Ο ακριβής ρόλος των μεταγραφικών παραγόντων AP-1, NF-κB και PPARγ στην καρκινογένεση του παχέος εντέρου δεν είναι πλήρως εξακριβωμένος. Είναι γνωστό ότι ο υποκινητής του γονιδίου cox-2 περιλαμβάνει περιοχές πρόσδεσης των μεταγραφικών παραγόντων AP-1 και NF-κB. ΣΚΟΠΟΣ Με σκοπό την διερεύνηση του ρόλου των AP-1, NF-κB και PPARγ στην καρκινογένεση του παχέος εντέρου, εξετάστηκε η έκφραση των c-FOS, pc-JUN (φωσφορυλιωμένος-ενεργός c-JUN), pIκB-α (φωσφορυλιωμένος IκB-α – δείκτης ενεργοποίησης του μονοπατιού του ΝF-κB), CBP (κοινός μεταγραφικός συνενεργοποιητής των AP-1, NF-κB και PPARγ), EGFR, p53, PPARγ και COX-2, τόσο στον φυσιολογικό εντερικό βλεννογόνο όσο και σε αδενοκαρκινώματα παχέος εντέρου. ΥΛΙΚΟ-ΜΕΘΟΔΟΣ Εφαρμόστηκε ανοσοϊστοχημική μεθοδολογία σε τομές μονιμοποιημένες σε ουδέτερη φορμόλη και εγκλεισμένες σε παραφίνη από 60 ασθενείς με καρκίνο παχέος εντέρου. Για κάθε ασθενή δημιουργήθηκε ένα “μοριακό προφίλ”, τόσο για τα φυσιολογικά επιθηλιακά κύτταρα όσο και για τα καρκινικά. Οι στατιστικές σχέσεις μεταξύ των μεταγραφικών παραγόντων και των γονιδίων-στόχων μελετήθηκαν με την χρήση του Spearman’s rho συντελεστή συσχετίσεως, και έγινε περαιτέρω ανάλυση και επιβεβαίωση των αποτελεσμάτων με την βοήθεια μη-παραμετρικής ανάλυσης Kruskall-Wallis. ΑΠΟΤΕΛΕΣΜΑΤΑ Ο pΙκΒ-α βρέθηκε υπερεκφρασμένος στο 81.7% των αδενοκαρκινωμάτων σε σχέση με το γειτονικό φυσιολογικό επιθήλιο και η έκφρασή του συσχετιζόταν θετικά με την COX-2 (Spearman’s rho = 0.513, P < 0.001). H έκφραση του PPARγ βρέθηκε ελαττωμένη στο 77.3% των αδενοκαρκινωμάτων και παρουσίαζε αρνητική συσχέτιση με την έκφραση της COX-2 (Spearman’s rho = -0.412, P < 0.001) και του pIκB-α (Spearman’s rho = -0.444, P < 0.001). Ο CBP βρέθηκε υπερεκφρασμένος στο 50% των αδενοκαρκινωμάτων σε σχέση με το γειτονικό φυσιολογικό επιθήλιο και η έκφρασή του συσχετιζόταν θετικά με την COX-2 (Spearman’s rho = 0.461, P < 0.001). Οι EGFR και pc-JUN βρέθηκαν υπερεκφρασμένοι στο 41.7% και στο 43.3% των αδενοκαρκινωμάτων, αντίστοιχα, σε σχέση με το γειτονικό φυσιολογικό επιθήλιο και η έκφρασή τους συσχετιζόταν θετικά με την COX-2 (Spearman’s rho = 0.444, P < 0.001 και Spearman’s rho = 0.431, P < 0.001, αντίστοιχα). Επιπλέον, η έκφραση του p53 εμφάνιζε θετική συσχέτιση με την έκφραση της COX-2 (Spearman’s rho = 0.435, P = 0.004). ΣΥΜΠΕΡΑΣΜΑΤΑ Η ανάλυση των παραπάνω αποτελεσμάτων οδηγεί στο συμπέρασμα ότι η επαγωγή του μονοπατιού EGFR–MAPK–AP-1 και του μονοπατιού του ΝF-κB, καθώς και η ελάττωση της έκφρασης του PPARγ, είναι σημαντικά γεγονότα κατά την διάρκεια της καρκινογένεσης του παχέος εντέρου. Οι σχέσεις μεταξύ των μεταγραφικών παραγόντων