Sara Jeannette Duncan and Stephen Leacock: Two Master Satirists of Religion and Politics

There is no hard evidence that when he wrote Sunshine Sketches of a Little Town (1912), Stephen Leacock had read Sara Jeannette Duncan’s The Imperialist (1904). In addition to circumstantial factors, however, internal evidence in the form of a tonal resemblance and key plot parallels — a bank robbery and a dominion election — suggests that Leacock had read Duncan. A comparative discussion of the novels throws into sharp relief not only the modulations of Leacock’s and Duncan’s satire, but also how Duncan’s liberal individualism contrasts suggestively with Leacock’s pragmatic conservatism. The striking similarities and engaging differences between the works suggest that the two authors would have had much to say to each other about the forces shaping Canadian life

Structually diverse Cu-64-labeled RGD peptide conjugates for PET imaging of αvβ3 expression

Radiolabeled receptor-binding peptides have emerged as an important class of radiopharmaceuticals for diagnostic imaging and cancer therapy. Following radionuclide labeling, the specific receptor-binding properties of the ligand can be exploited to guide the radioactivity to tissues expressing a particular receptor. This dissertation reports on the development of integrin αvβ3-targeting radiopharmaceuticals for medical imaging applications from the perspective of both the radiometal-labeled chelator as well as the targeting peptide. Several macrocyclic copper(II) chelators have been studied with the goal of improving kinetic and in vivo stability. Structurally diverse bifunctional RGD: arginine-glycine-aspartic acid) peptides were investigated for αvβ3 integrin affinity in vitro and in vivo. The goal of accomplishing higher binding affinity through multivalency has been pursued by evaluating the binding affinity of nanoparticles presenting multiple peptides on their surface. Copper radionuclides have been the subject of considerable research effort because they offer a varying range of half-lives and positron energies, making them useful for diagnostic imaging and/or targeted radiotherapy. Ensuring the stability of metal complexes in vivo remains a challenge in the development of radiometal-based radiopharmaceuticals. Reported here are data on the in vitro and in vivo evaluation of three macrocyclic chelators, C3B-DO2A, CB-TR2A, and NOTA. These studies were performed to improve Cu(II) complexation kinetics while retaining the high in vivo stability of our lead chelating agent, CB-TE2A. Optimal radiolabeling conditions were established for the 64Cu-labeled radiometal chelators and their in vivo biodistribution and excretion were studied in normal rats. Integrin αvβ3 is upregulated in tumor vasculature, osteoclasts, and areas of collateral circulation following ischemic injury. A series of structurally diverse bifunctional RGD: arginine-glycine-aspartic acid) peptides were investigated for αvβ3 affinity in vitro and in vivo. The RGD-peptide analogs were screened for affinity to the αvβ3 integrin and specificity compared to αvβ5 and αIIbβ3. Extent of internalization of these peptides by an αvβ3 expressing cell line, U87MG human glioblastoma cells, was determined. The compounds were screened via biodistribution studies and microPET imaging of a murine U87MG tumor model. Polyvalence has known to have a profound effect on receptor-binding affinity and in vivo kinetics of radiolabeled multimers. The goal of accomplishing higher binding affinity through multivalency has been pursued by evaluating the binding affinity of shell cross-linked: SCK) nanoparticles presenting multiple RGD peptides on their surface. Difficulties encountered in obtaining nanoparticles with high levels of bioavailable targeting peptide on the surface led to a systematic study of methods of shell functionalization and particle purification with chemical, physical, and biological evaluation of each compound. The development of radiometal-labeled peptides is a relatively slow process, thus in this research, optimization of various aspects was studied in parallel. Each chapter presents a small contribution, but the knowledge gained from these studies can be taken together to produce radiopharmaceuticals with optimal properties--high in vivo stability, high uptake in tumors, low uptake in non-target tissues, and rapid blood clearance, preferably through renal excretion

“Abundantly Worthy of its Past”: Agnes Maule Machar and Early Canadian Historical Fiction

While we tend to see the problematizing of history as a distinctly postmodern concern, two of Agnes Maule Machar's (1837-1927) nineteenth-century historical novels, For King and Country (1874) and Marjorie's Canadian Winter (1893), show that even the most (apparently) hegemonic narratives of the period remain concerned with problems of historical representation and the vexed relationship between past and present. Through the process of uncovering certain hidden moral 'truths,' various ethnic, political, and moral tensions of the period that complicated Canada's past— as well as its present— show through. Although Machar never fully subverted contemporary assumptions about history, her attempt to reconcile many of Canada's national conflicts provides a window onto nineteenth century Canada