Дисертації з теми "Medical physics – mathematics"
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1
Barker, Jolene. "APPLICATIONS OF THE BIVARIATE GAMMA DISTRIBUTION IN NUTRITIONAL EPIDEMIOLOGY AND MEDICAL PHYSICS." VCU Scholars Compass, 2008. http://scholarscompass.vcu.edu/etd/1623.
Повний текст джерелаАнотація:
In this thesis the utility of a bivariate gamma distribution is explored. In the field of nutritional epidemiology a nutrition density transformation is used to reduce collinearity. This phenomenon will be shown to result due to the independent variables following a bivariate gamma model. In the field of radiation oncology paired comparison of variances is often performed. The bivariate gamma model is also appropriate for fitting correlated variances. A method for simulating bivariate gamma random variables is presented. This method is used to generate data from several bivariate gamma models and the asymptotic properties of a test statistic, suggested for the radiation oncology application, is studied.
2
Caruyer, Emmanuel. "IRM de diffusion du Q-space : Acquisition et pré-traitements." Phd thesis, Université de Nice Sophia-Antipolis, 2012. http://tel.archives-ouvertes.fr/tel-00750144.
Повний текст джерелаАнотація:
Le but général de cette thèse est de proposer de nouvelles méthodes d'acquisition et de traitement du signal en imagerie par résonance magnétique (IRM) de diffusion, dans le but d'ouvrir de nouvelles perspectives dans la reconstruction de la structure de la matière blanche \emph{in vivo}. L'IRM de diffusion est une technique d'imagerie non invasive qui mesure localement, en chaque voxel, la diffusion des molécules d'eau. Le déplacement de ces dernières étant contraint par la présence de tissus, le fait de pouvoir caractériser la diffusion des molécules d'eau apporte des informations sur la nature, l'orientation, la microstructure des tissus biologiques sous-jacents. La forte anisotropie observée dans la matière blanche fait de l'IRM de diffusion un outil privilégié pour l'étude de la connectivité cérébrale. Une des premières techniques d'acquisition et de reconstruction, appelée IRM du tenseur de diffusion, est maintenant utilisée de manière routinière en clinique, pour le diagnostique de certaines maladies neurologiques, ou encore en planification préopératoire. L'IRM du tenseur de diffusion repose sur un modèle de diffusion gaussien cependant, qui est limité quand il s'agit de décrire des configurations de tissus complexes à l'intérieur d'un voxel, par exemple quand plusieurs faisceaux de fibres se croisent. Dès lors, on a cherché ces dernières années à développer des techniques qui ne reposent pas sur un modèle a priori, afin de décrire de manière plus précise le déplacement des molécules d'eau, et dépasser les limitations du modèle tensoriel. La plupart de ces techniques, dites à haute résolution angulaire, sollicitent un temps d'acquisition généralement long, et mettent en jeu des problèmes de reconstruction non triviaux. Dans la première partie de cette thèse, nous décrivons la structure microscopique des tissus de la matière blanche du cerveau, et présentons la physique de formation des images en IRM de diffusion. Nous faisons un état de l'art des méthodes de reconstruction, et des techniques d'acquisition proposées à ce jour. En ce qui concerne les méthodes de reconstruction, nous faisons la distinction suivant qu'elles soient basées sur un modèle ou non. La première contribution de cette thèse est liée à la reconstruction paramétrique du signal de diffusion dans une base de fonctions continues. Cette contribution fait suite à une méthode proposée récemment, appelée transformée de Fourier sphérique, et y apporte une modification pour une reconstruction continue. Nous réduisons de façon significative la dimension de la base, tout en décrivant aussi bien le signal de diffusion. Nous donnons également l'expression de l'opérateur de régularisation de Laplace en fonction des coefficients dans cette base, afin de limiter l'impact du bruit sur la reconstruction. La seconde contribution est également liée à la reconstruction du signal de diffusion, et à la fonction de distribution d'orientation, dans un contexte d'application clinique. Nous proposons une méthode de reconstruction en temps réel basée sur le filtre de Kalman pour la probabilité marginale de diffusion angulaire. Nous développons un algorithme pour détecter les mouvements du patient, de façon précise et avec une grande sensibilité, et ce sans surcoût, comparé aux systèmes utilisant une camera et des algorithmes de vision robotique. Les deux dernières contributions présentées dans cette thèse sont liées aux techniques d'acquisition en IRM de diffusion, en particulier pour l'élaboration de schémas d'acquisition sur une ou plusieurs sphères dans l'espace de Fourier. Nous présentons d'abord une méthode géométrique pour placer des points dans l'espace de Fourier sur plusieurs sphères, en optimisant la couverture angulaire sur chacune des sphères, mais également de façon globale. Puis nous cherchons à établir un lien entre le schéma d'acquisition et la base de fonctions utilisée pour la reconstruction, et nous proposons en particulier une méthode pour élaborer un protocole d'acquisition qui permette de minimiser le nombre de conditionnement, pour la reconstruction dans la base des harmoniques sphériques, et dans la base de Fourier sphérique modifiée, proposée dans cette thèse. En conclusion de cette étude sur l'acquisition, nous pensons que l'élaboration du schéma d'échantillonnage doit être motivée à la fois pour répondre aux contraintes physiques du scanner, et par le choix de la base dans laquelle le signal sera reconstruit. Ces nouveaux schémas d'échantillonnage sont disponibles au téléchargement sur mon site internet.
3
Valor, Sabatier Josep. "Mathematical tools and budgetary mechanisms for hospital cost control." Thesis, Massachusetts Institute of Technology, 1985. http://hdl.handle.net/1721.1/29513.
Повний текст джерелаАнотація:
Thesis (Sc. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology Program in Medical Engineering and Medical Physics, 1985.MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE
Bibliography: leaves 140-146.
by Josep Valor Sabatier.
Sc.D.
4
Hayward, Robert M. "A Coarse Mesh Transport Method with general source treatment for medical physics." Thesis, Atlanta, Ga. : Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/31696.
Повний текст джерелаАнотація:
Thesis (M. S.)--Nuclear and Radiological Engineering and Medical Physics, Georgia Institute of Technology, 2010.Committee Chair: Rahnema, Farzad; Committee Member: Wang, Chris; Committee Member: Zhang, Dingkang. Part of the SMARTech Electronic Thesis and Dissertation Collection.
5
Carley, David William. "The stability of respiratory control in man : mathematical and experimental analyses." Thesis, Massachusetts Institute of Technology, 1985. http://hdl.handle.net/1721.1/17192.
Повний текст джерелаАнотація:
Thesis (Ph. D.)--M.I.T., Harvard-MIT Division of Health Sciences and Technology Program in Medical Engineering and Medical Physics, 1985.MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIECNE.
Vita.
Includes bibliographical references.
by David William Carley.
Ph.D.
6
Cuerpo, Joanna Valencia. "Studies on yeasts of medical importance from Stockton, California." Scholarly Commons, 1992. https://scholarlycommons.pacific.edu/uop_etds/2235.
Повний текст джерелаАнотація:
This study deals with the identification of 114 yeast isolates from clinical material collected at Dameron Hospital, Stockton, California between August 15, 1990 and September 16, 1991 . The isolates were identified biochemically using the MicroScan Yeast Identification Panel. All isolates were also tested by four conventional cultural methods: germ tube formation, cycloheximide resistance, chlamydospore production, and spidery colony formation. Biochemically, the yeast isolates were identified to nine species of Candida: C. albicans (ll) , C. tropicalis (8), c. stellatoidea (3), c. guilliermondii (2), C. parapsilosis (2), and one of each species of c. catenulata, C. krusei, C. lusitaniae, and C. pseudotropicalis; one species of Torulopsis: T. glabrata (11) and one species of Kluyveromyces, K. lactis (2). Other than those identified as C. albicans, all the other yeasts identified to the species level were negative for all the four conventional tests except for one of two strains of C. guilliermondii which was positive for germ tube, cycloheximide resistance and chlamydospore production. Based on these three tests this isolate of C. guilliermondii would be identified as C. albicans. Five isolates could not be biochemically identified to species. One of the five was positive for the germ tube, resistance to cycloheximide and chlamydospores. Based solely on these three conventional cultural methods this isolate would be considered c. albicans. This isolate and one of the two strains of C. guilliermondii referred to above raise the question as to a possible shortcoming in the Microscan YIP .
An interesting observation was the finding that all nine strains of C. albicans recovered from stools of different patients belong to the same biotype.
7
LI, QI. "ENERGY EFFICIENT EMBEDDED SYSTEM DESIGN FOR MEDICAL CARE SYSTEM USING WIRELESS SENSOR NETWORK." VCU Scholars Compass, 2008. http://scholarscompass.vcu.edu/etd/1624.
Повний текст джерелаАнотація:
Recent surveys on medical service systems show that the cost of patient monitoring has grown significantly. The widespread use of portable digital medical device makes it possible to provide a more comprehensive tracking of patient conditions. However, the development of a full scale, distributed health monitoring system is much delayed due to the lack of efficient wireless communication in a large distributed network. This becomes a challenging research topic which is to find a way to provide accurate and real time patient information to medical experts in a fast, efficient and cost effective fashion. This paper proposes a novel solution on building a system which links patients and doctors together using embedded system technology and wireless sensor network. The content presented in this thesis introduces the design and implement of such a system.
8
Altaf, Fouzia. "Deep learning augmentation for medical image analysis." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2022. https://ro.ecu.edu.au/theses/2603.
Повний текст джерелаАнотація:
Deep learning is at the center of the current rise of computer aided diagnosis in medical imaging. This technology has the ability to mimic extremely complex mathematical functions for predictive tasks. These functions are encoded as computational models that are learned directly from data. Deep learning models are known to achieve human-level accuracy for predictive tasks. However, such a performance requires that the model is trained on a huge amount of training data. For computer aided diagnosis tasks, the relevant training data needs to be carefully annotated by medical experts. This process is laborious and expensive, which generally results in limited amount of training data for deep learning. Moreover, the data often suffers from the practical constraint of class-imbalance. These issues severely degrade the performance of deep learning in medical image analysis. The common strategy to sidestep the limited training data problem in medical imaging is to ‘transfer’ a model from the natural image domain to the medical image domain with the available limited data, and use that model to make predictions. Though useful, the transferred models still lack acceptable performance levels for medical tasks. This thesis develops a range of novel techniques to enhance deep learning based computer aided diagnosis performance, especially within the context of transfer learning paradigm. The research for this thesis was mainly conducted during the COVID-19 pandemic. Hence, COVID-19 detection and classification has received the main attention as evaluation tasks for the proposed techniques, among other thoracic diseases. Opening the research with an extensive literature review of deep learning in medical image analysis (Chapter 2), the thesis identifies lack of large-scale annotated data as the central challenge of effectively employing deep learning for the medical imaging tasks. Hence, it first develops a method to augment deep learning for a better transfer of natural image models to the medical image domain (Chapter 3). This technique also enhances the transferred models performance by reinforcing the model predictions with a sparse representation method. Our analysis revealed that the large domain gap between the natural images and the medical image data is a major source of transfer learning performance degradation. We hypothesize that first transferring a natural image model to the medical image domain with a large-scale data of possibly an irrelevant task, and subsequently transferring that model for the target task, can help. We verify this hypothesis with a novel hierarchical transfer learning method that used large-scale chest X-ray images to finally detect COVID-19 with computed tomography (CT) images (Chapter 4). In parallel, we made an important discovery that due to deep learning hype and urgency of developments in COVID-19 research, the performance of transfer learning for CT-based COVID-19 detection is severely over-estimated in the existing literature. We provide an extensive transparent study to reset the baseline of transfer learning performance for CT-based COVID-19 detection (Chapter 5). The thesis also introduces a novel concept of pre-text representation transfer that enables harnessing large amount of unlabelled data to improve transfer learning performance on balanced and imbalanced limited training data (Chapter 6). With this method, we are able to use un-annotated CT scan images from public domains and transfer the representation of natural image models to the CT data with these plentiful images. We use the resulting transferred representation for subsequent transfer learning with limited annotated COVID-19 CT images, achieving considerable performance gain over the conventional transfer learning.
9
Smith, Rebecca. "Analysis of Medical Images by Colonies of Prehending Entities." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/2095.
