Physical Sciences and Mathematics Commons^™

Construction And Performance Optimization Of Bioconjugated Nanosensors For Early Detection Of Breast Cancer And Pro-Inflammatory Diseases, Pooja Gaikwad

Dissertations, Theses, and Capstone Projects

In recent years, nanosensors have emerged as a tool with strong potential in medical diagnostics. Single-walled carbon nanotube (SWCNT) based optical nanosensors have notably garnered interest due to the unique characteristics of their near-infrared fluorescence emission, including tissue transparency, photostability, and various chiralities with discrete absorption and fluorescence emission bands. Additionally, the optoelectronic properties of SWCNT are sensitive to the surrounding environment, which makes them suitable for in vitro and in vivo biosensing. Single-stranded (ss) DNA-wrapped SWCNTs have been reported as optical nanosensors for cancers and metabolic diseases. Breast cancer and cardiovascular diseases are the most common causes of death …

Photodynamic Therapy Agents: The Power Of Mjöllnir To Eradicate Cancer, Sidney M. Hopper

Honors College Theses

After its discovery back in the 1900s, photosensitizers became a critical study for potential treatments and cures for medical issues, including cancer. It was discovered that porphyrins appeared to target and accumulate in proliferating cells, and to reach the cells, a certain wavelength of light with maximum absorbance associated with the porphyrin was necessary to achieve cell death. Photodynamic therapy involves making use of porphyrins or metalloporphyrins as activators when exposed to such light. When activated, these compounds generate reactive oxygen species (ROS), such as HO- or O2-, which can react with nucleic acids found in DNA and RNA. In …

Optimized Peptide Nanomaterials As Delivery Vehicles For Hydrophobic Metal-Based Anticancer Agents, Yaron Marciano

Dissertations, Theses, and Capstone Projects

Enzyme-responsive materials have been well explored, particularly as therapeutic and diagnostic agents. In this thesis we demonstrate that anionic self-assembling peptides can be utilized as delivery vehicles for metal-based hydrophobic payloads. The tunability of the system is highlighted as well as the increase in cytotoxicity and selectivity in vitro. The rapid degradation of peptides in cell media may lead to the formation of new peptide-drug bioconjugates with increased activity and selectivity. The physiological stability of these peptide delivery vehicles has been optimized by capping the N-terminus with an acetyl group. This simple backbone modification was shown to not prevent self-assembly, …

Investigating The Interactions Of The Iron-Sulfur Mitochondrial Protein, Mitoneet With Its Binding Partners, Ebenezer Osei Newton

Graduate Theses, Dissertations, and Problem Reports

MitoNEET belongs to the CDGSH Iron-Sulfur Domain (CISD)-gene family of proteins and is a [2Fe-2S] cluster-containing protein found on the outer membrane of mitochondria. The specific functions of mitoNEET/CISD1 remain to be fully elucidated, but the protein is involved in regulating mitochondrial bioenergetics in several metabolic diseases. Unfortunately, drug discovery efforts targeting mitoNEET to improve metabolic disorders are hampered by the lack of ligand-binding assays for this mitochondrial protein. We have developed a protocol amenable for high-throughput screening (HTS) assay, by modifying an ATP fluorescence polarization method to facilitate drug discovery targeting mitoNEET. Based on our observation that adenosine triphosphate …

Structural, Mutational, And Kinetic Characterization Of Ura4, An Isocytosine Deaminase, Ashlee Hoffman

WWU Graduate School Collection

Cytosine Deaminases (CD) are a class of enzymes found in prokaryotes and fungi that have been studied in the past due to their ability to deaminate the prodrug 5-fluorocytosine (5-FC) producing 5-fluorouracil (5-FU). 5-FU is a common anti-cancer drug that can inhibit DNA synthesis leading to cancer cell death. 5-fluorocytosine can interact with digestive bacteria leading to unwanted side effects for cancer patients. Isocytosine Deaminases (ICD) are enzymes that are of interest in the treatment of cancers using Gene Directed Enzyme Prodrug Therapy (GDEPT). ICDs can deaminate the prodrug 5-fluoroisocytosine (5-FIC) also producing the drug 5-FU.  5-FIC will likely not …

Development And Biological Evaluation Of Selective Small-Molecule Inhibitors Of The Human Cytochrome P450 1b1, Austin Hachey

