A presente pesquisa procura reunir as reflexões pictóricas de Anselm Kiefer no âmbito da tradição intelectual da literatura, do mito, da história e da religião, e que se condensam na categoria da catástrofe de O Drama Barroco Alemão e do Trabalho das Passagens de Walter Benjamin. Procuraremos mostrar o estatuto da metrópole como o lugar do Mal, inscrevendo as produções artísticas de Anselm Kiefer no campo do pensamento trágico da vida, no sentido de viver sem o Bem e sob o amparo do Mal. Kiefer apresenta-se como o pintor cujas produções oscilam entre a Hybris do progresso e o terror da máxima destruição, do silêncio e do automatismo voltados para uma permanente catástrofe. Ao fim, delineia-se uma utopia negativa de uma barbárie positiva em meio ao Mal, que se tornou radical na nossa contemporaneidade. / The present Dissertation attempts to bring together Anselm Kiefers pictorial reflections toward the intellectual tradition sphere that encompasses Literature, Myth, History and Religion, all condensed by the Catastrophe label detached from The Origin of the German Tragic Drama and The Arcades Project both written by Walter Benjamin. The depiction of the Modern Metropolis as an embodiment of Evil is part of Anselm Kiefer artistic poetics. Kiefer depicts himself as the painter whose pictorial masterpieces oscillate between the Progress Hybris and the Terror of the supreme destruction, silence abysses in an ineluctable catastrophe. Towards the end, a negative utopia is outline from a positive barbarism, among the Evil that became radical in our contemporary societies.

Made available in DSpace on 2016-04-28T20:37:57Z (GMT). No. of bitstreams: 1 Suzana Maria da Silva Ferreira Lima.pdf: 540059 bytes, checksum: a3651ac146e9876634f6c5eb53662120 (MD5) Previous issue date: 2011-11-21 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This research reflects on the psychic trauma and the affectations that emerge from this experience in the clinic. For this purpose, it will be used Freudian theory of trauma as a random event whose quantum of pain cannot be assimilated by the ego, as well as the Ferenczian concept of autoclivagem as a psychic mechanism used by the ego as protection from trauma. The construction of metapsychology is guided by the position of fundamental psychopathology that prioritizes the research of the affectations raised in the act of clinic. The guiding case is about a woman whose hair was pulled by the motor shaft of a boat. This accident occurs in riverside areas along the Northern Brazil and is called scalping . It is a catastrophic accident characterized by partial or total loss of the scalp, becoming an event that causes turnaround in the person who experienced, producing significant changes in that person s life. In the course of this work, we turn to the clinic to name the position of the analyst before the pain. In this sense, we highlight the writings of Nasio (1997) to elucidate: tune yourself with the pain, try to vibrate with it, and, in this state of resonance, expect to spend time and words. (p. 17) Thus, it is essential to be able to wait for a time when the pain may have another sense. The analyst offers his body as a mediator between the self and the pain so he can also bear witness to the narrative of trauma and lead to a possible transformation of traumatic experience in experience / A proposta desta pesquisa é refletir sobre o trauma psíquico e as afetações que emergem dessa vivência na clínica. Para tanto, utilizar-se-á a teoria freudiana do trauma como um evento surpresa que possui um quantum de dor impossível de ser assimilável pelo eu, bem como o conceito de autoclivagem de Ferenczi como mecanismo psíquico utilizado pelo eu para se proteger de um trauma. A construção da metapsicologia se pautou pela posição da psicopatologia fundamental que prioriza a pesquisa das afetações suscitadas no ato de clinicar. O caso clínico norteador foi o de uma mulher que teve seus cabelos arrancados pelo eixo do motor de um barco. Este acidente acontece nas regiões ribeirinhas do Norte do Brasil e é denominado de escalpelamento. É um acidente catastrófico caracterizado pela perda parcial ou total do couro cabeludo, configurando-se um evento que provoca reviravolta naquele que o vivencia, produzindo transformações significativas em sua vida. No transcurso deste trabalho, recorremos à clínica para citar a posição do analista perante a dor. Neste sentido, destacam-se os escritos de Nasio (1997) ao elucidar: afinar-se com a dor, tentar vibrar com ela e, nesse estado de ressonância, esperar que o tempo e as palavras gastem . (p. 17) Assim, é primordial estar em condições de espera de um tempo em que a dor possa ter um outro sentido. O analista oferece seu corpo como mediador entre o eu e a dor para que também possa suportar o testemunho da narrativa desse trauma e conduzir-se para uma possível transformação de vivência traumática em experiência

The thesis analyses recent important issues affecting the insurance industry (both global and local). 1.EU anti-discrimination policy's impact on insurance risk 2.Catastrophe Risks and Reinsurance, Earthquake in Japan, 2011 3.BankInsurance - Single-Premium Life Insurance 4.Pension reform: New opportunities for private insurers 5.The reasons of low performance of non-life insurance industry