AP-1, NF-κB, PPARγ και της COX-2 οδήγησαν στην δημιουργία ενός μοριακού μοντέλου, το οποίο εξηγεί την υπερέκφραση της COX-2 στα αδενοκαρκινώματα του παχέος εντέρου. Η κλινική σημασία αυτού του μοντέλου για την χημειοπροφύλαξη και την θεραπεία του καρκίνου παχέος εντέρου συζητείται διεξοδικά. / The exact role of AP-1, NF-κB and PPARγ in the development of colon cancer remains to be elucidated. Cox-2 promoter contains transcriptional regulatory elements for various transcription factors including AP-1 and NF-κB. OBJECTIVE The present study evaluated the expression of c-FOS, pc-JUN (phosphorylated-active c-JUN), pIκB-α (phosphorylated IκB-α, a signaling intermediate of the NF-κB pathway), CBP (a known AP-1, NF-κB and PPARγ transcriptional coactivator), EGFR, p53, PPARγ and COX-2 in normal colonic epithelial cells and colon adenocarcinoma cells. METHOD Immunohistochemical methodology was performed on formalin-fixed, paraffin-embedded sections from 60 patients with colon adenocarcinomas. A “molecular profile” was created for each patient both for normal colonic epithelial cells and colon adenocarcinoma cells. Relationships between transcription factors and downstream molecular targets were evaluated by Spearman’s rho correlation coefficient and all results were further validated by nonparametric Kruskall-Wallis test. RESULTS pIκB-α was overexpressed in 81.7% of adenocarcinomas as compared to adjacent normal colon and correlated positively with COX-2 (Spearman’s rho = 0.513, P < 0.001). PPARγ was down-regulated in 77.3% of the adenocarcinomas and correlated inversely with COX-2 (Spearman’s rho = -0.412, P = 0.001) and pIκB-α (Spearman’s rho = -0.444, P < 0.001). CBP was induced in 50% of the cases and its expression correlated positively with COX-2 (Spearman’s rho = 0.461, P < 0.001). Induction of EGFR and pc-JUN was detected in 41.7% and 43.3% of the cases, respectively, and their expression correlated positively with COX-2 (Spearman’s rho = 0.444, P < 0.001 and Spearman’s rho = 0.431, P < 0.001, respectively). Moreover, p53 expression correlated positively with COX-2 (Spearman’s rho = 0.435, P = 0.004). CONCLUSIONS The results of this study indicate that activation of the EGFR–MAPK–AP-1 and NF-κB pathways as well as down-regulation of PPARγ expression are important events in colon carcinogenesis. The correlations between AP-1, NF-κB, PPARγ and COX-2 lead to the proposal of a dynamic molecular model that explains COX-2 induction in colon adenocarcinomas. The clinical implications of this model in chemoprevention and treatment of colorectal cancer are thoroughly discussed.

