+publisher:"University of Toronto" +contributor:("Medical Biophysics")

University of Toronto

1. Shams, Nasim. Simultaneous EEG-fMRI Study of Audiovisual Sensory Processing.

Degree: PhD, 2017, University of Toronto

► Simultaneous acquisition of Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) enables studying of brain function with high spatial resolution of fMRI and high temporal… (more)

Subjects/Keywords: auditory; multivariate; sensory; Simulteneous EEG-fMRI; visual; 0317

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APA (6^th Edition):

Shams, N. (2017). Simultaneous EEG-fMRI Study of Audiovisual Sensory Processing. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/79479

Chicago Manual of Style (16^th Edition):

Shams, Nasim. “Simultaneous EEG-fMRI Study of Audiovisual Sensory Processing.” 2017. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/79479.

MLA Handbook (7^th Edition):

Shams, Nasim. “Simultaneous EEG-fMRI Study of Audiovisual Sensory Processing.” 2017. Web. 23 Sep 2018.

Vancouver:

Shams N. Simultaneous EEG-fMRI Study of Audiovisual Sensory Processing. [Internet] [Doctoral dissertation]. University of Toronto; 2017. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/79479.

Council of Science Editors:

Shams N. Simultaneous EEG-fMRI Study of Audiovisual Sensory Processing. [Doctoral Dissertation]. University of Toronto; 2017. Available from: http://hdl.handle.net/1807/79479

University of Toronto

2. Hossein khah, Nazanin. An Ultrasound Contrast Agent Microbubble in a Microvessel: A Numerical Approach.

Degree: PhD, 2015, University of Toronto

URL: http://hdl.handle.net/1807/79717

► The blood brain barrier (BBB), a selective barrier separating blood from the parenchyma of the central nervous system, restricts more than 98% of neurotherapeutics from… (more)

▼ The blood brain barrier (BBB), a selective barrier separating blood from the parenchyma of the central nervous system, restricts more than 98% of neurotherapeutics from traveling into the brain. Focused ultrasound (FUS) exposure combined with circulating microbubbles is an emerging technique capable of safely opening the BBB locally, transiently, and non-invasively, enabling targeted drug delivery in the brain. However, the mechanisms of the microbubble-vessel interactions central to this process are not fully understood. In this thesis, a comprehensive numerical model of a microbubble within a microvessel was developed aiming to shed light on bubble-vessel interactions, vessel wall mechanical stresses and acoustic emissions during FUS-induced BBB opening. An upward shift in the bubble's resonance frequency relative to unbound bubbles was calculated, whose magnitude was dependent on the vessel elasticity. The synergistic effects of acoustic frequency and vessel elasticity on wall stresses were investigated. Vessel wall stresses were found to be maximal when the bubble was driven above resonance. The numerical model was validated with ex vivo high-speed optical imaging experiments. Resultant amplitudes of bubble oscillation were within 15% of corresponding experimental measurements. Vessel wall stresses calculated during bubble compression (and vascular invagination) were larger than those during bubble expansion, implying that vascular damage could occur during this phase. The acoustic emissions from the ultrasound-stimulated microbubble were calculated, and their correlation with the vessel wall stresses was investigated. The normalized second harmonic decreased as a function of pressure until reaching a minimum, "transition point", after which point it was found to increase. The second and fourth harmonics of confined bubbles at this point were larger than those of unbound bubbles. Above the transition point, stresses induced by larger bubbles increased with a steeper slope. The results presented in this thesis could help in enhancing contrast imaging strategies, understanding bubble-vessel interactions, and optimizing ultrasound pulse parameters to maximize vessel wall stresses to improve drug delivery efficacy. Furthermore, the calculated acoustic emissions could provide feedback to online monitoring techniques and enable calibration of in vivo pressures. Advisors/Committee Members: Hynynen, Kullervo, Medical Biophysics.

Subjects/Keywords: Acoustic Emissions; Blood-Brain Barrier; Finite-Element Analysis; Focused Ultrasound; Ultrasound Contrast Agent; Vessel Wall Stresses; 0786

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APA (6^th Edition):

Hossein khah, N. (2015). An Ultrasound Contrast Agent Microbubble in a Microvessel: A Numerical Approach. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/79717

Chicago Manual of Style (16^th Edition):

Hossein khah, Nazanin. “An Ultrasound Contrast Agent Microbubble in a Microvessel: A Numerical Approach.” 2015. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/79717.

MLA Handbook (7^th Edition):

Hossein khah, Nazanin. “An Ultrasound Contrast Agent Microbubble in a Microvessel: A Numerical Approach.” 2015. Web. 23 Sep 2018.

Vancouver:

Hossein khah N. An Ultrasound Contrast Agent Microbubble in a Microvessel: A Numerical Approach. [Internet] [Doctoral dissertation]. University of Toronto; 2015. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/79717.

Council of Science Editors:

Hossein khah N. An Ultrasound Contrast Agent Microbubble in a Microvessel: A Numerical Approach. [Doctoral Dissertation]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/79717

University of Toronto

3. Medrano, Mauricio. Integrated Functional and Genomic Analysis of High-Grade Serous Ovarian Cancer.

Degree: PhD, 2015, University of Toronto

URL: http://hdl.handle.net/1807/79747

► Epithelial ovarian cancer is the fifth-leading cause of cancer-related death for women in North America and is responsible for over 100 000 deaths/year worldwide (Ferlay… (more)

▼ Epithelial ovarian cancer is the fifth-leading cause of cancer-related death for women in North America and is responsible for over 100 000 deaths/year worldwide (Ferlay et al., 2015). High-grade serous ovarian cancer (HGSC) is the most common and lethal subtype and the vast majority of women are diagnosed with advanced stage disease (Bowtell, 2010). The current standard treatment is aggressive surgery combined with adjuvant and/or neo-adjuvant platinum/taxane-based chemotherapy. Despite initial efficacy of standard therapy, resistant cancer recurs and 70% of patients die within 5 years after initial diagnosis (Bast et al., 2009). Further understanding of the molecular and cellular features that promote HGSC progression may assist in identifying new opportunities for therapeutic intervention and ultimately improve the prognosis of women with HGSC. My research has generated an extensive functional and genomic characterization of serous ovarian cancer cell lines and provides a framework for identifying vulnerabilities associated with distinct molecular features. Using this dataset, I have focused on the identification of genes encoding for highly expressed cell surface molecules. I have identified a novel role of the tetraspanin CD151 in serous ovarian cancer. I have found that CD151 depletion impairs survival, proliferation and tumor growth in murine models of a subset of HGSC cell lines. In search of the mechanism underlying CD151-dependency, I have uncovered a novel association for CD151-dependency in cancer cells with mesenchymal features. In particular, high ZEB1 and ZEB2 expression is tightly coupled with CD151-dependency and thus, may be used as biomarkers for stratifying tumors requiring CD151 for growth. Moreover, CD151-binding antibodies block the migratory capacity of CD151-dependent cells, thereby implicating CD151 in metastasis and dissemination of HGSC tumors. These studies provide a resource of characterized HGSC cell lines and suggest that CD151 may be a biological target in HGSC tumors. Advisors/Committee Members: Rottapel, Robert, Medical Biophysics.

Subjects/Keywords: cancer; CD151; genomics; high-grade; ovarian; rna interference; 0307

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APA (6^th Edition):

Medrano, M. (2015). Integrated Functional and Genomic Analysis of High-Grade Serous Ovarian Cancer. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/79747

Chicago Manual of Style (16^th Edition):

Medrano, Mauricio. “Integrated Functional and Genomic Analysis of High-Grade Serous Ovarian Cancer.” 2015. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/79747.

MLA Handbook (7^th Edition):

Medrano, Mauricio. “Integrated Functional and Genomic Analysis of High-Grade Serous Ovarian Cancer.” 2015. Web. 23 Sep 2018.

Vancouver:

Medrano M. Integrated Functional and Genomic Analysis of High-Grade Serous Ovarian Cancer. [Internet] [Doctoral dissertation]. University of Toronto; 2015. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/79747.

Council of Science Editors:

Medrano M. Integrated Functional and Genomic Analysis of High-Grade Serous Ovarian Cancer. [Doctoral Dissertation]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/79747

University of Toronto

4. Li, Li. Investigation of Ring Finger Protein 8 in Mammalian Physiology and Pathogenesis.

Degree: PhD, 2015, University of Toronto

URL: http://hdl.handle.net/1807/77730

►

While genomic stability is often viewed as a cellular shield against malignant transformation, DNA double-strand breaks (DSBs) are probably the most dangerous threat to the… (more)

Subjects/Keywords: 0306

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APA (6^th Edition):

Li, L. (2015). Investigation of Ring Finger Protein 8 in Mammalian Physiology and Pathogenesis. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/77730

Chicago Manual of Style (16^th Edition):

Li, Li. “Investigation of Ring Finger Protein 8 in Mammalian Physiology and Pathogenesis.” 2015. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/77730.

MLA Handbook (7^th Edition):

Li, Li. “Investigation of Ring Finger Protein 8 in Mammalian Physiology and Pathogenesis.” 2015. Web. 23 Sep 2018.

Vancouver:

Li L. Investigation of Ring Finger Protein 8 in Mammalian Physiology and Pathogenesis. [Internet] [Doctoral dissertation]. University of Toronto; 2015. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/77730.

Council of Science Editors:

Li L. Investigation of Ring Finger Protein 8 in Mammalian Physiology and Pathogenesis. [Doctoral Dissertation]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/77730

University of Toronto

5. Perampalam, Subodini. Cell Targeted Ribosome Inactivating Proteins Derived from Protein Combinatorial Libraries.

Degree: 2008, University of Toronto

URL: http://hdl.handle.net/1807/11244

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Combinatorial protein libraries based on a protein template offer a vast potential for deriving protein variants harboring new receptor specificity while retaining other tem-plate functions… (more)

Subjects/Keywords: Protein libraries; cytotoxicity; anti-cancer agents; shiga like toxin 1; ribosome inactivating protein; 0760

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APA (6^th Edition):

Perampalam, S. (2008). Cell Targeted Ribosome Inactivating Proteins Derived from Protein Combinatorial Libraries. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/11244

Chicago Manual of Style (16^th Edition):

Perampalam, Subodini. “Cell Targeted Ribosome Inactivating Proteins Derived from Protein Combinatorial Libraries.” 2008. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/11244.

