Life Sciences Commons^™

Characterizing The Combination Of Rpa Inhibitors With Parp Inhibitors In High-Grade Serous Ovarian Cancer, Yat Tang

Theses & Dissertations

High-grade serous ovarian cancer (HGSC) is the most common and deadly gynecologic malignancy. HGSC patients with BRCA1/2 mutations have homologous recombination deficiency (HRD), requiring parallel pathways to maintain genome integrity (e.g., PARP1, PARP2). Approximately 50% of ovarian carcinomas are estimated to exhibit HRD. For the remaining 50% and the large percentage of HRD patients with acquired or innate resistance to single-agent PARP inhibitors, there is a need to develop alternative therapeutic strategies.

Replication Protein A (RPA) is a heterotrimeric protein crucial for genome maintenance. Phosphorylation of RPA in DNA damage response (DDR) is a negative regulator of DNA end resection. …

Mechanism Of Bax/Bak Activation In Apoptotic Signaling, Kai Huang

Theses & Dissertations

The Bcl-2 family proteins, including the anti-apoptotic members, pro-apoptotic effectors Bax/Bak, and the BH3-only proteins, are key components of the mitochondrial apoptotic pathway. The BH3-only protein Bid is critical for the mitochondrial pathway of apoptosis after TRAIL-induced death receptor activation. However, the mechanism of Bid activation during TRAIL-induced apoptosis is unclear. By putting back wild-type and mutants of Bid in Bid deficient (Bid KO) and Bid/Bax/Bak TKO colon cancer cells, we demonstrated that cleavage by caspase 8 and mitochondrial targeting are critical events for Bid activation. One of the biggest mysteries in apoptosis is how Bax/Bak was activated by BH3-only …

Hdac1 Is A Required Cofactor Of Cbfβ-Smmhc And A Therapeutic Target In Inversion 16 Acute Myeloid Leukemia, Lisa E. Richter

Theses & Dissertations

Acute myeloid leukemia (AML) is a neoplastic disease characterized by the uncontrolled proliferation and accumulation of immature myeloid cells. A common mutation in AML is the inversion of chromosome 16 [inv(16)], which generates a fusion between the genes for core binding factor beta (CBFB) and smooth muscle myosin heavy chain (MYH11), forming the oncogene CBFB-MYH11. The expressed protein, CBFβ-SMMHC, forms a heterodimer with the key hematopoietic transcription factor RUNX1. Although CBFβ-SMMHC was previously thought to dominantly repress RUNX1, recent work suggests that CBFβ-SMMHC functions together with RUNX1 to activate transcription of specific target genes.

Targeting the …

The Role Of Reactive Oxygen Species In Regulating Macrophage And Fibroblast Activation Within The Breast Cancer Tumor Microenvironment, Brandon J. Griess

Theses & Dissertations

The tumor microenvironment (TME) is a key determining factor in breast cancer, especially the more aggressive subtype triple negative breast cancer (TNBC). The activated fibroblasts and macrophages within the TME have many tumor promoting functions. Therefore, targeting their activation presents a novel therapeutic approach in TNBC. My work studied the role of reactive oxygen species (ROS) during fibroblast and macrophage activation in breast cancer.

My studies showed that expression of the secreted antioxidant enzyme, EcSOD, is silenced in breast cancer samples, in part, via increased promoter methylation. The re-expression of EcSOD inhibited c-Met activation in the TNBC cell line, MDA-MB231. …

The Role Of Histone Chaperone Fact Complex In Base Excision Repair Pathway And Its Therapeutic Potential In Colon Cancer And Medulloblastoma, Heyu Song

Theses & Dissertations

Base excision repair (BER) pathway is required for the removal of damaged bases caused by alkylation, oxidation and ring-saturation. Human apurinic/apyrimidinic endonuclease 1 (APE1) plays a central role in BER pathway. Although repair of damaged bases by recombinant APE1 has been well investigated in vitro, how APE1 gains access to damaged bases in the context of chromatin is largely unknown. A prominent member of the histone chaperone family, FACT (Facilitates Chromatin Transcription) is thought to reorganize nucleosomes through the destabilization of multiple intra-nucleosome contacts. FACT complex is composed of two polypeptides identified as SPT16 (Suppressor of Ty 16) and SSRP1 …