La notion de cope with souvent traduite en France par l’expression « faire face », est régulièrement utilisée pour définir et expliquer la vulnérabilité et la résilience des sociétés. L’opérationnalisation de cette notion s’accomplit grâce aux coping capacities. Les cadres internationaux de prévention et de gestion insistent sur la nécessité de développer ces capacités à l’échelle des communautés et des territoires, en préparant les individus à « faire face », afin de réduire leur vulnérabilité et les rendre résilients.Le cope with n’a pourtant jamais été clairement décrit et surtout défini dans la littérature scientifique. En partant de ce constat, cette thèse va chercher à comprendre les liens existants entre la vulnérabilité, le cope with et la résilience. Pour cela, la recherche s’appuie sur l’étude des trajectoires de résilience territoriales et individuelles dans le contexte caribéen. Trois terrains d’étude, qui ont subi chacun des crises majeures, ont été choisis : La Martinique, La Guadeloupe et Haïti. L’enquête de terrain s’est appuyée sur la collecte de récits de vie, sur des entretiens et des questionnaires, sur de l’observation participante et non participante mais aussi sur un travail d’archives.Cette thèse démontre plusieurs résultats. Premièrement, les trajectoires de résilience territoriales ne coïncident pas avec les trajectoires de résilience individuelles. La résilience du territoire n’implique pas forcément celle de ses habitants et inversement. La thèse spécifie ici les différents états que peut prendre la résilience territoriale et individuelle et revient sur les notions de crise et de catastrophe. Ensuite, le cope with peut être appréhendé grâce aux réponses que les gens mettent en œuvre face aux perturbations. Ces réponses font l’objet d’une typologie, puis sont réinterprétées grâce aux notions d’ajustement et d’adaptation, ce qui permet de revenir sur la traduction du cope with. La thèse montre enfin qu’il n’y a pas de causalité linéaire entre la mise en œuvre des coping capacities des individus, les réponses observées et la résilience. L’approche par les capabilités, développée par A. Sen, est alors appliquée au champ des risques et des catastrophes. Elle permet de montrer l’importance des choix et de la liberté individuelle, et de recontextualiser le cope with. Cette thèse propose alors de remplacer la notion de coping capacities par celle de coping capabilities, pour comprendre comment chaque individu « fait face », dans une situation précise, dans un contexte territorial précis et dans une temporalité particulière à un événement singulier. / The notion of cope with, often translated in french by the expression "faire face", is usually used to define and explain the vulnerability and resilience of societies. This concept is made effective through coping capacities. International prevention and management frameworks emphasize the need to develop these capacities at the community and territorial scales by preparing individuals to "cope" in order to reduce their vulnerability and make them resilient.However the notion of cope with has never been clearly described and defined in scientific literature. Based on this observation, this thesis aims at understanding the existing links between vulnerability, cope with and resilience. To this end, the research is based on the study of territorial and individual trajectories of resilience in the Caribbean context. Three study areas which has suffered major crises, have been chosen : Martinique, Guadeloupe and Haiti. The investigation was based on the collection of life stories, interviews and questionnaires, participant and non-participant observation and archival work.This thesis demonstrates several results. First, territorial resilience trajectories do not coincide with individual resilience trajectories. The resilience of the territory does not necessarily imply the resilience of inhabitants and inversely. The thesis here specifies the different states that territorial and individual resilience can take on and goes back over the notions of crisis and disaster. Then, the notion of cope with can be grasped thanks to the answers that people implement in the face of disturbances. These answers are the subject of a typology, then reinterpreted thanks to the notions of adjustment and adaptation, which makes it possible to return to the translation of the cope with. Finally, the thesis demonstrates that there is no linear causality between the implementation of individuals' coping capacities, observed responses and resilience. The capability approach developed by A. Sen is then applied to the area of risks and disasters. It shows the importance of individual choices and freedom, and to recontextualize the notion of cope with. This thesis proposes then to replace the notion of coping capacities by the concept of coping capabilities, to understand how each individual "cope with", in a precise situation, on a given territory and in a particular temporality.

