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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
21

Structure-function Relationships in the Inositol 1,4,5-Trisphosphate Receptor

Chan, Jenny 05 August 2010 (has links)
The divalent Ca2+ metal ion acts as a universal second messenger in virtually all eukaryotic cells from fungi to plants to mammals. In mammals, Ca2+ signaling is vital to a variety of physiological processes including fertilization, cell proliferation, secretion, and muscular contraction. In electrochemically non-excitable tissues, the release of Ca2+ from intracellular stores such as the endoplasmic reticulum is tightly regulated by the inositol 1,4,5-trisphosphate receptor (IP3R). The IP3R Ca2+ release channel is activated by the binding of the small molecule inositol 1,4,5-trisphosphate (IP3) in response to extracellular stimuli such as hormones, growth factors, and neurotransmitters. The conformational changes accompanying IP3 binding were investigated using a biophysical approach. A specific focus of this work is to decipher how signals of ligand binding are transmitted from the N-terminal IP3-binding core to the C-terminal channel domain. To such end, biophysical studies of the ligand-induced conformational changes within the N-terminal domain of IP3R (a.a. 1 – 604) were performed. The results implicated the presence of two flexible linkers which join stably folded domains. This prompted the proposal of a model in which an equilibrium mixture of conformational substrates containing compact and more extended structures co-exist. Determinants within the N- and C-terminal regions of IP3R have previously been reported to be critical to channel function. Employing nuclear magnetic resonance (NMR) as well as biochemical methods, an intermolecular interaction between the S4-S5 linker, the cytoplasmic loop between the fourth and fifth transmembrane helices of IP3R, and the suppressor domain was identified. The determination of the crystal structure of the suppressor domain from isoform type 3 IP3R (IP3R3SUP) allowed us to map the residues involved in this interaction to one face of the molecule. The characterization of this interaction provides insight into the N- and C-terminal determinants essential to the IP3R channel gating mechanism.
22

Automated Segmentation of Head and Neck Cancer Using Texture Analysis with Co-registered PET/CT images

Yu, Huan 02 September 2010 (has links)
Radiation therapy is often offered as the primary treatment for head and neck cancer(HNC). Accurate target delineation is essential for the success of radiation therapy. The current target definition technique - manual delineation using Computed Tomography(CT) - is subject to high observer variability. Functional imaging modalities such as 2-[18F]-fluoro-2-deoxy-D-glucose Positron Emission Tomography(FDG-PET) can greatly improve the visualization of tumor. FDG-PET co-registered with CT has shown potential to improve the accuracy of target localization and reduce observer variability. Unfortunately, due to the limitation of PET, the degree of improvement obtained by qualitative and simple quantitative (e.g. thresholding) use of FDG-PET is not ideal. However, both PET and CT images contain a wealth of texture information that could be used to improve the accuracy of target definition. This thesis has investigated using texture analysis techniques to automatically delineate radiation targets. Firstly, PET and CT texture features with high discrimination ability were identified and a texture analysis technique- a decision tree based K Nearest Neighbour(DTKNN) classifier – was developed. DTKNN could accurately classify head and neck tissue with an area under curve(AUC) of a Receiver Operator Characteristic(ROC) of 0.95. Subsequently, an automated target delineation technique - CO-registered Multi-modality Pattern Analysis Segmentation System(COMPASS) - was developed that can delineate tumor on a voxel-by-voxel basis. COMPASS was found to accurately delineate HNC with 84% sensitivity and 95% specificity on a voxel basis per patient. To accurately evaluate the utility of the COMPASS in radiation targeting, a validation method which can combine biased observers' contours to generate a probabilistic reference for validation was developed. The method was based on maximum likelihood analysis using a simulated annealing(SA) algorithm. The results from this thesis show that texture features of both PET and CT images can enhance the discrimination between HNC and normal tissue, and an automated delineation method of HNC using texture analysis of PET and CT images can accurately and consistently define radiation targets in head and neck. This suggests that automated segmentation of radiation targets based on texture analysis techniques may significantly reduce observer variability and improve the accuracy of radiation targeting.
23

3D Magnetic Resonance Image-based Cardiac Computer Models of Cardic Electrophysiology

Pop, Mihaela Paula 22 February 2011 (has links)
There is a clear need for improved methods (e.g. computer modelling, imaging) to characterize the substrate of abnormal rhythms like ventricular tachycardia (VT) developed by patients who have suffered a heart attack. Progress leading to improved disease management and treatment planning (based on predictive models) as well as outcomes assessment will have immediate impact on the quality of life in this large patient population. Prior to integration into clinical applications, the predictive models have to be properly validated using experimental techniques selected to reflect the electrophysiological phenomena at spatio-temporal scales similar to those considered in simulations. This thesis advanced us toward this goal by addressing the challenge of building more accurate models of electrophysiology for individual hearts. A novel construction of a realistic 3D cardiac model from Magnetic Resonance Images (MRI), with a long-term aim to predict propagation of the electrical impulse in normal and pathologic large hearts (translatable to human hearts), and associated inducibility of VT is described. To parameterize the model, an original evaluation method of electrophysiological (EP) characteristics of the heart tissue was used. The method combined state-of-the-art experimental physiology tools like optical fluorescence imaging using voltage-sensitive dyes and a CARTO electro-anatomical system, with a cardiac computer model generated from high resolution MR scans of explanted normal and pathologic porcine hearts. Several input model parameters (e.g., conductivity, anisotropy, restitution) were successfully adjusted using the ex-vivo measurements of action potential to yield close correspondence between model output and experiments. Moreover, a simple, fast, and macroscopic mathematical model was used with computation times less than 1h, attractive for clinical EP applications.
24

