Physical Sciences and Mathematics Commons^™

Targeting Heat Shock 27 Kda Protein Induces Androgen Receptor Degradation, Yaxin Li

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Glioblastoma (GBM) is the most common and aggressive brain tumor, with very poor prognosis. Androgen receptor (AR) plays a significant role in the progression of GBM, and anti-androgen agents have the potential to be used for the treatment of GBM. However, AR mutation commonly happens in GBM, which makes the anti-androgen agents less effective. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein to stabilize AR. Inhibition of HSP27 results in AR degradation regardless the mutation status of AR, which makes HSP27 a good target to abolish AR in GBM. Identified compound I ((N-(3-((2,5-dimethoxybenzyl)oxy)-4-(methylsulfonamido) phenyl)-4-methoxybenzamide) inhibits GBM cell …

Biochemical Characterization Of Induced Pluripotent Stem Cell-Derived Cardiomyocytes As A Model Of Barth Syndrome, Alisha J. House

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Barth Syndrome (BTHS) is an X-linked inborn error of metabolism (IEM) which manifests as a multi-systemic disease. One of the primary symptoms is dilated cardiomyopathy, and alongside the cardiovascular disease that arises, patients often experience metabolic abnormalities such as 3-methylglutaconic aciduria, growth retardation, and neutropenia. There has been a need for the development of a suitable in vitro modeling system which will accurately recapitulate the biochemical and physical nature of BTHS. The purpose of this project has been to develop a model for studying the biochemical pathogenesis of Barth Syndrome using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). To achieve …

Reactivity Of Molybdenum And Tungsten Sulfido Complexes With First-Series Transition Metals, Khalil Mudarmah

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Ammonium tetrathiomolybdate (ATTM) is an important compound in bioinorganic chemistry, with medicinal applications. Metal complexes of sulfur-containing ligands have been widely used as building block in biology and inorganic chemistry. This project aims to increase the number of Mo-S and W-S complexes that may contribute to fields such as bioinorganic and medicinal chemistry, by the preparation of heterometallic complexes containing both Mo or S and a metal of the first transition series. The homobimetallic complex anion salts (Et4N)2[Mo2(S)2(μ-S)2(edt)2] (1) and (Et4N)2[W2(S)2(μ-S)2(edt)2] (2) have been prepared from ATTM and ammonium tetrathiotungstate (ATTW) in order to start our work. The overnight treatment …

Development Of Bioanalytical Methods For Quantitative Measurement Of Anticancer Agents, Sandeep R. Kunati

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The ever-growing need to develop new anticancer agents due to increased incidence of cancer and its recurrence has led to a broad range of investigational efforts in anticancer research. Drug discovery and development processes involve evaluations of pharmacokinetic and pharmacodynamic parameters of potential drug candidates in order to assess their safety, toxicity, and efficacy profiles. By providing sensitivity, assay precision, reliability, and high-throughput, mass spectrometry has become an indispensable tool in quantitative and qualitative analysis, from early-stage drug discovery and development processes to routine laboratory analysis. Development of bioanalytical methods requires knowledge of separation science with instrumentation, data interpretation and …

Biomimetic Macromolecules For Macrophage Targeting And Modulation, Joshua Whited

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Carbohydrate recognition has come to the forefront of biological aiming to uncover the mechanisms of physiological and pathological processes. Cell surface glycans are involved in processes including cellular adhesion, cell signaling, and immune response. A new approach for profiling cell surface glycans has great potential for a wide range of biomedical applications. Lectins have been conventionally used to determine the structure and function of glycoproteins, however, their numbers are still restricted compared to the number of glycan structures. Boronic acid has proven a remarkable small molecule capable of binding diols in aqueous solution. This interaction indicates boronic acid derived molecules …

Synthesis And Biological Evaluation Of Small Molecular Drug Candidates For The Treatment Of Her2 Overexpressed Breast Cancer, Anran Zhao

