedure of selection and amplification is typically carried out through multiple cycles to insure that the identified ligands exhibits the highest affinity toward the target. The procedure is very time- consuming often taking …

The Drug Discovery Of Potential Anti-Cancer Agents To Inhibit The Demethylation Catalytic Activity Of The Jmjc Domain Of Kdm3a, Balgees Alshanqeti

Electronic Theses & Dissertations

Lysine demethylase 3A (KDM3A) is an enzyme that specifically catalyzes the removal of 2 or three methyl groups from lysine 9 of histone 3 (KH3). It belongs to the family of histone demethylases that contain the Jumonji C (JmjC) domain, which means cruciform in Japanese. KDM3A also belongs to a family of hydroxylases that are alpha-ketoglutarate dependent. The role of KDM3A in the cell is not yet understood, however, and based on its demethylation of studies have showed that its expression is elevated in embryonic stem cells in humans and in mice. In general, patterns of elevated expression of KDM3A …

Harnessing The Physical Properties Of Zno Nanoparticles For Biological Applications And Factors That Impact Zno Nanoparticle Toxicity, Joshua Eixenberger

Boise State University Theses and Dissertations

The production of materials at the nanoscale leads to novel properties and has made the field of nanotechnology a part of everyday life. Numerous applications of nanomaterials have led to their use in electronics, optics, and medicine. However, creating materials at such a small size brings them on the same scale as many biomolecules and cellular components, altering their interactions with biological systems. This can lead to unintended biological impacts as many nanomaterials are considerably more toxic than their bulk counterpart material. ZnO nanoparticles (nZnO) are particularly interesting in this context. The FDA classifies ZnO as a generally recognized as …

Impedance Sensing Of Cancer Cells Directly On Sensory Bioscaffolds Of Bioceramics Nanofibers, Hanan Alismail

Graduate Theses and Dissertations

Cancer cell research has been growing for decades. In the field of cancer pathology, there is an increasing and long-unmet need to develop a new technology for low-cost, rapid, sensitive, selective, label-free (i.e. direct), simple and reliable screening, diagnosis, and monitoring of live cancer and normal cells in same shape and size from the same anatomic region. For the first time on using an impedance signal, the breast cancer and normal cells have been thus screened, diagnosed and monitored on a smart bioscaffold of entangled nanowires of bioceramics titanate grown directly on the surface of implantable Ti-metal and characterized by …

The Role Of Tumor Suppressor Dear1 In The Acquisition Of Mammary Stem/Progenitor Cell Properties, Uyen Le

Dissertations & Theses (Open Access)

Breast cancer is the most commonly diagnosed cancer in women in America. Ductal carcinoma in situ (DCIS), one of the earliest pre-invasive forms of invasive ductal carcinoma (IDC), has a 30-50% risk of progressing to IDC. Understanding the mechanisms regulating progression from DCIS to IDC would help identify biomarkers to stratify patients at higher risk of progression or metastasis. Cumulative literature suggests the earliest phase of dissemination from the primary tumor is driven by the epithelial-mesenchymal transition (EMT) program. DEAR1 is a tumor suppressor gene which is mutated, undergoes loss of heterozygosity in breast cancer, and is downregulated in DCIS …

Lcp1 Mutant Zebrafish: A Look At Neutrophils, Cancer, And Gene Compensation, Taylor Mitchell

College of Science and Health Theses and Dissertations

Lymphocyte cytosolic protein 1 (lcp1 or L-plastin) is a small actin-bundling protein that is typically only expressed in motile leukocytes, such as neutrophils and macrophages. However, it is also overexpressed in cancer cells, which may be related to tumor metastasis. Using CRISPR/Cas9 gene editing, our lab has created zebrafish that are genetic knockouts for lcp1 in order to better understand the relationship between L-plastin and cell motility.