Development and Use of Polarized Light Methods to Assess Structure and Composition of Biological Tissue

Wood, Michael Frank Gunter 31 August 2011 (has links)
The use of polarized light for characterization of biological tissues has received increased attention in recent years due to the wealth of information available in the interactions of polarized light with tissue and the noninvasive nature of optical radiation. While the depolarizing effects of multiple scattering complicate the use of polarimetry in tissue, many biological constituents affect the polarization of light such as collagen, muscle fibers, and glucose. Thus, if the effects of scattering can be accounted for⎯or utilized in the analysis⎯polarized light can potentially be used as a probe of tissue status. This thesis presents advancements in the techniques for the simulation of polarized light in tissue-simulating media, and explores two biomedical applications. Previous Monte Carlo models for simulation of polarized light propagation in tissue-simulating media do not include the effects of birefringence and optical activity, two polarizing effects of useful diagnostic potential. To overcome this limitation, our model was extended to include both these effects simultaneously, and then experimentally validated using a novel polarization phantom system. The use of polarized light for characterization of the myocardium, and specifically towards monitoring stem cell regenerative treatments of myocardial infarction, was investigated experimentally as a novel application for polarimetry. The potential for this technique is based on the changes in myocardial structure that occur with infarction and subsequent regeneration, and the associated changes in tissue birefringence. The use of polarized light for noninvasive tissue analyte monitoring, particularly glucose, was also investigated based on the optical activity exhibited by many tissue analytes due to their chiral structure. In this study, a novel combined optical polarization and intensity approach was developed and tested on Monte Carlo simulated data. The studies presented in thesis introduce new methods for polarization simulation and analysis in biological tissue and demonstrate potential for polarimetry in monitoring myocardial regeneration and noninvasive measurements of tissue analytes.
25

Characterization of Breast Cancer with Manganese-enhanced Magnetic Resonance Imaging

Nofiele Tchouala, Joris Igor 19 March 2014 (has links)
Highly metastatic cancer cells are more likely to escape and form metastases, and only minimal improvements in treatment can be achieved. Despite metas- tases being the primary cause of cancer-related mortality, they often proceed unnoticed. Current imaging modalities rely solely on the morphological fea- tures of the tumor for characterization, rather than cellular differences. Our goal is to develop an MR cellular imaging capability for characterizing the po- tential of breast cancer cells to metastasize and enable early cancer detection using manganese. Experiments on breast cell lines demonstrated that aggres- sive cancer cells significantly enhanced on T1 -weighted MR images as a result of a higher uptake and retention of manganese. These results suggest that dif- ferences in uptake of manganese can help the detection and characterization of breast cancers. The proposed technique can also be useful for other cancers, and could bring a critically needed dimension to cancer imaging.
26

Characterization of Breast Cancer with Manganese-enhanced Magnetic Resonance Imaging

Nofiele Tchouala, Joris Igor 19 March 2014 (has links)
Highly metastatic cancer cells are more likely to escape and form metastases, and only minimal improvements in treatment can be achieved. Despite metas- tases being the primary cause of cancer-related mortality, they often proceed unnoticed. Current imaging modalities rely solely on the morphological fea- tures of the tumor for characterization, rather than cellular differences. Our goal is to develop an MR cellular imaging capability for characterizing the po- tential of breast cancer cells to metastasize and enable early cancer detection using manganese. Experiments on breast cell lines demonstrated that aggres- sive cancer cells significantly enhanced on T1 -weighted MR images as a result of a higher uptake and retention of manganese. These results suggest that dif- ferences in uptake of manganese can help the detection and characterization of breast cancers. The proposed technique can also be useful for other cancers, and could bring a critically needed dimension to cancer imaging.
27