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In the US breast cancer is the most common cancer after skin cancer. Currently in the US the average risk of a woman to develop breast cancer in her life is roughly 12%. About 25-30% of breast cancer patients have HER2 overexpressed tumor, and the growth of tumor cell is depend on HER2 pathway. It has been well-documented that patients with over-expressed HER2 are associated with increased disease recurrence, worse prognosis and lower survival. Currently there are two type of HER2 targeting drug. The first group is HER2 monoclonal antibody drugs such as trastuzumab approved by FDA in 1998; the …

Quantitative Analysis Of Bleomycin In Rat Plasma By Lc-Ms/Ms, Huawen Li

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Bleomycin is the most commonly used compound in its group of antineoplastic drugs. It works on tumor cells by single and double stranded DNA cleavage after its activation, in which it blocks tumor cells’ DNA replication or transcription activities to inhibit tumor cells’ growth. Bleomycin sulfate (Blenoxane) is the most popular preparation used in clinical research, and contains Bleomycin fractions of A2 and B2, which causes difficulties in quantitative analysis. This work uses the metal chelating property of Bleomycin as an advantage to simplify and improve sensitivity of existing quantitative methods. Copper was spiked in excess to plasma samples, followed …

Computational Investigation Of Protein Assemblies, Sm Bargeen Alam Turzo

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Selective nitrosylation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) at Cys-247 affects gene regulation through the interferon-gamma (IFN- γ) activated inhibitor of translation (GAIT) complex. Oxidized low-density lipoprotein (LDL_ox) and INF-γ induce assembly of the nitrosylase complex composed of inducible nitric oxide synthase (iNOS), S100A8, and S100A9 proteins. Crystal structure of the complex of GAPDH and S100A8A9 is not known, structural prediction method were employed by protein-protein docking and binding energy calculation with PatchDock and FIREDock respectively. Candidate models were selected, based on a weight factor calculated, from the computational method developed from the "artificial protease" cleavage mapping Fe(III) (s)-1-(p- …

Oxidation Of Ferrocene Derivatives With Dibenzoyl Peroxide And Meta-Chloroperoxybenzoic Acid, Jos M. Halstead

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The chemical oxidation of ferrocene and related derivatives (RFc) via organic peroxides solvated in acetonitrile was studied spectrophotometrically by varying concentration and temperature to determine kinetics and activation parameters. The reaction rate of ferrocene with dibenzoyl peroxide depends strongly on whether electron withdrawing or donating substituents are present. Products were analyzed and the effect of different solvents on reactivity were studied. The rate law was first order in both oxidant and reductant, and steric and solvent effects are consistent with outer sphere electron transfer (ET) as the rate-controlling step. B3YLP calculations were conducted to determine reorganization energies using Marcus theory …

Model Chemistry Study Of Choline And Urea Based Deep Eutectic Solvents, Libby Nicole Kellat

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Gaussian and GaussView software were utilized to characterize interactions between choline salts and urea, which form a deep eutectic solvent (DES). The initial system studied was choline chloride and urea, at a 1:2 molar ratio, which is also known as reline. Subsequent systems, substituting the chloride anion with other anions (fluoride, bromide, and hydroxide), were studied to show that the system with greater calculated strength of interaction will have more non-ideal physical properties, such as melting point (found in literature). Observations regarding structure related to counterion electron density and hydrogen bonding were made throughout the studies.

Il-17 Drives Copper Uptake And Activation Of Growth Pathways In Colorectal Cancer Cells In A Steap4-Dependent Manner, Evan Martin

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Colorectal cancer is a disease characterized by abnormal, invasive cell growth beginning in the colon or rectum. The third most common type of cancer worldwide, approximately one million new cases of the disease are diagnosed across the globe annually, resulting in an estimated 700,000+ deaths. One major risk factor associated with development of colorectal cancer is the presence of chronic inflammation in the large intestine, also known as colitis. Inflammation is a complex immune response against harmful stimuli, characterized by symptoms including heat, redness, swelling and pain. One important molecular mediator of this process is interleukin 17 (IL-17), a pro-inflammatory …

Il-17 Drives Copper Uptake And Activation Of Growth Pathways In Colorectal Cancer Cells In A Steap4-Dependent Manner, Evan Martin