Previous studies on L-plastin knockout mice have shown that the mutants have a decreased immune response, and therefore I predicted that our zebrafish mutants might have impaired development or distribution of immune cells. …

Cd147 As A Potential Therapeutic Target In Glioblastoma Treatment, Beau Adams

All NMU Master's Theses

Glioblastoma (GBM) tumors are the most common and lethal form of cancer in the central nervous system (CNS). GBM tumors appear to contain a mixture of different cell types, which makes them difficult to treat. GBM cells exhibit altered morphology from normal cells on several different levels, which highlights different pathways to potentially target for therapeutic treatments. The human surface glycoprotein CD147, also known as basigin, is expressed at significantly higher levels in GBMs compared to non-neoplastic brain tissue. Furthermore, levels of CD147 expression correlate with brain tumor progression and show the highest expression in GBM. Here, we suppressed tumor …

Evaluation Of Drug-Loaded Gold Nanoparticle Cytotoxicity As A Function Of Tumor Tissue Heterogeneity., Hunter Allan Miller

Electronic Theses and Dissertations

The inherent heterogeneity of tumor tissue presents a major challenge to nanoparticle-medicated drug delivery. This heterogeneity spans from the molecular to the cellular (cell types) and to the tissue (vasculature, extra-cellular matrix) scales. Here we employ computational modeling to evaluate therapeutic response as a function of vascular-induced tumor tissue heterogeneity. Using data with three-layered gold nanoparticles loaded with cisplatin, nanotherapy is simulated with different levels of tissue heterogeneity, and the treatment response is measured in terms of tumor regression. The results show that tumor vascular density non-trivially influences the nanoparticle uptake and washout, and the associated tissue response. The drug …

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 …

Study Of Alpha Mangostin As A Chemoprotective Agent For Breast Cancer Via Activation Of The P53 Pathway, Vanessa Van Oost

Pence-Boyce STEM Student Scholarship

Breast carcinoma is the most frequently diagnosed cancer among women and causes over 400,000 deaths yearly worldwide. Current treatments such as chemotherapy are not selective for cancerous tissues but are destructive to normal tissues as well. This causes a range of side effects including pain, nausea, hair loss, weakness, and more. Inactivation of p53 is an almost universal mutation within human cancer cells. The ability to activate the p53 pathway which protects cells from tumor formation is lost in 50% of cancers. Due to the prevalence of this mutation, p53 is a uniquely valuable target for applied research. Alpha mangostin …

Multi-Omics Portraits Of Cancer, Kuan-Lin Huang

Arts & Sciences Electronic Theses and Dissertations

Precision oncology demands accurate portrayal of a disease at all molecular levels. However, current large-scale studies of omics are often isolated by data types. I have been developing computational tools to conduct integrative analyses of omics data, identifying unique molecular etiology in each tumor. Particularly, this dissertation presents the following contributions to the computational omics of cancer: (1) uncovering the predisposition landscape in 33 cancers and how germline genome collaborates with somatic alterations in oncogenesis; (2) pioneering methods to combine genomic and proteomic data to identify treatment opportunities; and (3) revealing selective phosphorylation of kinase-substrate pairs. These findings advance our …

Tumors Interrupt Irf8-Mediated Dendritic Cell Development To Overcome Immune Surveillance, Melissa Ann Meyer

Arts & Sciences Electronic Theses and Dissertations

Tumors employ multiple mechanisms to evade immune surveillance. One mechanism is tumor-induced myelopoiesis, which expands immune suppressive granulocytes and monocytes to create a protective tumor niche shielding even antigenic tumors. As myeloid cells and immune-stimulatory conventional dendritic cells (cDCs) are derived from the same progenitors, it is logical that tumor-induced myelopoiesis might also impact cDC development. The cDC subset cDC1 is marked by CD141 in humans and CD103 or CD8α in mice. cDC1s act by cross presenting antigen and activating CD8+ T cells. Given these functions, CD103+ cDC1s can support anti-tumor CD8+ T cell responses. However, CD103+ cDC1 numbers are …

Electrophysiological Biomarkers Of Chemotherapy-Related Cognitive Impairment In Hematological Malignancy Patients, David E. Anderson

Theses & Dissertations

Multiple cancer populations frequently report cognitive impairment following treatment with chemotherapy agents (“chemo-brain”). Impaired neuropsychological performance is commonly reported in cognitive domains of attention and executive function. Understanding neural mechanisms underlying cognitive impairments is essential to developing prevention and rehabilitation strategies. Brain imaging studies frequently show chemotherapy-related impairments within the attentional control network, which is comprised of a constellation of cortical regions that govern reportedly impaired cognitive functions. In the current dissertation research, I developed a novel electrophysiology battery aimed at recording near-instantaneous neural activity within the attentional control network during cognitive task performance. Cancer patients diagnosed with hematological malignancy …