The Role Of E3 Ubiquitin Ligase Fbxo9 In Normal And Malignant Hematopoiesis, R. Willow Hynes-Smith

Theses & Dissertations

Hematopoiesis is a critical system that provides blood cells necessary for nutrient and oxygen transfer throughout an organism and for protection from harmful agents. It is maintained throughout life by the hematopoietic stem cells (HSCs) that reside within the bone marrow (BM) and are responsible for providing billions of new cells each day. HSCs maintain a careful balance between a quiescent state, that sustains the integrity of the stem cells, and a proliferative state, that provides new cells to replenish those that undergo apoptosis. Hematopoiesis is regulated by a variety of intrinsic pathways and extrinsic signals such as cytokine signaling, …

Brca1 & Ctdp1 Brct Domainomics In The Dna Damage Response, Kimiko L. Krieger

Theses & Dissertations

Genomic instability is one of the enabling characteristics of cancer. DNA damage response pathways are important for genomic integrity and cell cycle progression. Defects in DNA damage repair can often lead to cell cycle arrest, cell death, or tumorigenesis. The activation of the DNA damage response includes tightly regulated signaling cascades that involve kinase phosphorylation and modular domains that scaffold phosphorylated motifs to coordinate recruitment of DNA repair proteins. Modular domains are conserved tertiary structures of a protein that can fold, function, and evolve independently from an intact protein. One of the most common modular domains involved in DNA damage …

Molecular Insights Into Major Peripheral T-Cell Lymphoma Entities With Advances In A Representative Model System, Tayla B. Heavican

Theses & Dissertations

Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the two most frequent categories accounting for more than 50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number analysis and targeted sequencing revealed unique genomic abnormalities and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited higher genomic complexity characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A/B-TP53 axis and PTEN-PI3K pathways. …

Investigating The Relationship Between Hormone Receptors Dax-1 And Estrogen Receptor Within Prostate Cancer Cell Lines, Meghana G. Vijayraghavan

Master's Theses

Prostate cancer (PCa) is estimated to be the second leading cause of cancer-related deaths among men in the United States in 2019. While most prostate tumors rely on androgens for growth signaling, there are subsets of tumors that become androgen-resistant, therefore resisting conventional androgen-depravation therapy. Consequently, research has focused on targeting different hormone receptors for novel therapeutics. One such receptor is Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1). DAX-1 is known to interact with other hormone receptors, such as androgen receptor (AR) and estrogen receptors (ERs) to suppress the proliferative effects …

The Black Identity, Hair Product Use, And Breast Cancer Scale, Dede Teteh, Marissa Ericson, Sabine Monice, Lenna Dawkins-Moultin, Nasim Bahadorani, Phyllis Clark, Eudora Mitchell, Lindsey S. Treviño, Adana Llanos, Rick Kittles, Susanne Montgomery

Health Sciences and Kinesiology Faculty Articles

Introduction
Across the African Diaspora, hair is synonymous with identity. As such, Black women use a variety of hair products, which often contain more endocrine-disrupting chemicals than products used by women of other races. An emerging body of research is linking chemicals in hair products to breast cancer, but there is no validated instrument that measures constructs related to hair, identity, and breast health. The objective of this study was to develop and validate the Black Identity, Hair Product Use, and Breast Cancer Scale (BHBS) in a diverse sample of Black women to measure the social and cultural constructs associated …

Generation Of A Fully Human Scfv That Binds Tumor-Specific Glycoforms, Zhongpeng Lu, Kalika Kamat, Blake P. Johnson, Catherin C. Yin, Nathalie Scholler, Karen L. Abbott