Theses and Dissertations--Chemistry

The human cytochrome P450 1B1 (CYP1B1) is an emerging target for small- molecule therapeutics. Several solid tumors overexpress CYP1B1 to the degree that it has been referred to as a universal tumor antigen. Conversely, its expression is low in healthy tissues. CYP1B1 may drive tumorigenesis through promoting the formation of reactive toxins from environmental pollutants or from endogenous hormone substrates. Additionally, the expression of CYP1B1 in tumors is associated with resistance to several common chemotherapies and with poor prognoses in cancer patients. However, inhibiting CYP1B1 with small molecules has been demonstrated in cellular and murine model systems to reverse this …

Modeling Vascular Diffusion Of Oxygen In Breast Cancer, Tina Giorgadze

Senior Projects Spring 2023

Oxygen is a vital nutrient necessary for tumor cells to survive and proliferate. Oxygen is diffused from our blood vessels into the tissue, where it is consumed by our cells. This process can be modeled by partial differential equations with sinks and sources. This project focuses on adding an oxygen diffusion module to an existing 3D agent-based model of breast cancer developed in Dr. Norton’s lab. The mathematical diffusion module added to an existing agent-based model (ABM) includes deriving the 1-dimensional and multi-dimensional diffusion equations, implementing 2D and 3D oxygen diffusion models into the ABM, and numerically evaluating those equations …

The Discovery And Characterization Of Novel Potent 5-Substituted 3, 3’, 4’, 7-Tetramethoxyflavonoid Dna Triplex Specific Binding Ligands, Vanessa Marie Rangel

University of the Pacific Theses and Dissertations

Chemotherapy works by killing fast dividing cells. Unfortunately, these drugs are not specific to cancer tissue and can damage normal cells. Chemotherapy is like taking poison and hoping it kills the cancer cells before it kills you. As an alternative, many researchers have investigated the use of antigene therapy to selectively target cancer causing genes to avoid off target effects. Although promising, the theory is limited by the stability of the triplex structure. Here, we report the discovery of potent triplex binding ligands derived from the natural product quercetin. Chemical derivatives of 5-substituted 3, 3’, 4’, 7-tetramethoxyquercetin derivatives were characterized …

Synthesis Of Bioactive Heterocycles, Shaila Akter Shetu

Theses and Dissertations

The Discovery of a variety of heterocyclic drugs for the treatment of cancer and other diseases (e.g, neglected tropical diseases) is a medical breakthrough and inspiring for the research community as a whole. A wide range of natural, semi-synthetic, and synthetic anticancer drugs are synthesized using various methods. Among them, β -lactams stand out as a novel class of antibiotics that has different types of biological as well as anti-cancer properties. β -lactam has become a premier and active research subject towards the development of revolutionary anti-cancer drugs. In recent years, a large amount of investigations have been done to …

Development Of Nucleic Acid Diagnostics For Targeted And Non-Targeted Biosensing, Christopher William Smith

Legacy Theses & Dissertations (2009 - 2024)

The field of nucleic acid technology is rapidly expanding with new impactful discoveriesbeing made each year. Starting from the discovery of the double-helix structure, cloning, gene editing, polymerase chain reaction (PCR), CRISPR technology, and even the late mRNA vaccines; nucleic acid technology is at the forefront of improving medicine. Nucleic acid technology is extremely versatile due to its easy programmability, automated cheap synthesis, and even its catalog for numerous chemical modifications that can be used to alter structure stability. For example, the number of permutations that can be made with DNA just by altering the code for adenine (A), cytosine …

Understanding The Complexities Of Anemia In Chronic Inflammatory Diseases From Diagnosis To Treatment, Naomi Rae Flindt

Theses and Dissertations

Iron is an essential nutrient for energy and DNA replication. Its homeostasis is commonly perturbed by chronic inflammatory mechanisms. Chronic inflammation upregulates a cytokine, hepcidin, that degrades the iron export protein ferroportin. Without a way to export iron into the bloodstream iron availability in blood becomes depleted. Iron depletion in the blood stream hinders erythropoiesis and is termed anemia. Herein I investigate and inhibit the mechanism of hepcidin activation. Inhibition of hepcidin activation has released iron from tissues and alleviated anemic conditions in a cancer model. I have laid the foundation to investigate this pathway in a 3D spheroid model. …

Alkylthiocarbamate Metal Complexes With Antiproliferation Activity., Kritika Bajaj