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Colorectal cancer is a disease characterized by abnormal, invasive cell growth beginning in the colon or rectum. The third most common type of cancer worldwide, approximately one million new cases of the disease are diagnosed across the globe annually, resulting in an estimated 700,000+ deaths. One major risk factor associated with development of colorectal cancer is the presence of chronic inflammation in the large intestine, also known as colitis. Inflammation is a complex immune response against harmful stimuli, characterized by symptoms including heat, redness, swelling and pain. One important molecular mediator of this process is interleukin 17 (IL-17), a pro-inflammatory …

Using Nucleotide Analogs As Biochemical Probes To Evaluate The Mechanisms Involved In Translesion Replication By A High Fidelity Dna Polymerase, Anvesh Dasari

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Translesion DNA synthesis (TLS) allows DNA polymerases to incorporate nucleotides opposite and beyond damaged DNA. This activity is an important risk factor for the initiation and progression of genetic diseases including cancer. My study evaluates the ability of a high-fidelity DNA polymerase to perform TLS with 8-oxo-guanine, a pro-mutagenic DNA lesion formed by reactive oxygen species. Using modified purine and non-natural indole analogs as biochemical probes, I have evaluated the influence of desolvation, hydrogen bonding interactions, and shape complementarity towards nucleotide binding and incorporation opposite the miscoding lesion 8-oxo-guanine by the high fidelity gp43exo- DNA polymerase. In Chapter II, I …

Profiling Cell Surface Sialylation And Desialylation Dynamics Of Immune Cells, Dan Wang

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Sialic acids (SAs) are a diverse family of naturally occurring 2-keto-3-deoxy-nononic acids that are involved in a wide range of biological processes, including early fetal development, cellular recognition, and utilization by microbes. While it is clear that cell surface SAs are highly involved in the immune system, the sialylation status of individual immune cells and functions are still unknown. In this study, I combined the newly developed LC-MS/MS methods with flow cytometry and confocal microscopy to systematically study the sialylation and desialylation dynamics of macrophages at different conditions.

First, I developed an accurate LC-MS/MS method to quantify free SA in …

Characterization Of Cold Drawn Poly L Lactic Acid By Raman Spectroscopy And Raman Hyperspectral Imaging, Ramya Sudha Muttavarapu

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Artificial modulation of bone growth and repair processes is an important area of current research. Studies have established that the micro mechanical and bulk physical properties of a polymer implant influence its performance behavior and degradation patterns in the body. One important parameter for the class of polymers known as polylactides is the degree of crystalline character. Hence, studying the bulk and micro crystalline composition of an important polymer implant, Poly-L-Lactic acid is the objective of this study. Poly-L-Lactic acid has elastic properties that can be tailored to resemble natural bone and its reaction to mechanical stress. Varying degrees of …

Enzyme-Based Nitric Oxide Releasing Thin Films And Scaffolds, Mutha Merenna Nuwan Bhagya Gunasekera

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Nitric oxide synthase enzyme (NOS) embedded in thin films and scaffolds, when exposed to a solution of its substrate arginine, a source of reducing equivalents, and other required ingredients of the NOS reaction, can release fluxes of nitric oxide (NO). The latter is a molecule known to counteract platelet aggregation, and thus can prevent the thrombosis cascade on the surfaces of implantable medical devices. Therefore NO antithrombogenic regimens such as active coatings and embedded scaffolds have the potential to increase the lifespan of implantable biomaterials. Layer-by-layer electrostatic adsorption allows for assembly of multi-component protein/polyelectrolytes nanostructured films. Electrospun fiber matrices may …

Development Of Quantitative Bioanalytical Methods For The Pharmacological Studies Of Anti-Cancer Drugs, Ye Feng

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In the anticancer drug discovery and therapy development, it is essential to understand the pharmacological properties of the drugs. Today, pharmaceutical analysis is employed throughout the whole drug discovery and development process. Pharmacokinetic-pharmacodynamic relationships are playing an increasingly important role in decisions on the rational development and use of new drugs and they can provide a detailed knowledge of the mechanism of the drug and a better understanding of the molecular targets on which they act. Due to the significance of pharmacological analysis, sensitive analytical methods are critically needed for pharmacological studies. Therefore, our long-term goal is to provide guidelines …

Optimization Of Gradient Chromatofocusing For The Protein Separation And Lc-Ms/Ms Determination Of Ngp1-01 In Mouse Serum, Brain, And Retina, Harini Jogiraju

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No abstract provided.

