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Mitochondria Imaging And Targeted Cancer Treatment, Tinghan Zhao

Dissertations

Mitochondria are essential organelles as the site of respiration in eukaryotic cells and are involved in many crucial functions in cell life. Dysfunction of mitochondrial metabolism and irregular morphology have been frequently found in human cancers. The capability of imaging mitochondria as well as regulating their microenvironment is important both scientifically and clinically. Mitochondria penetrating peptides (MPPs), certain peptides that are composed of cationic and hydrophobic amino acids, are good candidates for mitochondria targeting. Herein, a novel MPP, D-argine-phenylalanine-D-argine-phenylalanine-D-argine-phenylalanine-NH₂ (rFrFrF), is conjugated with a rhodamine-based fluorescent chromophore (TAMRA). The TAMRA-rFrFrF probe exhibits advantageous properties for long-term mitochondria tracking of …

Cancer Risk Prediction With Whole Exome Sequencing And Machine Learning, Abdulrhman Fahad M Aljouie

Dissertations

Accurate cancer risk and survival time prediction are important problems in personalized medicine, where disease diagnosis and prognosis are tuned to individuals based on their genetic material. Cancer risk prediction provides an informed decision about making regular screening that helps to detect disease at the early stage and therefore increases the probability of successful treatments. Cancer risk prediction is a challenging problem. Lifestyle, environment, family history, and genetic predisposition are some factors that influence the disease onset. Cancer risk prediction based on predisposing genetic variants has been studied extensively. Most studies have examined the predictive ability of variants in known …

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 …

Exploration Of Ataxia Telangiectasia And Rad3-Related’S (Atr’S) Role In Cell Death Regulation: Implications In Development, Cancer, And Stroke, Brian Cartwright

Electronic Theses and Dissertations

From gametogenesis until death an organism’s genome is under constant bombardment from endogenous and exogenous sources of DNA damage. To maintain genomic integrity amid this damage, cells have evolved responses which allow them to either preserve viability for recovery or initiate self-destructive pathways depending on the severity of DNA damage. One protein involved in initiating and carrying out these responses is the protein kinase ataxia telangiectasia and Rad3-related (ATR). ATR is known primarily for its regulatory role in initiating the checkpoint-signaling cascade following DNA damage and replicative stress. These signaling events lead to cell cycle arrest, DNA repair, or apoptosis …

Investigation Of Phosphoserine Aminotransferase 1(Psat1) In Breast Cancer Progression., Stephanie Metcalf

Electronic Theses and Dissertations

This dissertation describes my research into the involvement of phosphoserine aminotransferase 1 (PSAT1) in breast cancer progression; specifically, in triple negative breast cancer (TNBC) metastasis and endocrine resistance in estrogen receptor positive breast cancer (ER+BC). Breast cancer is the most common tumor diagnosis among women. While the overall 5-year survival for breast cancer is reaching 90%, the 5-year survival for metastatic disease is only 22%. Metastasis and endocrine resistance combined can affect over 50% of patients. One of the proteins and pathways implicated in both metastasis and endocrine resistance in breast cancer is phosphoserine aminotransferase 1 (PSAT1) and the serine …

Evidence For P53-Mediated Induction Of Wrap53a In Response To Dna Damage, Anne Shelton Hucks

Theses and Dissertations

p53 is a powerful tumor suppressor mutated in approximately half of all cancers. Its mRNA is stabilized post-transcriptionally via complementary base pairing with the transcript of its antisense gene, WRAP53α; without this interaction, p53 protein cannot accumulate enough to carry out its many functions related to apoptosis, cell cycle arrest, and DNA damage repair. Previous studies have shown that WRAP53α is induced in response to DNA damage. The purpose of this study was to determine which transcription factors might be responsible for this induction. After identifying three putative p53 binding sites on the WRAP53α promoter, we used chromatin immunoprecipitation …

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, …

Mechanosensitive Epithelial Cell Scattering And Migration On Layered Matrices, Christopher Michael Walter