MLA Handbook (7^th Edition):

Perampalam, Subodini. “Cell Targeted Ribosome Inactivating Proteins Derived from Protein Combinatorial Libraries.” 2008. Web. 23 Sep 2018.

Vancouver:

Perampalam S. Cell Targeted Ribosome Inactivating Proteins Derived from Protein Combinatorial Libraries. [Internet] [Doctoral dissertation]. University of Toronto; 2008. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/11244.

Council of Science Editors:

Perampalam S. Cell Targeted Ribosome Inactivating Proteins Derived from Protein Combinatorial Libraries. [Doctoral Dissertation]. University of Toronto; 2008. Available from: http://hdl.handle.net/1807/11244

University of Toronto

6. Bateman, David. Structural and Kinetic Characterization of Cell Surface and Internalized Alzheimer Amyloid Peptides in Neuronal Cells.

Degree: 2008, University of Toronto

URL: http://hdl.handle.net/1807/16781

►

Alzheimer’s disease is linked to the formation of amyloid fibrils, which are primarily composed of two Alzheimer amyloid peptides, Abeta40 and Abeta42. The peptides start… (more)

▼

Alzheimer’s disease is linked to the formation of amyloid fibrils, which are primarily composed of two Alzheimer amyloid peptides, Abeta40 and Abeta42. The peptides start to deposit in brains as plasma membrane-bound diffuse plaques. Current detection methods utilize dyes or antibodies that bind specific conformations of the peptides. However, these observation tools are limited, as they fail to detect the whole ensemble of pre-amyloid structural conformations. We adopted the approach of covalently attaching a fluorescent molecule to the N-terminus of Abeta, which allows for following the aggregation profile and examination of the association of Abeta with neuronal cells lines in real time. With the aid of confocal microscopy and flow cytometry, the rate of Abeta association to neuronal cell lines was found to correlate directly with their aggregation propensities. A non-aggregating mutant of Abeta42 did not bind to live cells and none of these peptides were found to associate with a non-neuronal human lymphoma cell line, U937, which is resistant to Abeta toxicity. Aggregation of Abeta42 on the surface of cells was characterized over time using photobleaching Forster resonance energy transfer, fluorescence quenching, and photobleaching recovery. Furthermore, exposed regions of Abeta aggregates on the cell surface were identified with sequence-specific antibodies. Two populations of aggregates were revealed; the first population displayed reduced energy transfer, showed fluorescence quenching, and bound antibodies specific for the C-terminal of Abeta, whereas the second population of aggregates was capable of energy transfer, was resistant to quenching, and increased in number over time. Interestingly, neither population of aggregates displayed photobleaching recovery. Addition of Abeta monomers to neuronal cells lead to the formation of cell surface aggregates that were eventually internalized into endosomes and lysosomes. The rate of internalization was greatly enhanced when the peptides were partially aggregated by exposure to conditions similar to the lumen of endosomes. Highly aggregated Abeta did not bind to neuronal cells. These studies have mapped out the aggregation pathway of Abeta in the physiologically relevant milieu of neuronal cells in culture, and have potentially revealed information about the formation of the pathological hallmark of Alzheimer’s disease, the senile plaque.

PhD

Advisors/Committee Members: Chakrabartty, Avijit, Medical Biophysics.

Subjects/Keywords: Alzheimer's disease; cell culture; 0760

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APA (6^th Edition):

Bateman, D. (2008). Structural and Kinetic Characterization of Cell Surface and Internalized Alzheimer Amyloid Peptides in Neuronal Cells. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/16781

Chicago Manual of Style (16^th Edition):

Bateman, David. “Structural and Kinetic Characterization of Cell Surface and Internalized Alzheimer Amyloid Peptides in Neuronal Cells.” 2008. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/16781.

MLA Handbook (7^th Edition):

Bateman, David. “Structural and Kinetic Characterization of Cell Surface and Internalized Alzheimer Amyloid Peptides in Neuronal Cells.” 2008. Web. 23 Sep 2018.

Vancouver:

Bateman D. Structural and Kinetic Characterization of Cell Surface and Internalized Alzheimer Amyloid Peptides in Neuronal Cells. [Internet] [Doctoral dissertation]. University of Toronto; 2008. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/16781.

Council of Science Editors:

Bateman D. Structural and Kinetic Characterization of Cell Surface and Internalized Alzheimer Amyloid Peptides in Neuronal Cells. [Doctoral Dissertation]. University of Toronto; 2008. Available from: http://hdl.handle.net/1807/16781

University of Toronto

7. Durbin, Adam. Studies on Signal Transduction Mechanisms in Rhabdomyosarcoma.

Degree: 2010, University of Toronto

URL: http://hdl.handle.net/1807/24739

►

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood, with two predominant histologic subtypes: embryonal and alveolar. These histologies display distinct clinical courses, and… (more)

▼

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood, with two predominant histologic subtypes: embryonal and alveolar. These histologies display distinct clinical courses, and despite refinements in dose and duration of multimodality therapy, the 5-year overall survival of patients diagnosed with metastatic RMS remains <30%. Thus, there is an urgent need to define novel targets for therapeutic intervention. Interrogation of cancer cell signal transduction pathways that regulate the pathogenic behaviours of tumor cells has been successful in defining targets in numerous tumor types. These have ultimately yielded clinically-relevant drugs that have improved the disease-free and overall survival of patients diagnosed with cancer. Work contained in this thesis describes the interrogation of several potential targets for inhibition in RMS. Interruption of RMS cell proliferation, survival and apoptosis is examined through disruption of the protein kinase integrin-linked kinase (ILK) and the nuclear receptor estrogen-receptor β. ILK, in particular, is demonstrated to have dual competing functions through the regulation of c-jun amino-terminal kinase (JNK) signaling: an oncogene in alveolar, and a tumor suppressor in embryonal RMS. These findings are recapitulated in other tumor cell lines, indicating that expression levels of JNK1 correlate with ILK function in a broad spectrum of tumor types. Furthermore, interruption of rhabdomyosarcoma cell migration as a surrogate marker of metastasis is examined through disruption of the stromal-cell derived factor 1α/chemokine (CXC)receptor 4 signaling network, as well as through cooperative interactions between ILK and the mammalian target of rapamycin. Finally, we demonstrate that the insulin-like growth factor pathway is a potential target for therapeutic inhibition, which also distinguishes tumors of embryonal and alveolar histology. These studies provide a rationale for the development of novel agents, as well as the use of established drugs targeting these pathways in rhabdomyosarcoma.

PhD

Advisors/Committee Members: Malkin, David, Medical Biophysics.

Subjects/Keywords: rhabdomyosarcoma; cell signaling; tumor suppressor; oncogene; metastasis; insulin-like growth factor; chemokine; cancer; translocation; signal transduction; estrogen receptor; integrin-linked kinase; JNK; c-jun; embryonal; alveolar; mTOR; myosin light chain; 0992; 0379; 0307

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APA (6^th Edition):

Durbin, A. (2010). Studies on Signal Transduction Mechanisms in Rhabdomyosarcoma. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/24739

Chicago Manual of Style (16^th Edition):

Durbin, Adam. “Studies on Signal Transduction Mechanisms in Rhabdomyosarcoma.” 2010. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/24739.

MLA Handbook (7^th Edition):

Durbin, Adam. “Studies on Signal Transduction Mechanisms in Rhabdomyosarcoma.” 2010. Web. 23 Sep 2018.

Vancouver:

Durbin A. Studies on Signal Transduction Mechanisms in Rhabdomyosarcoma. [Internet] [Doctoral dissertation]. University of Toronto; 2010. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/24739.

Council of Science Editors:

Durbin A. Studies on Signal Transduction Mechanisms in Rhabdomyosarcoma. [Doctoral Dissertation]. University of Toronto; 2010. Available from: http://hdl.handle.net/1807/24739

University of Toronto

8. Chan, Jenny. Structure-function Relationships in the Inositol 1,4,5-Trisphosphate Receptor.

Degree: 2010, University of Toronto

URL: http://hdl.handle.net/1807/24702

►

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+… (more)

▼

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.

PhD

Advisors/Committee Members: Ikura, Mitsuhiko, Medical Biophysics.

Subjects/Keywords: calcium; ion channel; 0760

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APA (6^th Edition):

Chan, J. (2010). Structure-function Relationships in the Inositol 1,4,5-Trisphosphate Receptor. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/24702

Chicago Manual of Style (16^th Edition):

Chan, Jenny. “Structure-function Relationships in the Inositol 1,4,5-Trisphosphate Receptor.” 2010. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/24702.

MLA Handbook (7^th Edition):

Chan, Jenny. “Structure-function Relationships in the Inositol 1,4,5-Trisphosphate Receptor.” 2010. Web. 23 Sep 2018.

Vancouver:

Chan J. Structure-function Relationships in the Inositol 1,4,5-Trisphosphate Receptor. [Internet] [Doctoral dissertation]. University of Toronto; 2010. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/24702.

Council of Science Editors:

Chan J. Structure-function Relationships in the Inositol 1,4,5-Trisphosphate Receptor. [Doctoral Dissertation]. University of Toronto; 2010. Available from: http://hdl.handle.net/1807/24702

University of Toronto

9. Rashid, Shahnaz Tahihra Al. The Role of the p53 Tumour Suppressor Protein in Relation to the Sensing of Ionizing Radiation-induced DNA Double-strand Breaks.