Gradient Chromatofocusing And Reversed Phase Hplc In Protein Analysis And Lc-Ms/Ms Determination Of Thiazolidinedione Nl-1 In Mouse Serum And Brain, Kiran K. Pedada

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No abstract provided.

Development Of Lc-Ms/Ms Methods For Quantitative Analysis Of Plant-Derived Anticancer Agent And Synthetic Estrogen In Complex Matrices, Simuli Lindah Wabuyele

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No abstract provided.

Design And Synthesis Of Antithrombotic Liposomal Protein Conjugate, Hailong Zhang

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Recent advances in the molecular bases of haemostasis have highlighted that endothelial thrombomodulin (TM) plays a critical role in local haemostasis by binding thrombin and subsequently converting protein C to its active form (APC). In addition, the binding of thrombin to TM drastically alters the thrombin's procoagulant activities to anticoagulant activities. The lipid bilayer in which it resides serves as an essential 'cofactor', locally concentrating and coordinating the appropriate alignment of reacting cofactors and substrates for protein C activation. On the other hand, liposomes have been extensively studied as cell membrane model as well as carrier for delivering certain vaccines, …

Methylation Markers In Hepatocellular Carcinoma, Avinash Gavicharla

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Hepatocellular Carcinoma is one of the major causes for mortality in the world and is usually asymptomatic until late stage decreasing the survival rate. There is an increase of incidence every year and current diagnostic and prognostic bio markers like AFP have their limitations in the wider context. Therefore, it is important to develop novel biomarkers. The aim of the Research is to understand the cytosine methylation and investigate the role of the p16 and SLIT-2 genes as biomarkers in Hepatocellular Carcinoma. The methylation profiles of the genes were assessed on bisulfite modified DNA samples with the aid of Real …

Quantitative And Qualitative Mass Spectrometric Analysis Of Anticancer Agents, Drugs Of Abuse And Enzyme-Inhibitor Complexes, Keri M. Smith

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Mass spectrometry is a valuable tool in the analysis of many types of compounds. From small molecules to large proteins, mass spectrometry can help to interrogate samples and give insights to the origins of disease as well as calculate an exact concentration. Bioanalytical method development is an integral component in the measurement of such compounds. To facilitate proper analytical investigation, the process of method development, analysis, and interpretation must be understood. This work describes the basis and procedure for bioanalytical method development and its detailed application to preclinical studies of the antineoplastic agent hexamethylene bisacetamide and measurement ofillicit drugs of …

Study Of Drug Delivery Behavior Through Biomembranes Using Thermal And Bioanalytical Techniques, Hareesha Reddy Venumuddala

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This Master of Science thesis encompasses two projects in chemical pharmaceuticals. The first is a study of excipients and the added new information collected beyond Thermal Gravimetric Analysis and Differential Scanning Calorimetry from Dielectric Analysis. These new properties enhance our global knowledge of excipients by thermal analytical methods. Excipients, the inactive ingredients in formulated drugs, aid different functions of the active pharmacy ingredient, the drugs. Low temperature transitions, by DEA including melting of frozen solvents, e.g. water, are more definitive than observed by low temperature DSC. Millions of dollars are expended annually on pharmaceutical testing to qualify excipients for fully …

Fabricating New Miniaturized Biosensors For The Detection Of Dna Damage And Dna Mismatches, N. Indika Perera

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A large number of genetic diseases and genetic disorders are simply caused by base alterations in the genome. Therefore, developing efficient and cost effective techniques for routine detection of these alterations is of great importance. Different methods involving gel electrophoresis and Polymerase Chain Reaction have been widely employed, but majority of these methods are costly, time consuming, and lack throughput, creating a fundamental gap between the current state-of-the-art and desired characteristics of low-cost, high-speed, simplicity, versatility, and potential for miniaturization. In this study, we attempt to bridge this gap by developing new sensing platforms to detect DNA base mismatches and …