Les carcinomes épidermoïdes de la tête et du cou sont souvent de mauvais pronostic, en raison de leur résistance aux traitements suivie de récidives loco-régionales, voire de métastases. Ce travail s'est focalisé sur le rôle des cellules souches cancéreuses (CSC) dans la radiorésistance d'un modèle cellulaire de cancer du larynx, SQ20B, ainsi que sur leur ciblage thérapeutique en association avec la radiothérapie photonique ou par ions carbone. Une sous-population a été isolée à partir de la lignée SQ20B par tris cellulaires successifs selon 3 critères spécifiques des CSC de tumeurs ORL : exclusion du Hoechst 33342, expression de CD44 et activité élevée de l'aldéhyde déshydrogénase (ALDH). Les cellules SQ20B/SP/CD44 high/ALDHhigh présentent bien les caractéristiques de CSC (tumorisphères, tumorigénèse, radiorésistance). La résistance des CSC aux 2 types d'irradiation, par rapport aux cellules « non souche » SQ20B/SP/CD44low/ALDHlow, implique une diminution de la mort par apoptose, une augmentation des capacités prolifératives ainsi qu'une surexpression de la voie de l'autorenouvellement Bmi1. L'effet radiosensibilisant de 3 molécules ciblant les CSC a été démontré : la mort apoptotique induite par l'UCN-01 en inhibant l'arrêt en phase G2/M ; les capacités prolifératives ciblées par l'acide trans-rétinoïque (ATRA) induisant la différenciation ; et la voie de l'autorenouvellement Bmi-1 inhibée par l'artésunate. Seule ou associées (UCN-01 + ATRA), elles agissent en synergie avec une irradiation par photons ou ions carbone. Des études pré-clinique, puis clinique, devraient confirmer l'intérêt du ciblage des CSC dans le contrôle de l'échappement de ces cancers radiorésistants / Head and neck squamous cell carcinomas (HNSCC) have a poor prognosis, due to their resistance to standard treatments. In most cases, locoregional recurrence or metastases occur. This study has focused on the role of cancer stem cells (CSC) in the radioresistance of the SQ20B HNSCC cell line and their therapeutic targeting in association with photon or carbon ions irradiation. A subpopulation of SQ20B-CSC has been isolated by cell sorting based on 3 specific characteristics of HNSCC-CSC : Hoechst 33342 exclusion, CD44 expression and high aldehyde dehydrogenase activity (ALDH). SQ20B/SP/CD44high/ALDHhigh cells show the CSC characteristics (in vitro and in vivo tumorigenesis, high radioresistance). The response of CSC to both types of irradiation was compared to the non-“stem cells” SQ20B/SP/CD44low sub-population. The observed radioresistance involves a decrease in apoptotic cell death, an increase in proliferative capacities and an overexpression of the Bmi1 self-renewing signaling pathway. The radiosensitizing effects of 3 molecules targeting the CSC has been demonstrated : an induction of apoptotic cell death by the inhibition of the G2/M phase arrest after a treatment with UCN01 ; an inhibition of proliferative capacities using the all-trans-retinoic acid (ATRA) which induce their differentiation ; and an inhibition of Bmi1 by artesunate. These treatments, alone or in combination (UCN01+ATRA) have a synergistic effect with photon or carbon ion irradiation to overcome CSC radioresistance. Preclinical and clinical studies should confirm the benefit of targeting CSC and improve the control of tumor escape in patients with radioresistant HNSCC cancers

This thesis seeks to answer the question of how Joseph Smith—History found in The Pearl of Great Price developed into a part of the canon of The Church of Jesus Christ of Latter-day Saints. When the prophet Joseph Smith first dictated the text to his scribes it seems he had not intended for the work to become scripture, but simply to follow the Lord's divine mandate to keep a record. Additionally he provided the purpose in his document to "disabuse the public mind, and put all inquirers after truth in possession of the facts, as they transpired." The format he proposed for the Manuscript History illustrates how it was originally not purposed for scripture. The compiling of that history took the efforts of many men and women and spanned the length of almost twenty years to complete. Joseph Smith had begun the dictation to his scribe George Robinson in 1838, but it was unfinished. Joseph later began the dictation anew to his scribe James Mulholland, first having the man rewrite what he had told to Robinson and then picking up the dictation from there. While the prophet had started and stopped histories before, this particular dictation began the enduring effort. The Manuscript History was developed from the original 59 pages that were scribed by Mulholland. By the efforts of other scribes, but mostly Willard Richards, the history was completed. The official statement of Brigham Young and Orson Pratt upon its completion said nothing of extracting portions for canon. But Mulholland's