Degree: 2010, University of Toronto

URL: http://hdl.handle.net/1807/26447

► Our cells are constantly dealing with DNA damage generated by endogenous cellular activity (e.g. DNA replication) and exogenous agents (e.g. ultraviolet and ionizing radiation (IR)).… (more)

▼ Our cells are constantly dealing with DNA damage generated by endogenous cellular activity (e.g. DNA replication) and exogenous agents (e.g. ultraviolet and ionizing radiation (IR)). The cellular stress response to DNA damage requires strict co-ordination between cell cycle checkpoint control and DNA repair. In response to DNA double-strand breaks (DNA-dsbs), members of the phosphatidylinositol 3-kinase–related kinase family (e.g. ATM and DNA-PKcs kinases) have been shown to redundantly phosphorylate substrates including the DNA-dsb marker, gamma-H2AX, and the p53 tumour suppressor protein. The p53 protein is best known as the guardian of the genome through its transcriptional-dependent and -independent functions. Despite a clear link between ATM-dependent phosphorylation of p53 with cell cycle checkpoint control and various modes of DNA damage repair, the intracellular biology and sub-cellular localization of p53 and specifically its phosphoforms during DNA damage induction and repair remains poorly characterized. Using G0/G1 confluent primary human diploid fibroblast cultures, this thesis shows that endogenous p53, phosphorylated at serine 15 (p53Ser15), accumulates as discrete, dose-dependent and chromatin-bound foci within 30 minutes following the induction of DNA breaks. This biologically distinct sub-pool of p53Ser15 is ATM-dependent and resistant to 26S-proteasomal degradation. p53Ser15 co-localizes and co-immunoprecipitates with gamma-H2AX with kinetics similar to that of biochemical DNA-dsb rejoining. Sub-nuclear microbeam irradiation studies confirm that p53Ser15 is recruited to sites of DNA damage containing gamma-H2AX, ATMSer1981 and DNA-PKcsThr2609 in vivo. Furthermore, studies using isogenic human and murine cells, which express Ser15 or Ser18 phosphomutant proteins, respectively, show defective nuclear foci formation, decreased induction of p21WAF, decreased gamma-H2AX-association and altered DNA-dsb kinetics following DNA damage. We further hypothesized that the non-specific DNA binding activity of the p53 carboxy-terminus mediates chromatin anchoring at sites of DNA damage. YFP-p53 fusion constructs expressing carboxy-terminus deletion mutants of p53 were transfected into p53-null H1299 cells to determine the role of the carboxy-terminus in chromatin-binding pre- and post-IR, independent of transcriptional activity. Within this isogenic human cell system, we observed exogenous YFP-p53WT associated with ATMSer1981 and 53BP1 within cellular chromatin in a dynamic manner. We confirmed that these associations also occurred between endogenous WTp53 with ATMSer1981 and 53BP1 within the chromatin of primary human diploid fibroblasts. YFP-p53del1-299 fusion proteins, which lack transcriptional activity and the Ser15-residue, also associated within chromatin. Ser15-phosphorylation was found not to be essential for DNA damage-induced association of p53 with chromatin or with ATMSer1981 and 53BP1. These data suggest a unique biology for p53Ser15 phosphoforms in the initial steps of DNA damage signaling… Advisors/Committee Members: Bristow, Robert, Medical Biophysics.

Subjects/Keywords: p53; Ionizing Radiation; ATM; 53BP1; Cancer; Cell cycle; DNA damage; DNA repair; 0760

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APA (6^th Edition):

Rashid, S. T. A. (2010). The Role of the p53 Tumour Suppressor Protein in Relation to the Sensing of Ionizing Radiation-induced DNA Double-strand Breaks. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/26447

Chicago Manual of Style (16^th Edition):

Rashid, Shahnaz Tahihra Al. “The Role of the p53 Tumour Suppressor Protein in Relation to the Sensing of Ionizing Radiation-induced DNA Double-strand Breaks.” 2010. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/26447.

MLA Handbook (7^th Edition):

Rashid, Shahnaz Tahihra Al. “The Role of the p53 Tumour Suppressor Protein in Relation to the Sensing of Ionizing Radiation-induced DNA Double-strand Breaks.” 2010. Web. 23 Sep 2018.

Vancouver:

Rashid STA. The Role of the p53 Tumour Suppressor Protein in Relation to the Sensing of Ionizing Radiation-induced DNA Double-strand Breaks. [Internet] [Doctoral dissertation]. University of Toronto; 2010. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/26447.

Council of Science Editors:

Rashid STA. The Role of the p53 Tumour Suppressor Protein in Relation to the Sensing of Ionizing Radiation-induced DNA Double-strand Breaks. [Doctoral Dissertation]. University of Toronto; 2010. Available from: http://hdl.handle.net/1807/26447

University of Toronto

10. Ellens, Nicholas Pieter Kennedy. Flat, Electronically Steered λ/2-Spaced Phased Arrays for Focused Ultrasound Surgery.

Degree: PhD, 2015, University of Toronto

URL: http://hdl.handle.net/1807/69265

► One of the promising applications of non-invasive focused ultrasound surgery is the treatment of women with uterine fibroids. Without any incision, fibroids can be thermally… (more)

▼ One of the promising applications of non-invasive focused ultrasound surgery is the treatment of women with uterine fibroids. Without any incision, fibroids can be thermally ablated in an outpatient procedure allowing patients to return to normal activity within two days.Despite its benefits and potential, the adoption of focused ultrasound surgery has been slow. Current applications of the technique are slow, exclude many women for physiological reasons, and rely on expensive MR-guidance. This thesis describes the development of a new type of focused ultrasound therapy array designed to reduce treatment time consisting of elements with half-wavelength spacing arranged in a flat array. Using simulations, this thesis will discuss the benefits and consequences of sparse phased arrays (a common technique to reduce complexity), and explore the ability of a flat, half-wavelength-spaced phased array to ablate fibroids efficiently and safely. Finally, preliminary feasibility results with a device prototype will be presented in vitro and in vivo.The first simulation study presented here compares flat phased arrays with half-wavelength inter-element spacing with randomly-spaced sparse arrays with element populations of 75%, 50%, and 25%. Though even the very sparse (and least complex) arrays were able to perform comparable ablations, it was found that they required much more power, which was preferentially deposited in the near-field of the transducer which could extend treatment time. The second simulation study claims that a half-wavelength-spaced array at 500 kHz could perform a realistic fibroid ablation as close as 40 mm from the spine without the need for any mechanical translation. Five simulated treatments were performed at an average treatment rate of 90 +/- 20 mL/hr.Finally, this thesis reports preliminary evidence that it is feasible to construct an array of over 1000 individually-controlled elements, arranged in 64-element blocks with half-wavelength element spacing, producing acoustic powers of over 100 W. In vitro, this array was shown to be capable of steering to its edge losing only 24% to 25% of its peak pressure. Extrapolating, this prototype suggests that it is feasible to construct a 6000+ element array suitable for efficient uterine fibroid ablation. Advisors/Committee Members: Hynynen, Kullervo, Medical Biophysics.

Subjects/Keywords: 0574

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APA (6^th Edition):

Ellens, N. P. K. (2015). Flat, Electronically Steered λ/2-Spaced Phased Arrays for Focused Ultrasound Surgery. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/69265

Chicago Manual of Style (16^th Edition):

Ellens, Nicholas Pieter Kennedy. “Flat, Electronically Steered λ/2-Spaced Phased Arrays for Focused Ultrasound Surgery.” 2015. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/69265.

MLA Handbook (7^th Edition):

Ellens, Nicholas Pieter Kennedy. “Flat, Electronically Steered λ/2-Spaced Phased Arrays for Focused Ultrasound Surgery.” 2015. Web. 23 Sep 2018.

Vancouver:

Ellens NPK. Flat, Electronically Steered λ/2-Spaced Phased Arrays for Focused Ultrasound Surgery. [Internet] [Doctoral dissertation]. University of Toronto; 2015. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/69265.

Council of Science Editors:

Ellens NPK. Flat, Electronically Steered λ/2-Spaced Phased Arrays for Focused Ultrasound Surgery. [Doctoral Dissertation]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/69265

University of Toronto

11. Hadley, Kevin Charles. Elucidating the Role of Protein Misfolding in Neurodegenrative Disease Using Multiphoton Microscopy.

Degree: PhD, 2014, University of Toronto

URL: http://hdl.handle.net/1807/68275

► This work develops a two-pronged approach to using multiphoton microscopy for the study of protein folding and misfolding in neurodegenerative disease. First, we present the… (more)

▼ This work develops a two-pronged approach to using multiphoton microscopy for the study of protein folding and misfolding in neurodegenerative disease. First, we present the use of 1,8-anilinonaphthalene sulfonate (ANS) in two-photon excitation (TPE) microsopy as a probe for protein misfolding in living cells and tissues. By using TPE microscopy, we are able to generate high-resolution images with confocal-like optical sectioning, while avoiding the phototoxicity and photobleaching effects that would otherwise be associated with the ultraviolet-excited ANS. ANS fluorescence is compatible with live-cell imaging, and ANS binding occurs principally in the endoplasmic reticulum (ER), the Golgi apparatus, and the lysosomes. ANS fluorescence responds to an array of stressors, including ER stress, hyperthermia, and proteasome inhibition. Strikingly, ANS fluorescence highlights the nucleolus as a structure exquisitely sensitive to protein-damaging stress. ANS fluorescence microscopy is also possible in transparent organisms - including Caenorhabditis elegans and larval Drosophila melanogaster. Second, we develop a new photo-tag reagent (6HisBP) which couples a benzophenone-derived photo-crosslinker to a hexahistidine affinity tag. Exposure to UV light covalently couples the 6HisBP tag to whatever protein molecules are nearby. At the microscope, TPE confines the photo-tag crosslinking to a single-micron-scale volume at the focus of the microscope objective. Using this precision TPE photo-tagging, we can selectively tag volumes of interest associated with microscopic pathological features. Photo-tagged proteins can subsequently be recovered from the tissue (after homogenization and solubilization) with affinity chromatography; proteins can be identified using liquid chromatography and tandem mass spectrometry (LC/MS/MS proteomic analysis). With this method (which we call spatially targeted optical microproteomics, or STOMP), we have inventoried the components of cortical plaques in the TgCRND8 mouse model of Alzheimer's disease. Strongly represented are proteins associated with presynaptic vesicle formation, transport, and fusion. Together, these two methods are tools that allow the identification of cells or tissues which are experiencing aberrant protein folding or misfolding and aggregation as part of a disease process; and then subsequently to photo-tag, isolate, and identify specific proteins involved in the disease. Advisors/Committee Members: Avijit, Chakrabartty, Medical Biophysics.

Subjects/Keywords: Alzheimer's disease; neurodegenerative disease; protein misfolding; proteomics; two-photon microscopy; 0786

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hadley, K. C. (2014). Elucidating the Role of Protein Misfolding in Neurodegenrative Disease Using Multiphoton Microscopy. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/68275

Chicago Manual of Style (16^th Edition):

Hadley, Kevin Charles. “Elucidating the Role of Protein Misfolding in Neurodegenrative Disease Using Multiphoton Microscopy.” 2014. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/68275.

MLA Handbook (7^th Edition):

Hadley, Kevin Charles. “Elucidating the Role of Protein Misfolding in Neurodegenrative Disease Using Multiphoton Microscopy.” 2014. Web. 23 Sep 2018.