Electronic Theses and Dissertations

Bis(thiosemicarbazones) (BTSCs) and their metal complexes have been extensively studied for various applications including catalysis for hydrogen evolution reactions, treatment of neurodegenerative diseases, hypoxia imaging, and a wide range of pharmacological purposes including antitumor, antiviral, antibacterial, and antifungal agents. The paramount property that makes BTSC metal complexes interesting for their use in these applications is the reduction potential of the coordinated metal, which can be selectively tuned by varying the substituents present on the ligand framework. Although the BTSCs have shown a great deal of success as potential cancer therapeutic agents, they lack selectivity towards cancer cells. For this matter, …

Mechanisms And Impact Of Hypoxia Regulated Inhibins In Cancer, Ben Allen Horst

Theses and Dissertations

Inhibins are heterodimeric ligands within the TGFβ superfamily, comprised of an α-subunit (INHA) and a β-subunit (either INHBA or INHBB) with emergent roles in cancer. Inhibins are biomarkers of disease burden and prognosis in a subset of cancers and utilize the coreceptors betaglycan (TGFBR3) and endoglin (ENG) for physiological or pathological outcomes. Previously, we found inhibin promotes angiogenesis in ovarian cancer however no mechanism of regulation for inhibin expression in cancer has been established. Hypoxia, a driver of tumor growth and metastasis, regulates angiogenic pathways that are targets for vessel normalization and ovarian cancer management. …

The Regulation Of Atg9a-Mediated Aggrephagy By An Ulk1-Independent Atg13-Atg101 Complex, Joshua Youngs

Undergraduate Honors Theses

Aggrephagy, a type of autophagy, is an essential cellular process by which protein aggregates are collected and broken down in the lysosome. Protein aggregates are implicated in several diseases including Alzheimer’s disease, diabetes, and cancer. Here, we investigate the ATG13-ATG101 protein complex, a sub-complex of the canonical ULK1 complex whose regulatory role in aggrephagy is not completely understood. We also develop a protein fragment complementation (PFC) assay using the biotin ligase TurboID to study the functions of the ATG13-ATG101 complex with increased specificity. We demonstrate that ATG13 is required for optimal degradation of p62-ubiquitin condensates. We also show that a …

System Measurements For X-Ray Phase And Diffraction Imaging, Erik Wolfgang Tripi

Legacy Theses & Dissertations (2009 - 2024)

In medical imaging, X rays are used to look inside the body to find fractures in bones, abnormal masses, cavities in teeth, and so on. What makes X rays so good at looking at these types of structures is the X ray’s penetration power. When imaging soft tissue to search for tumors, X-ray images tend to have difficulty performing well. The reason for this is that the background structures, such as fat or fibro glandular tissue have similar absorption coefficients as the tumor. Mammography tends to have a high false positive rate and can miss tumors entirely as well. There …

A Review Of Monte Carlo Methods And Their Application In Medical Physics For Simulating Radiation Transport, Joe Shields

Honors Theses and Capstones

Monte Carlo methods are used to calculate statistical behavior through the use of random number generators and probability density functions. They have been used extensively in medical physics for research in radiotherapy, designing technology, dosimetry, and advanced clinical applications. This paper provides a background on Monte Carlo methods and a review of radiation therapy physics and dosimetry. Additionally, there is a discussion of the different ways Monte Carlo methods are used in medical physics as well as a review of current research related to Monte Carlo methods. The final portion of this paper contains my own Monte Carlo simulation using …

A Multifunctional Solution Composed Of Tmpyp, 1,5-Dhn, And Fe(Iii) Ions That Produces Reactive Oxygen Species (Ros) In Aerobic, Anaerobic, And H2o2 Environments, Aqeeb Ali

Electronic Theses and Dissertations

Photodynamic therapy (PDT) has become a widely popular therapeutic approach for treating various types of cancer over the past several decades. PDT utilizes a photosensitizer, visible light, and oxygen, to produce reactive oxygen species (ROS) which can be used to treat cancer and inhibit growth of bacteria. In this study, a multifunctional solution that is comprised of Fe(III) ions, cationic meso-tetra(N-methyl-4-pyridyl)porphine tetrachloride (TMPyP), and 1,5-dihydroxynapthalene (1,5-DHN), was shown to produce reactive oxygen species (ROS) such as singlet oxygen (¹O₂) or hydroxyl radicals (ȮH) in aerobic or anaerobic environments, respectively, and in both environments, 1,5-DHN was oxidized …

Development Of Biomaterials For Drug Delivery, Raquel De Castro

Graduate Theses and Dissertations

Drug delivery systems (DDS) have highly evolved in the last decades with the development of hydrogels and nanoparticles. However, high systemic uptake, side effects, low bioavailability, and encapsulation efficiency continue to be a major hurdle faced by such DDSs.