PET Quantification for Assessing Tumour Response

Sattarivand, Mike 02 April 2014 (has links)
Treatment response assessment in advanced head and neck cancer patients using Positron Emission Tomography (PET) has potential to provide significant clinical benefit. PET quantification methods can be either static or dynamic. The static approach is simple and is widely used. The simplified dynamic PET quantification method is a promising approach as it provides a reasonable trade-off between accuracy and clinical practicality. This method requires a blood sample which makes it not ideal since the PET quantification accuracy may be compromised due to small activity and volume of the blood sample. The implementation of image-based simplified dynamic PET quantification in head and neck cancer patients requires partial volume correction due to small vessel sizes and limitted PET spatial resolution. The objective of this thesis is to evaluate the accuracy of current PET quantification methods for response assessment in advanced head and neck cancer patients and to develop a novel and robust partial volume correction technique to improve PET quantification. First, the static PET quantification method using fixed size ROI is evaluated. Significant variation in response assessment was observed suggesting that static PET quantification using a fixed-size ROI should be approached with caution in heterogeneous tumours. Second, the accuracy of blood activity measurements and its effect on the accuracy of quantitative response assessment is evaluated. Significant inaccuracies in the blood sample based simplified dynamic PET quantification method are identified. The results support a need to develop an image-based simplified dynamic PET quantification method with partial volume correction. Finally, a novel partial volume correction technique was developed, validated, and its robustness was investigated. In comparison to previously published partial volume correction techniques, it performed better with noisy PET images and it was more robust for errors in PET-CT registration. The partial volume correction technique was also implemented and validated in sinogram space to provide additional advantages such as applicability to iterative reconstructions. The proposed partial volume correction technique enables the use of image-based simplified dynamic PET quantification in advanced head and neck cancer patients. Furthermore, the technique establishes a framework for future research to address the inherent low spatial resolution of PET.
28

PET Quantification for Assessing Tumour Response

Sattarivand, Mike 02 April 2014 (has links)
Treatment response assessment in advanced head and neck cancer patients using Positron Emission Tomography (PET) has potential to provide significant clinical benefit. PET quantification methods can be either static or dynamic. The static approach is simple and is widely used. The simplified dynamic PET quantification method is a promising approach as it provides a reasonable trade-off between accuracy and clinical practicality. This method requires a blood sample which makes it not ideal since the PET quantification accuracy may be compromised due to small activity and volume of the blood sample. The implementation of image-based simplified dynamic PET quantification in head and neck cancer patients requires partial volume correction due to small vessel sizes and limitted PET spatial resolution. The objective of this thesis is to evaluate the accuracy of current PET quantification methods for response assessment in advanced head and neck cancer patients and to develop a novel and robust partial volume correction technique to improve PET quantification. First, the static PET quantification method using fixed size ROI is evaluated. Significant variation in response assessment was observed suggesting that static PET quantification using a fixed-size ROI should be approached with caution in heterogeneous tumours. Second, the accuracy of blood activity measurements and its effect on the accuracy of quantitative response assessment is evaluated. Significant inaccuracies in the blood sample based simplified dynamic PET quantification method are identified. The results support a need to develop an image-based simplified dynamic PET quantification method with partial volume correction. Finally, a novel partial volume correction technique was developed, validated, and its robustness was investigated. In comparison to previously published partial volume correction techniques, it performed better with noisy PET images and it was more robust for errors in PET-CT registration. The partial volume correction technique was also implemented and validated in sinogram space to provide additional advantages such as applicability to iterative reconstructions. The proposed partial volume correction technique enables the use of image-based simplified dynamic PET quantification in advanced head and neck cancer patients. Furthermore, the technique establishes a framework for future research to address the inherent low spatial resolution of PET.
29

Octaarginine Labelled 30 nm Gold Nanoparticles as Agents for Enhanced Radiotherapy

Latimer, Caitlin 03 December 2013 (has links)
Traditional radiation therapy is limited by the radiotoxic effects on surrounding healthy tissues. This project investigated the use of a gold nanoparticle (AuNP) conjugated to a cell-penetrating peptide (CPP) to increase tumour cell death during radiotherapy by maximizing the cellular import of the gold nanoparticles. ~8300 octaarginine CPPs were coupled per 30 nm AuNP through poly(ethylene glycol) spacers (AuNP-PEG-CPP). The CPPs enhanced the internalization of the AuNPs into three human breast cancer cell lines by a factor >2 as compared to untargeted AuNPs. Cells were treated with AuNP-PEG-CPP for 24 hours, prior to radiotherapy and their long-term proliferation was assessed in clonogenic assays. The increased internalization of AuNPs by the CPPs resulted in greater cell death following exposure to 300 kVp radiotherapy, by a dose enhancement factors between 1.3 and 2.1 depending on the cell line. These findings illustrate the potential of using AuNP-CPPs to enhance radiotherapy in patients.
30

Octaarginine Labelled 30 nm Gold Nanoparticles as Agents for Enhanced Radiotherapy

Latimer, Caitlin 03 December 2013 (has links)
Traditional radiation therapy is limited by the radiotoxic effects on surrounding healthy tissues. This project investigated the use of a gold nanoparticle (AuNP) conjugated to a cell-penetrating peptide (CPP) to increase tumour cell death during radiotherapy by maximizing the cellular import of the gold nanoparticles. ~8300 octaarginine CPPs were coupled per 30 nm AuNP through poly(ethylene glycol) spacers (AuNP-PEG-CPP). The CPPs enhanced the internalization of the AuNPs into three human breast cancer cell lines by a factor >2 as compared to untargeted AuNPs. Cells were treated with AuNP-PEG-CPP for 24 hours, prior to radiotherapy and their long-term proliferation was assessed in clonogenic assays. The increased internalization of AuNPs by the CPPs resulted in greater cell death following exposure to 300 kVp radiotherapy, by a dose enhancement factors between 1.3 and 2.1 depending on the cell line. These findings illustrate the potential of using AuNP-CPPs to enhance radiotherapy in patients.

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