McKelvey School of Engineering Theses & Dissertations

Epithelial cells form multi-layered tissue scaffolding that makes up every organ in the body. Along with epithelial cells, the basement membrane (BM) and connective tissue are composed of various proteins that sculpt the organs and protect them from foreign macromolecules. Epithelial cells respond to various cues, both chemical and mechanical, from their surrounding matrices to aid in maintenance and repair of these layers through degradation and deposition of extracellular matrix (ECM) proteins. In cancer progression, epithelial cells lose their normal function of supporting tissue structure and instead adopt more aggressive behaviors through an epithelial-to-mesenchymal transition (EMT) of their cellular traits. …

Functional Investigation Of The Role Of The Retinoblastoma Protein In Genome Stability, Aren E. Marshall

Electronic Thesis and Dissertation Repository

Genome instability is an enabling characteristic of cancerous cells. It has recently been discovered that the retinoblastoma protein (pRB), typically known for its role in cell cycle regulation, also aids in the maintenance of genome stability. Intriguingly, mutations to the pRB gene, RB1, can arise late in tumorigenesis in cancer cells whose cell cycle regulation is already compromised by another mutation. This suggests that pRB’s functions in genome stability could underlie cancer relevant characteristics that are independent of its ability to negatively regulate proliferation. The overall aim of this thesis is to characterize the different means through which pRB …

Investigating The Role Of Cd109 In Pancreatic Ductal Adenocarcinoma, Mennatallah Shaheen

Dissertations & Theses (Open Access)

Pancreatic Ductal Adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in the US. We performed loss of function genomic screening on a cohort of four patient derived PDAC cell populations and our data shows a cell surface receptor CD109 to be a common vulnerability, the biologic role of which in PDAC is yet unstudied and largely unknown. We hypothesized that CD109 expression provides PDAC cells with a survival advantage, and promotes cancer progression through activation of downstream signaling. We believe therefore that targeting CD109 could improve PDAC patients’ survival. Here we report that CD109 plays a role in …

Synthesis Of New Aliphatic Pseudo-Branched Polyester Co-Polymers For Biomedical Applications, Zachary Shaw

Electronic Theses & Dissertations

In this study, a hyperbranched polyester co-polymer was designed using a proprietary monomer and diethylene glycol or triethylene glycol as monomers. The synthesis was carried out using standard melt polymerization technique and catalyzed by p-Tolulenesulfonic acid. The progress of the reaction was monitored with respect to time and negative pressure, with samples being subjected to standard characterization protocols. The resulting polymers were purified using the solvent precipitation method and characterized using various chromatographic and spectroscopic methods including GPC, MALDI-TOF, and NMR. We have observed polymers with a molecular weight of 29,643 kDa and 33,996 kDa, which is ideal to be …

The Role Of Ifrd1 In The Recruitment And Function Of Reserve Stem Cells In Regeneration And Cancer, Mark Anthony Lewis

Arts & Sciences Electronic Theses and Dissertations

Mature cells can reprogram into a proliferative, progenitor-like state to repair tissue following injury and inflammation. Differentiated cells in diverse tissues can become proliferative via a dedicated, evolutionarily conserved program we termed paligenosis. We detailed how paligenosis occurs, in both gastric chief and pancreatic acinar cells, in a step-wise manner that involves: 1) autodegradation of mature cell components; 2) re-expression of progenitor genes; 3) re-entry into the cell cycle. This process is governed by mTORC1, a fundamental cellular energy sensor and regulator of protein translation. Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re-entry at S-phase. …

Development Of Novel Tumor-Targeted Compounds For Boron Neutron Capture Therapy, Micah John Luderer

Arts & Sciences Electronic Theses and Dissertations

Glioblastoma multiforme (GBM) represents the most common primary brain tumor among adults. Despite surgical resection and aggressive chemoradiotherapy regimens, the current 2- and 5-year survival rates are only 27% and 9.8%, respectively. The low survival stems from the poor response to conventional therapy and underscores the critical need to develop new therapeutic approaches for GBM treatment. The high recurrence rate observed in GBM is in part attributed to the hypoxic (poorly oxygenated) tumor microenvironment. Hypoxic tumor conditions have been shown to increase metastasis, promote angiogenesis, and confer resistance to chemotherapy and radiation.