Nanoparticles and hydrogels can be specifically designed for targeted DDSs to mitigate some of the problems. This dissertation aimed to design two DDSs for ocular drug delivery and one for cancer treatment. The first project sought to develop chitosan nanoparticles (Cs-NP) using PEGDA as a copolymer to encapsulate gentamicin (GtS) for ocular drug delivery. Cs-NPs contain positive charges that can interact …

Mixture Model Approaches To Integrative Analysis Of Multi-Omics Data And Spatially Correlated Genomic Data, Ziqiao Wang

Dissertations & Theses (Open Access)

Integrative genomic data analysis is a powerful tool to study the complex biological processes behind a disease. Statistical methods can model the interrelationships of the involved gene activities through jointly analyzing multiple types of genomic data from different platforms (vertical integration), or improve the power of a study through aggregating the same type of genomic data across studies (horizontal integration). In this dissertation, we propose statistical methods and strategies for integrative multi-omics data in association analysis of disease phenotypes, with an emphasis on cancer applications.

We develop a new strategy based on horizontal integration by leveraging publicly available datasets into …

Using Large Pre-Trained Language Models To Track Emotions Of Cancer Patients On Twitter, Will Baker

Computer Science and Computer Engineering Undergraduate Honors Theses

Twitter is a microblogging website where any user can publicly release a message, called a tweet, expressing their feelings about current events or their own lives. This candid, unfiltered feedback is valuable in the spaces of healthcare and public health communications, where it may be difficult for cancer patients to divulge personal information to healthcare teams, and randomly selected patients may decline participation in surveys about their experiences. In this thesis, BERTweet, a state-of-the-art natural language processing (NLP) model, was used to predict sentiment and emotion labels for cancer-related tweets collected in 2019 and 2020. In longitudinal plots, trends in …

Biophysical Characterization Of The Par-4 Tumor Suppressor: Evidence Of Structure Outside The Coiled Coil Domain And Interactions With Platinum Chemotherapeutics, Andrea Megan Clark

Chemistry & Biochemistry Theses & Dissertations

Prostate apoptosis response-4 (Par-4) is an apoptosis-inducing tumor suppressor protein. Full-length Par-4 has previously been shown to be a predominantly intrinsically disordered protein (IDP) under neutral conditions, with significant regular secondary structure evident only within the C-terminal coiled coil domain. However, IDPs can gain ordered structure through the process of induced folding, which often occurs under non-neutral conditions. Previous work has shown that the Par-4 leucine zipper, which is a subset of the C-terminal coiled coil domain, is disordered under neutral conditions, but forms a dimeric coiled coil at acidic pH. Increase in ionic strength was also shown to increase …

Development Of A Liquid Biopsy: Using A Synthetic Lectin Array For The Detection Of Cancer, Mary Grace Hollenbeck

Theses and Dissertations

Cancer is the second leading cause of death worldwide with 9.6 million deaths in 2019. It is well known that early detection of cancer often leads to a better prognosis. However, due to drawbacks associated with current cancer screens (i.e. invasiveness, high false positive and negative rates) new or updated early detection methods are needed. Chapter one overviews current breast, colon, and prostate detection methods and the drawbacks associated with them. Additionally, this chapter presents an alternative detection method that utilizes an array of boronic acid functionalized synthetic lectins. We describe the development and progression of this array and show …

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 Of Incident Cancer To Low-Value Care And Healthcare Cost Burden Among Elderly Medicare Beneficiaries, Chibuzo Iloabuchi

Graduate Theses, Dissertations, and Problem Reports

In the United States (US), 25% of healthcare spending is considered wasteful because it is spent reimbursing low-value care. Low-value care is the utilization of healthcare services, medical tests, and procedures that have unclear or no clinical benefit to patients but still exposes them to risk. World-wide, low-value care imposes a significant economic burden on patients, payers, governments, and society. Cancer care among older adults > 65 years is one of the biggest drivers of healthcare expenditure in the US and accounts for nearly 40% of all spending, and low-value care among cancer patients is prevalent and contributes to the financial …

