Advanced melanoma poses a major therapeutic challenge, and despite the development of recent promising therapeutic agents, resistance to treatment remains a problem. Until recently, despite low response rates, alkylating agents dacarbazine and temozolomide (TMZ) were the standard of care for the treatment of advanced melanoma. The cytotoxic effects of these agents relies upon the formation of alkylated base lesions such as O⁶-methylguanine (O⁶MeG), which is repaired by a protein implicated in TMZ resistance called O⁶-methylguanine-DNA methyltransferase (MGMT). Failure to resolve such alkylated bases results in DNA replication-associated double-strand breaks (DSBs). The type 1 insulin-like growth factor receptor (IGF-1R) mediates a number of characteristics common to cancers, including proliferation and survival, and evidence suggests it may also contribute to resistance to many anticancer agents. The aims of this study were to test whether melanoma cells could be sensitized to TMZ by small molecule IGF1R inhibitors, and to explore the mechanism of any chemosensitization. This study found an association between basal IGF1R phosphorylation and in vitro TMZ resistance in seven MGMT-proficient melanoma cell lines, suggesting that IGF1R activation may be linked with TMZ resistance. Furthermore, IGF1R inhibition caused dose-dependent sensitization of melanoma cells to TMZ, regardless of BRAF mutation status. This reduction in cell survival was not accompanied by an increase in apoptosis, but rather Chk2 activation and an accumulation of cells in the G2/M phase of the cell cycle, suggesting a possible effect of IGF1R inhibition on DNA repair. IGF1R depletion was found to increase MGMT protein levels and activity, but this effect was not seen in IGF1R inhibited cells. In addition, IGF1R inhibition was not epistatic with MGMT inhibition, and IGF1R inhibition reduced survival of TMZ treated MGMT-null cells. This suggested that TMZ sensitization by IGF1R inhibition was independent of MGMT. IGF1R inhibition did however cause an increase in the accumulation of TMZ-induced RPA foci, and delay in resolution of RAD51 foci. Together with the finding that IGF1R inhibition reduced survival in PARP inhibited melanoma cells, these results suggested that IGF1R inhibition influenced DSB repair by homologous recombination. Finally, the combination of IGF1R inhibition with TMZ was tested in a mouse model and was found to be tolerable. TMZ or IGF-1R inhibitor alone caused minor reduction in melanoma xenograft growth rates (rate reduction by 13% and 25% respectively), while combination treatment caused supra-additive growth delay (72%) that was significantly different from other treatment groups (p<0.05). The findings of this study suggest IGF1R inhibition as a possible option in overcoming alkylating drug resistance in melanoma.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

This dissertation addresses improvements to a consensus based task allocation algorithms for improving the Quality of Service in multi-task and multi-agent environments. Research in the past has led to many centralized task allocation algorithms where a central computation unit is calculating the global optimum task allocation solution. The centralized algorithms are plagued by creating a single point of failure and the bandwidth needed for creating consistent and accurate situational awareness off all agents. This work will extend upon a widely researched decentralized task assignment algorithm based on the consensus principle. Although many extensions have led to improvements of the original algorithm, there is still much opportunity for improvement in providing sufficient and reliable task assignments in real-world dynamic conditions and changing environments. This research addresses practical changes made to the consensus based task allocation algorithms for improving the Quality of Service in multi-task and multi-agent environments.

The world continues to face outbreaks of disease due to natural causes as well as the threat of biological warfare. Mathematical modeling provides an avenue by which to predict and ultimately prevent widespread outbreaks. A wide variety of modeling tools have been used in the study of the spread of diseases, including Ordinary Differential Equations, Partial Differential Equations, and Difference Equations. In this study, an agent-based model is used to study the spread and control of epidemics and is based on Sirakoulis, et al. [1]. The computer program NetLogo [2] is used for simulation. The development and set-up procedures for this model are fully discussed. The model is used to study the effectiveness of vaccination and quarantine as methods of epidemic control. It is determined that the most effective means of controlling an epidemic is to quarantine individuals with symptoms. In addition, the effect of the adjacent contact coefficient in the model is examined and further development and uses of the model are discussed.

