Добірка наукової літератури з теми "France, convention nationale, 1792-1795"

The article is devoted to the formation of republican and imperial emblems of the late 18th — early 19th centuries. in France, an important element of which was the state seal. A complete break with the heraldic tradition of the Old Order ended not in 1789, but in 1792 in connection with the overthrow of the monarchy. In August 1792, the National Convention approved a new state seal, which was used until 1804 with minor changes. The central element of the seal — the allegory of Liberty in the image of a woman was a well-known visual representation of the image of France from the very beginning of the Revolution, but in September 1792 it for the first time acquires the official status of a state emblem. The author shows how the revolutionary leaders made attempts to replace this image with others, wanting to emphasize the radical break and aspects of their political program. The projects of 1793 by Jean-Louis David and 1796 by Henri Gregoire differed significantly from each other. But the decree on the state seal of 1793, according to which the image of Liberty should be replaced by the image of Hercules, was not put into practice, and Gregoire’s proposals were completely rejected. On the basis of elements of revolutionary emblematic and neoclassical heraldic designs, in June — July 1804, a new state seal of the empire was created, the central elements of which are a golden eagle on an azure field and the image of Napoleon sitting on a throne in imperial insignia. The author emphasizes that the Napoleonic system of heraldic representation was originally conceived by Bonaparte and his advisers as an important political resource.

Drawing on the writings of Henri Grégoire, abbot and constitutional bishop, member of the French National Convention, and other sources, the authors of the article analyse various aspects of the religious policy of the French revolutionary authorities in the new French department of Alpes-Maritimes (until 1792 — the county of Nice within the Kingdom of Sardinia). In March — April 1793, members of the Convention, in their capacity as commissioners of Paris, were on a mission to Nice, where they were engaged in organising new institutions of power and dealing with other issues of social and religious life. In historiography there is a good tradition of research on the activities of Grégoire and Jagot in the Alpes-Maritimes Department (Henri Moris, Joseph Combet, Françoise Hildesheimer, Michèle-Helyett Siffre, Georges Doublet, Alyssa Goldstein Sepinwall, Marc Ortolani). However, a number of important pieces of evidence have remained out of the historians’ view. As the authors demonstrate, in many respects the members of the Convention were successful. They reorganised all the municipalities, formed three new districts, organised the election of administrators, magistrates, judges and members of the Convention, settled relations with people’s societies which, during the breakdown of power, had tried to take over some of the administrative powers, and forced the enrolment of “new citizens” in the National Guard and as volunteers. Only the “question of religion” remained unresolved. Grégoire and Jagot avoided radical steps: the time for the total “de-Christianisation” that swept across France in waves in 1793—1794 was not yet ripe. Examples of a cautious “preaching” strategy in this matter are the numerous letters and instructions of the Convention commissioners, as well as Grégoire’s “Address” to the citizens of Nice, published in Italian, apparently at the end of April 1793, which, so far, has not been studied by historians. The Appendix to this article contains the first Russian translation with commentary of “An Address to the Citizens of the Department of Alpes-Maritimes by Citizen Grégoire, Member the National Convention and Commissioner of the Same in This Department. Nice, 1793” (“Indirizzo a’ cittadini del dipartimento dell’ Alpi Marittime del cittadino Gregoire deputato, e commissario della Convenzione Nazionale in questo dipartimento. Nizza, 1793”).

Goethe’s novel Wilhelm Meister’s Apprenticeship, published in 1795, provides a fictional account of a theatrical production of Shakespeare’s Hamlet. Its initiator is young Wilhelm, whose experiences with this project, in the context of the novel, mark a decisive stage in his education and personal development; as well as, on another level, in the formation of a German national theatre, the mapping out of a theatrical space peculiar to the German national character. To realize his project Wilhelm has to negotiate with his manager and his fellow-actors; these negotiations can be considered reflections of the cultural aspirations and constraints prevalent late 18th-century Germany: – The project itself, as represented by Wilhelm, appears to be informed by a cultural movement towards emancipation from French culture: The character of Hamlet was interpreted as representing a role model for young Germans. – Informed by a theatrical practice based on French conventions, the manager objects to the lack of dramaturgical coherence of the Shakespeare play. As a compromise, Wilhelm composes an adapted version in which references to Wittenberg, Poland, France and England as well as several minor characters are cut, but the Hamlet scenes and speeches are retained. – Wilhelm and his friends also take account of German audiences’ preferences and capacities.The Hamlet project in Wilhelm Meister can be considered a case study of cultural appropriation. Shakespeare becomes a cultural import, used to define and map a cultural space for the German middle class, which in the nineteenth century set store by the quality of its educational make-up.