<p>The traditional standing in the practice of negotiation which is main concerned with the substance of the proposal for a solution has been somewhat altered by Zartman who do acknowledge the importance of the first idea but adds the dimension of the timing of the efforts for a resolution. Throughout the schools of crisis management and conflict resolution this concept has made its name as the ‘ripeness theory’. The focal point of the theory is termed as the ‘Mutually Hurting Stalemate’ (MHS), a situation where the conflicting parties sense their positions in a hurting impasse.</p><p>The concept of a ripe moment does not only centre on the parties’ perception of a MHS but is optimally associated with an impending, past or recently avoided catastrophe. Even though the catastrophe is not necessary to either the definition or the existence of a MHS it provides a deadline or a lesson that pain can be sharply increased in something is not done about it now. This in linked with the idea behind the concept that, when the parties find themselves locked into a conflict from which they cannot escalate to victory and this deadlock is painful to them (although not necessarily in equal degrees or for the same reasons), they seek a way out.</p><p>A unique opportunity presented itself when a earthquake struck the areas between India and Pakistan the 8th of October 2005. Did the post-quake scenario present a new opportunity to collaborate on immediate relief activity and long-term build up? Could suspicion be buried with the wreckage? Could the disaster be a push to intensify the peace process?</p><p>The aim of this study is to find out if the disaster has made the conflict ripe for resolution or more advanced mediation. The empirical chapters is going down two avenues including the political elites (and their actions) as well as the internal political process which in this study is made up by a) the militancy, and b) editorials from major Pakistani and Indian newspapers.</p><p>The results of the study can be summed with that the earthquake has not made the conflict ripe for resolution (as in final resolution) but definitely made it ripe for more advanced mediation. This is based on the numerous important counter building measures carried out by the elites of India and Pakistan and the fact that the Kashmiri people were involved in the process. As for the internal political process the militancy did not show any will of collaborate or changing position in the conflict. The results of the newspaper’s editorials is not entirely positive either although both Pakistan and Indian newspapers had a rather positive outlook towards the increased Indo-Pak cooperation and the prospects for the future.</p>

Radioimmunotherapy is becoming important as a new therapeutic strategy for treatment of tumour diseases. Lately monoclonal antibodies tagged with radionuclides have demonstrated encouraging results in treatment of hematological malignancies. The progress in treatment of solid tumours using radioimmunotherapy, however, has been slow. New strategies to improve the treatment response need to be evaluated. Such new strategies include the combination of radioimmunotherapy with other treatment modalities but also elucidation and exploration of the death effector mechanisms involved in tumour eradication. As the combination of radioimmunotherapy and radiotherapy provides several potential synergistic effects, we started out by optimising a treatment schedule to detect benefits combining these treatment modalities. An anti-cytokeratin antibody labelled with 125I administered before, after, or simultaneously with radiotherapy, indicated that the highest dose to the tumour was delivered when radiotherapy was given prior to the antibody administration. The optimised treatment schedule was then applied therapeutically in an experimental study on HeLa Hep2 tumour bearing nude mice given radiotherapy prior to administration of 131I-labelled