L'extinction du jugement civil désigne la privation des effets de l'acte juridictionnel, à la fois rouage technique commun aux différents procédés techniques extinctifs et moment choisi de la vie du jugement civil. La présente étude, qui propose une approche systématique des procédés techniques extinctifs, par la mise en lumière de leurs finalité et technique juridique, démontre leur irréductible diversité et leur complémentarité technique dans le droit du procès, qu'ils soient liés à une remise en cause de la chose jugée, à l'instar des voies de recours ou, au contraire, qu'ils soient indépendants d'une telle remise en cause, telle la prescription de la force exécutoire ou la caducité. L'analyse critique de la portée de l'extinction invite à vérifier, au-delà du jugement contentieux qui tranche définitivement en présence des parties leurs prétentions respectives et qui constitue l'archétype de l'acte juridictionnel, la résilience normative des autres jugements civils, en particulier des jugements provisoires et gracieux. Mis en lumière à partir des conditions plus ou moins restrictives auxquelles ces jugements civils peuvent être privés de leurs effets, leur degré variable de résistance à l'extinction à titre principal, dans le cadre des voies de recours, et à titre incident, en dehors d'elles, illustre les nuances de la force normative de ces autres jugements civils. La portée de l'extinction est encore révélatrice de la résilience des effets secondaires de l'acte juridictionnel. Elle est une mise à l'épreuve de leur qualification qui, jusqu'à présent, semble avoir été pensée sans autre perspective que la naissance du jugement civil et la permanence de ses effets. / The extinguishment of a civil judgment refers to the cancellation of the judgment’s effects, which is both a technical cog common to the various extinguishing technical processes and a crucial moment in the life of a civil judgment. This study, which proposes a systematic analysis of the extinguishing technical processes, by highlighting their purpose and legal technique, shows their irreducible diversity and technical complementarity in civil procedure, whether they involve challenging the res judicata (i.e. legal remedies) or not (i.e. time-barring of enforcement or lapsing). The critical analysis of the scope of the extinguishment entails checking, beyond the contentious judgment which definitively resolves the parties' respective claims (archetype of the civil judgment), the normative resilience of other civil judgments, in particular provisional and non-contentious judgments. The variable degree of resistance of the effects of civil judgments to their extinguishment, whether achieved via legal remedies or by other means, is highlighted by a consideration of the more or less restrictive conditions in which the judgments are deprived of their effects. This illustrates the nuances of the normative force of said civil judgments. The scope of the extinguishment is also indicative of the resilience of the secondary effects of the civil judgment. Examining such scope enables one to test the classification of the secondary effects which seem to have been considered so far only from the perspective of the issuance of the civil judgment and the permanence of its effects.

Nas últimas décadas, assistimos a uma verdadeira reabilitação da autoconsciência retórica – com Hayden White no papel de arauto – no âmbito da historiografia. Contudo, embora o trabalho de White tenha se mostrado para muitos – entre os quais me incluo – como uma tentativa de ―avanço‖ em nossa autoconsciência, ele foi, paradoxalmente, muitas vezes visto e apresentado em discursos escandalizados como sinônimo de ―retrocesso‖ e ―obscurantismo‖. Persuadido do contrário – de que o ―ceticismo‖ de White não é um mal – prejudicial, contraproducente ou pernicioso ao nosso ofício –, eu analiso críticas desferidas ao dito ―relativismo linguístico‖. Tendo em vista a controvérsia filosófica da linguagem como portadora de referencialidade ocorrida entre a primeira sofística e Platão no Mundo Antigo, demonstro como as censuras de Carlo Ginzburg – o mais virulento de seus críticos – buscaram fundamento na argumentação platônico-aristotélica contra o relativismo da primeira sofística. Reapresento também argumentos de outros historiadores escandalizados com o trabalho de White para evidenciar que um tópos comum na argumentação desses críticos constitui-se como platonismo: a noção de que o ―narrativismo‖ conduz ao dilema teórico da impossibilidade de dizer o falso, tese atribuída por Platão à primeira sofística, para quem os múltiplos discursos arruinariam a própria noção de verdade. Paralelamente, a fim de demonstrar que esse dilema existe apenas no horizonte platônico (que compartimenta verdade e ficção em dois blocos distintos e separados), reavalio a relação entre história, verdade e ficção. Por fim, e considerando a linguagem como um elemento inexpugnável do discurso nas ciências humanas, defendo as perspectivas de White e da primeira sofística contra o voo platônico de superação da nossa inevitável condição humana. / In the last decades, we have witnessed a true rehabilitation of rhetorical self-conscience – with Hayden White in the Herald paper – in the context of historiography. However, while White's work has been shown for many – including myself – as an attempt to ―advance‖ in our self-consciousness, he was, paradoxically, often seen and presented in scandalized discourses as a synonym for ―setback‖ and ―obscurantism‖. Persuaded otherwise – that the White‘s ―skepticism‖ is not an evil – harmful, counterproductive or pernicious to our craft – i analyze the criticisms triggered to the so-called ―linguistic relativism.‖ Considering the philosophical controversy of language as ―carrier of referentiality‖ occurred between the first sophistic and Plato in the Ancient World, I demonstrate how the reproaches of Carlo Ginzburg – the most virulent of his critics – sought essentials in the platonic-aristotelian arguments against the relativist of the first sophistry. I evaluate as well arguments of other scandalized historians with White's work to show that a common topos in the argument of these critics constitutes itself as Platonism: the notion that the ―narrativism‖ leads to the theoretical dilemma of the impossibility of say the false, argument given by Plato to first sophistic, and to whom the multiple discourses would undermine the very notion of truth. In parallel, in order to demonstrate that this dilemma exists only in the platonic horizon (which compartmentalize truth and fiction in two distinct and separate blocks), i evaluate again the relation between history, truth and fiction. Finally, and considering the language as an inexpugnable element of discourse in the human sciences, I advocate the prospects of White and the first sophistic against platonic flight overcoming our inevitable human condition.