Повний текст джерелаАнотація:
The concept of emergent behavior is difficult to define, but can be considered as higher-level activity created by the individual actions of a population of simple agents. A potential means to model such behavior has been previously developed using Alfred North Whitehead's concept of Actual Entities. In computational form, actual entities are agents which evolve over time in response to interactions with their environment via the process of prehension. This occurs within the context of a Colony of Prehending Entities, a framework for implementation of AE concepts. This thesis explores the practical application of this framework in analysis of medical images, with specific focus on Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) scans. Specialized Slice COPEs are developed for analysis of individual image slices from these scans, focusing on the detection and segmentation of structures of interest (such as bone matter, ventricular tissue, and tumors). These structures exist in 3D and can be extracted across multiple consecutive scan slices. Therefore, a specialized Scan COPE is also proposed which aims to render the structure's volume via interpolation between previously analyzed slice images. The software developed for the specified application also provides visualization of a COPE's evolution toward its goal. This has additional value in general study of the COPE framework and the emergent behavior it generates.
10
Freitas, Juliana Campos de. "O Uso de Mateheurísticas Para o Problema de Escolha dos Feixes de um Modelo de Otimização Aplicado ao Problema de Planejamento de Radioterapia." Botucatu, 2019. http://hdl.handle.net/11449/181650.
Повний текст джерелаАнотація:
Orientador: Daniela Renata CantaneResumo: A escolha do conjunto de feixes e a intensidade de dose a ser depositada nos tecidos são problemas de suma importância para se obter um eficiente planejamento da radioterapia, uma vez que o melhor conjunto de feixes é escolhido de maneira que haja uma melhor distribuição de dose no tumor e proteção das células sadias. Para um melhor planejamento, diversos modelos de otimização estão sendo propostos utilizando metaheurísticas e/ou métodos exatos para a resolução dos mesmos. Este trabalho consiste em propor um modelo de programação não linear inteiro misto para escolha de feixes e intensidade de dose de irradiação baseado em um modelo de programação linear da literatura. Para a escolha do conjunto de feixes, foram propostas duas metaheurísticas (Busca Tabu e Busca em Vizinhança Variável), já para o problema de intensidade de dose, foram utilizados métodos exatos (Método de Pontos Interiores Barreira Logarítmica, Primal Simplex e Dual Simplex). Os métodos exatos foram integrados a ambas metaheurísticas e foram aplicados em $4$ casos reais de tumor de próstata utilizando imagens de tomografia computadorizada. Os resultados obtidos através dessas mateheurísticas foram analisados e comparados quanto ao tempo computacional, quantidade de iterações e função objetivo. Conclui-se que o modelo proposto foi eficiente para o planejamento da radioterapia.
Abstract: The beam set choice and dose intensity to be deposited in all tissues are essential problems to obtain an efficient radiotherapy planning, since the best beam set is chosen in a way to achieve the best dose distribution in tumor, protecting the surrounding cells to absorb high dose amount. To a better treatment plan, some optimization models have been proposed using metaheuristic algorithms and/or exact methods to solve them. This thesis consists on proposing a mixed integer non linear programming model to beam choice and dose intensity based on a linear programming model from the literature. To beam set choice problem, two metaheuristic algorithms were proposed (Tabu Search and Variable Neighbourhood Search), and to intensity dose absorption problem, were used three exact methods (Log Barrier Interior Point Method, Primal Simplex and Dual Simplex). The exact methods were integrated with both metaheuristic algorithm and applied in $4$ real prostate cases using computerized tomography image. The results from the applied matheuristic were analysed and compared in terms of computational time, number of interactions and objective function. Concluding that the proposed model was efficient to radiotherapy planning.
Mestre
11
Lu, Andy. "Forensic analysis on wireless medical devices." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2022. https://ro.ecu.edu.au/theses/2541.
Повний текст джерелаАнотація:
The number of Internet of Things (IoT) devices is forecast to grow to over 25 billion by 2030, with the healthcare IoT market projected to grow to 25.9% of IoT devices by 2028 worldwide. However, with new and growing technologies come new types of risks. Current risk assessment and risk management methods haven’t been designed to anticipate or predict these risks. IoT risks relate to openness and lack of standardisation, linking and connectivity between the devices and the lack of skilled support for IoT devices and networks. These factors put medical IoT devices and, by extension, their users at risk from cyber threats. Additionally, the attack surface for the medical IoT has not been fully mapped, nor have the risks been fully assessed. The lack of coverage means increased risk for manufacturers, medical facilities, and potentially, patients. This project evaluates the effectiveness of how new and emerging wireless and connected medical devices can be managed and analysed through a digital forensic framework. An initial analysis of the currently available frameworks showed that they did not address the nuances of implementing a wireless or connected medical device into a healthcare organisation.
Digital forensic frameworks that were deemed relevant to wireless medical devices were selected and tested against several currently available wireless medical devices. Four frameworks were tested across four devices each. The outcome was that none of the frameworks was fully able to effectively manage wireless medical devices (at least in terms of the objectives of digital forensics), with each missing elements that would aid an investigator or a hospital organisation in the case of a cyber-related incident.
These results led to the synthesis and testing of a framework that addressed the missing elements. The framework emphasises forensic readiness planning and risk management. The synthesised framework was tested against a new device. The results of the test found that the synthesised framework was effective in both the proactive digital forensics approach and reactive approach. The testing found that the framework performed better than the other tested frameworks, containing additional phases and steps that were advantageous in preparing and reacting to incidents involving wireless medical devices.
12
Roncancio, Daniel. "Aptamer Sensors for Drugs of Abuse and Medical Biomarkers: Design, Engineering and Application in Complex Samples." FIU Digital Commons, 2018. https://digitalcommons.fiu.edu/etd/3826.
Повний текст джерелаАнотація:
Aptamers are short oligonucleotide sequences (DNA or RNA) capable of high affinity and specific binding to a molecule or a family of molecules. Aptamers are lower in cost and exhibit higher reproducibility when compared to antibodies and thus are well-suited for recognition and detection of small molecular targets such as drugs of abuse and small medical biomarkers. While aptamers have been extensively utilized for development of small molecule sensors, several limitations prevent measurements of complex or real-world samples. This dissertation describes methods, technologies, and assays that were developed with the goal of producing and/or improving aptamer-based sensors for target detection in complex samples. Aptamer engineering is detailed as an important facet of maximizing aptamer-sensor sensitivity and specificity, along with adaptation to various read-out mechanisms for improved selectivity. In chapter 3, an aptamer vii sensor for cocaine is developed based on binding between the fluorophore ATMND to the cocaine aptamer which results in quenching (i.e., ‘turn-off’) of the fluorescence of ATMND. Cocaine binding results in displacement of the ATMND and recovery of the fluorescence signal. Detection of cocaine is demonstrated with an engineered cocaine aptamer with higher affinity for cocaine, permitting over a 50-fold increase in sensitivity over other aptamer-based sensors. The method can be used in dilute biological fluids (e.g., saliva) with a single step reaction (seconds) and robust signal output. In chapter 4, a new adenosine specific aptamer is identified through rational engineering of a previously reported ATP-binding aptamer. The new adenosine aptamer is utilized to develop an electrochemical sensor for detection of adenosine in undiluted serum. The method displays 40-fold higher sensitivity in undiluted serum measurements over previously reported aptamer-based sensors for adenosine but also demonstrates specificity for adenosine over ATP, ADP and AMP that has not been previously reported. In chapter 5, a nuclease-guided truncation method is developed to yield optimal structure-switching aptamer sequences for the emergent illicit drug methylenedioxypyrovalerone (MDPV) and medical biomarkers ATP and deoxycorticosterone 21-glucoside (DOG). The method intelligently removes unessential nucleotides, producing truncated aptamer sequences with structure-switching functionality. This technique will be immediately useful for simple and low-cost development of aptamer-based electrochemical sensors.
13
Wenan, Chen. "Automated Measurement of Midline Shift in Brain CT Images and its Application in Computer-Aided Medical Decision Making." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/121.
Повний текст джерелаАнотація:
The severity of traumatic brain injury (TBI) is known to be characterized by the shift of the middle line in brain as the ventricular system often changes in size and position, depending on the location of the original injury. In this thesis, the focus is given to processing of the CT (Computer Tomography) brain images to automatically calculate midline shift in pathological cases and use it to predict Intracranial Pressure (ICP). The midline shift measurement can be divided into three steps. First the ideal midline of the brain, i.e., the midline before injury, is found via a hierarchical search based on skull symmetry and tissue features. Second, the ventricular system is segmented from the brain CT slices. Third, the actual midline is estimated from the deformed ventricles by shape matching method. The horizontal shift in the ventricles is then calculated based on the ideal midline and the actual midline in TBI CT images. The proposed method presents accurate detection of the ideal midline using anatomical features in the skull, accurate segmentation of ventricles for actual midline estimation using the information of anatomical features with a spatial template derived from a magnetic resonance imaging (MRI) scan, and an accurate estimation of the actual midline based on the robust proposed multiple regions shape matching algorithm. After the midline shift is successively measured, features including midline shift, texture information of CT images, as well as other demographic information are used to predict ICP. Machine learning algorithms are used to model the relation between the ICP and the extracted features. By using systematic feature selection and parameter selection of the learning model, promising results on ICP prediction are achieved. The prediction results also indicate the reliability of the proposed midline shift estimation.
14
Sample, Scott Alexander. "Evaluation of Beam Angle Scoring Using MCNP and Applied to IMRT." Thesis, Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/14570.
Повний текст джерелаАнотація:
Equispaced beam arrangements are typically used for IMRT plans. This beam arrangement provides adequate dose coverage to the target while sparing dose to other structures. However, an equispaced beam arrangement may not provide the best dose coverage to the target while sparing dose to the other structures.
Beam angle optimization attempts to optimize the beam directions to produce a better IMRT plan; this is achieved by increasing dose to the target while minimizing dose to the remaining structures. Most methods of beam angle optimization attempt to optimize the beam angles and the beam intensity profiles to find an optimal set of beam angles. This thesis attempts to optimize the beam angles without determining the beam intensity profiles. An MCNP simulation is run to score the beam directions; the simulation is run as an adjoint problem to reduce simulation time, with the target as the source and the detectors scoring the dose for the gantry angles of the beam. Then, an optimization algorithm is run to select a set of beam angles for an optimized IMRT plan. The optimized IMRT plan is compared to an equispaced IMRT plan on a commercial treatment planning system to determine if this method of beam angle optimization is better than using an equispaced beam arrangement.
The results of this thesis indicate that the coupling of an MCNP simulation for scoring with an optimization algorithm to select beam angles will produce a better IMRT plan than an equispaced IMRT plan. Three different geometries were used and for all geometries, the optimized IMRT plan had a higher average dose to the target while maintaining or increasing dose sparing to the critical structure and normal tissue.
15
Ahmed, Anwar. "COST AND ACCURACY COMPARISONS IN MEDICAL TESTING USING SEQUENTIAL TESTING STRATEGIES." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/103.
Повний текст джерелаАнотація:
The practice of sequential testing is followed by the evaluation of accuracy, but often not by the evaluation of cost. This research described and compared three sequential testing strategies: believe the negative (BN), believe the positive (BP) and believe the extreme (BE), the latter being a less-examined strategy. All three strategies were used to combine results of two medical tests to diagnose a disease or medical condition. Descriptions of these strategies were provided in terms of accuracy (using the maximum receiver operating curve or MROC) and cost of testing (defined as the proportion of subjects who need 2 tests to diagnose disease), with the goal to minimize the number of tests needed for each subject while maintaining test accuracy. It was shown that the cost of the test sequence could be reduced without sacrificing accuracy beyond an acceptable range by setting an acceptable tolerance (q) on maximum test sensitivity. This research introduced a newly-developed ROC curve reflecting this reduced sensitivity and cost of testing called the Minimum Cost Maximum Receiver Operating Characteristic (MCMROC) curve. Within these strategies, four different parameters that could influence the performance of the combined tests were examined: the area under the curve (AUC) of each individual test, the ratio of standard deviations (b) from assumed underlying disease and non-disease populations, correlation (rho) between underlying disease populations, and disease prevalence. The following patterns were noted: Under all parameter settings, the MROC curve of the BE strategy never performed worse than the BN and BP strategies, and it most frequently had the lowest cost. The parameters tended to have less of an effect on the MROC and MCMROC curves than they had on the cost curves, which were affected greatly. The AUC values and the ratio of standard deviations both had a greater effect on cost curves, MROC curves, and MCMROC curves than prevalence and correlation. The use of BMI and plasma glucose concentration to diagnose diabetes in Pima Indians was presented as an example of a real-world application of these strategies. It was found that the BN and BE strategies were the most consistently accurate and least expensive choice.
