Dinocyst biochronology and palynofacies : inferred systems tract character of Miocene sequences from New Jersey mid-Atlantic transect (ODP legs 174A and 174AX) /

One of the main objectives of the mid-Atlantic transect is to improve dating resolution of sequences and unconfonnity surfaces. Dinoflagellate cysts from two Ocean Drilling Program boreholes, the onshore Leg 174AX Ocean View Site and Leg 174A continental shelf Site 1071, are used to provide age estimates for sequences and unconfonnities fonned on the New Jersey continental margin during the Miocene epoch. Despite the occasional lack of dinocysts in barren and oxidized sections, dinocyst biochronology still offers greater age control than that provided by other microfossils in marginal marine environments. An early Miocene to late Miocene chronology based on ages detennined for the two study sites is presented. In addition, .palynofacies are used to unravel the systems tract character of the Miocene sequences and provide insight into the effects of taphonomy and preservation of palynomorphs in marginal marine and shelf environments under different ~ea level conditions. More precise placement of maximum flooding surfaces is possible through the identification of condensed sections and palynofacies shifts can also reveal subaerially exposed sections and surfaces not apparent in seismic or lithological analyses. The problems with the application of the pollen record in the interpretation of Miocene climate are also discussed. Palynomorphs provide evidence for a second-order lowering of sea level during the Miocene, onto which higher order sea level fluctuations are super-imposed. Correlation of sequences and unconfonnities is attempted between onshore boreholes and from the onshore Ocean View borehole to offshore Site 1071.

An analysis of the methyl rotation dynamics in the So (x' A) and T (a A) states of thioacetaldehyde from Pyrolysis jet spectra /

Jet-cooled, laser-induced phosphorescence excitation spectra (LIP) of thioacetaldehyde CH3CHS, CH3CDS, CD3CHS and CD3CDS have been observed over the region 15800 - 17300 cm"^ in a continuous pyrolysis jet. The vibronic band structure of the singlet-triplet n -* n* transition were attributed to the strong coupling of the methyl torsion and aldehydic hydrogen wagging modes . The vibronic peaks have been assigned in terms of two upper electronic state (T^) vibrations; the methyl torsion mode v^g, and the aldehydic hydrogen wagging mode v^^. The electronic origin O^a^ is unequivocally assigned as follows: CH3CHS (16294.9 cm"'' ), CH3CDS (16360.9 cm"'' ), CD3CHS (16299.7 cm"^ ), and CD3CDS (16367.2 cm"'' ). To obtain structural and dynamical information about the two electronic states, potential surfaces V(e,a) for the 6 (methyl torsion) and a (hydrogen wagging) motions were generated by ab initio quantum mechanical calculations with a 6-3 IG* basis in which the structural parameters were fully relaxed. The kinetic energy coefficients BQ(a,e) , B^(a,G) , and the cross coupling term B^(a,e) , were accurately represented as functions of the two active coordinates, a and 9. The calculations reveal that the molecule adopts an eclipsed conformation for the lower Sq electronic state (a=0°,e=0"') with a barrier height to internal rotation of 541.5 cm"^ which is to be compared to 549.8 cm"^ obtained from the microwave experiment. The conformation of the upper T^ electronic state was found to be staggered (a=24 . 68° ,e=-45. 66° ) . The saddle point in the path traced out by the aldehyde wagging motion was calculated to be 175 cm"^ above the equilibrium configuration. The corresponding maxima in the path taken by methyl torsion was found to be 322 cm'\ The small amplitude normal vibrational modes were also calculated to aid in the assignment of the spectra. Torsional-wagging energy manifolds for the two states were derived from the Hamiltonian H(a,e) which was solved variationally using an extended two dimensional Fourier expansion as a basis set. A torsionalinversion band spectrum was derived from the calculated energy levels and Franck-Condon factors, and was compared with the experimental supersonic-jet spectra. Most of the anomalies which were associated with the interpretation of the observed spectrum could be accounted for by the band profiles derived from ab initio SCF calculations. A model describing the jet spectra was derived by scaling the ab initio potential functions. The global least squares fitting generates a triplet state potential which has a minimum at (a=22.38° ,e=-41.08°) . The flatter potential in the scaled model yielded excellent agreement between the observed and calculated frequency intervals.