Synthesis Of Dual Small Molecule Hybrids To Probe The Synergy Between Dna Repair Enzymes And Ido1, Nathaniel George

Theses and Dissertations--Chemistry

Indoleamine 2 3-dioxygenase (IDO) has recently been highlighted as a promising target for small molecule based immunotherapy. IDO is often coopted by various cancer cells to promote an immune-suppressive environment around tumors. DNA damage repair (DDR) enzymes have recently been targeted for inhibition to promote genetic instability and bolster immune recognition. DDR enzymes such as PARP and POLγ are common inhibition targets due to their direct effects on cellular function. In the process of designing conjugate inhibitors of IDO and DDR enzymes, novel synthetic methodology was developed for the mild deprotection of N-Tert-butyloxycarbonyl (N-BOC) group from various amines. Conjugate …

Design, Synthesis, And Anticancer Properties Of Ru(Ii) Complexes With Organometallic, “Expanded” Bipyridine, And O,O’-Chelating Ligands, Raphael Ryan

Theses and Dissertations--Chemistry

Cancer is a worldwide public health crisis that requires new and improved drugs to be developed to extend survival rates and improve quality of life for the patient. Platinum-based drugs are used in approximately 50% of cancer treatment regimens. These drugs are highly effective in many kinds of cancer; however, cancers can develop platinum resistance and these drugs have troubling side effects that reduced their use and efficacy. To overcome these disadvantages, many other metals have been studied for their anticancer properties. Notably, the anticancer properties of ruthenium-based agents have drawn considerable attention with multiple ruthenium complexes entering clinical trials. …

Nonparametric Bayesian Deep Learning For Scientific Data Analysis, Devanshu Agrawal

Doctoral Dissertations

Deep learning (DL) has emerged as the leading paradigm for predictive modeling in a variety of domains, especially those involving large volumes of high-dimensional spatio-temporal data such as images and text. With the rise of big data in scientific and engineering problems, there is now considerable interest in the research and development of DL for scientific applications. The scientific domain, however, poses unique challenges for DL, including special emphasis on interpretability and robustness. In particular, a priority of the Department of Energy (DOE) is the research and development of probabilistic ML methods that are robust to overfitting and offer reliable …

Total Synthesis Of Cytotoxic Mansouramycins From Amino Acids, Beatriz Gamez

Theses and Dissertations

Natural products produced by plants, animals, and microorganisms are of significant importance in chemistry for being major sources of molecular scaffolds essential for new drug discovery. Mansouramycins are cytotoxic bioactive compounds containing isoquinoline skeletons with substituents on the quinone and pyridine rings that may be difficult to synthesize. Synthetic processes exist for compounds B and D, however, there exists an absence of simple synthetic approaches to all four alkaloids.

This project aims to provide a general total synthetic pathway to Mansouramycins A—D from amino acids for possible use in cancer treatment via these isoquinolinequinones. Preliminary experimentation suggests there may be …

Chemical Modification And In Silico Validation Of Medicinally Privileged Molecular Scaffolds As Kras And Sars-Cov-2 Protease Inhibitors, Precious M. Okwuchukwu

Theses and Dissertations

Coronavirus disease was declared a global pandemic by WHO in March 2020, cancer is the second leading cause of death by a disease. Several scientists around the world are working relentlessly to discover an effective remedy to eradicate these deadly diseases. A natural polyphenol (magnolol) has been isolated from a tree Magnolia grandiflora (family Magnoliaceae) found on UTRGV campuses. This research is focused on design of a series of chemically modified sulfonyl derivatives based on the isolated magnolol framework and other medicinally privileged molecular scaffolds framework that can effectively bind to the COVID-19 main protease, SARS- CoV-2 3CL protease …

Analysis Of The Functional Relationship Of Protein Kinase Families Using Phospho-Proteomics Data, David A. Parra Peña

Theses and Dissertations

As cancer research advances, Mass-spectrometry based proteomics is becoming a widely used technique for proteome characterization. Phosphoproteomics is a specific type of proteomics that characterizes proteins with the reversible post-translational modification of phosphorylation PTM), which has allowed the identifications of thousands of phosphorylation sites. These phosphorylation sites, also known as substrates, are known to interact with a protein type named kinases. Studies have shown that abnormal phosphorylation activity is related to cancer diseases. Moreover, these kinases are divided into families, based on the similarity of their catalytic domain, as this part of their amino acid sequence determines a large part …