The availability, distribution and control of freshwater resources have been at the centre of the human story since the start of the Neolithic revolution roughly 12,000 years ago. With the advent of the modern nation state and its attendant emphasis on sovereignty, self-sufficiency and rivalry, it comes as no surprise that interactions between states over shared watercourses have at times been tense and conflictual. This fact was elaborated by the Ex- UN Secretary General; Kofi Annan, Message during the World Water Day on 22nd March, 2002. He warned that… “Fierce national competition over water resources has prompted fears that water issues contain the seeds of violent conflict. By the year 2025 two thirds of the world’s population is likely to live in countries with moderate or severe water shortages as demand for water approaches the limit of the available supply”. Water as a fugitive resource, respects neither political boundaries nor commonly accepted notions of fairness or equity, hence posed the most complex management challenges to water managers of today. In the SADC region, shared waters cannot be viewed in a purely national context due to its fluidity and the mobility of its nature. It is factual that, over 70% of the water bodies in the region are transboundary in nature. In terms of state practice, the concept of community of interest is commonly traced back to a French decree of 1792 dealing with the opening of the Scheldt River to Navigation. The position expressed in this decree was quickly adopted in a number of instruments concerned primarily with rights of navigation in international rivers, but also in some early agreements not restricted to navigational uses. Therefore, the lakes, and watercourses which form the frontier between the two states or which are situated at the territory of both or which flow into the said lakes and watercourses shall continue to be considered as “common’. In this regard one may wish to refer to the recent global instruments namely; the UN Convention on the Law of the Non-Navigational uses of International Water (1997) which came into force on 17th August 2014 and the Convention on the Protection and Uses of Transboundary Watercourses and International Lakes (1992) which came into force on 6th October, 1996 and further in 2016 became an official global legal framework for transboundary water cooperation. These instruments are regarded as a vital step in building a strong foundation for global principles on water management and governance. Legal agreements between states during the colonial era as well as post-independence in the Southern Africa region, have formed the bedrock of cooperative water resources management regionally. The Anglo Germany Treaty of July, 1890 (The Helgoland Treaty), had established an agreement between the colonial powers of Great Britain, France, Portugal, Belgium and Germany and their respective spheres of influence over the African nations aimed to establish borders between the nations. Interesting to note in the presence of scarcity of geo-information over the areas in question; the water bodies (Rivers and Lakes) were used to mark the lines of influence hence boundaries of the sovereign states of today. This chapter therefore, will provide an account of the influence of the 1890 Anglo – Germany Treaty (Helgoland Treaty) and international customary law in regard to conflict resolution and transboundary water cooperation in the Southern Africa Region (SADC). It will also examine some of available information as well as the historical background of boundary treaties; legal frameworks for cooperation; importance of Africa Union(AU) resolutions on the same, such as Resolution AHG/Res16(1) of July 1964 as well as resolution CM/Res.1069(XLIV) of 1986 and finally a conclusion.