Heidegger's tragic Greeks : the relation between presence and deinon

Martin Heidegger's interpretation of the ancients was born out of something like a crisis in the interpretation of the Greeks, which can be characterized as nothing other than the realization of the idea that the Greek philosophers put a serious question mark over existence. This idea, which had its germination in Prussia with Jakob Burckhart and his teacher, but first came to be seriously cultivated in the Philosophy of Friedrich Nietzsche, was the first in depth investigation into whether the Greeks, on the one hand, questioned existence or, on the other hand, put a question mark over existence. To question existence is rather innocuous, since it amounts to little more, in the end, than a child looking up at the stars and asking what it all means. To put a question mark over existence, however, is another business entirely. For the Greeks, as the life work of Martin Heidegger amply demonstrates, the nature of Greek thinking and the objects towards which it is directed follows so absolutely from the tragic view of the human person that, in a certain sense, philosophy is Greek and could only have developed in Greece. Perhaps stating it a little less categorically, philosophy could have developed elsewhere at least to the extent that something like they way the Greeks understood life was at the forefront: presence, in other words. This thesis deals with the problem ofHeidegger's relation to the Greeks, specifically in terms of his understanding of the Greeks and presence. It is the position of this dissertation that the Greek notion of presence is, as Heidegger understands it, the homeliness of the hearth that radiates through all the things that humans concern themselves with. This is thought by Heidegger, as the Greeks did, specifically in contrast with the uncanninesslunhomeliness of the hqrnan apart from his or her concern with things. Therefore, the thesis is an attempt at exposing the relation between presence and the unhomely by situating it withing Greek existence and the meaning of the Greek Philosopher. In order to support this position, the thesis has been divided into five parts. The first two chapters deal with Heidegger's explanation of the relation between Greek notion of physics (Phusis), metaphysics (specifically in relation to an analysis of time and motion in Greek thought), and what Heidegger calls the fundamental attunement of Dasein (boredom). More exactly, it deals with these issues only so far as they allow us to bring out something like the notion of 'presence' in relation to things and homelessness or restlessness in relation to the human being. The rationale for these two chapters in relation to the central problem of the paper is that in Heidegger's elucidation of physics and metaphysics, he conducts his analysis in such a way that he explicitly uncovers that dimension of human existence that he calls the fundamental attunement of Dasein. This fundamental attunement is, in tum, similar to what the Greeks understood as the deinon, the uncanninesslunhomeliness of the human. The third and fourth chapters take as their explicit themes the problem of the Greek understanding of the assertion and the ways in which the person can comport himlherself toward things, two issues which are not separable. The rationale for these two chapters in relation to the central theme of the paper is that Heidegger's analysis of these two areas in Greek thought brings out precisely why the philosopher and the philosophical way of life is the highest mode of existence for the Greeks and how this is thought specifically in tenns of the uncanniness of humans. The final cijapter gives a complete elucidation of presence as the homeliness of the hearth and shows specifically how this is thought of in contradistinction to the uncanny/unhomely for the Greeks. 1I1 This last chapter also explains Martin Heidegger's reaction to the Greek's interpretation of the highest mode of existence, and what he posited as a counter-thought. The essay as a whole is an attempt to fully concertize an important dimension of Heidegger' s understanding of the Greeks, that is, the relation between presence and the deinon or Greek notion ofunhomely, which, to my la)owledge, has not been offered anywhere in commentaries on Heidegger.