monoclonal antibodies. Combining these treatment regimes enhanced the effect of either of the treatment modalities given alone, and a significant reduction in tumour volumes could be demonstrated. This treatment caused a dramatic change in tumour morphology, with increased amounts of connective tissue, giant cells and cysts. Furthermore cellular alterations like heterogeneity of nuclear and cytoplasmic size and shape were observed, and at least a fraction of the tumour cells presented some characteristics of apoptosis. The induced sequential events in Hela Hep2 cells exposed to 2.5-10 Gy of ionizing radiation were studied further, with special emphasis on cell cycle arrest, mitotic aberrations and finally cell death. Following radiation HeLa Hep2 cells initiated a transient G2/M arrest trying to repair cellular damage. This arrest was followed by a sequence of disturbed mitoses with anaphase bridges, lagging chromosomal material, hyperamplification of centrosomes and multipolar mitotic spindles. These mitotic disturbances produced multinuclear polyploid cells and cells with multiple micronuclei, cells that were destined to die via mitotic catastrophes and delayed apoptosis. Induction of apoptosis in HeLa Hep2 cells following radiation doses and dose-rates equivalent to those delivered at radioimmunotherapy was concurrently studied in vitro. Significant induction of apoptosis was obtained and found to be induced relatively slowly, peaking 72-168 hours post irradiation. Caspases from the intrinsic pathway as well as the extrinsic pathway were found to be activated in response to ionizing radiation. Furthermore caspase-2, which has recently been acknowledged for its role as an initiator caspase was found to be activated following radiation and seems to play an important role in this delayed apoptosis.

Le corpus des oeuvres volodiniennes met en scène des êtres qui résistent à la fin du monde: leur survivance est une résistance au temps de la fin qui bouleverse les conceptions classiques du temps, de l'espace et du corps. Le souffle collectif dans Des anges mineurs (1999) prolonge la puissance de la parole par laquelle émergent les sous-hommes dans des domaines aussi variés que l'ontologie, la politique et l'historiographie tout en portant à la conscience l'urgence de renouveler les bases d'un système de pensée effondré avec la chute des utopies du siècle dernier. L'étude des mutations de Will Scheidmann, porte-parole de la communauté des sous-hommes dans Des anges mineurs (1999), amorce une réflexion sur l'ampleur de la révolution proposée par Antoine Volodine avec ce recueil et dans l'ensemble de son oeuvre post-exotique. Inspirée du concept merleau-pontyen de la chair du monde, l'hypothèse de travail repose sur l'idée selon laquelle la révolution des paradigmes du temps, de l'espace et du corps fait muter l'ontologie, l'esthétique et le politique en prenant ancrage dans la chair-désastre du porte-parole. Retraçant les divers états du personnage-narrateur, nous montrons que le passage du corps individuel au corps collectif relève d'un rapport primaire au monde où l'être est intimement et charnellement connecté à la communauté des morts et des vivants qui le possèdent et auxquels il donne la parole qui fait survivre. Cette mise en abyme d'un corps individuel dans une chair du monde qui le transforme se répercute dans les processus d'élaboration du texte lui-même ainsi que dans la configuration d'une nouvelle Gestalt du corps politique. Le présent travail est donc l'analyse des mutations du corps comme métaphore des transformations des champs esthétique, politique et ontologique. La triple matrice anatomique, textuelle et communiste correspond au corps de Scheidmann et elle désigne la désuétude des anciennes Gestalts ainsi que les processus de transformation de la matière par lesquels émergent des formes neuves. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Mutation, Chair, Désastre, Communauté.