Este trabalho busca desvelar e sistematizar claramente os princípios straussianos de filosofia política clássica e, especificamente, os princípios straussiano-platônicos do melhor regime. Isto é, este trabalho busca desvelar o que Leo Strauss acredita ser o começo da filosofia política clássica, o que Leo Strauss acredita ser a “metodologia” clássica à filosofia política e, especificamente, as conclusões de Platão sobre o melhor regime. Os primeiros são princípios straussianos, porque advêm da interpretação de Leo Strauss sobre vários filósofos clássicos; os últimos são straussiano-platônicos, pois advêm de uma interpretação straussiana de Platão. Por fim, a análise de Leo Strauss sobre a crise da modernidade e sobre a historiografia da filosofia são apresentadas a fim de que possamos entender por que e como trilhar o caminho straussiano aos clássicos. / This work intends to state and arrange clearly the Straussian principles of classical political philosophy and, especially, the Straussian-Platonic principles of the best regime. That is, this work intends to state what Leo Strauss thought to be the beginnings of classical political philosophy, what Leo Strauss thought to be a classical “methodology” for political philosophy and, finally, Plato's conclusions about the best regime. The first two are Straussian principles because they ensued from Leo Strauss' interpretation of various classical political philosophers and the last ones are Straussian-Platonic because they ensued from a Straussian interpretation of Plato. That being said, Leo Strauss' analysis of the crisis of modernity and Leo Strauss' historiography of philosophy are presented as requirements for a better understanding of what consists the Straussian way back to the classics.

A presente dissertação visa analisar os conceitos de mimesis e tragédia nas diferentes abordagens dos filósofos Platão e Aristóteles. O problema principal que condiciona a análise é a relação entre, de um lado, as obras de arte e, de outro, a realidade e os juízos morais. Esse problema é estudado através de uma análise dos principais textos nos quais os respectivos filósofos elaboraram suas reflexões sobre o tema, a saber, os livros II-III e X da República de Platão e A Poética de Aristóteles. Nessas diferentes obras vemos progressivamente a elaboração da primeira reflexão ocidental sobre a atividade artística em geral, com ênfase especial sobre a poesia trágica. A polêmica platônica em torno da mimesis e da tragédia tem por objetivo servir de pano de fundo para a compreensão da tese aristotélica de que a ação poética é distinta da ação tal como estruturada na vida, e, isso, em função da prioridade “ontológica” concedida à ação trágica com relação aos caracteres. A tese platônica relativa à arte, é de que a mimesis está na origem da perversão da alma intelectiva e racional capaz de estabelecer a verdade a partir da rememoração da Forma transcendente. Como a tragédia é a imitação da aparência visível das coisas, o que o poeta faz é absorver a coisa sensível em uma imagem parcial, isto é, um pequeno pedaço da coisa, visto que ela, quando sustentada unicamente pela posição do olhar do artista, estilhaça-se em uma multiplicidade cambiante de imagens que essa mesma coisa pode fornecer. É apenas a Forma transcendente que pode bloquear essa proliferação incessante de imagens que distorcem a imagem absoluta das virtudes e da verdade. Ao contrário, em Aristóteles, não vemos nada dessa redução da intriga (mythos) trágica aos conceitos discursivos ou aos valores estáveis éticos. Ao estabelecer o mythos como princípio formal da tragédia, Aristóteles subordina as demais partes constituintes da tragédia à ação enquanto disposição dos fatos em sistema. Assim, caracteres, discursos racionalmente articulados, espetáculo, etc., situam-se em uma posição secundária e subordinada correspondente ao princípio material, deixando-se, dessa maneira, determinar-se pela estrutura simultaneamente lógica e emocional da tragédia. Isso tem como consequência interditar a redução e a imobilização da tragédia em juízos morais enfáticos. / This thesis aims to analyze the concepts of mimesis and tragedy in the different approaches of the philosophers Plato and Aristotle. The main problem which makes the analysis is the relationship between, on one hand, works of art and, on the other, reality