Electrophysiological and behavioural correlates of facial identity and expression perception deficits following a closed head injury /

A large variety of social signals, such as facial expression and body language, are conveyed in everyday interactions and an accurate perception and interpretation of these social cues is necessary in order for reciprocal social interactions to take place successfully and efficiently. The present study was conducted to determine whether impairments in social functioning that are commonly observed following a closed head injury, could at least be partially attributable to disruption in the ability to appreciate social cues. More specifically, an attempt was made to determine whether face processing deficits following a closed head injury (CHI) coincide with changes in electrophysiological responsivity to the presentation of facial stimuli. A number of event-related potentials (ERPs) that have been linked specifically to various aspects of visual processing were examined. These included the N170, an index of structural encoding ability, the N400, an index of the ability to detect differences in serially presented stimuli, and the Late Positivity (LP), an index of the sensitivity to affective content in visually-presented stimuli. Electrophysiological responses were recorded while participants with and without a closed head injury were presented with pairs of faces delivered in a rapid sequence and asked to compare them on the basis of whether they matched with respect to identity or emotion. Other behavioural measures of identity and emotion recognition were also employed, along with a small battery of standard neuropsychological tests used to determine general levels of cognitive impairment. Participants in the CHI group were impaired in a number of cognitive domains that are commonly affected following a brain injury. These impairments included reduced efficiency in various aspects of encoding verbal information into memory, general slower rate of information processing, decreased sensitivity to smell, and greater difficulty in the regulation of emotion and a limited awareness of this impairment. Impairments in face and emotion processing were clearly evident in the CHI group. However, despite these impairments in face processing, there were no significant differences between groups in the electrophysiological components examined. The only exception was a trend indicating delayed N170 peak latencies in the CHI group (p = .09), which may reflect inefficient structural encoding processes. In addition, group differences were noted in the region of the N100, thought to reflect very early selective attention. It is possible, then, that facial expression and identity processing deficits following CHI are secondary to (or exacerbated by) an underlying disruption of very early attentional processes. Alternately the difficulty may arise in the later cognitive stages involved in the interpretation of the relevant visual information. However, the present data do not allow these alternatives to be distinguished. Nonetheless, it was clearly evident that individuals with CHI are more likely than controls to make face processing errors, particularly for the more difficult to discriminate negative emotions. Those working with individuals who have sustained a head injury should be alerted to this potential source of social monitoring difficulties which is often observed as part of the sequelae following a CHI.

DEFORMATION OF INTERIOR LAYERED DEPOSITS (ILD) AND THEIR ASSOCIATED LANDFORMS IN WEST CANDOR CHASMA, MARS: IMPLICATIONS FOR THE TIMING OF ILD DEPOSITION

On Mars, interior layered deposits (ILD) provide evidence that water was once stable at the surface of the planet and present in large quantities. In West Candor Chasma, the ILD and their associated landforms record the depositional history of the chasma, and the deformation of those deposits provide insight into the stresses acting on them and the chasma as a whole. The post ILD structural history of West Candor is interpreted by analyzing the spatial relationships and orientation trends of structural features within the ILD. Therecording of stresses through brittle deformation of ILDs implies that the ILD had been lithified before the stress was imposed. Based on the prominent orientation trends of deformation features, the orientation of the stress regime acting upon the ILD appears to be linked to the regime that initially created the chasma-forming faults. An additional minor stress orientation was also revealed and may be related to large structures outside west Candor Chasma. The late depositional history of Ceti Mensa is herein investigated by examining the attributes and spatial relationship between unique corrugated, linear formations (CLF). The CLFs appear to be aeolian in origin but display clear indications of brittle deformation, indicating they have been Iithified. Evidence of lithification and the mineral composition of the surrounding material support the interpretation of circulating water in the area.

Electrophysiological constituents of the P100 and N170 ERP complex: De-constructing of face processing using independent component analysis and robust estimation.