16
Hinshaw, Kaitlyn. "The Role of Type-2 Cannabinoid Receptors in Calcification of Atherosclerotic Lesions." Digital Commons @ East Tennessee State University, 2013. https://dc.etsu.edu/honors/98.
Повний текст джерелаАнотація:
Introduction: Atherosclerosis is a chronic inflammatory disease characterized by the buildup of cholesterol, fat and other debris within arterial walls. Atherosclerotic lesions undergo a calcification process with similarities to bone remodeling. In mice, the type-2 cannabinoid receptor (CB2) is known to regulate bone remodeling processes and has also been shown to alter atherosclerotic lesion characteristics. However, the role of CB2 in lesion calcification is still unclear. CB2 modulates bone remodeling by affecting differentiation of osteogenic precursor cells; thus we hypothesize that CB2 alters lesion calcification by altering osteoblastogenesis and osteoclastogenesis of precursor cells of vascular origin. To test this hypothesis, we studied the role of CB2 receptor in mediating osteoclastogenesis and osteoblastogenesis from murine monocyte/macrophage and smooth muscle cell lines in vitro.
Methods: RAW264.7 cells are a murine monocyte/macrophage cell line known to undergo osteoclastogenesis in response to receptor activator of nuclear factor kappa B ligand (RANKL). RAW264.7 cells were cultured in media containing RANKL and supplemented with either CB2 agonists or antagonists. Effects on RANKL-induced osteoclastogenesis were then evaluated by measuring the osteoclast marker enzyme tartrate-resistant acid phosphatase (TRAP) activity and further verified by microscopic quantitation of multi-nucleate TRAP-positive osteoclasts. MOVAS-1 cells are a murine vascular aortic smooth muscle cell line known to differentiation into osteoblasts when cultured in osteogenic media. MOVAS-1 cells were cultured in osteogenic media supplemented with CB2 agonists or antagonists. Effects on osteoblastogenesis were evaluated by measuring marker enzyme activity. Alizarin red staining was performed to visualize and quantitate effects on calcium deposition.
Results: RAW264.7 cells treated with Win55, 212-2, a nonselective CB agonist, or HU-308, a selective CB2 agonist, displayed a dose-dependent decrease in RANKL-induced TRAP activity. Co-administration of a CB2-selective antagonist (SR144528), but not a CB1-selective antagonist (AM251), blocked this effect. Visual quantitation of multinucleated TRAP-positive cells confirmed Win55,212-2 treatment reduced osteoclastogenesis in RANKL-treated RAW264.7 cells. Induction of osteoblastic differentiation of MOVAS-1 cells, as determined by ALP activity, was enhanced by supplementation with Win55, 212-2 or 2-archidonyl glycerol. Co-administration of SR144528, but not AM251, reduced the induction of ALP activity in MOVAS-1 cells by Win55,212-2 and 2-AG. Alizarin red staining revealed increased calcium deposition in cultures of MOVAS-1 cells treated with Win55,212-2 compared to those cultured in osteogenic medium without Win55,212-2.
Conclusions: These results demonstrate that CB2 activation can affect osteogenic differentiation of vascular cells in vitro. These results support the hypothesis that CB2 signaling promotes lesion calcification by altering the balance of osteoclastic and osteoblastic differentiation of vascular precursors.
17
Hilton, Brian J. "Cationic Steroid Antimicrobials: Applications to Medical Device Coatings, Mechanism of Pro-Osteogenic Properties, and Potential Synergy with Common Antifungals." BYU ScholarsArchive, 2021. https://scholarsarchive.byu.edu/etd/9133.
Повний текст джерелаАнотація:
Cationic steroid antimicrobials (CSAs or ceragenins) are a novel class of synthetic, cholic acid-based mimics of endogenous antimicrobial peptides. These small molecule compounds display broad bactericidal activity against gram-negative and gram-positive bacteria, potent ability against fungal pathogens, and cidal effects against drug resistant and multidrug resistant microbes. Implantable medical devices provide an abiotic surface upon which bacteria and fungi can accumulate--thereby leading to localized or systemic infection. We proposed that CSA antibiotics can be incorporated into medical device surface coatings which can be optimized for the active release or elution of the CSA compounds over time to prevent device-associated infections. This report will discuss the progress of developing and testing coating systems for 3 such devices: cardiac implantable electronic devices (CIED), silicone nasal splints, and breast tissue expanders. In the case of CIEDs, an envelope material containing CSA was created using bioresorbable polymers. We found that this envelope elutes CSA antibiotics and kills all surrounding bacteria or fungi in both planktonic and biofilm forms within 1 hour of exposure. We also developed a nasal splint coating which is directly adhered to the surface of the silicone splint. This coating system demonstrated more than 8 days of protective ability (full microbicidal activity to the detection limit) against Candida albicans, and reduced microbial growth of P. aeruginosa, Candida auris, and MRSA for approximately 6 days. Lastly, in the case of tissue expanders, we developed a layered coating which displays fully-reductive antimicrobial activity against MRSA for 8 days with reintroduction of bacteria every 24 hours. Additionally, this work will discuss our investigations into the secondary properties of ceragenin compounds. On the basis of studies which have demonstrated the pro-osteogenic properties of CSA, we probed the mechanism of this effect. We studied the potential effects of ceragenins on the proliferation, differentiation, and migration of bone-derived mesenchymal stem cells (MSCs). We have determined the absence of any positive proliferative effects of ceragenins on these cells; however, we have demonstrated the significant migration-promoting chemoattractant properties of CSA. In the case of CSA-13, we have observed up to a 400% increase in migration compared to the control. Also, we demonstrated that the P2X7 receptor is strongly implicated in the cellular mechanism of this effect. Our studies of the differentiation-promoting properties of CSA on MSCs have been largely inconclusive, but further investigations are proposed in this report. Lastly, this work includes a report on our investigations into the potential synergistic interactions between CSA-131/CSA-44 with amphotericin B or caspofungin, two commonly used antifungal agents.
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Rigaud, Gaël. "Study of generalized Radon transforms and applications in Compton scattering tomography." Phd thesis, Université de Cergy Pontoise, 2013. http://tel.archives-ouvertes.fr/tel-00945739.
Повний текст джерелаАнотація:
Since the advent of the first ionizing radiation imaging devices initiated by Godfrey Newbold Hounsfield and Allan MacLeod Cormack, Nobel Prizes in 1979, the requirement for new non-invasive imaging techniques has grown. These techniques rely upon the properties of penetration in the matter of X and gamma radiation for detecting a hidden structure without destroying the illuminated environment. They are used in many fields ranging from medical imaging to non-destructive testing through. However, the techniques used so far suffer severe degradation in the quality of measurement and reconstructed images. Usually approximated by a noise, these degradations require to be compensated or corrected by collimating devices and often expensive filtering. These degradation is mainly due to scattering phenomena which may constitute up to 80% of the emitted radiation in biological tissue. In the 80's a new concept has emerged to circumvent this difficulty : the Compton scattering tomography (CST).This new approach proposes to measure the scattered radiation considering energy ranges ( 140-511 keV) where the Compton effect is the phenomenon of leading broadcast. The use of such imaging devices requires a deep understanding of the interactions between radiation and matter to propose a modeling, consistent with the measured data, which is essential to image reconstruction. In conventional imaging systems (which measure the primary radiation) the Radon transformdefined on the straight lines emerged as the natural modeling. But in Compton scattering tomography, the measured information is related to the scattering energy and thus the scattering angle. Thus the circular geometry induced by scattering phenomenon makes the classical Radon transform inadequate.In this context, it becomes necessary to provide such Radon transforms on broader geometric manifolds.The study of the Radon transform on new manifolds of curves becomes necessary to provide theoretical needs for new imaging techniques. Cormack, himself, was the first to extend the properties of the conventional Radon transform of a family of curves of the plane. Thereafter several studies have been done in order to study the Radon transform defined on different varieties of circles, spheres, broken lines ... . In 1994 S.J. Norton proposed the first modality in Compton scattering tomography modeled by a Radon transform on circular arcs, the CART1 here. In 2010, Nguyen and Truong established the inversion formula of a Radon transform on circular arcs, CART2, to model the image formation in a new modality in Compton scattering tomography. The geometry involved in the integration support of new modalities in Compton scattering tomography lead them to demonstrate the invertibility of the Radon transform defined on a family of Cormack-type curves, called C_alpha. They illustrated the inversion procedure in the case of a new transform, the CART3, modeling a new modeling of Compton scattering tomography. Based on the work of Cormack and Truong and Nguyen, we propose to establish several properties of the Radon transform on the family C_alpha especially on C1. We have thus demonstrated two inversion formulae that reconstruct the original image via its circular harmonic decomposition and itscorresponding transform. These formulae are similar to those established by Truong and Nguyen. We finally established the well-known filtered back projection and singular value decomposition in the case alpha = 1. All results established in this study provide practical problems of image reconstruction associated with these new transforms. In particular we were able to establish new inversion methods for transforms CART1,2,3 as well as numerical approaches necessary for the implementation of these transforms. All these results enable to solve problems of image formation and reconstruction related to three Compton scattering tomography modalities.In addition we propose to improve models and algorithms es
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Van, Cleve Shelley Marie. "Synthesis of a Resveratrol Glycinate Derivative." Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etd/1312.
Повний текст джерелаАнотація:
Recently, the compound resveratrol has had media attention as an anti carcinogen. However, the bioavailability of resveratrol is low in the human system due to its hydrophobic nature. Therefore, it must be administered in high dosages to be effective. A plethora of derivatives have been synthesized that have the potential of resveratrol but sadly share low bioavailability. The first effort of this research was an attempt to produce a more hydrophilic ester of resveratrol. Failing this, the final product was synthesized using a glycine derivative to produce 4-[(1E)-2-(3,5-diacetyloxyphenyl)ethenyl]phenyl N-[(1,1-dimethylethoxy)carbonyl]-glycinate.
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Samoshin, Andrey V. "Diastereoselective acylation of trans-2-substituted-cyclohexanols and glycosidase inhibition studies." Scholarly Commons, 2011. https://scholarlycommons.pacific.edu/uop_etds/275.
Повний текст джерелаАнотація:
Part I. The reaction between chiral acyl chlorides and trans -2-substituted-cyclohexanols proceeds diastereoselectively, i.e. produces mixtures of unequal amounts of diastereomers. We found for the first time that addition of pyridine or diisopropylethylamine accelerates the acylation, and unexpectedly for some substituents (RX) may completely invert its diastereoselectivity. These observations have been rationalized in terms of a stereoselective intramolecular assistance by the RX group to the acylation of the neighboring hydroxyl ("bait-and-hook" mechanism). A series of trans -2-substituted-cyclohexanols were synthesized and acylated with a racemic reagent in presence and absence of pyridine. The results showed that the presence of a nucleophilic group on the second carbon allowed for the preferred formation of one of the diastereomers in the absence of pyridine. However, in the presence of pyridine, the diastereoselectivity would inverse, and the reaction would favor the formation of the other diastereomer. To test the intramolecular acyl transfer hypothesis in detail a series of thioglucosides has been synthesized. Part II. The synthesized thioglucosides were tested as inhibitors of fungal glycosidases. Two compounds showed greater than 80% inhibition values in excess of the activity of β-D-glucosidases. More interestingly, the same compounds showed a marked enhancement of α-D-galactosidase activity by as much as 35%.
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Herrin, Amy Elizabeth. "Assessing, Modifying, and Combining Data Fields from the Virginia Office of the Chief Medical Examiner (OCME) Dataset and the Virginia Department of Forensic Science (DFS) Datasets in Order to Compare Concentrations of Selected Drugs." VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/1057.