Ce mémoire en création littéraire se compose de deux parties : la partie création présente un recueil de nouvelles : Des catastrophes naturelles. Les huit textes mettent en scène des énonciatrices de différents âges et de différents milieux, ayant en commun la solitude et une certaine apathie. Cette apathie, proche de l'engourdissement, est ébranlée par un « accident », un événement mineur qui tient lieu de rupture dans le texte, de blessure (réelle ou symbolique) ouvrant sur l'angoisse et l'agressivité des protagonistes. Selon la logique de l'accident, ce sont les corps des personnages qui sont d'abord atteints. À la suite du choc, ils expérimentent un rapport hors norme à la quotidienneté, ressentent son étrangeté de façon accrue. Intensifiant cette impression de décalage, les nouvelles prennent majoritairement place dans des intérieurs urbains (balcons, chambres, cours, voitures, bureaux), où les personnages sont confrontés à leur vertige. Le dossier d'accompagnement s'intitule Le corps accidenté de l'Amérique: une poétique des lieux clos. L'enjeu principal de cet essai est d'interroger ma pratique d'écriture à travers l'exploration des lieux clos de l'intimité, paradigme négligé de l'imaginaire nord-américain. Le premier chapitre tente de déterminer s'il est possible d'appréhender l'Amérique « par dedans », c'est-à-dire par l'entremise d'un parcours intériorisé, en étudiant notamment notre rapport à la quotidienneté et au corps. Le deuxième chapitre s'intéresse à un réseau de lieux clos (corps, maison, ville) dont l'interaction dans les textes littéraires révèle la tentative d'habiter le continent et ses résultats ambivalents. Tout en établissant un dialogue avec des textes d'écrivaines québécoises et étasuniennes du 20e siècle, je m'emploie à définir la poétique sous-jacente à la figure du corps accidenté, placée au centre de cette réflexion. En cernant les principes et les procédés qui ont présidé à la composition de mon recueil, je cherche à montrer que l'américanité d'une écriture ne se reconnaît pas aux décors qu'elle plante ou aux clichés qu'elle disperse ici et là, tel que l'a formulé René Lapierre, mais bien à une sensibilité particulière aux catastrophes les plus infimes. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : nouvelle, américanité, corps, quotidienneté, lieu, ville, imaginaire de la fin.

Ce mémoire est né du désir de comprendre le rôle du motif de la catastrophe inaugurale dans les rhapsodies de la mémoire du théâtre québécois des années 1980 à nos jours. Pour cela, nous avons choisi un corpus d'envergure, c'est-à-dire les œuvres complètes de deux auteurs qui marquent fortement le paysage théâtral contemporain : Daniel Danis et Normand Chaurette. Notre travail de recherche fait apparaître le caractère structurant du motif non seulement au sein des pièces considérées séparément, mais aussi dans l'ensemble des œuvres. En effet, celles-ci s'articulent autour d'une même problématique. Elles inscrivent leur cheminement dans sa remise en jeu, et le redéploiement autour de celle-ci d'un nombre limité de motifs. Notre démarche comparatiste nous permet de mettre en valeur les choix et les partis esthétiques des deux auteurs en montrant la complémentarité de démarches rarement rapprochées. Au sein des deux œuvres, la catastrophe inaugurale provoque les mouvements qui animent le texte. Le premier que nous identifions est « horizontal » : la catastrophe déclenche le mouvement des corps dans un espace donné. Nous l'abordons à l'aune du concept de « déterritorialisation » élaboré par Gilles Deuleuze et Félix Guattari dans L'Anti-Œdipe et Mille Plateaux. Ce mouvement est situé au sein d'un espace territorial caractérisé par une certaine organisation sociale, dont il va venir éprouver les rapports de pouvoir. Au sein du texte, ce mouvement est lui-même emporté par un autre : celui du retour. Les œuvres de notre corpus présentent en effet une dimension métapoétique, et réfléchissent sur leur propre genèse. Au centre de cette réflexion se trouve à nouveau l'événement catastrophique, qui, par son intensité, vient confronter le langage au silence de l'expérience sensible. C'est à l'aune du concept de « répétition », élaboré par G. Deleuze dans Différence et répétition, que nous interrogeons la dimension métapoétique de la forme rhapsodique, cherchant à comprendre comment le langage met en scène l'opération de sélection par laquelle il est parvenu à sa propre forme stylisée. Loin de résoudre les paradoxes qu'elle met en scène, la rhapsodie épouse les conflits qu'elle représente pour remettre sans cesse en jeu les interrogations qui la travaillent : comment transmet-on la mémoire catastrophique? Quels rôles l'écriture dramaturgique peut-elle tenir dans cette transmission? ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : dramaturgie québécoise des années 80 à nos jours, mémoire, catastrophe, rhapsodie, conflit des codes, mouvement.