The initial timing of face-specific effects in event-related potentials (ERPs) is a point of contention in face processing research. Although effects during the time of the N170 are robust in the literature, inconsistent effects during the time of the P100 challenge the interpretation of the N170 as being the initial face-specific ERP effect. The interpretation of the early P100 effects are often attributed to low-level differences between face stimuli and a host of other image categories. Research using sophisticated controls for low-level stimulus characteristics (Rousselet, Husk, Bennett, & Sekuler, 2008) report robust face effects starting at around 130 ms following stimulus onset. The present study examines the independent components (ICs) of the P100 and N170 complex in the context of a minimally controlled low-level stimulus set and a clear P100 effect for faces versus houses at the scalp. Results indicate that four ICs account for the ERPs to faces and houses in the first 200ms following stimulus onset. The IC that accounts for the majority of the scalp N170 (icNla) begins dissociating stimulus conditions at approximately 130 ms, closely replicating the scalp results of Rousselet et al. (2008). The scalp effects at the time of the P100 are accounted for by two constituent ICs (icP1a and icP1b). The IC that projects the greatest voltage at the scalp during the P100 (icP1a) shows a face-minus-house effect over the period of the P100 that is less robust than the N 170 effect of icN 1 a when measured as the average of single subject differential activation robustness. The second constituent process of the P100 (icP1b), although projecting a smaller voltage to the scalp than icP1a, shows a more robust effect for the face-minus-house contrast starting prior to 100 ms following stimulus onset. Further, the effect expressed by icP1 b takes the form of a larger negative projection to medial occipital sites for houses over faces partially canceling the larger projection of icP1a, thereby enhancing the face positivity at this time. These findings have three main implications for ERP research on face processing: First, the ICs that constitute the face-minus-house P100 effect are independent from the ICs that constitute the N170 effect. This suggests that the P100 effect and the N170 effect are anatomically independent. Second, the timing of the N170 effect can be recovered from scalp ERPs that have spatio-temporally overlapping effects possibly associated with low-level stimulus characteristics. This unmixing of the EEG signals may reduce the need for highly constrained stimulus sets, a characteristic that is not always desirable for a topic that is highly coupled to ecological validity. Third, by unmixing the constituent processes of the EEG signals new analysis strategies are made available. In particular the exploration of the relationship between cortical processes over the period of the P100 and N170 ERP complex (and beyond) may provide previously unaccessible answers to questions such as: Is the face effect a special relationship between low-level and high-level processes along the visual stream?

Narratives of Experience in Education: Living and Working Through Poverty in a Rural Community

In this study, I use my own experiences in education as a former elementary student, research assistant, and as a current secondary school teacher, to examine how living in a marginalised rural community challenged by poverty affected my formal education. The purpose of this study was to use stories to: (a) explore my formative elementary education growing up in a community that was experiencing poverty, and; (b) to examine the impact and implications of these experiences for me as a teacher and researcher considering the topic of poverty and education. This study used narrative inquiry to explore stories of education, focusing on experiences living and working in a rural community. My role in the study was both as participant and researcher as I investigate, through story, how I was raised in a marginalised, rural community faced with challenges of poverty and how I relate to my current role as a teacher working in a similar, rural high school. My own experiences and reflections form the basis of the study, but I used the contributions of secondary participants to offer alternative perspective of my interpretation of events. Participants in this study were asked to write about and/or retell their lived stories of working in areas affected by challenging circumstances. From my stories and those of secondary participants, three themes were explored: student authorship, teaching practice, and community involvement. An examination of these themes through commonplaces of place, sociality and time (Connelly and Clandinin, 2006) provide a context for other educators and researchers to consider or reconsider teaching practices in school communities affected by poverty.

Interpreting Quantifier Scope Ambiguity: Evidence of Heuristic First, Algorithmic Second Processing

The present work suggests that sentence processing requires both heuristic and algorithmic processing streams, where the heuristic processing strategy precedes the algorithmic phase. This conclusion is based on three self-paced reading experiments in which the processing of two-sentence discourses was investigated, where context sentences exhibited quantifier scope ambiguity. Experiment 1 demonstrates that such sentences are processed in a shallow manner. Experiment 2 uses the same stimuli as Experiment 1 but adds questions to ensure deeper processing. Results indicate that reading times are consistent with a lexical-pragmatic interpretation of number associated with context sentences, but responses to questions are consistent with the algorithmic computation of quantifier scope. Experiment 3 shows the same pattern of results as Experiment 2, despite using stimuli with different lexicalpragmatic biases. These effects suggest that language processing can be superficial, and that deeper processing, which is sensitive to structure, only occurs if required. Implications for recent studies of quantifier scope ambiguity are discussed.