and moral judgments. This problem is studied through an analysis of texts in which their philosophers developed their thoughts on the subject, namely, books II-III and X of Plato's Republic and Aristotle's Poetics. In these various works gradually we build the first Western reflection on the artistic activity in general, with special emphasis on the tragic poetry. The controversy around the Platonic mimesis and tragedy aims to serve as the backdrop for understanding the Aristotelian view that the action as structured in life is distinct from the poetic action, and this, according to the priority "ontological" given the tragic action in relation to the characters. The Platonic theory on art is that mimesis is the origin of the perversion of the intellect and rational able to establish the truth from the transcendent form of remembrance. As the tragedy is the imitation of the visible appearance of things, what the poet does is absorb the sensible thing in a partial image, ie, a small piece of it, since she sustained only when the position of the artist's eye, shatters into a multiplicity changing images that that same thing can provide. In the transcendent Form is assigned the role of this interdict ceaseless proliferation of images that distort the image absolute virtues and truth. In contrast, in Aristotle, we see nothing that reduction of the tragic plot (mythos) to the concepts or discursive ethical values stable. In establishing the mythos as a formal principle of tragedy, Aristotle makes the other constituent parts of the tragedy to action as the facts available in the system. Thus, characters, speeches rationally articulated, performance, etc., lie in a secondary and subordinate position corresponding to the material principle, leaving themselves in this way be determined by the tragic structure both logical and emotional. This has the effect of banning the reduction and immobilization of the tragedy in emphatic moral judgments.

A presente dissertação visa analisar os conceitos de mimesis e tragédia nas diferentes abordagens dos filósofos Platão e Aristóteles. O problema principal que condiciona a análise é a relação entre, de um lado, as obras de arte e, de outro, a realidade e os juízos morais. Esse problema é estudado através de uma análise dos principais textos nos quais os respectivos filósofos elaboraram suas reflexões sobre o tema, a saber, os livros II-III e X da República de Platão e A Poética de Aristóteles. Nessas diferentes obras vemos progressivamente a elaboração da primeira reflexão ocidental sobre a atividade artística em geral, com ênfase especial sobre a poesia trágica. A polêmica platônica em torno da mimesis e da tragédia tem por objetivo servir de pano de fundo para a compreensão da tese aristotélica de que a ação poética é distinta da ação tal como estruturada na vida, e, isso, em função da prioridade “ontológica” concedida à ação trágica com relação aos caracteres. A tese platônica relativa à arte, é de que a mimesis está na origem da perversão da alma intelectiva e racional capaz de estabelecer a verdade a partir da rememoração da Forma transcendente. Como a tragédia é a imitação da aparência visível das coisas, o que o poeta faz é absorver a coisa sensível em uma imagem parcial, isto é, um pequeno pedaço da coisa, visto que ela, quando sustentada unicamente pela posição do olhar do artista, estilhaça-se em uma multiplicidade cambiante de imagens que essa mesma coisa pode fornecer. É apenas a Forma transcendente que pode bloquear essa proliferação incessante de imagens que distorcem a imagem absoluta das virtudes e da verdade. Ao contrário, em Aristóteles, não vemos nada dessa redução da intriga (mythos) trágica aos conceitos discursivos ou aos valores estáveis éticos. Ao estabelecer o mythos como princípio formal da tragédia, Aristóteles subordina as demais partes constituintes da tragédia à ação enquanto disposição dos fatos em sistema. Assim, caracteres, discursos racionalmente articulados, espetáculo, etc., situam-se em uma posição secundária e subordinada correspondente ao princípio material, deixando-se, dessa maneira, determinar-se pela estrutura simultaneamente lógica e emocional da tragédia. Isso tem como consequência interditar a redução e a imobilização da tragédia em juízos morais enfáticos. / This thesis aims to analyze the concepts of mimesis