Physical Sciences and Mathematics Commons^™

Structure-Activity Relationship Of Anticancer Drug Candidate Quinones, Nadire Özenver, Neslihan Sönmez, Merve Yüzbaşıoğlu Baran, Ayşe Uz, Lütfiye Ömür Demi̇rezer

Turkish Journal of Chemistry

Breast cancer is one of the most prevalent cancer types worldwide. Chemotherapy is a substantial approach in the management of breast cancer despite the occurrence of chemotherapy-associated side effects and the development of multidrug resistance in cancer cells. At this point, a variety of quinone derivatives may represent potential as possible anticancer drug candidates due to possessing structural similarity towards clinically used anticancer drugs like doxorubicin. Therefore, we investigated the cytotoxic effects of various quinone derivatives with structural diversity towards a variety of breast cancer cells. We further determined their toxicity in healthy cells to evaluate their drug capability potential. …

Effect Of Resin Bleed Out On Compaction Behavior Of The Fiber Tow Gap Region During Automated Fiber Placement Manufacturing, Von Clyde Jamora, Virginia Rauch, Sergii G. Kravchenko, Oleksandr G. Kravchenko

Mechanical & Aerospace Engineering Faculty Publications

Automated fiber placement is a state-of-the-art manufacturing method which allows for precise control over layup design. However, AFP results in irregular morphology due to fiber tow deposition induced features such as tow gaps and overlaps. Factors such as the squeeze flow and resin bleed out, combined with large non-linear deformation, lead to morphological variability. To understand these complex interacting phenomena, a coupled multiphysics finite element framework was developed to simulate the compaction behavior around fiber tow gap regions, which consists of coupled chemo-rheological and flow-compaction analysis. The compaction analysis incorporated a visco-hyperelastic constitutive model with anisotropic tensorial prepreg viscosity, which …

Pharmacology Of Veratrum Californicum Alkaloids As Hedgehog Pathway Antagonists, Madison L. Dirks, Owen M. Mcdougal

Chemistry and Biochemistry Faculty Publications and Presentations

Veratrum californicum contains steroidal alkaloids that function as inhibitors of hedgehog (Hh) signaling, a pathway involved in the growth and differentiation of cells and normal tissue development. This same Hh pathway is abnormally active for cell proliferation in more than 20 types of cancer. In this current study, alkaloids have been extracted from the root and rhizome of V. californicum, followed by their separation into five fractions using high performance liquid chromatography. Mass spectrometry was used to identify the presence of twenty-five alkaloids, nine more than are commonly cited in literature reports, and the Bruker Compass Data Analysis software …

Machine Learning As A Tool For Early Detection: A Focus On Late-Stage Colorectal Cancer Across Socioeconomic Spectrums, Hadiza Galadima, Rexford Anson-Dwamena, Ashley Johnson, Ghalib Bello, Georges Adunlin, James Blando

Community & Environmental Health Faculty Publications

Purpose: To assess the efficacy of various machine learning (ML) algorithms in predicting late-stage colorectal cancer (CRC) diagnoses against the backdrop of socio-economic and regional healthcare disparities. Methods: An innovative theoretical framework was developed to integrate individual- and census tract-level social determinants of health (SDOH) with sociodemographic factors. A comparative analysis of the ML models was conducted using key performance metrics such as AUC-ROC to evaluate their predictive accuracy. Spatio-temporal analysis was used to identify disparities in late-stage CRC diagnosis probabilities. Results: Gradient boosting emerged as the superior model, with the top predictors for late-stage CRC diagnosis being anatomic site, …

Comparative Study Of Electrochemical-Based Sensors And Immunosensors In Terms Of Advantageous Features For Detection Of Cancer Biomarkers, Göksu Özçeli̇kay, Ahmet Çeti̇nkaya, Sari̇ye İrem Kaya, Si̇bel Ayşil Özkan

Turkish Journal of Chemistry

Cancer, becoming increasingly common globally, has a high mortality rate. Despite the much research on diagnosis and treatment methods, the benefits of technological developments, and newly developed sensor devices, cancer is still one of the leading causes of death worldwide. Early detection using powerful and noninvasive tools could be a future focus for prognosis and treatment follow-up. Therefore, electrochemical biosensors can be a strong choice for the detection of cancer biomarkers (such as alpha-fetoprotein, cytochrome c, prostate-specific antigen, myoglobin, carcinoembryonic antigen, alpha-fetoprotein, a cancer antigen, epidermal growth factor receptor, vascular endothelial growth factor, circulating tumor cell, and breast cancer antigen …

Precise Method To Identify Kinase Drug Targets In Complex Diseases: The First Step Towards Sustainable And Effective Treatment, Hasbanny Irisson, Marzieh Ayati