Computational Insights Into The Generation Of Chromosomal Copy Number Changes, Yihua Liu

Dissertations & Theses (Open Access)

Deviations from a diploid configuration of the human genome, spanning single genes or entire chromosomes, can have wide-ranging impacts on the variation of human phenotypes, including Mendelian and complex forms of diseases. These chromosomal alterations — such as duplications, deletions or copy-neutral loss-of-heterozygosity — are thus important forms of genetic variation for phenotyping populations of individuals as well as populations of cells. Indeed, copy number variants (CNVs) serve as hallmarks of critical changes in the development of particular diseases such as cancer and thus may be used as biomarkers. These CNVs may be either inherited (transmitted by germ cells, originating …

A Systematic Review Of Language Therapy In Pediatric Brain Tumor Survivors, Ari Watt

All Graduate Plan B and other Reports, Spring 1920 to Spring 2023

Purpose: Brain tumors and associated treatments in children have been shown to cause long term neurological damage. While there is a large body of research focusing on treating associated cognitive deficits, relatively little research has focused on improving linguistic ability in this population. This systematic review identified and summarized the available evidence related to language treatment for pediatric brain tumor survivors.

Methods: A systematic electronic database search resulted in the identification of four relevant treatment studies, two position papers and one online forum. A data extraction manual and form was used to methodically extract study information related to participant demographics, …

The Regulation Of Dna Methylation In Mammalian Development And Cancer, Nicolas Veland

Dissertations & Theses (Open Access)

DNA methylation is an essential epigenetic modification in mammals, as it plays important regulatory roles in multiple biological processes, such as gene transcription, maintenance of chromosomal structure and genomic stability, genomic imprinting, retrotransposon silencing, and X-chromosome inactivation. Dysregulation of DNA methylation is associated with various human diseases. For example, cancer cells usually show global hypomethylation and regional hypermenthylation, which have been implicated in genomic instability and tumor suppressor silencing, respectively. Although great progress has been made in elucidating the biological functions of DNA methylation over the last several decades, how DNA methylation patterns and levels are regulated and dysregulated is …

Bg-4, A Bioactive Peptide From Momordica Charantia, Promotes Apoptosis In Ovarian Cancer Cells, Ashley D. Bloom

Chancellor’s Honors Program Projects

No abstract provided.

Changes In Hepatic Extracellular Matrix During The Development Of Cancer-Cachexia In Mice, Kyle Turner

Health, Human Performance and Recreation Undergraduate Honors Theses

CHANGES IN HEPATIC EXTRACELLULAR MATRIX DURING THE DEVELOPMENT OF CANCER-CACHEXIA IN MICE

Turner K.W.¹, Rosa-Caldwell M.E.¹, Brown J.L.¹, Lee D.E.¹, Perry R.A.¹, Haynie W.A.¹ Washington T.A.¹, Wiggs M.P.², Greene N.P.¹: ¹University of Arkansas, Fayetteville, Arkansas; ²Univeristy of Texas at Tyler, Tyler, Texas

BACKGROUND: Cancer is one of the most widespread and deadly diseases in recent history. Cancer-cachexia is a systemic, metabolic disorder that greatly disrupts the patient’s energy balance, causing uncontrollable weight and, specifically, skeletal muscle loss. This cancer-induced cachexia is …

Pkm2 Influences The Metabolic Fate Of Butyrate In Colorectal Cancer Cells, Megan Louise Pence

Chancellor’s Honors Program Projects

No abstract provided.