The nature of compounds: A psychocentric perspective

Although compound words often seem to be words that themselves contain words, this paper argues that this is not the case for the vast majority of lexicalized compounds. Rather, it is claimed that as a result of acts of lexical processing, the constituents of compound words develop into new lexical representations. These representations are bound to specific morphological roles and positions (e.g., head, modifier) within a compound word. The development of these positionally bound compound constituents creates a rich network of lexical knowledge that facilitates compound processing and also creates some of the well-documented patterns in the psycholinguistic and neurolinguistic study of compounding.

Investigating Formative Assessment: Exploring the Impact on the Self-Efficacy and Motivation of Mathematics Students

This is a study of the implementation and impact of formative assessment strategies on the motivation and self-efficacy of secondary school mathematics students. An explanatory sequential mixed methods design was implemented where quantitative and qualitative data were collected and analyzed sequentially in 2 different phases. The first phase involved quantitative data from student questionnaires and the second phase involved qualitative data from individual student and teacher interviews. The findings of the study suggest that formative assessment is implemented in practice in diverse ways and is a process where the strategies are interconnected. Teachers experience difficulty in incorporating peer and self-assessment and perceive a need for exemplars. Key factors described as influencing implementation include teaching philosophies, interpretation of ministry documents, teachers’ experiences, leadership in administration and department, teacher collaboration, misconceptions of teachers, and student understanding of formative assessment. Findings suggest that overall, formative assessment positively impacts student motivation and self-efficacy, because feedback is provided which offers encouragement and recognition by highlighting the progress that has been made and what steps need to be taken to improve. However, students are impacted differently with some considerations including how students perceive mistakes and if they fear judgement. Additionally, the impact of formative assessment is influenced by the connection between self-efficacy and motivation, namely how well a student is doing is a source of both concepts.

The Supreme Court’s Understanding of Federalism: Efficiency at the Expense of Diversity

This paper is an examination of the Supreme Court of Canada's interpretation of federalism since constitutional repatriation in 1982. It argues that the lure of centralist efficiency is overpowering a fundamentally important part of our federal order: regionalism. The author contends that changes made by the Court to certain fundamental concepts of Canadian constitutional law now provide Parliament with greater latitude than before in the exercise of its legislative powers. According to the author, these changes are disturbing because they are structured so as to preclude consideration of the legitimate concerns of regional polities. Furthermore, he argues that the Court has reinforced the central government's power to regulate the economy, including intraprovincial matters affecting trade, by resorting to highly functional tests that emphasize economic efficiency over other criteria. This, he claims, makes it more difficult to invoke legitimate regional interests that would lead to duplication, overlapping and even, in the eyes of some, inefficiency. The author the focuses on the Court's treatment of environmental protection in an attempt to show the tension between the Court's desire to use a functional approach and the need to recognize regional interests. Finally, through an examination of recent case law, he attemps to demonstrate that the Court's dominant perspective remains functional despite its endorsement of a more community-oriented undestanding of federalism in Secession Reference. If the Court chooses to proceed in this manner, it will alienate regional polities and may encourage them to choose more radical means of asserting their differences. Further, the author argues that strict adherence to the functional effectiveness approach will undermine the very values that federalism is meant to promote.

Management renewal? Consequences of the new conception of the “best interests of the corporation” in North American and French Corporate Law

Corporate law integrates a stakeholder conception through the comprehensive meaning of the best interests of the corporation. In this paper, I address criticisms about classical definition of the firm’s purpose. Even if American law is more discreet and uncertain, it is possible to defend a broad conception of the best interests of the corporation. The interests of Canadian and French firms include their partners. While the notion of intérêt social is debatable in France, Canada has recently modified its point of view regarding the purpose of the firm. Indeed, the decision of the Supreme Court of Canada Magasins à rayons Peoples Inc. (Syndic de) v. Wise in 2004 changed the concept of corporate law. With respect to fiduciary duties, the Supreme Court set aside the traditional interpretation of the “best interests of the corporation” which gave primacy to shareholders’ interests. The Court held that the expression “best interests of the corporation” refers to the maximization of the corporation’s value. This innovative vision of the best interest of the corporation introduces stakeholder theory and corporate social responsibility (CSR) into corporate law and provides a new field for the firm’s management to frame their responsibilities. This paper concludes with an extended discussion of the implications of stakeholder and CSR influence for the future of corporate law, economy and financial researches.