Background. Radiation therapy is an important treatment regimen for malignant disease. Radiation therapy uses ionizing radiation to induce DNA damage in tumor cells in order to kill them. Tumor cells are more sensitive than normal cells, since they have an increased proliferation rate and often lack the ability to properly repair the induced damage. Radiation can be delivered by an external source outside the body, by brachytherapy delivered inside the patient near the tumor, or systemically by injection into the blood stream. When delivered systemically, the radiation is administered as radioisotope alone or conjugated to antibodies targeting tumor antigens (radioimmunotherapy). Radiotherapy (RT) usually is administered using high doses, causing necrotic cell death. Low doses of radiation (by RT or RIT) have been observed to induce different types of cell deaths, like apoptosis, mitotic catastrophe or senescence.Aims. We wanted to elucidate the molecular and cellular events responsible for the induction of cell death in cells of different origin and p53 status. We also wanted to identify the kinetics behind gene expression alterations induced in response to irradiation and correlate these to cell death specific molecular and cellular events. In the end this research aims to identify key regulators of the main radiation induced cell death modalities in order to improve our understanding and potentially use this knowledge to increase treatment efficacy of radiation therapy. Methods. Four different cell lines were used in these studies to elucidate the role of p53 status cell origin in radiation induced cell death. HeLa Hep2 tumor cells have been used previously in our group in several RIT and RT studies. During these studies we observed morphological alterations in shrinking tumors that were typical for mitotic catastrophe. This led to studies on the underlying mechanisms causing these aberrations. Isogenic solid tumor cell lines HCT116 p53 +/+ and HCT116 p53 -/- were included to further elucidate the role of p53, and also to study senescence, one of the main outcomes in irradiated tumor cells. MOLT-4 was finally included to compare these finding to classical apoptosis. Gene expression analysis was done using Illumina bead chip arrays, and pathway analysis was performed using MetaCore (Thomson Reuters). Results. In paper I, II, and III, transient G2/M arrests were observed in HeLa Hep2 and HCT116 p53 -/- cells following irradiation. The lack of p53 in these cells caused checkpoint adaptation due to an unscheduled accumulation of genes promoting mitosis. Anaphase bridges were observedivin HeLa Hep2 cells, as a consequence of premature mitotic entry with unrepaired DNA damage. Centrosome amplification, as well as deregulation of genes involved in centrosome amplification and clustering was observed in both cell lines. We observed changes in expression of several genes responsible for maintaining the spindle assembly checkpoint (SAC) arrest. A prolonged SAC arrest has been shown to be important for execution of mitotic catastrophe. SAC activation was followed by mitotic slippage and a subsequent failure of cytokinesis. We observed multipolar mitoses (both cell lines), multiple- and micronuclei (HeLa Hep2, paper I), and an increased frequency of tetraploid cells (HeLa Hep2 and HCT116 p53 -/- cells). A fraction of HeLa Hep2 cells also displayed apoptotic features, including caspase activation and DNA fragmentation (paper I). These findings indicate that mitotic catastrophe and the activation of a delayed type of apoptosis are involved in cell death following RIT.HCT116 p53 +/+ cells induced both G1 and G2 arrest following irradiation (paper III). Gene expression analysis revealed significantly decreased expression of genes responsible for cell cycle progression (pronounced decrease compared to HeLa Hep2 and HCT116 p53 -/-), especially mitotic genes. The prolonged arrest transitioned into senescence starting 3 days following irradiation and peaked after 7 days. Several genes associated with