Vancouver:

Hadley KC. Elucidating the Role of Protein Misfolding in Neurodegenrative Disease Using Multiphoton Microscopy. [Internet] [Doctoral dissertation]. University of Toronto; 2014. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/68275.

Council of Science Editors:

Hadley KC. Elucidating the Role of Protein Misfolding in Neurodegenrative Disease Using Multiphoton Microscopy. [Doctoral Dissertation]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/68275

University of Toronto

12. Bassi, Christian. Nuclear PTEN Controls DNA Repair and Sensitivity to Genotoxic Stress.

Degree: PhD, 2015, University of Toronto

URL: http://hdl.handle.net/1807/69214

► Loss of function of the phosphatase and tensin homolog (PTEN) tumor suppressor is frequently found in many human malignancies. PTEN antagonizes the Phosphatidylinositide 3-kinase (PI3K)… (more)

▼ Loss of function of the phosphatase and tensin homolog (PTEN) tumor suppressor is frequently found in many human malignancies. PTEN antagonizes the Phosphatidylinositide 3-kinase (PI3K) pathway by dephosphorylating the 3 position of phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] (PIP3). PIP3 serves as a second messenger whose levels in the plasma membrane are elevated following cell stimulation with growth factors, mediated by the activity of PI3Ks. Proteins containing pleckstrin homology (PH) domains physically interact with PIP3, bringing them into close proximity with other PH domain-containing proteins and facilitating further functional interactions that serve to propagate the membranous signal. Although the cytoplasmic role of PTEN in antagonizing PI3K signaling has been well studied, PTEN also resides in the nucleus, where its function remains poorly understood. Here, I demonstrate that SUMOylation (SUMO) of PTEN controls its nuclear localization. Consistent with its restricted cytoplasmic localization, a SUMO-deficient PTEN mutant is fully competent for regulating PI3K signaling. Upon exposure to genotoxic stress, SUMO-PTEN is rapidly excluded from the nucleus in an ATM-dependent manner, identifying a connection between these two major tumor suppressors. Further, ATM phosphorylated PTEN on threonine 398, and a PTEN mutant that cannot be phosphorylated at this position (PTEN T398A) resist nuclear exclusion following genotoxic stress. Judging by various readouts of the DNA damage response, cells lacking nuclear PTEN are hypersensitive to DNA damage and display impaired homologous recombination-mediated repair of double-strand DNA breaks. Moreover, unlike cells with Wt PTEN, PTEN-deficient cells are susceptible to killing by a combination of genotoxic stress and a small molecule inhibitor of PI3K both in vitro and in vivo. The synergistc effect of genotoxic stress and PI3K inhibition on PTEN-null cells is dependent on the simultaneous inhibition of both p110alpha and p110beta isoform. Further in vivo studies revealed that effective inhibition of PI3K pathway can be achieved with a discontinuous administration schedule in order to reduce the adverse effects associated with this treatment. My findings have considerable implications for individualizing therapy for patients with PTEN-deficient tumors. Advisors/Committee Members: Stambolic, Vuk, Medical Biophysics.

Subjects/Keywords: Cancer; DNA damage; PTEN; tumor suppressor; 0307

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APA (6^th Edition):

Bassi, C. (2015). Nuclear PTEN Controls DNA Repair and Sensitivity to Genotoxic Stress. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/69214

Chicago Manual of Style (16^th Edition):

Bassi, Christian. “Nuclear PTEN Controls DNA Repair and Sensitivity to Genotoxic Stress.” 2015. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/69214.

MLA Handbook (7^th Edition):

Bassi, Christian. “Nuclear PTEN Controls DNA Repair and Sensitivity to Genotoxic Stress.” 2015. Web. 23 Sep 2018.

Vancouver:

Bassi C. Nuclear PTEN Controls DNA Repair and Sensitivity to Genotoxic Stress. [Internet] [Doctoral dissertation]. University of Toronto; 2015. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/69214.

Council of Science Editors:

Bassi C. Nuclear PTEN Controls DNA Repair and Sensitivity to Genotoxic Stress. [Doctoral Dissertation]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/69214

University of Toronto

13. Nhan, Tam Quy. Drug Delivery to the Brain by Focused Ultrasound and Microbubble Mediated Blood-brain Barrier Disruption: Vascular-level Investigation using Two-photon Fluorescent Microscopy.

Degree: PhD, 2015, University of Toronto

URL: http://hdl.handle.net/1807/69459

► The use of focused ultrasound (FUS) in combination with microbubbles (MBs) to transiently and noninvasively disrupt the blood-brain barrier (BBB) has been an active research… (more)

▼ The use of focused ultrasound (FUS) in combination with microbubbles (MBs) to transiently and noninvasively disrupt the blood-brain barrier (BBB) has been an active research topic which could ultimately revolutionize the way drugs are delivered into the brain parenchyma for treatment of central nervous system (CNS) pathologies. Stemmed from its prospective clinical application, the overarching goal of this research is to explore the underlying physical mechanisms and fundamental biological effects via the use of two-photon fluorescence microscopy (2PFM). In addition, this research aims to draw the connection between the kinetics of blood-brain barrier disruption (BBBD) and the localized drug deposition in the treated brain. To provide a robust solution for dorsal approach of FUS exposure and in vivo 2PFM imaging of the cerebral microvasculature, a ring-shaped transducer has been designed and characterized. Two modes of vibration (thickness and height) were investigated for their effectiveness at inducing BBBD in a rat model. By operating the transducer in thickness mode, we induced BBBD at different acoustic pressure levels and delivered fluorescent dyes into the rat's blood circulatory system while capturing a series of 2PFM images. These microscopic data allowed for quantitative measurement of the enhanced permeability of blood vessels upon BBBD. The dependency of the vascular permeability on the substance size and the applied acoustic pressured was established. We identified two types of leakage kinetics - fast and slow - that exhibit distinctive permeability constants, temporal disruption onsets, and pertinent vessel diameter. To translate these preclinical findings into the clinical setting, we developed a mathematical framework that depicts the kinetics of BBBD and rendered the spatio-temporal distribution of the intended drug at a targeted brain region. Here, we considered Doxorubicin (Dox) as the drug of choice. The constructed model predicts Dox concentrations within the plasma, extracellular and intracellular compartments that are governed by various transport processes. By examining several clinical treatment parameters, our simulation outputs were validated against experimental findings in a rat model. Considering the flexibility of the FUS+MBs assisted BBBD technique, this simulation study can be adapted for other drugs to assist the treatment planning process for different CNS conditions. Advisors/Committee Members: Hynynen, Kullervo, Medical Biophysics.

Subjects/Keywords: Brain Diseases; Drug Delivery; Focused Ultrasound; Microbubble; Two-photon Fluorescent Microscopy; 0786

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APA (6^th Edition):

Nhan, T. Q. (2015). Drug Delivery to the Brain by Focused Ultrasound and Microbubble Mediated Blood-brain Barrier Disruption: Vascular-level Investigation using Two-photon Fluorescent Microscopy. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/69459

Chicago Manual of Style (16^th Edition):

Nhan, Tam Quy. “Drug Delivery to the Brain by Focused Ultrasound and Microbubble Mediated Blood-brain Barrier Disruption: Vascular-level Investigation using Two-photon Fluorescent Microscopy.” 2015. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/69459.

MLA Handbook (7^th Edition):

Nhan, Tam Quy. “Drug Delivery to the Brain by Focused Ultrasound and Microbubble Mediated Blood-brain Barrier Disruption: Vascular-level Investigation using Two-photon Fluorescent Microscopy.” 2015. Web. 23 Sep 2018.

Vancouver:

Nhan TQ. Drug Delivery to the Brain by Focused Ultrasound and Microbubble Mediated Blood-brain Barrier Disruption: Vascular-level Investigation using Two-photon Fluorescent Microscopy. [Internet] [Doctoral dissertation]. University of Toronto; 2015. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/69459.

Council of Science Editors:

Nhan TQ. Drug Delivery to the Brain by Focused Ultrasound and Microbubble Mediated Blood-brain Barrier Disruption: Vascular-level Investigation using Two-photon Fluorescent Microscopy. [Doctoral Dissertation]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/69459

University of Toronto

14. Sepiashvili, Lusia. From Integrative Omics to Improved Molecular Classification of Head and Neck Cancers.

Degree: PhD, 2015, University of Toronto

URL: http://hdl.handle.net/1807/69538

► Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous disease originating in multiple subsites. Over 60% of HNSCCs are diagnosed at late stages… (more)

▼ Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous disease originating in multiple subsites. Over 60% of HNSCCs are diagnosed at late stages and about 40% recur. Survival and quality of life for these patients is expected to improve upon identification of novel biomarkers, development of new therapies, and obtaining a better understanding of the molecular progression of the disease. Recently, mass spectrometry-based shotgun proteomics technologies have emerged as powerful tools for in-depth proteome characterization, thereby enabling identification of cancer-related proteoforms and surging biomarker discovery efforts. I applied shotgun proteomics towards the identification of novel HNSCC biomarkers and obtaining biologic insight into oropharyngeal carcinoma (OPC) progression. In order to identify secreted biomarker candidates, proteomic analysis of HNSCC cell line secretomes integrated with global gene expression was followed by data mining utilizing published patient tumor expression data and protein annotations. Through subsequent verifications involving IHC and ELISA against patient tissue and sera, respectively, I identified two potential biomarkers (IGFBP7 and PLAU). Their levels were significantly elevated in HNSCC patient sera vs. sera from healthy volunteers. Further evaluation of the clinical utility of these markers is warranted. To gain biologic insight into OPC subtypes, global proteomic analysis of archival patient biopsies with and without HPV was conducted. As a result, 2,633 protein groups were identified, 34 of which were differentially abundant and therefore, may play a role in the distinct clinical behavior of OPC subtypes. Genomic alterations associated with these proteins were determined using The Cancer Genome Atlas; importantly, they were not always predictive of protein abundance. Among the 34 proteins, cortactin is known to mediate radioresistance via the β1-integrin/FAK/cortactin/JNK1/AP-1 pathway. Downstream AP-1 target gene expression analysis revealed HPV-dependent regulation of this pathway, pointing to a putative mechanism for increased radioresistance in HPV-negative vs. HPV-positive OPC. The contribution of this mechanism to therapeutic response requires further evaluation. Advisors/Committee Members: Kislinger, Thomas, Medical Biophysics.