and tragedy in the different approaches of the philosophers Plato and Aristotle. The main problem which makes the analysis is the relationship between, on one hand, works of art and, on the other, reality and moral judgments. This problem is studied through an analysis of texts in which their philosophers developed their thoughts on the subject, namely, books II-III and X of Plato's Republic and Aristotle's Poetics. In these various works gradually we build the first Western reflection on the artistic activity in general, with special emphasis on the tragic poetry. The controversy around the Platonic mimesis and tragedy aims to serve as the backdrop for understanding the Aristotelian view that the action as structured in life is distinct from the poetic action, and this, according to the priority "ontological" given the tragic action in relation to the characters. The Platonic theory on art is that mimesis is the origin of the perversion of the intellect and rational able to establish the truth from the transcendent form of remembrance. As the tragedy is the imitation of the visible appearance of things, what the poet does is absorb the sensible thing in a partial image, ie, a small piece of it, since she sustained only when the position of the artist's eye, shatters into a multiplicity changing images that that same thing can provide. In the transcendent Form is assigned the role of this interdict ceaseless proliferation of images that distort the image absolute virtues and truth. In contrast, in Aristotle, we see nothing that reduction of the tragic plot (mythos) to the concepts or discursive ethical values stable. In establishing the mythos as a formal principle of tragedy, Aristotle makes the other constituent parts of the tragedy to action as the facts available in the system. Thus, characters, speeches rationally articulated, performance, etc., lie in a secondary and subordinate position corresponding to the material principle, leaving themselves in this way be determined by the tragic structure both logical and emotional. This has the effect of banning the reduction and immobilization of the tragedy in emphatic moral judgments.

Nas últimas décadas, assistimos a uma verdadeira reabilitação da autoconsciência retórica – com Hayden White no papel de arauto – no âmbito da historiografia. Contudo, embora o trabalho de White tenha se mostrado para muitos – entre os quais me incluo – como uma tentativa de ―avanço‖ em nossa autoconsciência, ele foi, paradoxalmente, muitas vezes visto e apresentado em discursos escandalizados como sinônimo de ―retrocesso‖ e ―obscurantismo‖. Persuadido do contrário – de que o ―ceticismo‖ de White não é um mal – prejudicial, contraproducente ou pernicioso ao nosso ofício –, eu analiso críticas desferidas ao dito ―relativismo linguístico‖. Tendo em vista a controvérsia filosófica da linguagem como portadora de referencialidade ocorrida entre a primeira sofística e Platão no Mundo Antigo, demonstro como as censuras de Carlo Ginzburg – o mais virulento de seus críticos – buscaram fundamento na argumentação platônico-aristotélica contra o relativismo da primeira sofística. Reapresento também argumentos de outros historiadores escandalizados com o trabalho de White para evidenciar que um tópos comum na argumentação desses críticos constitui-se como platonismo: a noção de que o ―narrativismo‖ conduz ao dilema teórico da impossibilidade de dizer o falso, tese atribuída por Platão à primeira sofística, para quem os múltiplos discursos arruinariam a própria noção de verdade. Paralelamente, a fim de demonstrar que esse dilema existe apenas no horizonte platônico (que compartimenta verdade e ficção em dois blocos distintos e separados), reavalio a relação entre história, verdade e ficção. Por fim, e considerando a linguagem como um elemento inexpugnável do discurso nas ciências humanas, defendo as perspectivas de White e da primeira sofística contra o voo platônico de superação da nossa inevitável condição humana. / In the last decades, we have witnessed a true rehabilitation of rhetorical self-conscience – with Hayden White in the Herald paper – in the context of historiography. However, while White's work has been shown for many – including myself – as an attempt to ―advance‖ in our self-consciousness, he was, paradoxically, often seen and presented in scandalized discourses as a synonym for ―setback‖ and ―obscurantism‖. Persuaded otherwise – that the White‘s ―skepticism‖ is not an evil – harmful, counterproductive or pernicious to our craft – i analyze the criticisms triggered to the so-called ―linguistic relativism.