work seemed destined for a different purpose than the rest of the Manuscript History. It was printed serially in the Times and Seasons, and a few apostles seemed to catch a vision of what the manuscript could do for potential converts and members of the Church. Orson Pratt was especially a proponent of communicating certain key events as illustrated in his missionary tract "Remarkable Visions." A later apostle, Franklin D. Richards, would see the benefit of using the official history to distribute the history of the restoration of the Church to others. He extracted portions from Mulholland's text that covered certain main events in Joseph's life and printed them in his missionary tract The Pearl of Great Price. This pamphlet would eventually be canonized by The Church of Jesus Christ of Latter-day Saints in 1880. Joseph Smith-History's inclusion in the reclamation of revelation that occurred in 1880 was deserved. This is evidenced by examining the process of canonization and the guiding principles of canonization employed by the Church of Jesus Christ of Latter-day Saints. It was canonized at the same time as many other revelations and at a General Conference saturated with many important events. Consequently it is difficult to gauge the reaction to its inclusion in canon, except in how it has been used since its canonization. After its inclusion into scripture the text has become a foundational piece of literature for the Church. The impact the text has had can be seen in the culture, missionary work, and doctrine of the Church. The focus of this thesis is to map the text's journey from birth to canonization.

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The thesis uses the case study of the experience of middle-class northern white women in America during the period 1800-1860 to explore several issues of wider significance. Firstly, the research focuses upon the dynamic relationships between the culturally-constructed categories of public/formal and private/informal power and participation at both the practical and symbolic levels, suggesting ways in which they intersected on the lives of women. Secondly, consideration is given to the validity of the stereotyped view that 'domestic' women were necessarily disadvantaged and dominated relative to those who aspired to public political and economic roles. Thirdly, the relationship of religious belief to these two areas is discussed, in order to discover its relevance to the way in which women both perceived themselves and were perceived by others. In seeking to explore these issues, the research has analysed the patterns of social and cultural change in the era under question, indicating how those changes influenced the perceptions and experiences of both women and men. Their reactions in terms of discourse and activity are located as strategies of negotiation in redefining both social role and participation for the sexes. The rhetoric of 'separate spheres', which was used by men and women to order their mental and physical surroundings, is reduced to its symbolic constituents in order to illustrate that the distinction between male and female arenas was more perceptual than actual. The motivating forces behind the activities and ideas of women themselves are investigated to determine the role of religion in the construction of both female self-images and wider negotiational strategies. The context of nineteenth-century social dynamics has been revealed by detailed analysis of extensive primary sources originated by both women and men for private as well as public consumption. Feminist tools of analysis which enable the conceptualisation of 'meaningful discourse' as including female contributions have further enhanced the specific focus on how women constructed their own world-views and approaches to reality. 'Traditional' approaches and tools are shown to have seriously skewed and misrepresented the reality and variety of both discourse and female experience in the era. Great efforts have been made to allow women to speak in their own words. This has produced an insight into a richness of female social participation and discourse which would otherwise be obscured. The research indicates that women were indeed actors and negotiators during the period. Those women who advocated as primary the duties of women in the domestic and social arenas were by no means setting narrow limitations on female participation in both society and discourse. The religious impulses and eschatological frameworks derived by women (varied as they were) served to order and renegotiate reality and meaning, whilst they produced female roles and influence of great significance. Women were not passive victims of male oppression. Religion can thus be perceived as a positive force which women were able to approach both for its own sake, and for their own particular ends.