Hypoxic tissues are inherently radiation resistant due to …

Molecular Mechanisms Governing Muscle Wasting In Cancer, Aneesha Dasgupta

Theses & Dissertations

Pancreatic cancer is the third-leading cause of cancer-related deaths in the United States. About 80 percent of the pancreatic cancer patients suffer from cachexia and, about one-third die due to complexities related to the syndrome. Cachexia leads to a loss in body weight and cachectic patients are refractory to chemotherapy. Despite recent advances, the mechanisms of pancreatic cancer- cachexia and the potential therapeutic interventions remain poorly evaluated.

Sirtuins represent a class of proteins that are regulated by metabolic fluctuations in tissues. We observed a reduced expression of Sirt1 in spontaneous PDAC mice muscles, human pancreatic cancer muscles, and myotubes treated …

The Role Of Zyxin And Limd1 In Mitosis And Cancer, Jiuli Zhou

Theses & Dissertations

The Hippo signaling pathway, originally discovered in Drosophila, consists of a core kinase cascade and has been subsequently demonstrated to control tissue growth and tumorigenesis. The core of this pathway contains MST1/2 (Mammalian sterile 20-like kinase 1/2), LATS1/2 (large tumor suppressor 1/2) and downstream effector named Yes-associated protein (YAP) and PDZ-binding motif (TAZ). MST1/2 transduce their kinase activity mainly through directly phosphorylating LATS1/2. Once phosphorylated and activated, LATS1/2 subsequently phosphorylate and inhibit YAP/TAZ from translocating to nucleus, thereby suppressing the expression of downstream pro-growth and survival genes. While recent studies provide important insight into the tumor suppressor properties of …

Relationships Of Protein Biomarkers Of The Urokinase Plasminogen Activator System With Expression Of Their Cognate Genes In Primary Breast Carcinomas., Seth B. Sereff

College of Arts & Sciences Senior Honors Theses

Background: Urokinase plasminogen activator (uPA), its receptor uPAR and serine protease inhibitors PAI-1 or PAI-2 play key roles in tissue membrane remodeling and invasion of basement membranes by induction of a fibrinolytic pathway. Earlier studies reported that uPA and PAI-1 protein levels in breast carcinomas assist in prediction of response to chemotherapy. Our goal is to develop molecular signatures of candidate genes and identify novel relationships with these four protein biomarkers that demonstrate clinical utility for assessment of breast carcinoma outcomes.

Methods: This retrospective study used de-identified biomarker results and clinical outcomes from primary breast cancers that were stored in …

An Oxanthroquinone Derivative Disrupts Ras Plasma Membrane Localization And Function By Inhibition Of Acylpeptide Hydrolase And Perturbation Of Sphingomyelin Metabolism, Lingxiao Tan

Dissertations & Theses (Open Access)

Oncogenic RAS proteins are commonly expressed in human cancer. To be functional, RAS proteins must undergo post-translational modification and localize to the plasma membrane (PM). Therefore, compounds that prevent RAS PM targeting have potential as putative RAS inhibitors. Here we examined the mechanism of action of oxanthroquinone G01 (G01), a recently described inhibitor of KRAS PM localization. We show that G01 mislocalized HRAS and KRAS from the PM with similar potency and disrupted the spatial organization of RAS proteins remaining on the PM. G01 also inhibited recycling of epidermal growth factor receptor and transferrin receptor, but did not impair internalization …

The Total Western Diet And Vancomycin Treatment Increase Inflammation-Mediated Colorectal Cancer, Niklas David Joakim Aardema

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

Prior work by our research group showed that the total Western diet (TWD), a rodent diet which models the typical American diet, promoted the development of colon tumors when fed to mice. Other researchers previously showed that vancomycin, an antibiotic that changes the gut microbiome composition, causes differential changes in the severity of colon inflammation and CRC. Our goal was to determine the combined effects of feeding the TWD and vancomycin treatment on colitis and CRC, and if these factors interact. We hypothesized that vancomycin treatment would mitigate colitis and CRC in mice fed the TWD. To this end, mice …