Subjects/Keywords: Biomarkers; Head and neck cancer; Human papillomavirus; Mass spectrometry; Proteomics; 0992

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Sepiashvili, L. (2015). From Integrative Omics to Improved Molecular Classification of Head and Neck Cancers. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/69538

Chicago Manual of Style (16^th Edition):

Sepiashvili, Lusia. “From Integrative Omics to Improved Molecular Classification of Head and Neck Cancers.” 2015. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/69538.

MLA Handbook (7^th Edition):

Sepiashvili, Lusia. “From Integrative Omics to Improved Molecular Classification of Head and Neck Cancers.” 2015. Web. 23 Sep 2018.

Vancouver:

Sepiashvili L. From Integrative Omics to Improved Molecular Classification of Head and Neck Cancers. [Internet] [Doctoral dissertation]. University of Toronto; 2015. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/69538.

Council of Science Editors:

Sepiashvili L. From Integrative Omics to Improved Molecular Classification of Head and Neck Cancers. [Doctoral Dissertation]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/69538

University of Toronto

15. Pajek, Daniel. The Application of Transcranial High Intensity Focused Ultrasound to Clot Lysis.

Degree: PhD, 2014, University of Toronto

URL: http://hdl.handle.net/1807/70427

► The primary method for treating acute ischemic stroke - the administration of thrombolytics - is associated with a relatively low efficacy and a large number… (more)

▼ The primary method for treating acute ischemic stroke - the administration of thrombolytics - is associated with a relatively low efficacy and a large number of patients are contraindicated against the use of the drug. This research was motivated by the need to develop a new treatment modality for acute ischemic stroke that is localized, does not require the use of thrombolytics, and is capable of quickly recanalizing an occluded vessel. A simulation model was developed to investigate the feasibility of employing high intensity focused ultrasound to induce non-invasive clot lysis through the human skull at frequencies capable of producing a focus small enough to fit within the major vessels of the brain. The results suggest that an array with approximately 16,000 elements would be required to electronically treat all but the most distal sonication targets. The element numbers required for this array are over an order of magnitude higher than what currently exists today and so this study motivates the need for further research into reducing the acoustic pressures required for clot lysis and optimizing array design. The ability of intravascular droplets to lower the acoustic power required for high intensity clot lysis was explored. The application of droplet-enhanced clot lysis was investigated in an embolic rabbit model. Recanalization was demonstrated in 73% of cases at approximately 24% of the acoustic power required without droplets. The results demonstrated that red blood cell extravasations were confined to the acoustic focus, suggesting that a transducer capable of placing the entire focus within a vessel would be able to confine the bioeffect within the same volume. Transcranial focused ultrasound sparse arrays at relatively high frequencies that could produce a tighter focus than the prototypes in existence today were investigated through simulations. The results showed that a hemispherical array with a 10% population of 3 mm elements - 1588 elements in total - would be capable of steering 4 cm in each direction with acceptable grating lobes. These sparse arrays could potentially be well-suited to lower power applications, such as low intensity sonothrombolysis with thrombolytic agents or blood-brain barrier disruption. Advisors/Committee Members: Hynynen, Kullervo, Medical Biophysics.

Subjects/Keywords: Cavitation; Focused Ultrasound; HIFU; Stroke; Therapy; 0574

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pajek, D. (2014). The Application of Transcranial High Intensity Focused Ultrasound to Clot Lysis. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/70427

Chicago Manual of Style (16^th Edition):

Pajek, Daniel. “The Application of Transcranial High Intensity Focused Ultrasound to Clot Lysis.” 2014. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/70427.

MLA Handbook (7^th Edition):

Pajek, Daniel. “The Application of Transcranial High Intensity Focused Ultrasound to Clot Lysis.” 2014. Web. 23 Sep 2018.

Vancouver:

Pajek D. The Application of Transcranial High Intensity Focused Ultrasound to Clot Lysis. [Internet] [Doctoral dissertation]. University of Toronto; 2014. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/70427.

Council of Science Editors:

Pajek D. The Application of Transcranial High Intensity Focused Ultrasound to Clot Lysis. [Doctoral Dissertation]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/70427

University of Toronto

16. Izrailit, Julia. Notch Regulation in Breast Cancer.

Degree: PhD, 2015, University of Toronto

URL: http://hdl.handle.net/1807/70834

► Breast cancer affects thousands of Canadian women every year, and ranks as the second most common cause of cancer death. Our group has previously shown… (more)

▼ Breast cancer affects thousands of Canadian women every year, and ranks as the second most common cause of cancer death. Our group has previously shown that patients whose breast cancers abnormally express genes of the Notch family have poor survival rates. In addition, abnormalities in Notch are most common in the aggressive triple negative (TN) subtype of breast cancer for which there is currently no effective treatment. In order to understand what drives Notch activation in TN breast cancer cells, a novel Notch reporter system was developed and optimized for high throughput screens (HTS). Using the Notch reporter system, a chemical kinase inhibitor screen identified the MAPK-ERK signaling pathway as a predominant regulator of Notch ligand (JAG1) expression and Notch activation. Consistent with this, a kinome siRNA screen identified the pseudokinase Tribbles homolog 3 (TRB3), a known regulator of MAPK-ERK, among the most significant hits. We demonstrated that TRB3 is a master regulator of Notch through the MAPK-ERK and TGFβ pathways. Supporting our findings, in vitro and in vivo studies showed that TRB3 inhibition decreases breast cancer cell proliferation in a JAG1-dependant fashion and reduces the growth of MDA MB231 TN breast cancer xenografts. To understand how TRB3 is regulated, a proteomic screen of TRB3-associated cellular complexes was performed and identified the deubiquitinase USP9x as a novel interacting protein for TRB3. We showed that TRB3 serves as a scaffold for USP9x that regulates JAG1 function through two mechanisms: (1) through TRB3 deubiquitination and stabilization and (2) through deubiquitination and activation of Mind Bomb 1 (MIB1), an E3 ligase required for JAG1 activity. We also demonstrated that USP9x is required for TRB3 and JAG1 up-regulation in response to cellular stress. Taken together, the work presented in this thesis, contributes to a better understanding of Notch regulation in breast cancer and identifies novel pathways that may be therapeutically targeted in TN disease. Advisors/Committee Members: Reedijk, Michael, Medical Biophysics.

Subjects/Keywords: Breast Cancer; Cellular stress; MAPK; Notch; TRB3; USP9x; 0307

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Izrailit, J. (2015). Notch Regulation in Breast Cancer. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/70834

Chicago Manual of Style (16^th Edition):

Izrailit, Julia. “Notch Regulation in Breast Cancer.” 2015. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/70834.

MLA Handbook (7^th Edition):

Izrailit, Julia. “Notch Regulation in Breast Cancer.” 2015. Web. 23 Sep 2018.

Vancouver:

Izrailit J. Notch Regulation in Breast Cancer. [Internet] [Doctoral dissertation]. University of Toronto; 2015. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/70834.

Council of Science Editors:

Izrailit J. Notch Regulation in Breast Cancer. [Doctoral Dissertation]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/70834

University of Toronto

17. Mohammed, Arshiya Fatima. Exploring the Therapeutic Potential of Pseudomonas aeruginosa Exotoxin A and Identifying Eukaryotic Factors Involved in its Intracellular Routing Pathway.

Degree: PhD, 2015, University of Toronto

URL: http://hdl.handle.net/1807/71556

► Pseudomonas aeruginosa Exotoxin A (ETA) is a 66.6 kDa bacterial toxin comprised of a single polypeptide chain that folds into three distinct structural and functional… (more)

▼ Pseudomonas aeruginosa Exotoxin A (ETA) is a 66.6 kDa bacterial toxin comprised of a single polypeptide chain that folds into three distinct structural and functional domains. Domain I serves as a ligand for binding susceptible eukaryotic cells. Domain II facilitates the transport of ETA to the cytosol. Domain III contains the active site by which ETA inhibits protein synthesis and initiates cell death. Although extensive research has gone into characterizing each domain and manipulating ETA to create targeted therapies, the intracellular routing of ETA and the role of domain II in this pathway remains uncertain. We hypothesized that ETA domain II interacts with intracellular components in the human cell to facilitate transport of the toxin from the endosome to the cytosol. This thesis investigates the use of ETA domain II as a strategy to increase the intracellular delivery of protein therapeutics, and explores cellular components that may be involved in the routing pathway of ETA in human cells. The first study demonstrated that fusing ETA domain II to cell penetrating peptides (CPPs) and their cargos enhanced the delivery of these recombinant proteins to the cytosol through retrograde transport. The second study identified 33 putative eukaryotic genes required for ETA cytotoxicity using a high-throughput lentiviral screen. Additionally, a number of proteins involved in endosome ←→ Golgi apparatus ←→ endoplasmic reticulum ←→ cytosol trafficking were identified from human cell lysate pull-down assays using ETA domain II and full-length ETA, supporting the retrograde transport hypothesis. Overall, the results of these studies confirm that ETA follows a retrograde transport pathway in human cells and that domain II plays a role in this routing. ETA can be manipulated in creative ways for both investigative and therapeutic purposes and, as such, a further understanding of ETA and other such toxins is beneficial for converting them into useful tools. Advisors/Committee Members: Gariépy, Jean, Medical Biophysics.

Subjects/Keywords: 0306

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Mohammed, A. F. (2015). Exploring the Therapeutic Potential of Pseudomonas aeruginosa Exotoxin A and Identifying Eukaryotic Factors Involved in its Intracellular Routing Pathway. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/71556

Chicago Manual of Style (16^th Edition):

Mohammed, Arshiya Fatima. “Exploring the Therapeutic Potential of Pseudomonas aeruginosa Exotoxin A and Identifying Eukaryotic Factors Involved in its Intracellular Routing Pathway.” 2015. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/71556.

MLA Handbook (7^th Edition):

Mohammed, Arshiya Fatima. “Exploring the Therapeutic Potential of Pseudomonas aeruginosa Exotoxin A and Identifying Eukaryotic Factors Involved in its Intracellular Routing Pathway.” 2015. Web. 23 Sep 2018.

Vancouver:

Mohammed AF. Exploring the Therapeutic Potential of Pseudomonas aeruginosa Exotoxin A and Identifying Eukaryotic Factors Involved in its Intracellular Routing Pathway. [Internet] [Doctoral dissertation]. University of Toronto; 2015. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/71556.