Повний текст джерелаАнотація:
The Medical Examiner of Virginia (ME) dataset and the Virginia Department of Forensic Science Driving Under the Influence of Drugs (DUI) datasets were used to determine whether people have the potential to develop tolerances to diphenhydramine, cocaine, oxycodone, hydrocodone, methadone, and morphine. These datasets included the years 2000-2004 and were used to compare the concentrations of these six drugs between people who died from a drug-related cause of death (of the drug of interest) and people who were pulled over for driving under the influence. Three drug pattern groups were created to divide each of the six drug-specific datasets in order to compare concentrations between individuals with the drug alone, the drug and ethanol, or a poly pharmacy of drugs (multiple drugs). An ANOVA model was used to determine if there was an interaction effect between the source dataset (ME or DUI) and the drug pattern groups. For diphenhydramine and cocaine, an interaction was statistically significant, but for the other drugs, it was not significant. The other four drug-specific datasets showed that the DUI and ME were statistically significantly different from each other, and all of those datasets except for methadone showed that there was a statistically significant difference between at least two drug pattern groups. Showing that all of these datasets showed differences between the ME and DUI datasets did not provide sufficient evidence to suggest the development of tolerances to each of the six drugs. One exception was with methadone because there were 14 individuals that had what is defined as a "clinical 'lethal' blood concentration". These individuals provide some evidence for the possibility of developing tolerances.The main outcomes of this study include suggesting changes to make to the ME datasets and the DUI datasets with regard to the way data is kept and collected. Several problems with the fields of these datasets arose before beginning the analysis and had to be corrected. Some of the changes suggested are currently being considered at the Virginia Office of the Chief Medical Examiner as they are beginning to restructure their database.
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Lynch, Jonathan D. "Breaking the Organic Mold: Introducing Copper into the Influenza A Arena with Neutral and Divalent Complexes." BYU ScholarsArchive, 2020. https://scholarsarchive.byu.edu/etd/8677.
Повний текст джерелаАнотація:
Influenza A (IVA) continues to pose a growing global threat even as current medications are becoming less effective. One of the main avenues of research into new anti-IVA drugs is its homotetrameric Matrix 2 proton channel (M2A), without which the virus would be unable to release its viral RNA into the host cell. The drug amantadine used to bind and block M2A until near-ubiquitous resistance formed as an M2A-S31N mutation, starting around 1995 and proceeding to 2005 when amantadine was disallowed for use as an anti-IVA drug. The standard organic structure currently being used for M2A inhibitor research comprises an adamantyl foot group, a heterocyclic aryl body group, and a cyclic head group. A sample set of compounds with this standard structure was compared and reviewed, focusing on positive and negative moieties and modifications. Modifications on the foot group were all more or less detrimental, body groups with two heteroatoms were advantageous, and larger head groups appeared better. Four other scaffolds known to literature were proposed for further study due to beneficial aspects of each. Where most anti-M2A research deals exclusively with organic compounds, metals and their potential in drugs have been almost entirely ignored due to the increased toxicity they bring. Free copper was found in past research to be the only first-row transition metal to show significant M2A-inhibitory activity, proposed to do so by binding the H37 cluster that acts as a pH-dependent control switch for the channel. Six overall-neutral copper complexes were synthesized as a combination of amantadine, cyclooctylamine, and null scaffolds with two of either acetate or acetamide arms as chelators. The complexes were found to block both M2A-WT and M2A-S31N. Along with CuCl¬¬2, though, they had little to no effect on M2A-H37A, providing confirming evidence that the copper binds at the H37 tetrad. Only one complex, Cu(cyclooctylamineiminodiacetate), outperformed CuCl2 in channel block studies and efficacy against two IVA strains, but all of the complexes were found to have lower cytotoxicity. Because M2-H37 is highly conserved, these complexes show promise for further testing against all strains of influenza A. Five net-divalent copper complexes were then synthesized with multiple aza or amine groups as chelators. The complexes failed to show any significant activity against M2A, however, which was thought to be due to size or polarity rejection or electromagnetic repulsion. One of the ligands, though, an adamantyl derivative of a tetraaza macrocycle, was a novel compound, and its copper complex, along with two others, were unknown to the CCDC database. The three complexes were characterized by X-ray diffraction and discussed.
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Mehraban, Nahid. "Synthesis of Phenothiazinium Derivatives." Digital Commons @ East Tennessee State University, 2012. https://dc.etsu.edu/etd/1464.
Повний текст джерелаАнотація:
Photodynamic Therapy (PDT) of cancer involves radiating photosensitizing drugs with light in tumors, which results in generating active singlet oxygen that kills cancer cells. Photosensitizers currently used in PDT are of low quantum yield and require high energy radiation, normally laser. Therefore there is always need for more effective PDT drugs. In this project we synthesized new derivatives of phenothiazinium for potential applications in PDT. Phenothiazinium was synthesized and derivatized by linking it to side groups containing imidazole rings. These derivatives are also expected to catalyze certain hydrolytic reactions. Such ôhydrolase modelsö use molecular recognition based on ??? stacking between the phenothiazinium ring and aromatic rings of specific substrates, such as anthracene monophosphate, while imidazole groups catalyze the hydrolysis of the phosphate ester by general acid-base mechanism.
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Mai, Yvonne M. "Use of various health care providers and the associated clinical and humanistic outcomes in an ambulatory Medicare population." Scholarly Commons, 2016. https://scholarlycommons.pacific.edu/uop_etds/265.
Повний текст джерелаАнотація:
Background: The use of complementary and alternative medicine (CAM) and other non-physician health care providers (dentists, optometrists, etc.) has steadily increased in the United States; however, the associated outcomes reported in the Medicare beneficiary population are limited. Objective: To evaluate the utilization of different healthcare providers by Medicare beneficiaries and assess resultant beneficiary outcomes. Methods: Fourteen outreach events targeting Medicare beneficiaries were conducted throughout Northern/Central California during the 2014 open enrollment period. Trained student pharmacists (working under licensed pharmacist supervision) provided beneficiaries with comprehensive medication therapy management (MTM) services. During each intervention, demographic, quality-of-life, health behavior and health provider/service utilization data were collected. Results: Of 620 respondents, 525 (84%) and 84 (14%) reported using at least one non-physician healthcare professional or CAM provider, respectively. Beneficiaries who reported using non-physician healthcare providers were significantly (p < 0.05) more likely to indicate being ‘very confident’ in managing their chronic health conditions. The number of providers seen with prescriptive authority was positively correlated with the number of prescription medications taken (r s =0.342, p < 0.001). The total number of providers seen was positively correlated with the number of drug-related issues identified (r s = 0.179, p < 0.001). Conclusion: Many beneficiaries have multiple chronic conditions and increasingly utilize a variety of healthcare professionals. As such, bridging the communication chasm between these professionals can improve humanistic outcomes and minimize medication related issues of Medicare beneficiaries. Coordinated care, a key strategy for improving healthcare delivery under the Affordable Care Act, is a step in the right direction.
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Tejomurthula, Sravanthi. "Overexpression of Human Aryl Hydrocarbon Receptor in E.coli Using Two Different Solubility Enhancing Tags." Scholarly Commons, 2017. https://scholarlycommons.pacific.edu/uop_etds/261.
Повний текст джерелаАнотація:
Dioxins such as TCDD are environment pollutants whose toxic effects are mediated via aryl hydrocarbon receptor (AhR) signaling pathway. AhR is a ligand sensitive transcription factor. The unbound AhR resides in cytoplasm as a complex containing p23, Hsp90 and XAP2. Upon ligand binding, AhR undergoes conformational change and translocates into the nucleus. Once the AhR dimerizes with AhR nuclear translocator (Arnt), the chaperone proteins in the complex get dissociated followed by the activation of transcription of various genes such as CYP1A1 and CYP1A2 by AhR-ARNT heterodimer. Various cancers have altered levels of AhR in the absence of ligand. Our current knowledge is only limited in the regulation of AhR protein levels in its ligand bound state. However, the mechanism involved in the regulation of AhR protein levels in the absence of ligand is still unknown. To make the study of AhR signaling pathway possible, our lab has been working on the expression of various AhR constructs in E.coli using recombinant DNA technology. As AhR forms inclusion bodies due to its poor solubility in the cytoplasm of the host bacteria, it is tagged as a “difficult to express” protein. Therefore, it is challenging to generate functional recombinant AhR protein. My thesis documents the expression of human AhR construct amino acid 108-400 using two different solubility enhancing tags (thioredoxin and maltose binding protein). Western blot data revealed that the soluble expression of the human AhR construct by thioredoxin solubility enhancing tag has outperformed the other.
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Patlolla, Karthik Reddy. "Predicting aqueous solubility of pharmaceutical agents by solid dispersion prepared by solvent evaporation method." Scholarly Commons, 2015. https://scholarlycommons.pacific.edu/uop_etds/268.
Повний текст джерелаАнотація:
Solubility of active pharmaceutical agents is a crucial process that determines drug absorption and ultimately its bioavailability. Many of the new therapeutically beneficial compounds discovered are lipophilic requiring various solubility enhancement strategies to improve their solubility. Among these strategies, solubility enhancement using solid dispersions is a leading method. To obtain a desirable increase in the solubility of a poorly-soluble compound, a good understanding of the molecular descriptors influencing the enhancement of solubility is essential. Therefore, the major research objective was to determine the descriptors which significantly influence the solubility enhancement by solid dispersions. After enhancing the solubility of selected poorly-soluble model compounds, a regression analysis was performed to determine the correlation of molecular descriptors of the active agent, polymer, and solvent with solubility enhancement. The partition co-efficient, hydrogen bonding and solubility parameters of polymer and water were found to influence the aqueous solubility of the poorly-soluble compounds. Aqueous solubility of a compound had an inverse relation with difference in solubility parameters of polymer and water. Similarly partition coefficient was found to be inversely related to aqueous solubility. However for an increase in hydrogen bond acceptors present in pharmaceutical agents increased their solubility, while the higher number hydrogen bond donors resulted in lower solubility. This complexity can be attributed to the contribution of hydrogen bonding in a crystal lattice and in aqueous environment. In conclusion, the contribution of partition co-efficient, solubility parameter and hydrogen bonding were found to be significant for a given set of poorly-soluble model compounds selected with a wide range of descriptors. Several models estimating aqueous solubility of compounds have been employed as screening tool in drug development process. However, all such models were developed to estimate aqueous solubility of pure active agents. Hence, the second research objective was to develop a model that could estimate aqueous solubility of Active Pharmaceutical Ingredient (API) in solubility-enhanced solid dispersions. Using multiple linear regression, a computational model was developed using the molecular descriptors of poorly-soluble compound, polymer and water. S=(2.02*HBA)-(3.37*??)-(11.56*log?P )-(0.9*HBD)+119.66 The model showed a regression (R2) value of 0.858. Upon validation, the model estimated the aqueous solubility of 79% of the compositions evaluated with within 20% variability.
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Yang, Dazhou. "Synthesis and biophysical evaluation of thiazole orange derivatives as DNA binding ligands." Scholarly Commons, 2014. https://scholarlycommons.pacific.edu/uop_etds/141.
Повний текст джерелаАнотація:
Guanine-rich telomeric DNA at the end of chromosomes can form a unique DNA tertiary structure - G-quadruplex, which is known to inhibit the binding of telomerase to telomeric regions in cancer cells and thus regulate unrestricted cancer cell growth. Hence, G-quadruplex DNA has recently become a promising target in oncology. The formation of G-quadruplex structures is greatly facilitated by G-quadruplex binding ligands such as Thiazole orange (TO). Compared with other G-quadruplex binding ligands, TO has an intriguing tunable fluorescence property. Upon binding to DNA, the fluorescence of TO can increase up to 1000-fold, making it an attractive probe for studying ligand-DNA interactions. However, the poor binding affinity and minimal binding selectivity towards different DNA conformations greatly limit its applications. My research focuses on developing G-quadruplex binding ligands using TO as a scaffold. In the first part of this work, we investigated the feasibility of increasing the TO binding affinity and selectivity toward G-quadruplex DNA by introducing side chains to the molecule. TO derivatives containing various side chains were successfully synthesized and characterized. Biophysical and biochemical studies with duplex and G-quadruplex DNA showed that tethering side chains to TO is an effective approach to tune its ability of binding to duplex or G-quadruplex DNA. Possible binding modes of the effective derivatives were studied using AutoDock. Their inhibition of telomerase activities was studied using the TRAP assay. The cytotoxicity of these derivatives toward three cancer cell lines was also investigated using the MTS assay. The second part of this work focuses on development of TO-based G-quadruplex DNA binding ligands that can bind to DNA via the dual recognition mode. TO was tethered with pyrene, naphthalene diimide, and anthraquinone respectively to yield three novel conjugates. Further investigation suggested that the conjugate of TO with naphthalene diimide (TO-NF) gave the best G-quadruplex binding affinity. It binds to G-quadruplex DNA via the end stack mode and strongly inhibits the telomerase activity. The cytotoxicity results will also be discussed in this presentation.