Paraoxonase 2 Is Critical For Non-Small Cell Lung Carcinoma Proliferation., Aaron Whitt

Electronic Theses and Dissertations

Non-small cell lung carcinoma (NSCLC) comprises 85% of lung cancer diagnoses and is plagued by drug resistance. Thus, elucidating the underlying mechanisms of NSCLC is paramount to expand future treatment options. Paraoxonase 2 (PON2), an intracellular enzyme with arylesterase and lactonase functions, has well-established anti-atherosclerotic activity. Recent studies show PON2 is overexpressed in a variety of tumors and confers drug resistance, although these interactions have not been thoroughly examined in NSCLC. Thus, we sought to investigate the role of PON2 in cellular proliferation using PON2-knockout mice, primary mouse cells, and NSCLC cell lines. Using these approaches, we demonstrate that PON2 …

The Molecular Mechanisms Underlying The Cancer Killing Effect Of Interleukin-24, Leah Eshanie Persaud

Dissertations, Theses, and Capstone Projects

Interleukin-24 (IL-24) is an immunomodulatory cytokine that also displays specific anti-tumor effects across many cancer cell types. The tumor suppressor activities of IL-24 include inhibition of angiogenesis, metastasis, toxic autophagy, cancer-specific apoptosis, and sensitization to traditional cancer treatments like chemotherapy and radiation. Overexpression of IL-24 can selectively induce apoptosis in various cancer cells while having no adverse effects on normal cells. Due to this favorable killing effect, IL-24 is currently in phase II clinical trials. There is accumulating evidence that IL-24’s anti-cancer activity is primarily through the endoplasmic reticulum (ER) stress pathway but other pathways leading to cell death are …

Identifying Pathogenic Variants In Hereditary Cancer Syndrome Genes Via Tumor Molecular Profiling, Carol Nowlen

Dissertations & Theses (Open Access)

Tumor molecular profiling is often performed in order to direct cancer treatment options. However, because many of the genes analyzed on tumor molecular profiling overlap with genes known to be associated in the germline with hereditary cancer predisposition syndromes, tumor molecular profiling can unknowingly uncover germline predisposition to cancer development. In this study, we determined the number of patients with pathogenic variants (PVs) identified in BRCA1 and BRCA2 (BRCA1/2) via tumor molecular profiling at The University of Texas MD Anderson Cancer Center, then performed a retrospective chart review to determine the proportion of such patients that received germline …

Applications Of Phosphotyrosine Superbinding Sh2 Domain Variants, Xuguang Liu

Electronic Thesis and Dissertation Repository

Protein tyrosine kinases (PTKs, or TKs) have emerged as one of the most intensively pursued targets in the development of anti-cancer therapeutics, due to their critical roles in the phosphotyrosine (pTyr)-mediated signaling network that regulates many cancer-related cellular activities. The TKs, tyrosine phosphorylation phosphatases (PTPs) and pTyr recognition SH2 proteins are intensively tyrosine phosphorylated, which play a pivotal role in determining the signaling outcome of this network. More than 50% of all human proteins are tyrosine phosphorylated and many of these TK substrates have been proven functional in TK regulated cellular activities. Therefore, proteomics studies of tyrosine phosphorylation are of …

Characterization Of Genomic Copy Number Variation In Mus Musculus Associated With The Germline Of Inbred And Wild Mouse Populations, Normal Development, And Cancer, Maja Milojevic

Electronic Thesis and Dissertation Repository

Mus musculus is a human commensal species and an important model of human development and disease with a need for approaches to determine the contribution of copy number variants (CNVs) to genetic variation in laboratory and wild mice, and arising with normal mouse development and disease. Here, the Mouse Diversity Genotyping array (MDGA)-approach to CNV detection is developed to characterize CNV differences between laboratory and wild mice, between multiple normal tissues of the same mouse, and between primary mammary gland tumours and metastatic lung tissue.