Council of Science Editors:

Mohammed AF. Exploring the Therapeutic Potential of Pseudomonas aeruginosa Exotoxin A and Identifying Eukaryotic Factors Involved in its Intracellular Routing Pathway. [Doctoral Dissertation]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/71556

University of Toronto

18. Merino, Diana M. Choroid Plexus Tumours: Elucidating the Genomic Complexity of Rare Pediatric Brain Tumours.

Degree: PhD, 2015, University of Toronto

URL: http://hdl.handle.net/1807/71585

► Choroid plexus tumours (CPTs) are rare intraventricular neoplasms, most commonly found in children, with variable clinical presentation and patient outcome. CPT biology is poorly understood… (more)

Subjects/Keywords: brain tumours; cancer genomics; choroid plexus tumours; pediatric cancer; 0369

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Merino, D. M. (2015). Choroid Plexus Tumours: Elucidating the Genomic Complexity of Rare Pediatric Brain Tumours. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/71585

Chicago Manual of Style (16^th Edition):

Merino, Diana M. “Choroid Plexus Tumours: Elucidating the Genomic Complexity of Rare Pediatric Brain Tumours.” 2015. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/71585.

MLA Handbook (7^th Edition):

Merino, Diana M. “Choroid Plexus Tumours: Elucidating the Genomic Complexity of Rare Pediatric Brain Tumours.” 2015. Web. 23 Sep 2018.

Vancouver:

Merino DM. Choroid Plexus Tumours: Elucidating the Genomic Complexity of Rare Pediatric Brain Tumours. [Internet] [Doctoral dissertation]. University of Toronto; 2015. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/71585.

Council of Science Editors:

Merino DM. Choroid Plexus Tumours: Elucidating the Genomic Complexity of Rare Pediatric Brain Tumours. [Doctoral Dissertation]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/71585

University of Toronto

19. Mazhab-Jafari, Mohammad T. Structure, Catalytic Mechanism, and Membrane Interaction of the mTOR Activator Rheb.

Degree: PhD, 2014, University of Toronto

URL: http://hdl.handle.net/1807/72603

►

The activator of mammalian target of rapamycin complex 1 (mTORC1), Ras homolog enriched in brain (Rheb), is a membrane-associated protein belonging to the Ras subfamily… (more)

▼

The activator of mammalian target of rapamycin complex 1 (mTORC1), Ras homolog enriched in brain (Rheb), is a membrane-associated protein belonging to the Ras subfamily of small GTPases. Rheb's slow GTPase activity is stimulated by the GTPase activating protein (GAP) domain of tuberous sclerosis complex 1 and 2 (TSC1/2). Rheb hyperactivation, through its overexpression or loss of TSC1/2 GAP function, results in hyperactivated mTORC1 signaling culminating in tumourigenesis. The molecular details of Rheb GTP hydrolysis and the effect of membrane association on Rheb structure, dynamics and its GTPase function are currently not fully understood. The studies presented in this thesis focus on two key determinants of Rheb function i) the mechanism of Rheb GTP hydrolysis and ii) the structural and functional consequence of Rheb-bilayer membrane interaction. Through studies of fluorescent nucleotides, we revealed that the conserved G2-box residue Tyr35 auto-inhibits GTP hydrolysis in Rheb. We demonstrated that a non-canonical catalytic residue, Asp65, in the switch II region of Rheb, contributed more to the GTP hydrolysis rate than Gln64, which corresponds to the canonical Ras Gln61. This non-canonical auto-inhibited mechanism of GTP hydrolysis was required for optimal mTORC1 regulation. These structural insights were then used to guide the design of novel gain- and loss-of function mutants by substitutions of the ultra-conserved G3-box Gly63 of Rheb. Finally, using solution NMR spectroscopy, we monitored the Rheb GTPase cycle and characterized its nucleotide-dependent membrane orientations on nanodisc-based phospholipid bilayers. Rheb was shown to sample two orientations in which its C-terminal helix was semi-perpendicular or semi-parallel with respect to the bilayer plane. The semi-parallel orientation, where switch II residues critical for mTORC1 communication are accessible, was favored in the GTP bound conformation, suggesting that membrane-tethering modulates Rheb function. These structural insights into the catalytic machinery of Rheb and its membrane interface suggest new approaches to modulate these key determinants of Rheb function through small molecules towards development of therapeutic avenues for Rheb-mediated pathogenesis such as tuberous sclerosis or cancer.

2016-06-16 00:00:00

Advisors/Committee Members: Ikura, Mitsuhiko, Medical Biophysics.

Subjects/Keywords: Crystallography; GTPase; mTOR; Nanodisc; NMR; Rheb; 0786

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APA (6^th Edition):

Mazhab-Jafari, M. T. (2014). Structure, Catalytic Mechanism, and Membrane Interaction of the mTOR Activator Rheb. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/72603

Chicago Manual of Style (16^th Edition):

Mazhab-Jafari, Mohammad T. “Structure, Catalytic Mechanism, and Membrane Interaction of the mTOR Activator Rheb.” 2014. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/72603.

MLA Handbook (7^th Edition):

Mazhab-Jafari, Mohammad T. “Structure, Catalytic Mechanism, and Membrane Interaction of the mTOR Activator Rheb.” 2014. Web. 23 Sep 2018.

Vancouver:

Mazhab-Jafari MT. Structure, Catalytic Mechanism, and Membrane Interaction of the mTOR Activator Rheb. [Internet] [Doctoral dissertation]. University of Toronto; 2014. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/72603.

Council of Science Editors:

Mazhab-Jafari MT. Structure, Catalytic Mechanism, and Membrane Interaction of the mTOR Activator Rheb. [Doctoral Dissertation]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/72603

University of Toronto

20. Anderson, Gregory Arthur. Mammalian Cardiovascular Patterning as Determined by Hemodynamic Forces and Blood Vessel Genetics.

Degree: PhD, 2016, University of Toronto

URL: http://hdl.handle.net/1807/72941

► Cardiovascular development is a process that involves the timing of multiple molecular events, and numerous subtle three-dimensional conformational changes. Traditional developmental biology techniques have provided… (more)

▼ Cardiovascular development is a process that involves the timing of multiple molecular events, and numerous subtle three-dimensional conformational changes. Traditional developmental biology techniques have provided large quantities of information as to how these complex organ systems develop. However, the major drawback of the majority of current developmental biological imaging is that they are two-dimensional in nature. It is now well recognized that circulation of blood is required for normal patterning and remodeling of blood vessels. Normal blood vessel formation is dependent upon a complex network of signaling pathways, and genetic mutations in these pathways leads to impaired vascular development, heart failure, and lethality. As such, it is not surprising that mutant mice with aberrant cardiovascular patterning are so common, since normal development requires proper coordination between three systems: the heart, the blood, and the vasculature. This thesis describes the implementation of a three-dimensional imaging technique, optical projection tomography (OPT), in conjunction with a computer-based registration algorithm to statistically analyze developmental differences in groups of wild-type mouse embryos. Embryos that differ by only a few hoursâ gestational time are shown to have developmental differences in blood vessel formation and heart development progression that can be discerned. This thesis describes how we analyzed mouse models of cardiovascular perturbation by OPT to detect morphological differences in embryonic development in both qualitative and quantitative ways. Both a blood vessel specific mutation and a cardiac specific mutation were analyzed, providing evidence that developmental defects of these types can be quantified. Finally, we describe the implementation of OPT imaging to identify statistically significant phenotypes from three different mouse models of cardiovascular perturbation across a range of developmental time points. Image registration methods, combined with intensity- and deformation-based analyses are described and utilized to fully characterize myosin light chain 2a (Mlc2a), delta-like ligand 4 (Dll4), and Endoglin (Eng) mutant mouse embryos. We show that Eng mutant embryos are statistically similar to the Mlc2a phenotype, confirming that these mouse mutants suffer from a primary cardiac developmental defect. Thus, a loss of hemodynamic force caused by defective pumping of the heart is the primary developmental defect affecting these mice. Advisors/Committee Members: Henkelman, Mark, Medical Biophysics.

Subjects/Keywords: Cardiovascular Development; Developmental Biology; Dll4; Endoglin; Mlc2a; Optical Projection Tomography; 0786

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APA (6^th Edition):

Anderson, G. A. (2016). Mammalian Cardiovascular Patterning as Determined by Hemodynamic Forces and Blood Vessel Genetics. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/72941

Chicago Manual of Style (16^th Edition):

Anderson, Gregory Arthur. “Mammalian Cardiovascular Patterning as Determined by Hemodynamic Forces and Blood Vessel Genetics.” 2016. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/72941.

MLA Handbook (7^th Edition):

Anderson, Gregory Arthur. “Mammalian Cardiovascular Patterning as Determined by Hemodynamic Forces and Blood Vessel Genetics.” 2016. Web. 23 Sep 2018.

Vancouver:

Anderson GA. Mammalian Cardiovascular Patterning as Determined by Hemodynamic Forces and Blood Vessel Genetics. [Internet] [Doctoral dissertation]. University of Toronto; 2016. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/72941.

Council of Science Editors:

Anderson GA. Mammalian Cardiovascular Patterning as Determined by Hemodynamic Forces and Blood Vessel Genetics. [Doctoral Dissertation]. University of Toronto; 2016. Available from: http://hdl.handle.net/1807/72941

University of Toronto

21. Alkins, Ryan. Selective Neuro-oncological Therapies Using Focused Ultrasound to Disrupt the Blood-brain Barrier.

Degree: PhD, 2015, University of Toronto

URL: http://hdl.handle.net/1807/73611

►

Ultrasound in clinical medicine is most commonly associated with imaging, but can be harnessed to yield an array of bioeffects. Of particular interest in neuro-oncology… (more)

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Ultrasound in clinical medicine is most commonly associated with imaging, but can be harnessed to yield an array of bioeffects. Of particular interest in neuro-oncology is the interaction of ultrasound with pre-formed ultrasound contrast agents, the combination of which can be used to increase the permeability of the cerebrovasculature in a reversible manner [blood-brain barrier (BBB) disruption]. Many promising therapeutic agents have in vitro efficacy but fail in vivo due to their inability to accumulate to any significant degree in the central nervous system (CNS). While primary brain tumours alone do not impose an enormous healthcare burden compared with many other cancers, as many as 40% of all cancer patients will eventually develop brain metastasis, making the potential impact of drug delivery with ultrasound significantly larger. We focused particularly on therapeutic agents that, once in the brain, selectively targeted malignant cells, as existing therapies cause much morbidity in their wake secondary to collateral neuronal injury. We investigated the effects of BBB disruption on boron neutron capture therapy with the delivery agent boronophenylalanine. BBB disruption increased the absolute boron concentration, important for tumour killing, by almost 150%, and improved the ratio between normal brain and tumour, minimizing radiation to healthy cells. It also increased the uptake in infiltrating cells, particularly important for tumours like glioblastoma. We then demonstrated that an even more selective agent - engineered, targeted immune cells - could be delivered to a brain tumour in a viable state. Furthermore, we demonstrated improved survival in a brain metastasis model of HER2 amplified breast cancer. Both of these targeted therapies have been investigated in early clinical trials, and with the mounting evidence for the safety of BBB disruption with ultrasound, there exists real potential to translate these promising therapies into the clinical realm and offer new treatments to patients with little hope for a cure.