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Naidu, Prathyusha. "Catalase-loaded liposomal magnesium phosphate nanoparticles for intracellular protein delivery." Scholarly Commons, 2016. https://scholarlycommons.pacific.edu/uop_etds/266.
Повний текст джерелаАнотація:
Proteins are large biomolecules that have great therapeutic potential in treating many human diseases. Proteins exert higher specificity and more complicated functions; they are well endured and less inclined to evoke immune responses when compared to small molecule drugs. However, exogenous proteins when administered intravenously are prone to immune reactions. Chemical and enzymatic denaturation, and poor penetration into cells are some other challenges for clinical use of intracellular proteins. Proteins that enter cells through endocytosis will be eventually degraded in lysosomes if they do not escape the endosomal pathway before reaching lysosomes. Therefore, the development of protein delivery systems, including liposomal and/or polymeric nanoparticles would substantially facilitate the clinical use of proteins. This approach can protect the proteins from denaturation and immune reactions. Previously, our group has developed cationic lipid-coated magnesium phosphate nanoparticle (CAT-LP MgP NP) formulations to enhance the intracellular delivery of the protein, catalase. The objective of the current research is to improve the physicochemical properties of CAT-LP MgP NP. The magnesium phosphate (MgP) nanoparticles were prepared by water-in-oil micro emulsion precipitation. The cargo protein catalase was complexed with cationic liposome prepared by lipid hydration and extrusion. Then magnesium phosphate (MgP) nanoparticles were mixed with the catalase-complexed cationic liposome to form the final complexed CAT-LP MgP NP formulation. By sonication, extrusion and modification of the lipid composition, we have successfully prepared complexed CAT-LP MgP NP formulations of reduced size. The pH-sensitivity of the improved delivery system was observed at pH 6.0. Furthermore, the improved delivery system reduced the Reactive Oxygen Species (ROS) level inside EA.hy.926 cells (human umbilical vein endothelial cells) to 35% of the control, whereas the previously reported catalase formulation of our group reduced the ROS levels to 50%, indicating that the complexed formulation delivers functional catalase more efficiently into the EA.hy.926 cells. Complexed CAT-LP MgP NP with reduced size has delivered cargo protein more efficiently than encapsulated CAT-LP MgP NP.
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Kondepudi, Karthik Chalam. "Computational prediction of enhanced solubility of poorly aqueous soluble drugs prepared by hot melt method." Scholarly Commons, 2015. https://scholarlycommons.pacific.edu/uop_etds/267.
Повний текст джерелаАнотація:
Solubility is the concentration of a solute in a saturated solution at a given temperature and pressure. Solubility of a drug in aqueous media is a pre-requisite to achieve desired concentration of a drug in the systemic circulation. Low aqueous solubility is a major problem encountered with formulation development of recently designed new chemical entities. Solubility of poorly soluble drugs is enhanced by physical and chemical modifications of drug. Shake flask method is the most commonly used experimental method to determine solubility. However, this method has several limitations. A single solubility experiment can go on for several days and even weeks. Besides this, a large amount of drug is required to carry out the experiment. In order to overcome this and make initial screening easier, computational method can be used to predict solubility. In this study, the solubility of 12 small molecules of BCS class II having a wide range of physicochemical properties were studied to enhance their solubility by hot melt method. Three different grades of PEG (1450, 4000, 8000), PVP K17 and Urea as the hydrophilic carriers was employed for the solubility enhancement. The overall objective of this investigation is to develop a model that could estimate enhanced solubility using physicochemical descriptors. Multiple linear regression (MLR), a statistical tool, was used to generate a equation for the solubility by correlating physicochemical properties of the drug like- molecular size, logP, pKa, HBA, HBD, melting point, polar surface area, and number of rotatable bonds. Solubility enhancement is also influenced by the carrier used, we included the physicochemical properties of the carriers like molecular weight and solubility parameter in the development of the model. MLR analysis model, resulted in an equation, where, Log solubility = 5.982-0.010 MW (drug)-0.452 LogP-0.320 HBA-0.095 ?solubility parameter+0.015 MV. A regression analysis yielded a good fit with a regression value (adjusted R2) of 0.74. The model has been validated by leave one out method. This model has the potential to estimate the solubility of a physically modified drug in screening stages of drug development.
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Vutukuru, Naresh Kumar Reddy. "Apparent dissolution rate enhancement of poorly-water soluble drugs by adsorption technique." Scholarly Commons, 2015. https://scholarlycommons.pacific.edu/uop_etds/269.
Повний текст джерелаАнотація:
Nearly 70% of the new chemical entities (NCE’s) discovered are poorly-water soluble drugs and the number of poorly-water soluble drugs are increasing rapidly in the drug discovery. Most of the NCE’s are lipophilic and have dissolution rate issues. Low dissolution rate of the drugs result in poor bioavailability. To overcome poor bioavailability, an adsorption technique is developed to enhance the apparent dissolution rate of poorly-water soluble drugs. In this study, two poor-water soluble model drugs, ibuprofen and carvedilol were used. Methanol, DMF, DMSO and PEG400 were used as solvents and microcrystalline cellulose was used as an adsorbent. Pure model drugs, physical mixtures and prepared composites were characterized by using FTIR, DSC, XRD and dissolution testing. Results showed that the composites prepared with solvents DMF, DMSO and PEG400 showed enhancement in dissolution rates of two model drugs. Characterization of the composites prepared by using non-volatile solvents showed successful conversion of crystalline model drugs into solution state. Whereas, composites prepared by using volatile solvent showed similar results like physical mixtures and pure drug. Ibuprofen composites containing DMF, DMSO and PEG400 showed 9.4, 7.4 and 1.8 folds of increase in apparent dissolution rate, respectively. Whereas carvedilol composites containing DMF and DMSO showed 11.52 and 3.4 folds of increase in apparent dissolution rate. Four months of stability study were conducted on prepared composites at both 40°C and room temperature. It was observed that prepared composites were stable after 4 months and exhibited similar dissolution rate. In conclusion, the use of non-volatile solvents disrupted the crystal structure but also retained the drug in solution state which in turn enhanced the apparent dissolution rate of model drugs used. From the observed results we conclude that this method has a potential to replace existing techniques to enhance the apparent dissolution rate of the drug and stability of the composites.
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Vangala, Swathi. "Human Cytochrome P450 3A4 Over-Expressing IEC-18 and MDCK Cell Lines as an In-Vitro Model to Assess Gut Permeability and the Enzyme Metabolism." Scholarly Commons, 2013. https://scholarlycommons.pacific.edu/uop_etds/273.
Повний текст джерелаАнотація:
Purpose. The fate of an orally administered drug is dependent on many parameters before it can reach the systemic circulation, including drug absorption and first-pass metabolism in the gut and the liver. Mammalian cells lines such as MDCK and Caco-2 are commonly employed to assess drug permeability but they lack or have low expression level of drug metabolism enzyme expression such as CYP3A4, which contributes to significant first-pass gut and liver metabolism for many drugs. Consequently, these cell lines are not sufficient to integrate metabolism when assessing drug absorption. Here, we tested MDCK and IEC-18 cells transiently over-expressing CYP3A4 as models that can simultaneously assay a compound's permeability and metabolism potential in a single experiment. Method. A recombinant adenovirus carrying the hCYP3A4 cDNA was constructed according to Stratagene's AdEasy XL Adenoviral system. This adenovirus was used to transiently transfect hCYP3A4 into MDCK and IEC-18 cells. Western blot was performed to assess the level of hCYP3A4 expression in the wild type and CYP3A4 over-expressing IEC-18 and MDCK cells. In situ metabolism and transport studies were performed with wild-types and IEC-18-3A4 or MDCK-3A4 cells. Results. The amount of CYP3A4 present in MDCK-3A4 cells was 250 times to that of wild type cells which 1/4th the amount present in human liver microsomes. The amount of CYP3A4 present in IEC-18-3A4 cells was 150 times to that of wild type cells which 1/6th the amount present in human liver microsomes. In metabolism studies, there was higher formation of metabolites in cells transfected with hCYP3A4 compared to controls. In addition, apical to basal transport studies of several drugs in IEC-18-3A4 and MDCK-3A4 showed increased appearance of metabolites compared to the wild-type cells. Conclusions. This model may be a useful to assess the extent of drug absorption into systemic circulation after oral administration.
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Nannapaneni, Vijaysri. "Preparation of amorphous forms to increase the solubility of poorly soluble drugs using spray drying." Scholarly Commons, 2011. https://scholarlycommons.pacific.edu/uop_etds/274.
Повний текст джерелаАнотація:
Spray drying is widely used in enhancing the aqueous solubility of poorly soluble compounds. In this study, the mechanism of solubility enhancement was characterized using three model drugs-naproxen, ketoprofen and furosemide. Physical mixtures of the model drug with polyvinylpyrrolidine and spray dried composites were subjected to Fourier Transform Infrared Sprectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction (XRPD). The data showed that the crystalline model drugs were converted to amorphous form upon spray drying, whereas the physical mixtures did not change their crystallinity. The effect of the amorphous forms produced by Spray drying on apparent solubility and intrinsic dissolution rate was determined. All the spray dried composites exhibited higher apparent solubility and intrinsic dissolution rate when compared to the pure drugs and their physical mixtures. The stability of the spray dried composites upon storage was also determined. The amorphous nature of the compounds in the spray dried composites were retained during 3 months storage as shown by FTIR, DSC and XRPD characterization and their apparent solubility and intrinsic dissolution rates also did not change.
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Easter, Chrissa Michelle Mozaffari. "A tale of two small oxygenated molecules as told by photoelectron photoion coincidence spectroscopy." Scholarly Commons, 2016. https://scholarlycommons.pacific.edu/uop_etds/263.
Повний текст джерелаАнотація:
Photoelectron Photoion Coincidence (PEPICO) Spectroscopy studies on two small oxygenated species are presented here. Diethyl Ether (Et2O) and Acetic Anhydride (AcOAc) were chosen because of their and their fragments' relevance to combustion chemistry. The Imaging PEPICO (iPEPICO) experiment at the VUV beamline of the Swiss Light Source (SLS) was utilized to provide dissociative ionization data of the two molecules of interest. In this experiment, the unimolecular fragmentation pathways of energy selected ions can be studied with high energy resolution. The iPEPICO experimental setup also allows the measurement of the dissociation rates, which is indispensable to derive accurate thermochemical information on large ions. The experimental data on the fragmentation of ions of interest are then examined through modeling the experimental ion fractional abundances (breakdown curves, BDCs) and reaction rates, in a modeling framework based on the RRKM statistical theory. In our first project, diethyl ether was studied to provide the appearance energies of its daughter ions along with the dissociation pathways of the molecular ion, leading to thermochemical data (such as heats of formation) pertinent to combustion chemistry. A revised ionization energy (IE) differing from the reviewed National Institute of Standards and Technology (NIST) was also proposed. In the second project presented, AcOAc was also measured on the iPEPICO apparatus to understand its dissociative photoionization processes. The appearance of trace amounts of acetone in the ionization spectra, discrepancies in the statistical models of the branching ratios, and the quantum chemical calculations all point to the existence of a post-transition-state bifurcation, when a single TS separates multiple products, namely a methyl-loss fragment and acetone, as well. The acetyl cation, as well as the methyl cation at higher energies, appear to be formed by both parallel and sequential dissociation processes.
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Ansari, Sardar. "Optimization and Spatial Queueing Models to Support Multi-Server Dispatching Policies with Multiple Servers per Station." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/3249.