The Role Of Oxidative Stress And Signal Transduction In Chemotherapy-Mediated Cognitive Impairment In The Menopause Rat Model, Ciara Bagnall

Dissertations, Theses, and Capstone Projects

Systemic chemotherapy treatment is associated with long-term cognitive impairment in breast cancer survivors. While many studies have established the forms of cognition and corresponding regions in the brain most affected, very little is revealed about the potential molecular mechanisms that mediate these changes. The effects of systemic treatment on the brain is likely attributed to many different mechanisms including oxidative stress and immune dysregulation. Earlier studies from our lab have investigated the effects of the chemotherapy cocktail doxorubicin and cyclophosphamide (AC Chemotherapy) in an ovariectomized menopause animal model of ‘chemo brain’ (Salas-Ramirez et al., 2015). We observed that animals injected …

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 …

Phosphorylation Impairs Dicer1 Function To Accelerate Aging And Tumorigenesis In Vivo, Neeraj Aryal

Dissertations & Theses (Open Access)

Altered DICER1 protein levels are associated with developmental disorders, infertility, macular degenerative blindness, aging, and cancer in humans. Recently, post-translational regulation of Dicer1 via phosphorylation has been described in C. elegans. Oscillation of Dicer1 phosphorylation to regulate its activity is essential for germ cell development and embryogenesis in worms. These observations led us to posit that Dicer1 protein levels and activity are under tight regulation for normal mammalian homeostasis. To test whether phosphorylation of Dicer1 regulates its activity in mammals, I generated phospho-mimetic knock-in mouse models by replacing Serines 1712 and 1836 with Aspartic acids individually or together (dual …

The Role Of Thymine-Dna Glycosylase In Transcriptional Regulation, Bart Kolendowski

Electronic Thesis and Dissertation Repository

Precise control over transcriptional regulation is required for normal cell function. Errors in transcriptional regulation underpin many diseases including cancer. Thymine DNA Glycosylase (TDG) is a base excision repair protein and a coregulator that has been implicated in a diverse set of fundamental biological processes including embryonic development, nuclear receptor signaling and Wnt signaling. Importantly, TDG has been shown to play an important role in transcriptional regulation in a wide variety of systems. Details surrounding the mechanism through which TDG acts remain unclear. In this thesis we explore the role of TDG in Estrogen Receptor (ER)-dependent signaling and in cellular …

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.

Comparison Between The Structure-Function Relationship In The Wild Type Gαi1 Protein And Its Oncogenic Mutant, Jesse Lee Goossens

Dissertations

Many signal transduction pathways are regulated by guanine nucleotide-binding (G?) proteins, which function as molecular switches fluctuating between active and inactive conformations. Proper function depends on three flexible switch regions that are involved in the relatively slow hydrolysis of GTP. Deep sequencing studies have found mutations in the GNAS and GNAI1 genes involved in tumorigenesis, among which include a mutation corresponding to a highly conserved arginine residue in the switch II region. A mutation in GNAI1 encoding an R208Q change in G?i1 has been linked to intestinal cancers. We investigated the molecular basis of oncogenesis of this mutant by studying …

Biochemical And Cellular Studies Of Apobec3 Family Dna-Cytosine Deaminases, Sachini Umedi Siriwardena

Wayne State University Dissertations

The AID/APOBEC family of enzymes deaminate cytosines in single-stranded DNA to uracils leading to base substitutions and strand breaks. Members of APOBEC3 family in humans are induced by cytokines produced during the body's inflammatory response to infections and provide innate immunity against viruses. However, there is emerging consensus that these enzymes can cause mutations in the cellular genome depending on the physiological state of the cell and the phase of the cell cycle they are expressed. Since aberrant expression of APOBEC3B was recently identified as a possible source of cancer, we initiated a study to determine the maximally active catalytic …

Missing Heritability And Novel Germline Risk Loci In Hereditary Ovarian Cancer: Insights From Whole Exome Sequencing And Functional Analyses, Jaime Lyn Stafford

Wayne State University Dissertations

While 25% of ovarian cancer (OVCA) cases are due to inherited factors, most of the genetic risk remains unexplained. This study addressed this gap by identifying previously undescribed OVCA risk loci through the whole exome sequencing (WES) of 48 BRCA1/BRCA2 wild type women diagnosed with OVCA, selected for high risk of genetic inheritance. Five clearly pathogenic variants were identified in this sample, four of which are in two genes featured on current multi-gene panels; (RAD51D, ATM). In addition, a high impact variant in FANCM (R1931*) was identified. FANCM has been recently implicated in familial breast cancer risk but is not …

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 …