2016-09-22 00:00:00

Advisors/Committee Members: Hynynen, Kullervo, Medical Biophysics.

Subjects/Keywords: Blood-brain barrier disruption; Brain tumour therapy; HIFU; Image-guided therapy; MRI-guided focused ultrasound; Therapeutic ultrasound; 0564

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APA (6^th Edition):

Alkins, R. (2015). Selective Neuro-oncological Therapies Using Focused Ultrasound to Disrupt the Blood-brain Barrier. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/73611

Chicago Manual of Style (16^th Edition):

Alkins, Ryan. “Selective Neuro-oncological Therapies Using Focused Ultrasound to Disrupt the Blood-brain Barrier.” 2015. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/73611.

MLA Handbook (7^th Edition):

Alkins, Ryan. “Selective Neuro-oncological Therapies Using Focused Ultrasound to Disrupt the Blood-brain Barrier.” 2015. Web. 23 Sep 2018.

Vancouver:

Alkins R. Selective Neuro-oncological Therapies Using Focused Ultrasound to Disrupt the Blood-brain Barrier. [Internet] [Doctoral dissertation]. University of Toronto; 2015. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/73611.

Council of Science Editors:

Alkins R. Selective Neuro-oncological Therapies Using Focused Ultrasound to Disrupt the Blood-brain Barrier. [Doctoral Dissertation]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/73611

University of Toronto

22. Huynh, Elizabeth. Porphyrin Microparticles for Biological and Biomedical Applications.

Degree: PhD, 2015, University of Toronto

URL: http://hdl.handle.net/1807/73613

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Lipids are one of the critical building blocks of life, forming the plasma membrane of cells. In addition, porphyrins also play an equally important role… (more)

Subjects/Keywords: 0574

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APA (6^th Edition):

Huynh, E. (2015). Porphyrin Microparticles for Biological and Biomedical Applications. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/73613

Chicago Manual of Style (16^th Edition):

Huynh, Elizabeth. “Porphyrin Microparticles for Biological and Biomedical Applications.” 2015. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/73613.

MLA Handbook (7^th Edition):

Huynh, Elizabeth. “Porphyrin Microparticles for Biological and Biomedical Applications.” 2015. Web. 23 Sep 2018.

Vancouver:

Huynh E. Porphyrin Microparticles for Biological and Biomedical Applications. [Internet] [Doctoral dissertation]. University of Toronto; 2015. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/73613.

Council of Science Editors:

Huynh E. Porphyrin Microparticles for Biological and Biomedical Applications. [Doctoral Dissertation]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/73613

University of Toronto

23. Witty, Alec Drake. The Derivation of the Myocardial, Epicardial and Endocardial Lineages from Human Pluripotent Stem Cells.

Degree: PhD, 2014, University of Toronto

URL: http://hdl.handle.net/1807/73785

► The adult heart is composed of cells from three major lineages: the myocardium, the epicardium and the endocardium. The myocardium is the working muscle and… (more)

Subjects/Keywords: cardiomyocytes; endocardium; epicardium; Pluripotent Stem Cells; 0379

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APA (6^th Edition):

Witty, A. D. (2014). The Derivation of the Myocardial, Epicardial and Endocardial Lineages from Human Pluripotent Stem Cells. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/73785

Chicago Manual of Style (16^th Edition):

Witty, Alec Drake. “The Derivation of the Myocardial, Epicardial and Endocardial Lineages from Human Pluripotent Stem Cells.” 2014. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/73785.

MLA Handbook (7^th Edition):

Witty, Alec Drake. “The Derivation of the Myocardial, Epicardial and Endocardial Lineages from Human Pluripotent Stem Cells.” 2014. Web. 23 Sep 2018.

Vancouver:

Witty AD. The Derivation of the Myocardial, Epicardial and Endocardial Lineages from Human Pluripotent Stem Cells. [Internet] [Doctoral dissertation]. University of Toronto; 2014. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/73785.

Council of Science Editors:

Witty AD. The Derivation of the Myocardial, Epicardial and Endocardial Lineages from Human Pluripotent Stem Cells. [Doctoral Dissertation]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/73785

University of Toronto

24. Jackson, Hartland Warren. TIMPs in Mammary Stem Cell Homeostasis and Breast Cancer Progression.

Degree: PhD, 2014, University of Toronto

URL: http://hdl.handle.net/1807/74482

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The mammary gland repeatedly undergoes reorganization and cellular turnover in the adult female. Ductal invasion and branching morphogenesis during puberty, cyclical expansion during reproductive cycles,… (more)

Subjects/Keywords: aging; breast cancer; mammary gland; mammary stem cell; stem cell; TIMP; 0306

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APA (6^th Edition):

Jackson, H. W. (2014). TIMPs in Mammary Stem Cell Homeostasis and Breast Cancer Progression. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/74482

Chicago Manual of Style (16^th Edition):

Jackson, Hartland Warren. “TIMPs in Mammary Stem Cell Homeostasis and Breast Cancer Progression.” 2014. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/74482.

MLA Handbook (7^th Edition):

Jackson, Hartland Warren. “TIMPs in Mammary Stem Cell Homeostasis and Breast Cancer Progression.” 2014. Web. 23 Sep 2018.

Vancouver:

Jackson HW. TIMPs in Mammary Stem Cell Homeostasis and Breast Cancer Progression. [Internet] [Doctoral dissertation]. University of Toronto; 2014. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/74482.

Council of Science Editors:

Jackson HW. TIMPs in Mammary Stem Cell Homeostasis and Breast Cancer Progression. [Doctoral Dissertation]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/74482

University of Toronto

25. Alali, Sanaz. Polarized Light Imaging for Assessment of Anisotropy in Turbid Media: Instrumentation and Application in Urology.

Degree: PhD, 2014, University of Toronto

URL: http://hdl.handle.net/1807/74487

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Assessment of anisotropy has many applications in tissue engineering and early detection of disease such as cancer or stroke. One of the emerging optical technologies… (more)

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Assessment of anisotropy has many applications in tissue engineering and early detection of disease such as cancer or stroke. One of the emerging optical technologies for quantifying anisotropy in biological tissues is polarized light imaging. In this technique, the full Mueller matrix of the tissue is measured and then decomposed to yield optical retardance, which is proportional to the tissue anisotropy. The theory of polarized light imaging, its biomedical application and instrumentation are the subject of this thesis. To retrieve more information from the Mueller matrix, a quantitative analysis of generic turbid media's Mueller matrices beyond their decompositions was proposed. Two new metrics based on Mueller matrix were established in this thesis: 1) Tissue depolarization, calculated from the Mueller matrix, can be used to estimate its optical properties, and 2) Symmetry of the off-diagonal elements of a turbid medium's Mueller matrix can be used to detect the axial heterogeneity of anisotropy. Polarized light imaging, followed by Mueller matrix decomposition, was then successfully applied to locate the structural disorders induced by bladder outlet obstruction disease, in ex vivo functioning rat bladders. Motivated by the result of this study and to enable in vivo polarized light measurements of the bladder, a novel thin fiber based polarimetric probe which can measure the full Mueller matrix of the turbid media was suggested. Finally, to enhance the speed of the ex vivo examinations of biological tissues and avoid artifacts, a new rapid benchtop polarized light imaging system based on photoelastic modulators (PEM) and a charge-coupled device (CCD) was proposed and implemented. The demonstrated scheme does not involve using mechanically moving components and thus reduces systematic errors. This imaging system proved to be the fastest high resolution polarimetric characterization tool for imaging turbid media to date.

2016-11-16 00:00:00

Advisors/Committee Members: Vitkin, Alex, Medical Biophysics.

Subjects/Keywords: anisotropy; bladder; imaging; polarization; turbid media; 0574

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Alali, S. (2014). Polarized Light Imaging for Assessment of Anisotropy in Turbid Media: Instrumentation and Application in Urology. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/74487

Chicago Manual of Style (16^th Edition):

Alali, Sanaz. “Polarized Light Imaging for Assessment of Anisotropy in Turbid Media: Instrumentation and Application in Urology.” 2014. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/74487.

MLA Handbook (7^th Edition):

Alali, Sanaz. “Polarized Light Imaging for Assessment of Anisotropy in Turbid Media: Instrumentation and Application in Urology.” 2014. Web. 23 Sep 2018.

Vancouver:

Alali S. Polarized Light Imaging for Assessment of Anisotropy in Turbid Media: Instrumentation and Application in Urology. [Internet] [Doctoral dissertation]. University of Toronto; 2014. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/74487.

Council of Science Editors:

Alali S. Polarized Light Imaging for Assessment of Anisotropy in Turbid Media: Instrumentation and Application in Urology. [Doctoral Dissertation]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/74487

University of Toronto

26. Aiken, Alison. The Fundamental Roles of the Tissue Inhibitor of Metalloproteinase Family in Mammalian Biology.

Degree: PhD, 2014, University of Toronto

URL: http://hdl.handle.net/1807/74489

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The metalloproteinases are a family of extracellular proteases responsible for degrading components of the extracellular matrix as well as shedding growth factors, cytokines and their… (more)

Subjects/Keywords: chondrocyte; CXCL12; IHH; metalloproteinase; skeleton; TIMP; 0307

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APA (6^th Edition):

Aiken, A. (2014). The Fundamental Roles of the Tissue Inhibitor of Metalloproteinase Family in Mammalian Biology. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/74489

Chicago Manual of Style (16^th Edition):

Aiken, Alison. “The Fundamental Roles of the Tissue Inhibitor of Metalloproteinase Family in Mammalian Biology.” 2014. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/74489.