Повний текст джерелаАнотація:
In this thesis, we propose novel optimization and spatial queueing models that expand the currently existing methods by allowing multiple servers to be located at the same station and multiple servers to be dispatched to a single call. In particular, a mixed integer linear programming (MILP) model is introduced that determines how to locate and dispatch ambulances such that the coverage level is maximized. The model allows multiple servers to be located at the same station and balances the workload among them while maintaining contiguous first priority response districts. We also propose an extension to the approximate Hypercube queueing model by allowing multi-server dispatches. Computational results suggest that both models are effective in optimizing and analyzing the emergency systems. We also introduce the M[G]/M/s/s queueing model as an extension to the M/M/s/s model which allows for multiple servers to be assigned to a single customer.
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Borkar, Sampada N. "Very accurate gas-phase thermochemistry through photoelectron photoion coincidence (PEPICO) spectroscopy." Scholarly Commons, 2013. https://scholarlycommons.pacific.edu/uop_etds/144.
Повний текст джерелаАнотація:
Five projects are presented here that use Photoelectron Photoion Coincidence (PEPICO) Spectroscopy to determine high-accuracy thermochemical data on small and intermediate size molecules and radicals that are relevant in modeling combustion and atmospheric processes. Some of the experiments were carried out on the laboratory-based Threshold PEPICO (TPEPICO) apparatus which has the advantage of having a low-temperature inlet system and unlimited measurement time, while most of the projects involved the use of the Imaging PEPICO (iPEPICO) apparatus at the Swiss Light Source, which is capable to determine ionic dissociation energies to sub-kJ/mol accuracy. The iPEPICO on the synchrotron beamline was also useful where measurements required energies in excess of 14 eV. The modeling framework of PEPICO is based on the RRKM statistical theory of dissociation kinetics and statistical energy distributions and models complex dissociation pathways to extract both kinetics and thermochemical data from the experiment. In the first project, we measured the onsets of Br- and I-loss reactions for C 2 H 5 Br and C 2 H 5 I using TPEPICO, respectively. The heats of formations of the two molecules are related through the ethyl cation, which was used in their determination. The second project involved measuring Cl-loss from four S i O j Cl k compounds viz. SCl 2 , S 2 Cl 2 , SOCl 2 , and SO 2 Cl 2 to obtain reliable thermochemistry. The second Cl-loss from S 2 Cl 2 + and SOCl 2 + helped us conclude that assuming three-dimensional translational degrees of freedom yields a more reliable statistical model of product-energy distributions. The third project investigated methanol and its isotopologues to explore the dissociation pathways through the H/D-losses. The 0 K appearance energies were used to determine the accurate heat of formation of CH 2 OH and the proton affinity of formaldehyde. The fourth project explores the dissociation pathways of cis -1-bromopropene, trans -1-bromopropene, 2-bromopropene, 3-bromopropene and bromocyclopropane to find that except for 2-bromopropene, all other isomers dissociate into the allyl cation. To derive accurate thermochemical information on the neutral precursors, a mixed theoretical and experimental thermochemical network was used to determine their 0 K heats of formation. The last project involves measurements on dimethyl disulfide (DMDS) and dimethyl diselenide, which are the simplest models that can be used to study disulfide and diselenide linkages. There are several discrepancies in the thermochemistry of DMDS, whereas ours is the first experimental attempt to study the ionic thermochemistry of dimethyl diselenide experimentally.
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Ponnakanti, Himaja. "Soluble and Functional Overexpression of the Ligand Binding Domain of Mouse Aryl Hydrocarbon Receptor in E.Coli." Scholarly Commons, 2017. https://scholarlycommons.pacific.edu/uop_etds/260.
Повний текст джерелаАнотація:
The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor whose toxicity and carcinogenesis is mediated through various polyaromatic hydrocarbons and other environmental pollutants. The role of AhR in carcinogenesis is an area of concern due its altered levels in various tumors. AhR binds structurally diverse ligands and may elicit different responses upon ligand binding. The crystal structure of mouse AhR PAS-A domain was already obtained due to the robustness of mouse AhR in comparison to human. There is a possibility of overexpressing mouse AhR ligand binding domain in its soluble and functional form, which could be used to perform ligand binding studies. This forms the aim of this thesis. Mouse AhR ligand binding domain was constructed as mAhR aa211-384, which was purified under native conditions with the use of 6 histidine tag but soluble overexpression was not possible. Thus a solubility enhancing tag called maltose binding protein (MBP) was used for purification of mAhR aa211-384 under native conditions, which still did not yield soluble overexpression. The strategy was modified to solubilize the protein by denaturation with the use of 8M Urea, which solubilized the protein but included an issue of protein binding to column. Subsequent use of an even stronger denaturant, 6M guanidine hydrochloride, solubilized most of the protein and purified mAhR aa211-384 in huge amount. Successful refolding of mAhR aa211-384 with the help of MBP was made possible by gradual reduction of denaturant in the presence of arginine, but 6 histidine tag failed to refold the protein. The refolded protein was tested for its secondary structure by circular dichroism. Thus, mAhR aa211-384 was solubilized and purified under denaturing conditions with the help of both 6 histidine and MBP, however efficient refolding of mAhR aa211-384 was only possible with the help of MBP but not 6 histidine. The MBP-refolded mAhR aa211-384 stayed in solution even after the removal of 0.1 M arginine, thus confirming the effectiveness of MBP in protein refolding in comparison to 6 histidine tag.
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Fang, Yunzhou. "A novel intracellular protein delivery system - Magnesium phosphate nanoparticles with cationic lipid coating for catalase intracellular delivery." Scholarly Commons, 2014. https://scholarlycommons.pacific.edu/uop_etds/270.
Повний текст джерелаАнотація:
Protein therapeutics have great potential in treating human disease, especially for those caused by alternations in the functions of intracellular proteins. However, clinical use of protein by intracellular delivery has been hampered by the instability due to proteins' physicochemical properties, and some barriers in the delivery pathway. This study was to prepare and test a novel intracellular protein delivery system - magnesium phosphate nanoparticles with cationic lipid coating for catalase intracellular delivery (LP MgP NP-CAT), and investigate whether it can release the encapsulated catalase to cytosol. LP MgP NP-CAT was designed, prepared and characterized, showing that it had an average diameter around 300 nm and zeta potential around +40mV. The pH - triggered catalase release from LP MgP NP-CAT was determined by a hydrogen peroxide degradation assay, where the concentration of remaining hydrogen peroxide was measured by UV-Vis spectroscopy, indicating catalase was released in response to the drop of pH, which was confirmed by the morphology change of LP MgP NP-CAT observed by transmission electron microscopy. The in vitro catalase release behavior was conducted on MCF-7 cells and EA.hy926 cells. LP MgP NP-CAT was delivered into MCF-7 cells and the release behavior was determined by the resultant resistance of the cells against hydrogen peroxide using MTS cell viability assay. The delivery of LP MgP NP-CAT into EA.hy926 cells was determined by the decrease of the reactive oxygen species level. Both of the studies showed that catalase was successfully delivered and released which is supported by the reduction of hydrogen peroxide.
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Sachdeva, Sameer. "Design and applications of antibody mimics against epidermal growth factor receptor." Scholarly Commons, 2015. https://scholarlycommons.pacific.edu/uop_etds/132.
Повний текст джерелаАнотація:
Antibodies have been widely used as reagents, homing devices, diagnostics and as therapeutic agents against different targets in clinic and research. Recently a number of monoclonal antibodies and their drug conjugates have been approved as therapeutic agents. While these molecules have great potential in various applications and therapeutics, extensive use of full length antibodies has been hampered by the high cost of production, large molecular weight and limited ability to penetrate tumor tissues. These limitations have led to the research for antibody alternatives with lower molecular weight, similar binding and affinity properties but without the lengthy and complicate process of generating antibodies. Some examples of these efforts include minibodies, fragment antigen binding (FAB), ScFv, and synthetic antibody mimics. Although these antibody alternatives have low molecular weight, as compared to the antibody, they are either derived from full size antibodies or by a long and tedious in vitro screening process. Therefore, a rational design of molecules that mimic antibody binding is a logical first step for the development of antibody alternatives. In this study, a novel approach to design antibody mimics without involving massive experimental screening was developed. The design was developed by mapping and identifying EGFR epitope region where Cetuximab CDR binds and modifying sequences using knob-socket computational model. The binding of antibody mimics were first analyzed by using MOE to obtain the binding energy, total and preserved interactions as compared to the interactions between EGFR and Cetuximab. Further, the designed antibody mimics were used to form a peptide drug conjugate (PDC). Antibody mimics were found to specifically bind and internalized by EGFR overexpressing cell lines with three to four folds higher than control cells. Antibody mimics showed binding in nanomolar range with Pep11 with binding affinity (K D ) of 252nM as shown by SPR studies. EGFR phosphorylation studies also showed that antibody mimics were able to inhibit the binding of EGF to the EGFR in a similar fashion as Cetuximab. Specific binding, affinity and functional activity of the antibody mimics demonstrated that these peptides were able to mimic all the three important characteristics of antibodies. Peptide drug conjugate (PDC) was found to be around 10 fold more potent as compared to the drug itself towards EGFR overexpressed cancer cells. PDC also showed more than 100 fold low potency against control cells. These studies demonstrated that a rational design of molecules to mimic the antibody characteristics is feasible. The antibody mimics were also successfully applied and used as targeting moiety to design peptide drug conjugates for efficient targeted drug delivery system than antibody drug conjugates.
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Sun, Jingjing. "Exploring the effect of alpha2 receptor on brain 5-HT via a mechanism-based pharmacodynamic model." Scholarly Commons, 2012. https://scholarlycommons.pacific.edu/uop_etds/154.
Повний текст джерелаАнотація:
Purpose: 5-hydroxytryptamine (5-HT) is an important neurotransmitter in depression. It is believed that α 1 and α 2 adrenoceptors mediate the 5-HT level in the brain. The mechanism is complex and not well explored. Especially in different combination treatments, the receptor systems may show varied modulation capability. Additionally, some research has suggested that α 2 heteroceptors may contribute to the time delay problem in dual depression treatment which is thought as the time needed for certain inhibition receptor to get desensitized. We hypothesized that the α 2 adrenoceptors had inhibition effect on 5-HT level in dorsal raphé nucleus (DRN), Prefrontal cortex (PFC) and Hippocampus (HP) with the dual reuptake inhibition. The present study was undertaken to explore the effect of BRL44408 (α 2 receptor antagonist) on 5-HT level in rat PFC, DRN and HP under dual antidepressant with blocking the α 1 receptor. Method: Serotonin reuptake inhibitor and norepinephrine reuptake inhibitor were used to mimic the dual reuptake inhibition antidepressant. To differentiate the α 2 adrenoceptors effect from al adrenoceptors effect, prazosin, an antagonist of α 1 adrenoceptors, was added to block α 1 adrenoceptors. Using the microdialysis method, the drug combination was examined in HP area and then DRN area to explore the drug effect on time course of 5-HT release in DRN and PFC. Based on the experiment results from DRN and PFC, a mechanism-based pharmacodynamic model was developed. Result: BRL44408 increased the serotonin (5-HT) level in rat PFC, DRN and HP to different degrees with the dual reuptake inhibition (p < 0.05). The overall model reasonably captured the time course of 5-HT in both DRN and PFC with different dose schemes of BRL44408. The model predicted EC50 of BRL44408 (0.0075 µM) for the α 2 heteroreceptor which control PFC 5-HT is close to the reported value of BRL44408 for α 2 adrenorceptor (0.008 µM). However, the model predicted EC50 of BRL44408 on the α 2 heteroreceptor which control DRN 5-HT need to be explained. Simulation result from this model suggested varied modulation capability of α 2 adrenoceptors on the 5-HT in DRN and the 5-HT in PFC. Conclusion: α 2 heteroceptor play a role in regulation 5-HT level under dual reuptake inhibition. Further exploration may bring a potential target for depression treatment. The mechanism model was developed to characterize and better understand the neurotransmitter mechanisms, providing estimations of various parameters of the disease related receptor system.
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Tsai, Yi-Ju. "Two approaches to the design and synthesis of bimetallic complexes." Scholarly Commons, 2014. https://scholarlycommons.pacific.edu/uop_etds/272.