Systematic analysis of protein complexes involved in the human RNA polymerase II machinery

La transcription, la maturation d’ARN, et le remodelage de la chromatine sont tous des processus centraux dans l'interprétation de l'information contenue dans l’ADN. Bien que beaucoup de complexes de protéines formant la machinerie cellulaire de transcription aient été étudiés, plusieurs restent encore à identifier et caractériser. En utilisant une approche protéomique, notre laboratoire a purifié plusieurs composantes de la machinerie de transcription de l’ARNPII humaine par double chromatographie d’affinité "TAP". Cette procédure permet l'isolement de complexes protéiques comme ils existent vraisemblablement in vivo dans les cellules mammifères, et l'identification de partenaires d'interactions par spectrométrie de masse. Les interactions protéiques qui sont validées bioinformatiquement, sont choisies et utilisées pour cartographier un réseau connectant plusieurs composantes de la machinerie transcriptionnelle. En appliquant cette procédure, notre laboratoire a identifié, pour la première fois, un groupe de protéines, qui interagit physiquement et fonctionnellement avec l’ARNPII humaine. Les propriétés de ces protéines suggèrent un rôle dans l'assemblage de complexes à plusieurs sous-unités, comme les protéines d'échafaudage et chaperonnes. L'objectif de mon projet était de continuer la caractérisation du réseau de complexes protéiques impliquant les facteurs de transcription. Huit nouveaux partenaires de l’ARNPII (PIH1D1, GPN3, WDR92, PFDN2, KIAA0406, PDRG1, CCT4 et CCT5) ont été purifiés par la méthode TAP, et la spectrométrie de masse a permis d’identifier de nouvelles interactions. Au cours des années, l’analyse par notre laboratoire des mécanismes de la transcription a contribué à apporter de nouvelles connaissances et à mieux comprendre son fonctionnement. Cette connaissance est essentielle au développement de médicaments qui cibleront les mécanismes de la transcription.

Didactique des grandeurs en mesure et élèves en difficulté d'apprentissage du 2e cycle du primaire