Myocardial perfusion imaging (MPI) is an effective technique used to study the left ventricular ejection function (LVEF), myocardial perfusion, wall motion, and wall thickening. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are two modalities that can be used to quantify the left global and regional perfusion at rest and stress. While PET and SPECT rely on similar principles to produce images, important differences in instrumentation and experimental applications are dictated by inherent differences in their respective physics of radioactive decay. With a sensitivity > 90% in combination with a high specificity, PET is today the best available nuclear imaging technique for the diagnosis of coronary artery disease (CAD). The short half-life of the perfusion tracers in combination with highly sophisticated hard- and software enables rapid PET studies with high patient throughput. Rubidium-82 (82Rb) is a PET perfusion imaging agent that has a shot half-life of 76 seconds which enables multiple sequential data acquisitions in a short duration of time. It also reduces the number of false-positive SPECT scans and artifacts from soft tissue attenuation due to the routine application of attenuation correction. However 82Rb PET imaging is under-utilized clinically due to difficulty optimizing the imaging parameters. The major challenge of 82Rb imaging is determining when to begin the image acquisition post infusion, as imaging too early results in images with high background (low contrast), and imaging too late results in noisy images due to low count statistics. 82Rb rest/stress dynamic and gated data from 16 patients were available for analysis. The FWHM of the 82Rb infusion, LV cavity and LV myocardial uptake in time activity curves were generated and compared to isolate the dominant parameter in determining image quality. The measured and actual infusion-time correlated only at rest (r = 0.93, P = 0.006). Splitting-time at rest and stress correlated (r = 0.74, P = 0.09). But the study was not able to identify a single dominant parameter that would determine the image quality due to the unpredictable nature of hemodynamics during the vasodilatory induced cardiovascular stress. First pass radionuclide angiography (FPRNA) is the gold standard for quantification of ejection fraction. We examined the quantification of the ejection function (LVEF) to determine whether the gated 82Rb PET data, using quantitative gated SPECT (QGS), would accurately predict changes in the chamber volume and correlated the results with those obtained from FPRNA technique. There was a good correlation between the resting FPRNA data and resting gated 82Rb QGS data (r= 0.81, P=0.0005) showing that this method can be applied to 82Rb PET.99mTc SPECT was considered the gold standard for this study, as it is the most widely used technique for myocardial perfusion imaging. The under-perfused area of the myocardium is defined as defect. 99mTc agents, 18F-FDG, and 82Rb can all be used for cardiac imaging 1-7. However, count rates, energy and camera differences can yield image differences that are independent of the actual biological distribution. We examined whether PET with an 82Rb-labeled tracer would provide information on defect size similar to that provided by 99mTc SPECT, using a cardiac phantom in which the true defect size is known. Since 82Rb has such a short half-life (76 seconds), filling and imaging a phantom was going be a great challenge. Hence 124I which is a high-energy radioisotope like 82Rb, was used in this phantom study as a surrogate for 82Rb. Static cardiac phantom studies with 99mTc, 18F and 124I (surrogate for 82Rb) were conducted. The percent defect sizes were measured and compared with the true defect size. Our results demonstrated that at 45% threshold, the measured defect size was representative of true defect size for 99mTc SPECT data. Using this threshold as the standard, we smoothed the 18F and 124I PET data until the measured defect size for PET was representative of the true defect size. An optimal filter cutoff frequency (Butterworth filter, cutoff = 0.80 cycles/pixel, order=5 at 45% threshold for 124I or 82Rb) was found for the PET data within the range of values studied, and this frequency was higher than the clinical norm for SPECT data. Our results also illustrated that the measured SPECT defect size varied greatly depending on the thresholds used to define a defect, whereas measure PET defect size was relatively constant over the range of cutoffs tested7. The optimal cutoff may depend on defect size, patient variability, and noise level. When assessing myocardial defect size, physical properties need to be taken into consideration, particularly when comparing images obtained using different nuclides (i.e. 82Rb or 99mTc agent perfusion and 18F FDG viability).

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

The Pogamut toolkit designed for rapid prototyping of computer game agents has been so far used for prototyping the agents based on 3D FPS Unreal Tournament 2004 and its sequels. After the environment of RTS Defcon was connected to Pogamut a question arose how difficult it would be to connect some other significantly different environments and action selection mechanisms. In order to test this flexibility of Pogamut we have interconnected it with more complex RTS video game StarCraft:Brood War and large neural network simulator Emergent, together with Jason and POSH action selection mechanisms. The work analyzes created connections to detail and demonstrates their functionality on examples. An integral part of the work is also web with video tutorials and guides. In this work we also analyze Pogamut's readiness to be connected to other environments.

M.Sc.(Computer Science) / The dissertation investigates trust and reputation as a specialisation of agent technology. The research presented herein aims to establish and demonstrate how it is possible for one rational agent to trust another entity. Furthermore, the research presented herein aims to determine the extent of the limitations of trust and reputation models, and of the demonstrable solution in particular. To this end, the dissertation investigates theoretical aspects of trust. The dissertation investigates several existing trust models and establishes criteria for a qualitative analysis. Supplementary techniques aimed at enhancing trust evaluation are also investigated. The research also identifies architectural abstractions suitable for developing agents capable of intelligent trust evaluation. The main focus of the research is enhancing agent protection through a trust-based approach. A particular problem is the threats posed to mobile agents from malicious agent hosts. Therefore, a solution is sought that can be used to augment existing mechanisms aimed at mobile agent protection and agent protection in general. Thus, the research also examines mobile agents and mobile agent systems in an effort to produce a general trust-based solution that can be applied in most mobile agent systems. The solution presented in the dissertation proposes the concept of an evaluator agent as an add-on to existing mobile agent systems. The evaluator agent is presented as a rational agent with an embedded intelligent trust evaluation capability. The intelligent trust evaluation capability is provided via a set of reusable components. The solution demonstrates how a rational agent may evaluate the trustworthiness of other entities. The dissertation further analyses the strengths and limitations of the approach. The dissertation provides results that quantitatively demonstrate the extent of the limitations of the trust-based approach. The contribution of the dissertation partly lies in the service orientation of the evaluator agent approach. The service orientation of the solution provides an abstraction and a degree of heterogeneity suitable for handling the challenges of open environments. The solution can be deployed in most mobile agent systems to provide a trust evaluation service without the need to redesign existing mobile agent systems. More broadly, the research is another step towards the development of cognitive social agents.

The microbiota has a strong influence on health and disease in humans. A causative shift favoring pathobionts is strongly linked to diseases. Therefore, anti-microbial agents selectively targeting potential pathogens as well as their biofilms are urgently demanded. Here we demonstrate the impact of ethyl pyruvate, so far known as ROS scavenger and antiinflammatory agent, on planktonic microbes and biofilms. Ethyl pyruvate combats preferably the growth of pathobionts belonging to bacteria and fungi independent of the genera and prevailing drug resistance. Surprisingly, this anti-microbial agent preserves symbionts like Lactobacillus species. Moreover, ethyl pyruvate prevents the formation of biofilms and promotes matured biofilms dissolution. This potentially new anti-microbial and anti-biofilm agent could have a tremendous positive impact on human, veterinary medicine and technical industry as well.