SASP were upregulated in the same time frame as senescence was induced, further supporting the fact that senescence is the main radiation induced response in HCT116 p53 +/+ cells.MOLT-4 cells, similar to HCT116 p53 +/+ cells, induced both G1 and G2 arrests in response to irradiation (paper IV). Morphological studies revealed apoptotic features like shrunken cells with condensed DNA. Caspase assays showed increased activity of caspases -3, -8, and -9. Gene expression analysis confirmed an increased expression of genes important for both extrinsic (FAS and TRAIL) and intrinsic (BAX) apoptosis. Furthermore, changed expression also included genes involved in cell cycle checkpoints and their regulation and genes important for T-cell activation/proliferation. Conclusions. RIT is successfully used to treat lymphoma, but treatment of solid tumors with RIT is still difficult. This thesis elucidates cellular alterations characteristic for the 3 main radiation death modalities, i.e. mitotic catastrophe, senescence and apoptosis. Furthermore, cell death specific traits are correlated to alterations in gene expression. Treatment efficacy can potentially be improved by finding key cell death mediators to inhibit in combination with radiation. / Bakgrund. Strålbehandling används för att bota eller lindra symptomen av cancer och består av joniserande strålning vars syfte är att skada DNAt i cellerna vilket leder till att de dör. Tumörceller är känsligare för strålning än normala celler eftersom de delar sig i snabbare takt och ofta saknar förmågan att reparera skadorna som uppstår. Det finns flera typer av strålbehandling: extern strålbehandling, d.v.s. när strålkällan är placerad utanför kroppen, brachyterapi, när strålkällan placeras i en kapsel inuti kroppen, eller systemisk strålning, där en radioisotop injiceras, antingen själv eller kopplad till en antikropp, då kallad radioimmunoterapi (RIT). Vid extern strålbehandling använder man sig ofta av relativt höga doser av strålning under ett kortare tidsintervall. Dessa celler dör ofta en nekrosliknande död. Med RIT kan man behandla patienterna med lägre doser under en längre tid och strålningen kan riktas specifikt till tumören, vilket minskar risken för bieffekter. Dessa celler dör av andra former av celldöd, apoptos, senescence eller mitotisk katastrof. Apoptos är för många synonymt med programmerad celldöd, och sker till exempel i respons till DNA skada. En apoptotisk cell känns igen på sitt utseende med fragmenterat DNA, nedbrutet cytoskelett och apoptotiska kroppar. Senescence är associerat med cellens åldrande men kan även orsakas av DNA-skador, och är en vanlig form av celldöd hos solida tumörceller med funktionell p53-signalering. Bestrålade solida tumörceller som saknar p53-signalering, antingen på grund av mutationer eller på grund av virusinducerad inaktivering, dör oftast i en helt annan celldöd, kallad mitotisk katastrof. Avsaknad av p53 leder till att en cell som erhållit skador på DNAt inte klarar av att uppehålla cellcykeln länge nog för att reparera skadorna. Inte heller apoptos induceras, eftersom p53 saknas. Detta leder till att cellen kommer att gå in i mitos med skador i sitt DNA som ej hunnit repareras. Celler i mitotisk katastrof har ett väldigt typiskt utseende med multipla kärnor, mikrokärnor (kromosomrester), multipla centrosomer och multipolära mitotiska spindlar. En del celler dör i mitosen medan andra försöker dela sig och kan överleva i flera generationer till, dock med skador på DNA. Målet med denna avhandling var att utreda de molekylära och transkriptionella mekanismerna bakom strålningsinducerad celldöd, och p53s roll i detta. Dessa studier kan så småningom leda till att viktiga regulatoriska proteiner av de strålnigsinducerade celldödsmekanismerna kan identifieras. Specifika inhibitorer riktade mot dessa proteiner kan med ökad kunskap strategiskt användas i kombination med strålning och potentiellt leda till förbättrade behandlingseffekter. Metoder. Vi använde fyra cellinjer med olika bakgrund och p53 status. Vi