Le programme -Une école adaptée à tous ses élèves-, qui s'inscrit dans la réforme actuelle de l'éducation au Québec, nous a amenée à nous intéresser aux représentations dans les grandeurs en mesure en mathématiques des élèves en difficulté d'apprentissage. Nous nous sommes proposés de reconduire plusieurs paramètres de la recherche de Brousseau (1987, 1992) auprès de cette clientèle. La théorie des champs conceptuels (TCC) de Vergnaud (1991), appliquée aux structures additives, a été particulièrement utile pour l'analyse et l'interprétation de leurs représentations. Comme méthode de recherche, nous avons utilisé la théorie des situations didactiques en mathématiques (TSDM), réseau de concepts et de méthode de recherche appuyé sur l'ingénierie didactique qui permet une meilleure compréhension de l'articulation des contenus à enseigner. Grâce à la TSDM, nous avons observé les approches didactiques des enseignants avec leurs élèves. Notre recherche est de type exploratoire et qualitatif et les données recueillies auprès de 26 élèves de deux classes spéciales du deuxième cycle du primaire ont été traitées selon une méthode d'analyse de contenu. Deux conduites ont été adoptées par les élèves. La première, de type procédural a été utilisée par presque tous les élèves. Elle consiste à utiliser des systèmes de comptage plus ou moins sophistiqués, de la planification aux suites d'actions. La deuxième consiste à récupérer directement en mémoire à long terme le résultat associé à un couple donné et au contrôle de son exécution. L'observation des conduites révèle que les erreurs sont dues à une rupture du sens. Ainsi, les difficultés d'ordre conceptuel et de symbolisation nous sont apparues plus importantes lorsque l'activité d'échange demandait la compétence "utilisation" et renvoyait à la compréhension de la tâche, soit les tâches dans lesquelles ils doivent eux-mêmes découvrir les rapports entre les variables à travailler et à simuler les actions décrites dans les énoncés. En conséquence, les problèmes d'échanges se sont révélés difficiles à modéliser en actes et significativement plus ardus que les autres. L'étude des interactions enseignants et élèves a démontré que la parole a été presque uniquement le fait des enseignants qui ont utilisé l'approche du contrôle des actes ou du sens ou les deux stratégies pour aider des élèves en difficulté. Selon le type de situation à résoudre dans ces activités de mesurage de longueur et de masse, des mobilisations plurielles ont été mises en oeuvre par les élèves, telles que la manipulation d'un ou des étalon(s) par superposition, par reports successifs, par pliage ou par coupure lorsque l'étalon dépassait; par retrait ou ajout d'un peu de sable afin de stabiliser les plateaux. Nous avons également observé que bien que certains élèves aient utilisé leurs doigts pour se donner une perception globale extériorisée des quantités, plusieurs ont employé des procédures très diverses au cours de ces mêmes séances. Les résultats présentés étayent l'hypothèse selon laquelle les concepts de grandeur et de mesure prennent du sens à travers des situations problèmes liées à des situations vécues par les élèves, comme les comparaisons directes. Eles renforcent et relient les grandeurs, leurs propriétés et les connaissances numériques.

Immuno-oncology of human prostate cancer : phenotypical characterization and study of the tumor-derived, androgen-regulated immunosuppressive microenvironment