‖ Considering the philosophical controversy of language as ―carrier of referentiality‖ occurred between the first sophistic and Plato in the Ancient World, I demonstrate how the reproaches of Carlo Ginzburg – the most virulent of his critics – sought essentials in the platonic-aristotelian arguments against the relativist of the first sophistry. I evaluate as well arguments of other scandalized historians with White's work to show that a common topos in the argument of these critics constitutes itself as Platonism: the notion that the ―narrativism‖ leads to the theoretical dilemma of the impossibility of say the false, argument given by Plato to first sophistic, and to whom the multiple discourses would undermine the very notion of truth. In parallel, in order to demonstrate that this dilemma exists only in the platonic horizon (which compartmentalize truth and fiction in two distinct and separate blocks), i evaluate again the relation between history, truth and fiction. Finally, and considering the language as an inexpugnable element of discourse in the human sciences, I advocate the prospects of White and the first sophistic against platonic flight overcoming our inevitable human condition.

Este trabalho busca desvelar e sistematizar claramente os princípios straussianos de filosofia política clássica e, especificamente, os princípios straussiano-platônicos do melhor regime. Isto é, este trabalho busca desvelar o que Leo Strauss acredita ser o começo da filosofia política clássica, o que Leo Strauss acredita ser a “metodologia” clássica à filosofia política e, especificamente, as conclusões de Platão sobre o melhor regime. Os primeiros são princípios straussianos, porque advêm da interpretação de Leo Strauss sobre vários filósofos clássicos; os últimos são straussiano-platônicos, pois advêm de uma interpretação straussiana de Platão. Por fim, a análise de Leo Strauss sobre a crise da modernidade e sobre a historiografia da filosofia são apresentadas a fim de que possamos entender por que e como trilhar o caminho straussiano aos clássicos. / This work intends to state and arrange clearly the Straussian principles of classical political philosophy and, especially, the Straussian-Platonic principles of the best regime. That is, this work intends to state what Leo Strauss thought to be the beginnings of classical political philosophy, what Leo Strauss thought to be a classical “methodology” for political philosophy and, finally, Plato's conclusions about the best regime. The first two are Straussian principles because they ensued from Leo Strauss' interpretation of various classical political philosophers and the last ones are Straussian-Platonic because they ensued from a Straussian interpretation of Plato. That being said, Leo Strauss' analysis of the crisis of modernity and Leo Strauss' historiography of philosophy are presented as requirements for a better understanding of what consists the Straussian way back to the classics.

Les thérapies moléculaires ciblées ont changé la prise en charge des patients atteints de cancer, et en particulier dans le cancer colorectal (CCR). Il est important d’identifier des biomarqueurs de sensibilité ou de résistance à ces traitements. En premier, la signalisation en aval de l’EGFR au niveau tumoral pourrait conditionner la réponse au cétuximab dans les cancers colorectaux (CCR). Notre premier travail a évalué le niveau d’expression tumorale de phosphoprotéines de signalisation en aval de l’EGFR (p-MEK, p-ERK1/2, p-AKT, p-GSK3b, p-P70S6K) analysés par Bioplex phosphoprotein array chez 42 patients avec un CCR métastatique, traités par anti-EGFR. L’expression de p-P70S6K est plus faible chez les patients répondeurs (p=0,02). La survie sans progression (SSP) est supérieure en cas d’expression faible de p-P70S6K (p=0,0001) et p-MEK (p=0,0006). p-MEK et p-P70S6K ont une expression plus élevée chez les KRAS mutés et apparaissent comme deux marqueurs pronostiques indépendants de KRAS (HR 0,34, p=0,01 et HR 0,42, p=0,03). Ainsi, le niveau d’expression des phosphoprotéines en aval de l’EGFR pourrait prédire la