Повний текст джерелаАнотація:
Dirhodium complexes have been known for their catalytic reactivities toward C-H bond activation for nearly two decades. However, both experimental and theoretical studies have not given a clear explanation on the roles of each metal in the reactivities, largely due to the limited number of available bimetallic species. To study the system systematically, we set our goal to synthesize bimetallic complexes from two independent approaches. In the first approach, five N, N’ -diarylformamidines with symmetric or asymmetric substituents on the phenyl groups were synthesized and fully characterized. Formamidines without bulky substituents exhibited fluxionality in solution, which was proved by a single set of signal in 1 H NMR. In contrast, two sets of signals were observed for formamidines with bulky substituents in the ortho positions, indicating two major stereoisomers ( E and Z conformers) co-existing in solution. In solid state, strong stability for E conformers was gained from a pair of H bonds between two ligands facing each other. The phenomenon was observed for all ligands but N, N’ -bis(2,6-dimethylphenyl)formamidine ( L2 ), in which ligands in Z conformation were connected through H bonds from both sides of a ligand and an infinite chain structure formed in solid state. Metallation of the formamidines with diethylzinc and mesitylmagnesium bromide produced ten complexes in a variety of geometries, indicating a rich diversity in geometry for the formamidine family as coordination ligands. Among these complexes, three bimetallic complexes, with metal atoms close in distance, are potential candidates for the formation of complexes with metal-metal bonds. In each dizinc complex, two formamidinates (deprotonated formamidines) spanned over the two Zn atoms and brought them together, while in the dimagnesium complex, the two Mg atoms were bridged by two bromides, resulting in a Mg 2 Br 2 cubic core. In the other approach, two newly designed tripodal ligands were obtained at relatively high yields. Each of the ligands contains three branches built up from a central atom C or N. Lone pairs on the three branches of a deprotonated ligand working together could behave like a three-prong clamp and secure two metal centers closely in the pocket. A dichromium complex with a geometry matching our initial design was successfully synthesized. Meanwhile, two monometallic complexes, potential candidates as precursors to heterobimetallic complexes, were obtained.
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Ho, Dan. "BAYESIAN-DERIVED VANCOMYCIN AUC24H THRESHOLD FOR NEPHROTOXICITY IN SPECIAL POPULATIONS." Scholarly Commons, 2021. https://scholarlycommons.pacific.edu/uop_etds/3760.
Повний текст джерелаАнотація:
A Bayesian-derived 24-hour area under the concentration-time curve over minimum inhibitory concentration from broth microdilution (AUC24h/MICBMD) ratio of 400 to 600 is recommended as the new monitoring parameter for vancomycin to optimize efficacy and minimize nephrotoxicity. The AUC24h threshold of 600 mg*h/L for nephrotoxicity was extrapolated from studies that assessed the general population. It is unclear if this upper threshold is consistent or varies when used in special populations such as critically ill patients, obese patients, patients with preexisting renal disease, and patients on concomitant nephrotoxins.The purpose of this study is to investigate the generalizability of the proposed vancomycin AUC24h threshold of 600 mg*h/L for nephrotoxicity. The objective is to determine the optimal Bayesian-derived AUC24h threshold to minimize vancomycin-associated nephrotoxicity in special populations such as critically ill patients, obese patients, patients with preexisting renal disease, and patients on concomitant loop diuretics, ACEIs, ARBs, NSAIDs, aminoglycosides, piperacillin-tazobactam, and IV contrast dyes.
The study design is a single-center, retrospective cohort study. For each patient, nephrotoxicity was assessed and the Bayesian-derived AUC24h was estimated. Using classification and regression tree (CART) analysis, the AUC24h threshold for nephrotoxicity was determined for each special population that had at least ten nephrotoxic patients. The predictive performances (e.g., positive predictive value [PPV], negative predictive value [NPV], sensitivity, specificity, and area under the receiver operating characteristic [ROC] curve) of each CART-derived threshold were then compared to the guideline threshold’s predictive performances. PPV and sensitivity were given greater weight when comparing the thresholds.
Of the 336 patients, 29 (8.6%) nephrotoxic patients were observed after initiating vancomycin. Among the special populations of interest, critically ill patients, obese patients, patients with preexisting renal disease, and patients on concomitant loop diuretics included at least ten nephrotoxic patients and thus were further analyzed to determine the CART-derived AUC24h thresholds. The CART-derived AUC24h thresholds were 544 mg*h/L for critically ill patients (n=116), 586 mg*h/L for obese patients (n=111), 539 mg*h/L for patients with preexisting renal disease (n=54), and 543 mg*h/L for patients on concomitant loop diuretics (n=126). Compared to the guideline threshold of 600 mg*h/L, the CART-derived thresholds for critically ill patients, patients with preexisting renal disease, and patients on concomitant loop diuretics had comparable PPVs but significantly higher sensitivities. On the other hand, the CART-derived threshold for obese patients did not have a significantly different PPV, NPV, sensitivity, specificity, and area under the ROC curve.
For critically ill patients, patients with preexisting renal disease, and patients on concomitant loop diuretics, a lower vancomycin AUC24h threshold for nephrotoxicity such as 544 mg*h/L, 539 mg*h/L, and 543 mg*h/L, respectively, may be considered to minimize the risk of nephrotoxicity. On the other hand, this study supports the continued use of the guideline threshold of 600 mg*h/L to minimize the risk of nephrotoxicity in obese patients.
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Stowell, Yoshiko Katori. "Mechanistic study of nanoemulsion absorption and its application for permeation enhancement." Scholarly Commons, 2014. https://scholarlycommons.pacific.edu/uop_etds/139.
Повний текст джерелаАнотація:
Oil in water (o/w) nanoemulsion is a two-phase dispersed system in which the oil can incorporate poorly water soluble drugs to form a liquid dosage form. The enhancement of bioavailability with a use of nanoemulsion has often been reported empirically and speculated to be a result of the enhanced dissolution due to a larger surface area, however, the mechanism of nanoemulsion permeation was yet to be explored. The goal of this dissertation was to understand the mechanism of nanoemulsion permeation and to control permeation and bioavailability. The first objective was to delineate the effect of thermodynamic activities of the drug in nanoemulsion on the permeation through a barrier. The flux from nanoemulsion depended on the thermodynamic activities of both ionized and unionized species in the aqueous phase of nanoemulsion. A simple nanoemulsion was not favorable to enhance the permeation over the saturated solution due to the reduced thermodynamic activity. Thus, the second objective was to elucidate the role of transient supersaturation on permeation enhancement using nanoemulsion. In vitro permeation using self-nanoemulsifying drug delivery system (SNEDDS) was enhanced over the saturated solution due to the transient supersaturation; however the enhancement of bioavailability in rats was not due to the enhanced passive permeation. Therefore there was a need to increase or prolong the supersaturation. The third objective was to control the supersaturation to enhance in vitro permeation by formulation approaches. The optimum drug loading was determined based on the precipitation kinetics; however the ability to modulate the thermodynamic activity to enhance permeation by changing the drug loading was limited. The precipitation inhibitor, hydroxypropylmethyl cellulose was able to retard the precipitation and enhanced in vitro permeation due to the increased thermodynamic activity. The significance of this work was the systematic approach to understand the mechanism of nanoemulsion absorption and to utilize nanoemulsion for permeation enhancement. The knowledge gained in this work will help rationally design the formulation in the future.
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Estari, Rohit Kumar. "Effect of rutaecarpine on caffeine pharmacokinetics in rats." Scholarly Commons, 2015. https://scholarlycommons.pacific.edu/uop_etds/276.
Повний текст джерелаАнотація:
Many people like to drink caffeinated beverages, such as coffee or tea, but are sensitive to effects of caffeine. Therefore, they either avoid drinking caffeinated beverages altogether, or they avoid drinking them close to bedtime to prevent caffeine from interfering with their sleep. Ruta Cleanse and Ruta Sleep are natural supplements containing rutaecarpine that are designed to speed up the removal of caffeine from the blood. The recommendation is to take two capsules (equivalent to 100 mg rutaecarpine), as needed, to reduce caffeine level. Customers have reported positive effects, when taken 30 minutes to 2 hours prior. However, there is no scientific data to show how soon Ruta Cleanse and Ruta Sleep need to be taken in order for it to work. Therefore, we tested in rats the effect of single dose after 3, 6, 12, 24 hour and 7 doses (once a day, for seven days) of oral 100 mg/kg rutaecarpine (in suspension) induction on caffeine pharmacokinetics upon 15 mg/kg intravenous bolus and 20 mg/kg oral caffeine doses. The MROD data showed that as early as 3 hours after oral rutaecarpine administration, CYP1A2 activity in the liver tissue is increased by almost 3-fold compared to control rats and highest activity (9-fold compared to control) is found in the liver of rats administered with daily oral dose of rutaecarpine, for seven days. A suspension form of 100 mg/kg orally administered rutaecarpine significantly decreases the oral systemic exposure and mean residence time of caffeine and its metabolites (paraxanthine, theophylline and theobromine), as early as 3 hours before oral caffeine administration. The oral caffeine bioavailability (F) decreases by about 50% for the 3, 6 and 12-hour, 70% for the 24 hour and 80% for the one week daily rutaecarpine treatment groups. Currently we do not know the mechanism by which rutaecarpine significantly decreases the F values of caffeine upon oral administration. The systemic exposure of caffeine and its metabolites are also decreased when caffeine is given intravenously, though the effect is less pronounced compared to when caffeine is given orally. Interestingly, rutaecarpine achieves this effect without achieving detectable plasma level (less than 10 ng/mL). However, since the target organ for rutaecarpine is the liver, rutaecarpine can still induce CYP1A2 enzyme in the liver (as indicated by MROD data), without having to get absorbed into blood circulation.
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Shallal, Hassan M. "The discovery and anticancer preclinical investigation of novel piperazinylpyrimidine derivatives designed to target the human kinome." Scholarly Commons, 2011. https://scholarlycommons.pacific.edu/uop_etds/158.
Повний текст джерелаАнотація:
The current dissertation describes a multidisciplinary research project centered on the discovery and investigation of the anticancer activities exhibited by novel piperazinylpyrimidine derivatives designed to target kinases protein family. Primary screening of the antiproliferative effects implemented by these successfully synthesized new agents has resulted in the candidacy of 4 , 15 , and 16 as not only prototype representatives of the class, but surprisingly also as optimized agents for either globally cytotoxic, 16 , or selectively cytostatic, 4 and 15 , agents. Subjecting 4 , 15 , and 16 to screening tests aiming at measuring their binding to or their functional inhibition of selected sets of kinases has revealed the tendency of 4 to target PDGFR subfamily and the ability of 4 , 15 , and 16 to recognize CSNK1D. Docking as well as binding profiles comparative studies hypothesize 4 , 15 , and 16 as type-I kinase inhibitors. Further preclinical investigation of 15 against MDA-MB-468 triple negative breast cancer cell line revealed that 15 exhibits a time as well as dose-dependent antiproliferative activity mediated by the induction of both time and dose independent G2/M arrest and dose dependent apoptosis. Globally studying the molecular events accompanied with the 15 /MDA-MB-468 incidence has revealed the phosphorylation of TP53 and the consequent activation of its transcriptional activity as a hallmark molecular event relevant to the above observed effects on the cellular, cell cycle, and programmed cell death levels. Apart from the above experimentally oriented investigation, another theoretically driven inquiry was pursued aiming at studying the inherent ability of certain kinases to be more promiscuous towards binding to small molecules than others. Throughout the analysis of a reported dataset, dephosphorylated members of PDGFR subfamily were found to more potently bind to structurally diverse kinase inhibitors compared to INSR subfamily. A molecular dynamics study was performed to compare between the topological, energetic, and dynamic properties of the binding area usually targeted by kinase inhibitors in both KIT, as a representative of the more promiscuous PDGFR subfamily, and INSR, as a representative of the less promiscuous INSR subfamily. Interestingly enough, the binding area in both kinases showed significantly different properties which, to a large extent, can explain their different overall attitudes towards binding small molecules. As a representative example, the binding area of INSR tends to be more energetically self-stabilizing than that in KIT. Additionally, the topological analysis revealed that the binding are in KIT tends to be more rigid and to have bigger size than that of INSR. The current work has successfully cross-implemented experimental, theoretical, and computational studies aiming at the development of novel kinase inhibitors and/or promising anticancer preclinical candidates.