Articles

Tumor-specific glycosylation changes are an attractive target for the development of diagnostic and therapeutic applications. Periostin is a glycoprotein with high expression in many tumors of epithelial origin including ovarian cancer. Strategies to target the peptide portion of periostin as a diagnostic or therapeutic biomarker for cancer are limited due to increased expression of periostin in non-cancerous inflammatory conditions. Here, we have screened for antibody fragments that recognize the tumor-specific glycosylation present on glycoforms of periostin containing bisecting N-glycans in ovarian cancer using a yeast-display library of antibody fragments, while subtracting those that bind to the periostin protein with glycoforms …

Mechanisms And Consequences Of Myb Gene Activation In Salivary Gland Tumors, Candace Frerich

Biomedical Sciences ETDs

Salivary gland adenoid cystic carcinoma (ACC) is an aggressive tumor with a tendency to infiltrate surrounding nerves and metastasize to distant sites. The standard treatment often fails to control local tumor recurrence and distant metastases and no approved targeted therapeutic options exist for these tumors. The goal of our studies was to reveal the molecular mechanisms driving ACC tumor development and novel drug targets to improve patient morbidity and mortality.

We first analyzed clinical and RNA-sequencing (RNA-seq) data for 68 formalin-fixed paraffin-embedded (FFPE) ACC tumor samples and described previously unappreciated molecular heterogeneity that predicts patient outcome. The poor outcome subgroup …

Anti-Inflammatory Effects Of Cruciferous And Apiaceous Vegetables In C57bl/6j Mice Colon, Rosa Moreno Narvaez

Graduate Theses and Dissertations

Previous studies have demonstrated chemo-preventive potential of cruciferous and apiaceous vegetables against colon cancer. Colon inflammation is one condition closely related with colon cancer initiation. Therefore, we wanted to compare if total western diet (TWD) was as pro-inflammatory as died-induced obesity (DIO) and a better dietary model for human conditions, and determine if diet supplementation with cruciferous (broccoli, watercress and cabbage) or apiaceous vegetables (celery and parsnip) could reduce dietary inflammation, and which vegetable was more effective.

Male CBL57/6J mice were fed chow for seven days, on day eight, mice were assigned to one of the following diets: American Institute …

Uncovering The Zeb1 Interactome To Identify Novel Regulators Of Metastatic Non-Small Cell Lung Cancer, Roxsan Manshouri

Dissertations & Theses (Open Access)

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States, due in part to the robust affinity of lung cancer cells to metastasize. Understanding the processes that contribute to metastasis provides promise for the discovery of novel therapeutic targets. Epithelial-tomesenchymal transition (EMT) is a proposed model for the initiation of metastasis. During EMT cell adhesion and polarity is reduced, allowing epithelial cancer cells to dissociate from the primary tumor and invade distant organs. The transcription factor zinc finger E-box-binding homeobox 1 (ZEB1) has been reported to uniquely correlate with NSCLC disease progression and to …

In Vivo Metabolic And Vascular Response To Hypoxia In Twist Knockdown Murine Breast Cancer, Brandon Sturgill

Graduate Theses and Dissertations

Twist transcription factor is often overexpressed in aggressive tumors. Although needed in early embryonic development for organogenesis, Twist is known to induce an epithelial to mesenchymal transition in cells. In cancer, epithelial to mesenchymal transitions can lead to increased motility and invasiveness. It has also been linked to metabolic reprogramming and increased metastatic risk. Furthermore, metabolic preferences can increase proliferation, enhance metastatic potential, and influence the site of metastasis. We hypothesize that Twist directly affects the metabolism of cancer cells. We expect to see in vivo what we have seen in vitro; Twist overexpression should promote a shift away from …

A Systematic Comparison Of Lipopolymers For Sirna Delivery To Multiple Breast Cancer Cell Lines: In Vitro Studies, Hamidreza Montazeri Aliabadi, Remant Bahadur Kc, Emira Bousoik, Ashley Barbarino, Bindu Thapa, Melissa Coyle, Parvin Mahdipoor, Hasan Uludağ