har tidigare studerat HeLa Hep2 (en solid tumörcellslinje infekterad medviHPV som slår ut funktionen av p53) och sett vid både RT och RIT studier, att cellernas morfologi avviker från klassiks apoptos (stora celler med stora mängder DNA, istället för små celler med lite DNA). Detta ledde till studier av mekanismerna bakom denna avvikande cellmorfologin, som är typisk för mitotisk katastrof. Vi utökade studien med HCT116 p53 +/+ och HCT116 p53 -/- som är identiska så när som på p53, där ena cellinjen saknar denna gen. Detta skulle ge ökad förståelse för p53s roll vid mitotisk katastrof och även visa mekanismerna bakom senescence, en annan vanlig celldödsmekanism i strålade solida tumörceller. Även MOLT-4 inkluderades i studien för att kunna jämföra våra resultat med en cellinje som genomgår klassisk apoptos och är mer känslig för strålning. Resultat. I celler där mitotisk katastrof inducerades efter strålning (HeLa Hep2, HCT116 p53-/-) såg vi ett övergående G2 arrest. Eftersom cellerna inte klarade av att underhålla detta arrest, då de saknar p53, fortsatte de in i nästa fas av cellcykeln, mitos. Detta ledde till att DNA skador kvarstod och en ökad frekvens av anafasbryggor. Dessutom skedde en centrosomamplifiering i dessa celler vilket gav upphov till multipolära mitotiska spindlar och en efterföljande icke fungerande cytokines. Detta gav i sin tur celler med multipla kärnor eller mikrokärnor. En ökad frekvens av tetraploida och polyploidaEn förändrad expression av gener som kunde kopplas till flera av dessa för mitotisk katastrof specifika karaktäristika observerades också. Flera gener associerade med reglering av centrosomen och dess amplifiering, med kontrollen av cellens progression från G2 till M-fasen av cellcykeln, samt involverade i kontrollen av en rätt utförd mitos (SAC) hade en ändrad genexpression som korrelerade väl i tid med de ovan nämda fenotyperna. Caspaser som är viktiga för apoptos visade sig vara aktiva i HeLa Hep2, vilket indikerar att mitotisk katastrof kan leda till fördröjd apoptos. Men en del celler lyckas smita undan från apoptosinduktionen och fortsätter i en ny runda i cellcykeln, och detta kunde ses som en växande population viabla celler med ökad mängd DNA (tetraploida celler).HCT116 p53 +/+ celler som har funktionellt p53 kunde inducera både G1 and G2 arrest och genexpressionen visade att många gener som styr övergången till mitos var nedreglerade och förhindrade detta (till skillnad från HeLa Hep2 och HCT116 p53 -/-, där dessa nivåer var högre). Dessa arrester övergick till senescence 3 dagar efter strålning och många gener kopplade till senescence visade ett ökat uttryck. Vi såg ingen markant ökning av centrosomer eller polyploida celler vilket skiljde sig från HeLa Hep2 och HCT116 p53 -/-. Detta tyder på att senescence skiljer sig markant åt från mitotisk katastrof och att p53 är viktig för induktionen av denna form av celldöd.viiVi såg att MOLT-4, precis som HCT116 p53 +/+, inducerar både G1 and G2 arrest. Denna arrest resulterade dock i ökad expression av gener viktiga för cellcykelarrest och apoptosinduktion, och vi såg även en ökad aktivitet av caspaser. Morfologiska studier visade att strålade MOLT-4 celler ofta var små och hade kondenserat DNA, vilket är typiska kännetecken för apoptos. Strålning av MOLT-4 celler ledde till aktivering av klassisk apoptos, och tidsförloppet var mycket snabbare jämfört med de övriga cellinjerna. Slutsats. RIT är en framgångsrik metod för att behandla hematologiska maligniteter, men solida tumörer svarar fortfarande dåligt på denna form av behandling. Denna avhandling visar på komplexiteten bakom strålningsinducerad celldöd och att det är viktigt att identifiera de reglerande mekanismerna för att kunna förbättra RIT av solida tumörer. Vi visar även på vikten av p53 vad gäller tumörens respons av strålbehandling. Genom att identifiera viktiga proteiner för mitotisk katastrof, senescence, och apoptos, kan man utveckla inhibitorer mot dessa och använda de i kobination med RT och RIT för att förbättra behandlingseffekten.