Research Symposium

Background: Kinases are enzymes that have proven to be important drug targets due to their role in critical biological mechanisms such as phosphorylation. Phosphorylation happens when a kinase catalyzes the transfer of a phosphate group to a protein in a phosphorylated site, which then becomes known as the substrate of the kinase. Any dysregulation of protein phosphorylation causes a wide range of complex diseases including cancer. Thus, discovering the links between kinases and their substrates (i.e. predicting kinase-substrate associations (KSAs)) is crucial in developing effective and sustainable treatments. Presently, less than 5% of phosphorylated sites have an associated kinase, and …

An Ngqd Based Diagnostic Tool For Pancreatic Cancer, Ryan Ketan Ajgaonkar, Bong Lee, Alina Valimukhametova, Anton Naumov, Giridhar Akkaraju

Research Symposium

Background: Pancreatic cancer remains difficult to detect at early stages which contributes to a poor five-yearsurvival rate. Therefore, early detection approaches based on novel technologies should be explored to address this critical health issue. Nanomaterials have recently emerged as frontrunners for diagnostic applications due to their small size in the 1-100 nm range, which facilitates one-on-one interactions with a variety of biomolecules like oligonucleotides and makes them suitable for a plethora of detection and delivery applications. In this work, the presence of specific pancreatic cancer miRNA (pre-miR-132) is detected utilizing the fluorescence properties of highly biocompatible nitrogen-doped graphene quantum dots …

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 …

Boron Neutron Capture Therapy In The New Age Of Accelerator-Based Neutron Production And Preliminary Progress In Canada, Dominik Dziura, Sana Tabbassum, Amanda Macneil, Dalini D. Maharaj, Robert Laxdal, Oliver Kester, Ming Pan, Hiroaki Kumada, Drew Marquardt

Chemistry and Biochemistry Publications

Each year more than 3000 Canadians are diagnosed with brain cancers like glioblastoma multiforme or recurrent head and neck cancers, which are difficult to treat with conventional radiotherapy techniques. One of the most clinically promising treatments for these cancers is boron neutron capture therapy (BNCT). This procedure involves selectively introducing a boron delivery agent into tumor cells and irradiating them with a neutron beam, which kills the cancer cells due to the high-linear energy transfer radiation produced by the 10B(n,α)7Li capture reaction. The theory of BNCT has been around for a long time since 1936, but has historically been limited …

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, …

Msdrp: A Deep Learning Model Based On Multisource Data For Predicting Drug Response, Haochen Zhao, Xiaoyu Zhang, Qichang Zhao, Yaohang Li, Jianxin Wang

Computer Science Faculty Publications

Motivation: Cancer heterogeneity drastically affects cancer therapeutic outcomes. Predicting drug response in vitro is expected to help formulate personalized therapy regimens. In recent years, several computational models based on machine learning and deep learning have been proposed to predict drug response in vitro. However, most of these methods capture drug features based on a single drug description (e.g. drug structure), without considering the relationships between drugs and biological entities (e.g. target, diseases, and side effects). Moreover, most of these methods collect features separately for drugs and cell lines but fail to consider the pairwise interactions between drugs and cell …

Para-Methoxybenzylidene Acetal-Protected D-Glucosamine Derivatives As Ph-Responsive Gelators And Their Applications For Drug Delivery, Jonathan Bietsch, Logan Baker, Anna Duffney, Alice Mao, Mary Foutz, Cheandri Ackermann, Guijun Wang

Chemistry & Biochemistry Faculty Publications

Carbohydrate-based low molecular weight gelators (LMWGs) are compounds with the capability to self-assemble into complex molecular networks within a solvent, leading to solvent immobilization. This process of gel formation depends on noncovalent interactions, including Van der Waals, hydrogen bonding, and π–π stacking. Due to their potential applications in environmental remediation, drug delivery, and tissue engineering, these molecules have emerged as an important area of research. In particular, various 4,6-O-benzylidene acetal-protected D-glucosamine derivatives have shown promising gelation abilities. In this study, a series of C-2-carbamate derivatives containing a para-methoxy benzylidene acetal functional group were synthesized and characterized. These compounds exhibited good …

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 …

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 …

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 …

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 …

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 …

(R1980) Effect Of Climate Change On Brain Tumor, Pardeep Kumar, Sarita Jha, Rajiv Aggarwal, Govind Kumar Jha

Applications and Applied Mathematics: An International Journal (AAM)

In this paper, we introduce a new dynamical model addressing the variation in climate condition due the presence of microorganisms. We also introduce a new dynamical model of cancer growth which includes three interactive cell populations with drug free environment, namely tumor cells, healthy host cells, and immune effector cells. In this, we considered the super growth of tumor cells. For the choice of certain parameters, both of the systems exhibit chaotic behavior. The aim of this work is to design the controller to control the chaos and to provide sufficient conditions which achieve synchronization of two non-identical systems, which …