Pharmacy Faculty Articles and Research

Small interfering RNA (siRNA) therapy is a promising approach for treatment of a wide range of cancers, including breast cancers that display variable phenotypic features. To explore the general utility of siRNA therapy to control aberrant expression of genes in breast cancer, we conducted a detailed analysis of siRNA delivery and silencing response in vitro in 6 separate breast cancer cell models (MDA-MB-231, MDA-MB-231-KRas-CRM, MCF-7, AU565, MDA-MB-435 and MDA-MB-468 cells). Using lipopolymers for siRNA complexation and delivery, we found a large variation in siRNA delivery efficiency depending on the specific lipopolymer used for siRNA complexation and delivery. Some lipopolymers were …

The Role Of Inositol Polyphosphate-4-Phosphatase Type Ii B (Inpp4b) In Obese Models And Endocrine Cancers, Manqi Zhang

FIU Electronic Theses and Dissertations

INPP4B is a dual-specificity phosphatase and a tumor suppressor in prostate and breast cancers. Progression of the prostate and breast cancers depends on the androgen receptor (AR) or estrogen receptor alpha (ERα) signaling, respectively. In this work we demonstrated that INPP4B reprograms ERα transcriptional activity in breast cancer. INPP4B maintains expression and protein levels of progesterone receptor (PR), an ERα direct target gene required for mammary gland development. Consistently we demonstrated that Inpp4b knockout severely impairs lateral branching in the mammary gland of maturing virgin females. In advanced prostate cancer, activation and transcriptional reprogramming of AR frequently coincides with the …

Regulation Of Telomerase Activity By Rab5 Guanine Nucleotide Exchange Factors, Patric J. Hambleton

FIU Electronic Theses and Dissertations

Many cancerous cells display abnormalities in the signal transduction pathways responsible for responding to extracellular growth factors. Growth factors, such as insulin-like growth factor I, represent a major class of mitogenic ligands that can initiate the mitogen activated protein kinase (MAPK) pathway. The role of the MAPK pathway in transducing growth signals to the interior of the cell and subsequently stimulating cell growth and proliferation is highlighted by the fact that roughly one quarter of all human tumors contain mutant forms of Ras proteins. Ras interference 1 (Rin1) is involved in key steps of receptor mediated endocytosis and can potentially …

Discovery Of An Egfr Inhibitor For The Treatment Of Lung And Other Cancers, Jodie Meng '20

Student Publications & Research

The Epidermal Growth Factor Receptor (EGFR), a transmembrane protein involved in the regulation of signaling pathways, is frequently overexpressed in epithelial tumors. First generation EGFR TKIs, such as erlotinib and gefitinib, traditionally improved outcomes for non-small-cell lung carcinoma and pancreatic cancer patients by attaching competitively and reversibly to the ATP binding domain of EGFR. Second-generation EGFR TKIs have been developed to combat resistance among patients, despite demonstrating toxic side effects. In the present study, 1400 selective inhibitors were designed based on the molecular scaffolds of first and second generation EGFR TKIs. Results were refined by parameters outlined in Lipinski’s rule. …

Cul3 Regulates Cyclin E1 Protein Abundance Via A Degron Located Within The N-Terminal Region Of Cyclin E, Brittney Marie Davidge, Katia De Oliveira Rebola, Larry N. Agbor, Curt D. Sigmund, Jeffrey D. Singer

Biology Faculty Publications and Presentations

mammalian cells. Increased levels of cyclin E are found in some cancers. Additionally, proteolytic removal of the cyclin E N-terminus occurs in some cancers and is associated with increased cyclin E–Cdk2 activity and poor clinical prognosis. Cyclin E levels are tightly regulated and controlled in part through ubiquitin-mediated degradation initiated by one of two E3 ligases, Cul1 and Cul3. Cul1 ubiquitylates phosphorylated cyclin E, but the mechanism through which Cul3 ubiquitylates cyclin E is poorly understood. In experiments to ascertain how Cul3 mediates cyclin E destruction, we identified a degron on cyclin E that Cul3 targets for ubiquitylation. Recognition of …

Environmental Risk Factors For Inflammatory Bowel Disease: Triclosan And Other Consumer Antimicrobials, Katherine Z. Sanidad