MLA Handbook (7^th Edition):

Aiken, Alison. “The Fundamental Roles of the Tissue Inhibitor of Metalloproteinase Family in Mammalian Biology.” 2014. Web. 23 Sep 2018.

Vancouver:

Aiken A. The Fundamental Roles of the Tissue Inhibitor of Metalloproteinase Family in Mammalian Biology. [Internet] [Doctoral dissertation]. University of Toronto; 2014. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/74489.

Council of Science Editors:

Aiken A. The Fundamental Roles of the Tissue Inhibitor of Metalloproteinase Family in Mammalian Biology. [Doctoral Dissertation]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/74489

University of Toronto

27. Kim, Yunee. Proteomic Identification and Systematic Verification of Biomarkers for Aggressive Prostate Cancer.

Degree: PhD, 2015, University of Toronto

URL: http://hdl.handle.net/1807/75684

►

Despite prostate cancer’s status as the most common cancer to affect men in the Western world, only an estimated 20% of men will die from… (more)

▼

Despite prostate cancer’s status as the most common cancer to affect men in the Western world, only an estimated 20% of men will die from it. Due to the lack of effective means of prognostication, many men are unnecessarily biopsied and treated. The early and non-invasive identification of lethal disease would have a profound impact on the current practice of prostate cancer management. To this end, the work presented in this thesis describes efforts to characterize proteins in a prostatic fluid known as expressed prostatic secretions (EPS), and to delineate factors in this fluid that demonstrate a high potential as prognostic biomarkers. Using different mass spectrometry-based platforms, I present both a global view of the EPS proteome, as well as targeted, quantitative measures of promising biomarker candidates in this fluid. In order to generate an archive of soluble and secreted factors present in the proteome of EPS, I used shotgun proteomics to analyze direct-EPS and EPS-urine. This led to the identification of over 2000 proteins that comprise the EPS proteome. The data was integrated with other publicly accessible information, such as gene expression profiles and immunohistochemistry images, to characterize this proteome. Furthermore, a collection of prostate-enriched proteins was identified by comparing the proteomes of EPS-urine and urine, demonstrating the unique protein profile of EPS. Next, comparative proteomic profiling of direct-EPS from organ confined and extracapsular tumors produced a long list of potential biomarker candidates. A targeted assay was systematically developed in order to quantitatively assess the performance of the most promising candidates in cohorts of EPS-urines from a heterogeneous population of prostate cancer patients and controls. Utilizing the assay, a number of candidates were verified to be putative biomarkers for prostate cancer diagnosis and prognosis. This information needs to be further validated and holds promise for improved prostate cancer management.

2017-02-12 00:00:00

Advisors/Committee Members: Kislinger, Thomas, Medical Biophysics.

Subjects/Keywords: Biomarker; Mass spectrometry; Prostate cancer; Proteomics; Translational research; 0564

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APA (6^th Edition):

Kim, Y. (2015). Proteomic Identification and Systematic Verification of Biomarkers for Aggressive Prostate Cancer. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/75684

Chicago Manual of Style (16^th Edition):

Kim, Yunee. “Proteomic Identification and Systematic Verification of Biomarkers for Aggressive Prostate Cancer.” 2015. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/75684.

MLA Handbook (7^th Edition):

Kim, Yunee. “Proteomic Identification and Systematic Verification of Biomarkers for Aggressive Prostate Cancer.” 2015. Web. 23 Sep 2018.

Vancouver:

Kim Y. Proteomic Identification and Systematic Verification of Biomarkers for Aggressive Prostate Cancer. [Internet] [Doctoral dissertation]. University of Toronto; 2015. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/75684.

Council of Science Editors:

Kim Y. Proteomic Identification and Systematic Verification of Biomarkers for Aggressive Prostate Cancer. [Doctoral Dissertation]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/75684

University of Toronto

28. Kim, Bo Ram. Investigation of the Role of Chromosome 3q26-28 Amplification in Lung Squamous Cell Carcinoma Pathogenesis.

Degree: PhD, 2016, University of Toronto

URL: http://hdl.handle.net/1807/76494

► Lung cancer is the leading cause of cancer mortality with squamous cell carcinoma (SQCC) being the second most common form. Lung SQCCs likely originate from… (more)

Subjects/Keywords: 0379

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APA (6^th Edition):

Kim, B. R. (2016). Investigation of the Role of Chromosome 3q26-28 Amplification in Lung Squamous Cell Carcinoma Pathogenesis. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/76494

Chicago Manual of Style (16^th Edition):

Kim, Bo Ram. “Investigation of the Role of Chromosome 3q26-28 Amplification in Lung Squamous Cell Carcinoma Pathogenesis.” 2016. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/76494.

MLA Handbook (7^th Edition):

Kim, Bo Ram. “Investigation of the Role of Chromosome 3q26-28 Amplification in Lung Squamous Cell Carcinoma Pathogenesis.” 2016. Web. 23 Sep 2018.

Vancouver:

Kim BR. Investigation of the Role of Chromosome 3q26-28 Amplification in Lung Squamous Cell Carcinoma Pathogenesis. [Internet] [Doctoral dissertation]. University of Toronto; 2016. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/76494.

Council of Science Editors:

Kim BR. Investigation of the Role of Chromosome 3q26-28 Amplification in Lung Squamous Cell Carcinoma Pathogenesis. [Doctoral Dissertation]. University of Toronto; 2016. Available from: http://hdl.handle.net/1807/76494

University of Toronto

29. Shao, Yang Washington. Identification and Validation of DLG2 as a Novel Tumor Suppressor in Osteosarcoma.

Degree: PhD, 2016, University of Toronto

URL: http://hdl.handle.net/1807/76827

► Biological events including mechanisms underlying tumorigenesis are frequently well conserved within mammals. We here report a cross-species comparative genomics study across human, dog, and mouse… (more)

Subjects/Keywords: aCGH; comparative oncogenomics; DLG2; mouse model; osteosarcoma; 0307

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APA (6^th Edition):

Shao, Y. W. (2016). Identification and Validation of DLG2 as a Novel Tumor Suppressor in Osteosarcoma. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/76827

Chicago Manual of Style (16^th Edition):

Shao, Yang Washington. “Identification and Validation of DLG2 as a Novel Tumor Suppressor in Osteosarcoma.” 2016. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/76827.

MLA Handbook (7^th Edition):

Shao, Yang Washington. “Identification and Validation of DLG2 as a Novel Tumor Suppressor in Osteosarcoma.” 2016. Web. 23 Sep 2018.

Vancouver:

Shao YW. Identification and Validation of DLG2 as a Novel Tumor Suppressor in Osteosarcoma. [Internet] [Doctoral dissertation]. University of Toronto; 2016. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/76827.

Council of Science Editors:

Shao YW. Identification and Validation of DLG2 as a Novel Tumor Suppressor in Osteosarcoma. [Doctoral Dissertation]. University of Toronto; 2016. Available from: http://hdl.handle.net/1807/76827

University of Toronto

30. Carias, Mathew Anibal Fortes. Intra-Cardiac Ultrasound Ablation And Treatment Monitoring.

Degree: PhD, 2017, University of Toronto

URL: http://hdl.handle.net/1807/77451

► Cardiac ablation procedures in the ventricles of the heart have been a difficult challenge for electrophysiologists. The current procedural workflow of these procedures uses radio… (more)

▼ Cardiac ablation procedures in the ventricles of the heart have been a difficult challenge for electrophysiologists. The current procedural workflow of these procedures uses radio frequency ablation under X-ray guidance with little to no treatment monitoring. The current challenges associated with this minimally invasive procedure can be separated into three categories. The first challenge is that the current image guidance technique, X-ray, offers poor soft tissue contrast and deposits radiation dose into the patient and interventionalist. As a second challenge, treatment monitoring techniques are limited for cardiac ablation therapies. Current treatment monitoring includes temperature and force sensors. Lastly, radio frequency ablation does not have the ability to cause deep tissue or clinically relevant lesions in the ventricles. To address these challenges, an interventional MRI surgical platform for cardiac ablation therapies has been developed. This platform entails the use of therapeutic ultrasound, a treatment modality that has the potential to create clinically relevant lesions in the ventricles. The interventional MRI surgical platform will address the three specific challenges mentioned above. This begins with the development of MRI-compatible steerable ultrasonic catheters. Secondly, an MRI-based form of treatment monitoring has been developed that allows temperature information to be obtained from intra-cardiac radio frequency receivers. Lastly, a fully ultrasound method to both treat and acquire real-time ultrasound signals for treatment monitoring provides additional treatment monitoring information. Future work for this project is largely based on the additional safety and regulation compliance experiments needed to transition this work from a pre-clinical environment to a small-scale patient clinical trial. In addition, there are several MRI and ultrasound-based methods that could enhance the current treatment monitoring. Advisors/Committee Members: Hynynen, Kullervo, Medical Biophysics.

Subjects/Keywords: Ablation; Cardiac; Catheters; MRI; Treatment Monitoring; Ultrasound; 0564

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APA (6^th Edition):

Carias, M. A. F. (2017). Intra-Cardiac Ultrasound Ablation And Treatment Monitoring. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/77451

Chicago Manual of Style (16^th Edition):

Carias, Mathew Anibal Fortes. “Intra-Cardiac Ultrasound Ablation And Treatment Monitoring.” 2017. Doctoral Dissertation, University of Toronto. Accessed September 23, 2018. http://hdl.handle.net/1807/77451.

MLA Handbook (7^th Edition):

Carias, Mathew Anibal Fortes. “Intra-Cardiac Ultrasound Ablation And Treatment Monitoring.” 2017. Web. 23 Sep 2018.

Vancouver:

Carias MAF. Intra-Cardiac Ultrasound Ablation And Treatment Monitoring. [Internet] [Doctoral dissertation]. University of Toronto; 2017. [cited 2018 Sep 23]. Available from: http://hdl.handle.net/1807/77451.

Council of Science Editors:

Carias MAF. Intra-Cardiac Ultrasound Ablation And Treatment Monitoring. [Doctoral Dissertation]. University of Toronto; 2017. Available from: http://hdl.handle.net/1807/77451

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