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Buen, Zachary. "Establishment of gas-phase thermochemical values of various small organic compounds and oligopeptides." Scholarly Commons, 2016. https://scholarlycommons.pacific.edu/uop_etds/262.
Повний текст джерелаАнотація:
The thesis describes utilizing mass spectrometry and computational methods to study two groups of molecular systems: small organic molecules and oligopeptides. The gas-phase acidities were measured and the structures of the molecular species were calculated. The small molecules investigated included methylparaben, ibuprofen, and triclosan, all known to have some biological activity. The gas-phase acidity measurements made for these small molecules had the solvent and collisional gas pressures adjusted in order to observe their potential influences. The results obtained provide insight into the ion chemistry of these molecules and how the energetics may change the observed behavior of the ion as well as the resulting thermochemical properties measured. The oligopeptides studied were a family of tri-peptides in which a cysteine probe was placed within an alanine backbone. The cysteine probe was either in the L- or D- configuration in order to detect any fundamental differences among the diastereotopic peptides. Compared to the L-cysteine isomers, the D-cysteine peptides appear to display a change in gas-phase behavior and their respective dissociation profiles. These changes may have an implication of altering the biochemical properties when chirality changes in biological systems.
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Zhou, Zhu. "Exploring the effects of 5-HT2A and AMPA receptors on brain 5-HT via a mechanism-based pharmacodynamic model." Scholarly Commons, 2014. https://scholarlycommons.pacific.edu/uop_etds/143.
Повний текст джерелаАнотація:
Depression is a common mood disorder. Although major ethical challenges make it nearly impossible to invasively and directly measure serotonin (5-hydroxytryptamine, 5-HT) levels in human brains, neuroimaging technologies have shown macroscopic structural and functional abnormalities in the prefrontal cortex (PFC) of depressed patients. The monoamine hypothesis of depression is based on the neurotransmitter imbalance, such as deceased serotonin brain levels are implicated in the cause of depression. Research has focused on the control mechanisms involved in the dorsal raphé nucleus (DRN) which is the serotonergic control center located in the midbrain. We hypothesized that activation 5-HT 2A receptor in PFC would increase serotonin levels by an AMPA-dependent mechanism in both DRN and PFC. Enhancement of the 5-HT in DRN may inhibit 5-HT level in PFC by 5-HT 1A receptor. This becomes the full feedback loop system. While 5-HT levels in the PFC have been well studied, pathway that modulate this DRN pool through upstream cascade interactions leading to a downstream feedback loop have been difficult to elucidate. Developing a mechanism-based pharmacokinetics (PK) and pharmacodynamics (PD) model to quantitatively describe the effect of 5-HT 2A receptors regulation to serotonin in the DRN and PFC would help us to better understand the complex brain. 5-HT 2A receptor agonist and AMPA receptor agonist and antagonist were used to activate or block the related receptor. Male Wistar rats underwent neurosurgery for implantation of microdialysis (MD) probes. Three to five rats were randomly assigned to experimental arms. Using the MD method, the drug combination was examined to explore the drug effect on time course of 5-HT release in DRN and PFC. Based on the experiment results, a mechanism-based PD model was developed. Phoenix WinNonlin ® and Berkeley Madonna™ were used for model estimation, external validation with secondary data set, and simulation. The result supports the possibility of a 5-HT 2A /AMPA feedback control circuit that originates in the PFC and modulates DRN and PFC 5-HT levels through feedback coupling of 5-HT. The time-course profiles of 5-HT in both DRN and PFC was well modeled and model parameters were estimated with good precision (CV% ranged from 1.37% to 35.03%). The mechanism model was developed to characterize and better understand the neurotransmitter mechanisms, providing estimations of various parameters of the disease related receptor system.
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Batoon, Patrick Henry M. "Thermochemical differences in lysine and lysine-homolog containing oligopeptides: Determination of basicity and gas-phase structure through mass spectrometry, infrared spectroscopy, and computational chemistry." Scholarly Commons, 2016. https://scholarlycommons.pacific.edu/uop_etds/127.
Повний текст джерелаАнотація:
The data presented in this thesis is a comprehensive study on the nature of peptide structure and how subtle and systematic changes in sequence and sidechain affect the basicity, ion stability, and conformation of a peptide. The peptides characterized were acetylated polyalanine di-, tri-, and tetra- peptides containing a proton-accepting probe: lysine and or the non-proteinogenic lysine-homologs: ornithine, 2,4-diaminobutyric acid, and 2,3-diaminopropionic acid. Peptides were studied in isomeric pairs for which the basic amino acid was placed closest to the N-terminus or the C-terminus of each peptide family (A n Probe vs. ProbeA n ). Using a variety of mass spectrometry based techniques and infrared multiphoton dissociation ion spectroscopy, the isomeric families of polyalanine peptides were characterized. Quantum chemical techniques were employed in parallel to provide theoretical predictions of three-dimensional structure, physical properties (dipole moment, polarizability, and accessible surface area), thermochemical values, and vibrational IR spectra, to gain further understanding of the peptides studied and to push the limits of current theoretical models. Overall it was found that the AnProbe peptide was more basic than their ProbeAn isomer. For the dipeptide systems, the greater basicity of AProbe peptides was due to efficiently charge-solvated ions which formed more compact structures compared to their ProbeA counterpart. For the tri- and tetra- peptide systems, greater basicity of the A 2,3 Probe peptides was likely due to formation of α or 3 10 helix-like structures in the protonated forms., introducing the macrodipolar effect, which cooperatively encouraged helical formation while stabilizing the charged site. On the other hand, ProbeA 2,3 peptides formed charge-solvated coils which do not exhibit any kind of dipole effect, resulting in lower basicity than their A2,3Probe counterpart.
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Yao, Yuan. "Performance and mechanism on a high durable silica alumina based cementitious material composed of coal refuse and coal combustion byproducts." Scholarly Commons, 2012. https://scholarlycommons.pacific.edu/uop_etds/155.
Повний текст джерелаАнотація:
Coal refuse and combustion byproducts as industrial solid waste stockpiles have become great threats to the environment. Recycling is one practical solution to utilize this huge amount of solid waste through activation as substitute for ordinary Portland cement. The central goal of this dissertation is to investigate and develop a new silica-alumina based cementitious material largely using coal refuse as a constituent that will be ideal for durable construction, mine backfill, mine sealing and waste disposal stabilization applications. This new material is an environment-friendly alternative to ordinary Portland cement. The main constituents of the new material are coal refuse and other coal wastes including coal sludge and coal combustion products (CCPs). Compared with conventional cement production, successful development of this new technology could potentially save energy and reduce greenhouse gas emissions, recycle vast amount of coal wastes, and significantly reduce production cost. A systematic research has been conducted to seek for an optimal solution for enhancing pozzolanic reactivity of the relatively inert solid waste-coal refuse in order to improve the utilization efficiency and economy benefit for construction and building materials. The results show that thermal activation temperature ranging from 20°C to 950°C significantly increases the workability and pozzolanic property of the coal refuse. The optimal activation condition is between 700°C to 800°C within a period of 30 to 60 minutes. Microanalysis illustrates that the improved pozzolanic reactivity contributes to the generated amorphous materials from parts of inert aluminosilicate minerals by destroying the crystallize structure during the thermal activation. In the coal refuse, kaolinite begins to transfer into metakaol in at 550°C, the chlorite minerals disappear at 750°C, and muscovite 2M 1 gradually dehydroxylates to muscovite HT. Furthermore, this research examines the environmental acceptance and economic feasibility of this technology and found that this silica alumina-based cementitious material not only meets EPA requirements but also shows several advantages in industrial application.
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Chen, Eric H. "Studies on the detection of nucleotides and oligonucleotides by mass spectrometry." Scholarly Commons, 2006. https://scholarlycommons.pacific.edu/uop_etds/633.
Повний текст джерелаАнотація:
The long-term goal of this project is to develop novel methods for the detection of nucleotides, oligonucleotides, and modified nucleotides such as DNA adducts by mass spectrometry. DNA adducts are important because they are formed during chemical carcinogenesis as well as during anti-cancer chemotherapy. However, DNA adducts are not routinely monitored due to difficulties associated with their detection. Mass spectrometry is a promising method for the detection of DNA adducts because it can detect almost any type of adduct, and in addition mass spectrometers can provide structural information. The work presented here shows successful detection of nucleotides and oligonucleotides of various sizes. Specific sizes detected include mononucleotides, 6-mer, 8-mer, 1 O-rner, and 16-mer oligonucleotides, and enzyme digests of genomic DNA and oligonucleotides. Through researchinvolving several separation methods (HPLC, TLC, and PAGE) and alternative detection methods (32P postlabeling and mass spectrometry), a novel method for the separation and detection of DNA adducts has been developed. The present research has shown promising results for tracking nucleotides in TLC using biomimetic dyes in order to eliminate the need for radioactive isotopes. In addition, progress has been made involving elution of nucleotides from a TLC plate and subsequent detection of these nucleotides by mass spectrometry. Together, these results will facilitate future studies that involve testing samples that contain altered DNA by different mass spectrometers, which are expected to be particularly useful for the detection and identification of mixed or novel DNA ' modifications.
50
Sacasa, Pablo R. Jr. "Developing of Germyldesulonylation and Thiodesulfonylation Reactions for the Synthesis of Novel Nucleoside Analogues. Efficient Synthesis of Novel (α-Fluoro)vinyl Sulfides". FIU Digital Commons, 2010. http://digitalcommons.fiu.edu/etd/265.
Повний текст джерелаАнотація:
S-adenosyl-L-homocysteine (AdoHcy) hydrolase effects hydrolytic cleavage of AdoHcy to produce both adenosine and L-homocysteine and is a feedback inhibitor of S-adenosyl-L-methionine (SAM). Nucleoside analogues bearing an alkenyl or fluoroalkenyl chain between sulfur and C5′ utilizing Negishi coupling reactions were synthesized. Palladium-catalyzed cross-coupling between the 5′-deoxy-5′-(iodomethylene) nucleosides and alkylzinc bromides gives analogues with the alkenyl unit. Palladium-catalyzed selective monoalkylation of 5′-(bromofluoromethylene)-5′-deoxy-adenosine with alkylzinc bromide afford adenosylhomocysteine analogues with a 6′-(fluoro)vinyl motif. The vinylic adenine nucleosides produced time-dependent inactivation of the S-adenosyl-L-homocysteine hydrolases. Stannydesulfonylation reaction is a critical step in the synthesis of E-fluorovinyl cytidine (Tezacitabine) a ribonucleoside reductase inhibitor with a potent anticancer activity. The synthesis involves the removal of the sulfonyl group by a radical-mediated stannyldesulfonylation reaction using tributyltin hydride. In order to eliminate the toxicity of tin, I developed a radical-mediated germyldesulonylation utilizing less toxic germane hydrides. Treatment of the protected (E)-5'-deoxy-5'-[(p-toluenesulfonyl)-methylene]uridine and adenosine derivatives with tributyl- or triphenylgermane hydride effected radical-mediated germyldesulfonylations to give 5'-(tributyl- or triphenylgermyl)methylene-5'-deoxynucleoside derivatives as single (E)-isomers. Analogous treatment of 2'-deoxy-2'-[(phenylsulfonyl)methylene]uridine with Ph3GeH afforded the corresponding vinyl triphenylgermane product. Stereoselective halodegermylation of the (E)-5'-(tributylgermyl)-methylene-5'-deoxy nucleosides with NIS or NBS provided the Wittig-type (E)-5'-deoxy-5'-(halomethylene) nucleosides quantitatively. Radical-mediated thiodesulfonylation of the readily available vinyl and (α-fluoro) vinyl sulfones with aryl thiols in organic or aqueous medium to provide a bench and environmentally friendly protocol to access (α-fluoro)vinyl sulfides were developed. Methylation of the vinyl or (α-fluoro)vinyl phenyl sulfide gave access to the corresponding vinyl or (α-fluoro)vinyl sulfonium salts. These sulfonium ions were tested as possible methyl group donors during reactions with thiols, phenols or amino groups which are commonly present in natural amino acids.