A CNV detection pipeline was used in conjunction with evaluated probe sets, targeting 925,378 loci …

Synthetic Lectins, A Diagnostic And Prognostic Tool For Detecting Glycans In Breast Cancer, Daniel James Gordon

Theses and Dissertations

Cancer diagnostic tools have been pushed to the forefront of medical research because a person’s chance of survival is directly correlated with how early the tumor is identified and treatment is begun. In searching for the subtle differences between healthy and tumor cells, almost every type of cancer has been shown to under, over, or neo express glycans, and these changes in the glycan fingerprint can continue as the disease progresses. This provides a powerful diagnostic opportunity that’s works by screening for glycoproteins and glycosylation patterns that deviate from normal cells.

Boronic acids have a useful and tunable property in …

Exploring Patient Perceptions And Misconceptions: Beliefs Regarding Hereditary Cancer, Margaret Flach

Theses and Dissertations

Many patients who enter a genetic counseling session have preconceived notions about why they or their family members developed a genetic condition. Often these perceptions are deeply rooted in personal, familial, and/ or cultural beliefs; individuals typically have a personal framework, or schema, into which they incorporate new information. There is limited research on what information patients are retaining during a genetic counseling session and how they are assimilating that knowledge into their existing views. We attempted to characterize these patient perceptions with respect to hereditary cancer, in order to assess how patients are adopting the information presented in a …

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 …

Evaluating The Therapeutic Potential Of Crocin Against Diethylnitrosamine Induced Experimental Hepatocellular Carcinoma In Rats, Basma Ali Mustafa Awad

Theses

Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the third cause of cancer-related death worldwide. Liver cancer is the result of repeated injuries to the liver triggered by different causes. Currently, sorafenib is the only drug U.S. Food and Drug Administration approved targeted therapy. Sorafenib, an oral multikinase inhibitor, which inhibits the proliferation of tumor cells and blocks angiogenesis. Sorafenib has been shown to treat early and mild HCC lesions and it helped increase the survival rates at one year, but for only 44% of patients. Chemotherapies are an important line of defense when it comes …

Structure-Guided T Cell Receptor Mutations That Alter Antigen Specificity, Cross-Reactivity, And Polyfunctional Phenotypes In Gene-Modified T Cells, Kendra Foley

Dissertations

Adoptive cell transfer of T cell receptor (TCR) gene-modified T cells targeting specific tumor antigens is currently in clinical trials for patients with advanced malignancies. Despite the clinical responses, there are still hurdles to be overcome in achieving an effective and safe therapy. One of the limitations in the success of this type of therapy is the potential for cross-reactivity and unanticipated off-target reactivity which could lead to autoimmunity. Adverse events encompassing these "off-target, off-tumor" cross-reactivities leading to autoimmunity have been seen in patients in different clinical trials. Here, we demonstrate a novel approach to improve antigen specific reactivity and …

Modulating The Tumor Microenvironment To Induce Cross-Priming For Cancer Immunotherapy, Erica Fleming-Trujillo

Dissertations

Adoptive cell transfer (ACT) using T cells engineered to express tumor-specific T cell receptors (TCR) holds great promise in treating cancer patients. ACT involves the in vitro generation of large numbers of tumor-specific T cells, which are then administered back to the patient, to establish an in vivo response and effective tumor control. Our lab conducted a phase I clinical trial in which metastatic melanoma patients received systemic infusions of autologous T cells transduced to express a tyrosinase-specific TCR (TIL 1383I). We observed tumor regression in one of seven patients and the development of vitiligo, indicative of T cell-mediated killing …

Using Fundamental Properties Of Light To Investigate Photonic Effects In Condensed Matter And Biological Tissues, Laura A. Sordillo

Dissertations and Theses

Light possesses characteristics such as polarization, wavelength and coherence. The interaction of light and matter, whether in a semiconductor or in a biological sample, can reveal important information about the internal properties of a system. My thesis focuses on two areas: photocarriers in gallium arsenide and biomedical optics. Varying the excitation wavelength can be used to study both biological tissue and condensed matter. I altered the excitation wavelengths to be in the longer near-infrared (NIR) optical windows, in the shortwave infrared (SWIR) range, a wavelength region previously thought to be unusable for medical imaging. With this method, I acquired high …