Cancer Incidence And Stage At Diagnosis Among People With Psychotic Disorders: Systematic Review And Meta-Analysis., Jared C Wootten, Joshua C Wiener, Phillip S Blanchette, Kelly K. Anderson

Epidemiology and Biostatistics Publications

Research regarding the incidence of cancer among people with psychotic disorders relative to the general population is equivocal, although the evidence suggests that they have more advanced stage cancer at diagnosis. We conducted a systematic review and meta-analysis to examine the incidence and stage at diagnosis of cancer among people with, relative to those without, psychotic disorders. We searched the MEDLINE, EMBASE, PsycINFO, and CINAHL databases. Articles were included if they reported the incidence and/or stage at diagnosis of cancer in people with psychotic disorders. Random effects meta-analyses were used to determine risk of cancer and odds of advanced stage …

Cancer Incidence And Stage At Diagnosis Among People With Recent-Onset Psychotic Disorders: A Retrospective Cohort Study Using Health Administrative Data From Ontario, Canada., Jared C Wootten, Lucie Richard, Phillip S Blanchette, Joshua C. Wiener, Kelly K. Anderson

Epidemiology and Biostatistics Publications

OBJECTIVE: Prior evidence on the relative risk of cancer among people with psychotic disorders is equivocal. The objective of this study was to compare incidence and stage at diagnosis of cancer for people with psychotic disorders relative to the general population.

METHOD: We constructed a retrospective cohort of people with a first diagnosis of non-affective psychotic disorder and a comparison group from the general population using linked health administrative databases in Ontario, Canada. The cohort was followed for incident diagnoses of cancer over a 25-year period. We used Poisson and logistic regression models to compare cancer incidence and stage at …

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. …

Veratrum Parviflorum: An Underexplored Source For Bioactive Steroidal Alkaloids, Jared T. Seale, Owen M. Mcdougal

Chemistry and Biochemistry Faculty Publications and Presentations

Plants of the Veratrum genus have been used throughout history for their emetic properties, rheumatism, and for the treatment of high blood pressure. However, inadvertent consumption of these plants, which resemble wild ramps, induces life-threatening side effects attributable to an abundance of steroidal alkaloids. Several of the steroidal alkaloids from Veratrum spp. have been investigated for their ability to antagonize the Hedgehog (Hh) signaling pathway, a key pathway for embryonic development and cell proliferation. Uncontrolled activation of this pathway is linked to the development of various cancers; most notably, basal cell carcinoma and acute myeloid leukemia. Additional investigation of Veratrum …

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 …

Probing The Link Between Pancratistatin And Mitochondrial Apoptosis Through Changes In The Membrane Dynamics On The Nanoscale, Stuart R. Castillo, Brett W. Rickeard, Mitchell Dipasquale, Michael H.L. Nguyen, Aislyn Lewis-Laurent, Milka Doktorova, Batuhan Kav, Markus S. Miettinen, Michihiro Nagao, Elizabeth G. Kelley, Drew Marquardt

Chemistry and Biochemistry Publications

Pancratistatin (PST) is a natural antiviral alkaloid that has demonstrated specificity toward cancerous cells and explicitly targets the mitochondria. PST initiates apoptosis while leaving healthy, noncancerous cells unscathed. However, the manner by which PST induces apoptosis remains elusive and impedes the advancement of PST as a natural anticancer therapeutic agent. Herein, we use neutron spin-echo (NSE) spectroscopy, molecular dynamics (MD) simulations, and supporting small angle scattering techniques to study PST's effect on membrane dynamics using biologically representative model membranes. Our data suggests that PST stiffens the inner mitochondrial membrane (IMM) by being preferentially associated with cardiolipin, which would lead to …

Synthesis Of A Novel Ras Farnesyl Protein Transferase Inhibitor, Mark F. Mechelke, Anna Mikolchak

Chemistry Faculty Publications

Mutant RAS proteins are associated with 30% of all human cancers. Unregulated cell growth caused by mutant RAS proteins can be prevented by RAS farnesyl protein transferase (FPTase) inhibitors. A novel FPTase inhibitor has been synthesized incorporating a modified farnesyl “tail” and a customized diphosphate “head”. It is anticipated that the modified “tail”, incorporating a phenyl substituent, will bind more tightly to FPTase due to nonbonding interactions between the aromatic ring and ten aromatic amino acid residues that line the enzyme active site. The altered polar “head”, designed from L-aspartic acid, has already been shown to mimic the natural substrate’s …