Doctoral Dissertations

Inflammatory bowel disease (IBD) has become a serious health problem since the incidence and prevalence of IBD has dramatically increased throughout the world. There is evidence that environmental factors are primarily responsible for the increase of IBD, therefore, it is important to identify novel environmental risk factors to reduce the risk of IBD and its associated diseases. Antimicrobials used in consumer products might serve as environmental risk factors for IBD and its associated diseases. Triclosan (TCS), triclocarban (TCC), benzalkonium chloride (BAC), benzethonium chloride (BET), and chloroxylenol (PCMX) are widely used antimicrobial ingredients in consumer products and are ubiquitous contaminants in …

Methylselenol Producing Selenocompounds Enhance The Efficiency Of Mammaglobin‑A Peptide Vaccination Against Breast Cancer Cells, Duaa Babaer, Mu Zheng, Michael T. Ivy, Roy Zent, Venkataswarup Tiriveedhi

Biology Faculty Research

Previous phase I DNA‑vaccine based clinical trials using Mammaglobin‑A (Mam‑A), a human breast tumor associated antigen (TAA), demonstrated that this agent was safe and efficient at treating patients with stage IV breast cancer. The long‑term success of cancer vaccines is limited by the diminished expression of human leukocyte antigen (HLA) class I molecules in the tumor microenvironment. The current study assessed the impact of various selenocompounds on the expression of HLA class I molecules in THP‑1 cells, an apparent proficient antigen that presents a human monocyte‑like cell line, and their eventual activation of MamA2.1 (HLA‑A2 immunodominant epitope of Mam‑A) specific …

Heterogeneity And Plasticity Of Human Breast Cancer Cells In Response To Molecularly-Targeted Drugs, Emira Bousoik, Ramina Nabiee, Farideh Amirrad, Ashley Nichols, Rebecca Witt, Parvin Mahdipoor, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

Non-responsive subpopulation of tumor cells, and acquired resistance in initially responsive cells are major challenges for cancer therapy with molecularly-targeted drugs. While point mutations are considered the major contributing factor to acquired resistance, in this study we explored the role of heterogeneity and plasticity of selected human breast cancer cell lines (MDA-MB-231, MDA-MB-468, and AU565) in their initial and adjusted response, respectively, to ruxolitinib, everolimus, and erlotinib. After determination of lethal concentration for 50% cell death (LC50), cells were exposed to selected drugs using three different approaches: single exposure to 4 × LC50 and collection of surviving cells, multiple exposures …

Optimal Control Applied To Cancer Vaccine Protocols, Brady Fritz

Student Summer Scholars Manuscripts

This article is written to document the research conducted by student Brady Fritz and mentor Dr. Norma Ortiz-Robinson during the 2019 Student Summer Scholars Program at Grand Valley State University. The mathematical model used was developed by Dr. Ami Radunskaya and Dr. Sarah Hook, and it describes the population of certain groups of cells over time after administration of a certain cancer vaccine. The model was programmed into specialized software that evaluates the optimal control of the vaccine given specified control parameters. The output was then analyzed to properly describe the solution obtained.

Immediate-Early Genes And Delayed Primary Response Genes Regulated By Nmu In Skbr3 Her-2 Positive Breast Cancer Cell Line, Jessica Murphy, Sweta Rani

SURE Journal: Science Undergraduate Research Experience Journal

Background
Breast cancer is a heterogeneous disease that consists of varying genetic, cellular and molecular subtypes with unique characteristics. Due to the multiple subtypes and molecular markers of breast cancer, successful clinical treatment is hampered by the lack of reliable biomarkers. HER2-positive breast cancer is an aggressive subtype associated with poor patient prognosis. Although survival rates have dramatically increased due to the development of Trastuzumab in 1997, many patients develop a resistance to this therapeutic treatment and relapse over time. Rani et al. (2014), have associated the acquirement of resistance to HER2-treatment with Neuromedin U, but the mechanisms by …

9th Annual Postdoctoral Science Symposium, University Of Texas Md Anderson Cancer Center Postdoctoral Association

Annual Postdoctoral Science Symposium Abstracts

The mission of the Annual Postdoctoral Science Symposium (APSS) is to provide a platform for talented postdoctoral fellows throughout the Texas Medical Center to present their work to a wider audience. The MD Anderson Postdoctoral Association convened its inaugural Annual Postdoctoral Science Symposium (APSS) on August 4, 2011.