Le cancer de la prostate est le cancer le plus fréquemment diagnostiqué chez les hommes canadiens et la troisième cause de décès relié au cancer. Lorsque diagnostiqué à un stade précoce de la maladie, le cancer de la prostate est traité de manière curative par chirurgie et radiothérapie. Par contre, les thérapies actuelles ne peuvent éradiquer la maladie lorsqu’elle progresse à des stades avancés. Ces thérapies, comme la chimiothérapie et l’hormonothérapie, demeurent donc palliatives. Il est primordial d’optimiser de nouvelles thérapies visant l’élimination des cellules cancéreuses chez les patients atteints des stades avancés de la maladie. Une de ces nouvelles options thérapeutiques est l’immunothérapie. L’immunothérapie du cancer a fait des progrès considérables durant les dernières années. Cependant, les avancements encourageants obtenus lors d’essais précliniques ne se sont pas encore traduits en des résultats cliniques significatifs. En ce qui concerne le cancer de la prostate, les résultats négligeables suivants des interventions immunothérapeutiques peuvent être causés par le fait que la plupart des études sur le microenvironnement immunologique furent effectuées chez des modèles animaux. De plus la majorité des études sur l’immunologie tumorale humaine furent effectuées chez des patients atteints d’autres cancers, tels que le mélanome, et non chez les patients atteints du cancer de la prostate. Donc, le but central de cette thèse de doctorat est d’étudier le microenvironnement immunologique chez les patients atteints du cancer de la prostate afin de mieux définir les impacts de la tumeur sur le développement de la réponse immunitaire antitumorale. Pour réaliser ce projet, nous avons établi deux principaux objectifs de travail : (i) la caractérisation précise des populations des cellules immunitaires infiltrant la tumeur primaire et les ganglions métastatiques chez les patients atteints du cancer de la prostate; (ii) l’identification et l’étude des mécanismes immunosuppressifs exprimés par les cellules cancéreuses de la prostate. Les résultats présentés dans cette thèse démontrent que la progression du cancer de la prostate est associée au développement d’un microenvironnement immunosuppressif qui, en partie, est régulé par la présence des androgènes. L’étude initiale avait comme but la caractérisation du microenvironnement immunologique des ganglions drainant la tumeur chez des patients du cancer de la prostate. Les résultats présentés dans le chapitre III nous a permis de démontrer que les ganglions métastatiques comportent des signes cellulaires et histopathologiques associés à une faible réactivité immunologique. Cette immunosuppression ganglionnaire semble dépendre de la présence des cellules métastatiques puisque des différences immunologiques notables existent entre les ganglions non-métastatiques et métastatiques chez un même patient. La progression du cancer de la prostate semble donc associée au développement d’une immunosuppression affectant les ganglions drainant la tumeur primaire. Par la suite, nous nous sommes intéressés à l’impact de la thérapie par déplétion des androgènes (TDA) sur le microenvironnement immunologique de la tumeur primaire. La TDA est associée à une augmentation marquée de l’inflammation prostatique. De plus, les protocoles d’immunothérapies pour le cancer de la prostate actuellement évalués en phase clinique sont dirigés aux patients hormonoréfractaires ayant subi et échoué la thérapie. Cependant, peu d’information existe sur la nature de l’infiltrat de cellules immunes chez les patients castrés. Il est donc essentiel de connaître la nature de cet infiltrat afin de savoir si celui-ci peut répondre de manière favorable à une intervention immunothérapeutique. Dans le chapitre IV, je présente les résultats sur l’abondance des cellules immunes infiltrant la tumeur primaire suivant la TDA. Chez les patients castrés, les densités de lymphocytes T CD3+ et CD8+ ainsi que des macrophages CD68+ sont plus importantes que chez les patients contrôles. Nous avons également observé une corrélation entre la densité de cellules NK et une diminution du risque de progression de la maladie (rechute biochimique). Inversement, une forte infiltration de macrophages est associée à un plus haut risque de progression. Conjointement, durant cette étude, nous avons développé une nouvelle approche informatisée permettant la standardisation de la quantification de l’infiltrat de cellules immunes dans les échantillons pathologiques. Cette approche facilitera la comparaison d’études indépendantes sur la densité de l’infiltrat immun. Ces résultats nous ont donc permis de confirmer que les effets pro-inflammatoires de la TDA chez les patients du cancer de la prostate ciblaient spécifiquement les lymphocytes T et les macrophages. L’hypothèse intéressante découlant de cette étude est que les androgènes pourraient réguler l’expression de mécanismes immunosuppressifs dans la tumeur primaire. Dans le chapitre V, nous avons donc étudié l’expression de mécanismes immunosuppressifs par les cellules cancéreuses du cancer de la prostate ainsi que leur régulation par les androgènes. Notre analyse démontre que les androgènes augmentent l’expression de molécules à propriétés immunosuppressives telles que l’arginase I et l’arginase II. Cette surexpression dépend de l’activité du récepteur aux androgènes. Chez les patients castrés, l’expression de l’arginase II était diminuée suggérant une régulation androgénique in vivo. Nous avons observé que l’arginase I et l’arginase II participent à la prolifération des cellules du cancer de la prostate ainsi qu’à leur potentiel immunosuppressif. Finalement, nous avons découvert que l’expression de l’interleukin-8 était aussi régulée par les androgènes. De plus, l’interleukin-8, indépendamment des androgènes, augmente l’expression de l’arginase II. Ces résultats confirment que les androgènes participent au développement d’une microenvironnement immunosuppressif dans le cancer de la prostate en régulant l’expression de l’arginase I, l’arginase II et l’interleukin-8. En conclusion, les résultats présentés dans cette thèse témoignent du caractère unique du microenvironnement immunologique chez les patients atteints du cancer de la prostate. Nos travaux ont également permis d’établir de nouvelles techniques basées sur des logiciels d’analyse d’image afin de mieux comprendre le dialogue entre la tumeur et le système immunitaire chez les patients. Approfondir les connaissances sur les mécanismes de régulation du microenvironnement immunologique chez les patients atteint du cancer de la prostate permettra d’optimiser des immunothérapies mieux adaptées à éradiquer cette maladie.