réponse et la SSP dans les CCR traités par anti-EGFR, indépendamment du statut KRAS. Il est difficile dans certain cas d’avoir accès au tissu tumoral. L’ADN circulant (cADN) dans les stades avancés de cancer peut aider à la caractérisation moléculaire des tumeurs, en tant que biopsie. Notre deuxième travail a étudié la faisabilité, la sensibilité et la spécificité d’une technique de spectrométrie de masse (Sequenom) pour détecter des mutations (238 mutations parmi 19 oncogènes) à partir du tissu tumoral et du cADN de 105 patients ayant un cancer avancé. La concentration médiane de cADN était de 17ng/ml de plasma (0,5-1600), soit 3 fois le niveau chez les volontaires sains. En analyse multivariée, la concentration de cADN, l’albumine et l’état général étaient des facteurs prédictifs indépendants de la survie globale des patients. De plus, il existait une concordance élevée des statuts mutationnels (KRAS, BRAF et PIK3CA) entre le tissu tumoral et le cADN dans plusieurs types tumoraux (CCR, sein, mélanome): un taux de concordance de 70% pour le gène KRAS et de 100% pour le gène BRAF ont été retrouvés dans le CCR. Notre Étude suggère que l’analyse du cADN pourrait être un matériel utilisable pour la recherche de mutations, notamment dans le suivi des patients ayant un cancer du colon traités par thérapies ciblées. Notre travail a donc montré l’intérêt de poursuivre l’étude de facteurs moléculaires qui pourraient prédire la réponse ou la résistance à des thérapies ciblées utilisées dans les cancers du colon, au niveau du tissu tumoral (phosphoprotéines) ou au niveau du sang (cADN). / Especially in CRC, it is important to identify molecular targeted therapies biomarkers. First, additional markers of resistance to KRAS mutations could predict resistance to anti-epidermal growth factor receptor (EGFR) antibodies in advanced colorectal cancer (CRC). In our first study, in a series of 42 patients with advanced CRC treated with cetuximab/panitumumab, for whom KRAS status was previously determined, we retrospectively analyzed the intratumor expression of EGFR downstream signaling phosphoproteins of the RAS/MAPK and PI3K/AKT pathways (pERK1/2, pMEK1, pAKT, pP70S6K and pGSK3beta) using Bio-Plex phosphoprotein array. The expression of all the phosphoproteins was higher in KRAS mutated tumors than in WT tumors. The expression of pP70S6K was lower in responders than in nonresponder patients. In multivariate analysis, PFS was shorter for patients with high pMEK1 or pP70S6K expression, independently of KRAS status, as OS for patients with high pP70S6K expression. Our results suggest the importance of EGFR downstream signaling phosphoproteins expression in addition to KRAS status to define the subgroup of patients who will not benefit from anti-EGFR therapy. We hypothesized that circulating plasma DNA (cpDNA) in advanced cancer patients is largely derived from tumor, and can be utilized for tumor mutation sequencing when repeat biopsy is not feasible. In our second study, we utilized the Sequenom MassArray System and OncoCarta panel for somatic mutation profiling. Matched samples, acquired from the same patient but at different time points were evaluated; these comprised formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (primary and/or metastatic) and cpDNA. The feasibility, sensitivity, and specificity of this high-throughput, multiplex mutation detection approach was tested utilizing specimens acquired from 105 patients with solid tumors referred for participation in Phase I trials of molecularly targeted drugs. The median cpDNA concentration was 17 ng/ml (range: 0.5-1600); this was 3-fold higher than in healthy volunteers. In multivariate analyses, cpDNA concentration, albumin, and performance status remained independent predictors of OS. We also observed high detection concordance for critical "hot-spot" mutations (70% for KRAS, 100% for BRAF) in matched cpDNA and archival tumor tissue. This multiplex sequencing assay can be utilized to detectsomatic mutations from plasma in advanced cancer patients, when safe repeat tumor biopsy is not feasible and genomic analysis of archival tumor is deemed insufficient. Our work did show the importance to search for molecular markers to predict response to targeted therapies, both in tumor tissu (phosphoproteins) and in blood (cpDNA).

Pas de résumé / No abstract