The APSS provides a professional venue for postdoctoral scientists to develop, clarify, and refine their research as a result of formal reviews and critiques of faculty and other postdoctoral scientists. Additionally, attendees discuss current research on a broad range of subjects while promoting academic interactions and enrichment and developing new collaborations.

Cold Atmospheric Plasma Induces Accumulation Of Lysosomes And Caspase-Independent Cell Death In U373mg Glioblastoma Multiforme Cells, Gillian Conway, Zhonglei He, Ana L. Hutanu, George P. Cribaro, Eline Manaloto, Alan Casey, Damien Traynor, Vladimir Milosavljevic, Orla Howe, Carlos Barcia, James T. Murray, Patrick Cullen, James Curtin

Articles

Room temperature Cold Atmospheric Plasma (CAP) has shown promising efficacy for the treatment of cancer but the exact mechanisms of action remain unclear. Both apoptosis and necrosis have been implicated as the mode of cell death in various cancer cells. We have previously demonstrated a caspase-independent mechanism of cell death in p53-mutated glioblastoma multiforme (GBM) cells exposed to plasma. The purpose of this study was to elucidate the molecular mechanisms involved in caspase-independent cell death induced by plasma treatment. We demonstrate that plasma induces rapid cell death in GBM cells, independent of caspases. Accumulation of vesicles was observed in plasma …

Anti-Cancer Effects Of Oleocanthal And Extra Virgin Olive Oil, Limor Goren

Dissertations, Theses, and Capstone Projects

Oleocanthal is a phenolic compound found in varying concentrations in extra virgin olive oil. Oleocanthal has been shown to be active physiologically, benefiting several diseased states by conferring anti-inflammatory and neuroprotective benefits. Recently, we and other groups have demonstrated its specific and selective toxicity toward cancer cells; however, the mechanism leading to cancer cell death is still disputed. The current study demonstrates that oleocanthal induced damage to cancer cells’ lysosomes leading to cellular toxicity in vitro. Non-cancer cells were significantly less affected. Lysosomal membrane permeabilization following oleocanthal treatment in various cell lines was assayed via three complementary methods. Additionally, …

Towards A Mathematical Model Of Motility Using Dictyostelium Discoideum: Proteins And Geometric Features That Regulate Bleb-Based Motility, Zully Santiago

Dissertations, Theses, and Capstone Projects

A variety of biological functions depend on actin organization. The organization of actin is tightly regulated by a plethora of extracellular and intracellular signaling, scaffolding, and actin-binding proteins. Dysfunctions in this regulation lead to immune diseases, increased susceptibility to pathogens, neurodegenerative diseases, developmental disorders, and cancer metastasis. A variety of actin-dependent processes, including cell motility, are regulated by several proteins of interest: Paxillin, a scaffolding protein; WASP, an actin nucleating protein; SCAR/WAVE, another WASP family actin nucleating protein; Talin, a cortex-to-membrane binding protein; Myosin II, an F-actin contracting motor protein; and Protein Kinase C, a protein kinase. D. discoideum cells …

Activation Of Lxrβ Inhibits Tumor Respiration And Is Synthetically Lethal With Bcl-Xl Inhibition, Trang Thi Thu Nguyen, Chiaki Tsuge Ishida, Enyuan Shang, Chang Shu, Consuelo Torrini, Yiru Zhang, Elena Bianchetti, Maria J. Sanchez-Quintero, Giulio Kleiner, Catarina M. Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Peter Canoll, Markus D. Siegelin

Publications and Research

Liver-X-receptor (LXR) agonists are known to bear anti-tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti-proliferative effect of BH3 mimetics in solid tumor malignancies, which is predominantly mediated by cell death with features of apoptosis and is rescued by exogenous cholesterol. Extracellular flux analysis and carbon tracing experiments (U-¹³C-glucose and U-¹³C-glutamine) reveal that within 5 h, activation of LXRβ results in reprogramming of tumor cell metabolism, leading …