Abstract Acute myeloid leukemia (AML) blasts and leukemia stem cells highly express the α chain of the IL-3 receptor (CD123), compared to normal hematopoietic stem cells. CD123 expression is associated with high-risk features, increased risk of induction failure and poor prognosis (Vergez F, et al. Haematologica 2011; 96: 1792-8). Flotetuzumab (FLZ), a CD123 × CD3 bispecific DART molecule, is being tested in a phase 1/2 study in patients with relapsed/refractory (R/R) AML. The recommended Phase 2 dose (RP2D) of FLZ is 500 ng/kg/day (d) administered as a 7-day/week continuous infusion. Patients receive a lead-in dose (30 ng/kg/d x 3d then 100 ng/kg/d x 4d) during week (W) 1, followed by 500 ng/kg/d during W2-4 of cycle 1, and a 4d on/3 d off schedule for cycle 2 and beyond. Disease status was assessed by modified IWG criteria; samples were collected to investigate candidate biomarkers, including CD123 receptor density/cell (RD), and gene expression profiling using the NanoString® PanCancer IO 360™ assay. This platform was used to assess the expression of 770 genes, including 14 immune cell types and 32 immuno-oncology biological signatures in bone marrow (BM) samples from patients treated with FLZ. Thirty patients with R/R AML, median age 64.5 years, received FLZ at the RP2D. Most patients enrolled had primary refractory disease (60% [18/30; 14 to cytotoxic chemotherapy (refractory to ≥ 2 induction attempts, or first CR with initial CR <6 months), and 4 to hypomethylating agents (HMA; failure of ≥ 4 cycles of HMA)]). 25/30 (83.3%) of patients had high-risk disease (ELN adverse (18)/intermediate risk cytogenetics [CTG] (7)). At baseline, the median percentage of CD123+ BM blasts was 85% (range 1.4100%), and the median CD123 receptor density on BM blasts was 4,084 (range 357-28,818 RD). Infusion-related reaction/cytokine release syndrome (IRR/CRS), the most common AE, occurred in all patients, including grade ≥3 in 4/30 (13.3%) of patients. IRR/CRS was managed with conventional supportive care and a management paradigm based on early intervention with tocilizumab (anti-IL-6R) to ameliorate the progression of CRS. Most IRR/CRS events were of short duration and reversible with protocol-specified supportive care. Antileukemic activity was reported in 18/27 (67%) response-evaluable patients, with an overall response rate (ORR) of 22% (6/27) and a CR/CRi rate of 19% (5/27). Interestingly, responsiveness to FLZ appeared quite distinct in patients with relapsed disease versus those who were refractory to standard induction chemotherapy. Estimates from the literature indicate that up to 45% of AML patients are refractory to standard front-line therapy. In patients treated with FLZ, the CR/CRi rate was 31% (4/13) among patients with primary chemotherapy refractory AML, while no responses (0/11) were observed in relapsed patients. A prior report suggests that AML patients with an immune-enriched tumor microenvironment (TME) as evidenced by increased expression of genes associated with CD8 T cells, Th1 cells, B cells, cytotoxicity, CXCL9 and CXCL10, are less likely to respond to anthracycline-based cytotoxic chemotherapy and experience significantly shorter relapse-free survival (Vadakekolathu J, et al. Blood 2017; 130: 3942A). We hypothesized that the presence of an immune-enriched gene signature in the BM TME of patients with AML could help to identify patients more likely to respond to FLZ immunotherapy. Initial exploratory studies suggest that the expression of inflammatory genes may be increased in patients with refractory AML, including patients that respond to FLZ. In conclusion, among this initial cohort of patients treated at the RP2D (500 ng/kg/day), FLZ demonstrates antileukemic activity with an acceptable safety profile, in particular, among refractory patients, a difficult-to-treat patient population that represents a significant area of unmet medical need. Enrollment to the current study has now been expanded to further define the antileukemic activity of FLZ in patients with refractory AML, and investigate candidate biomarkers to enable identification of patients more likely to respond to FLZ. In addition, studies are now being initiated to investigate opportunities to expand the antileukemic activity of FLZ via combined administration with either concurrent or sequenced anti-PD-1 checkpoint blockade. Disclosures Uy: GlycoMimetics: Consultancy; Curis: Consultancy. Rettig:Novimmune: Research Funding; Amphivena Therapeutics: Research Funding. Foster:Celgene: Research Funding; Macrogenics: Research Funding; Pfizer: Research Funding; Shire: Honoraria. Rizzieri:Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arellano:Cephalon: Research Funding. Topp:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet:Phizer: Consultancy; BMS: Honoraria; BMS: Honoraria; Agios: Consultancy; Jazz: Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Astellas: Consultancy; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau. Ravandi:Abbvie: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Xencor: Research Funding; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Abbvie: Research Funding. Church:NanoString Technologies: Employment. Rutella:NanoString Technologies: Research Funding. Sun:MacroGenics: Employment. Yang:MacroGenics: Employment. Baughman:MacroGenics: Employment. Curtis:MacroGenics: Employment. Timmeny:MacroGenics: Employment. Cali:MacroGenics: Employment. Tran:MacroGenics: Employment. Muth:MacroGenics: Employment. La Motte-Mohs:MacroGenics: Employment, Equity Ownership. Poirot:Servier: Employment. Pallis:Servier: Employment. Cesano:NanoString Technologies: Employment. Bonvini:MacroGenics: Employment, Equity Ownership. Wigginton:MacroGenics: Employment. Lowenberg:Astex: Consultancy; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherlands: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; international Scientific Advisory Board, Institute Gustave Roussy, Paris: Membership on an entity's Board of Directors or advisory committees; Editorial Board "International Journal of Hematology": Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands): Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Editorial Board "The Netherlands Journal of Medicine": Membership on an entity's Board of Directors or advisory committees; "Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees. Davidson-Moncada:MacroGenics: Employment.

Approximately 40% of patients (pts) with newly diagnosed (AML) either fail to achieve complete remission with intensive induction therapy or experience disease recurrence after a short remission duration (&lt; 6 months). These pts, herein considered to have primary refractory disease, are an extremely challenging population to treat, with only 14% achieving remission following conventional chemotherapy and with subsequent salvage attempts being nearly universally ineffective (1). Increased immune infiltration of the tumor microenvironment (TME) and high CD123 expression on AML blasts have been associated with primary induction failure and poor prognosis (2, 3). Flotetuzumab (FLZ), a CD123 x CD3 bispecific DART molecule, is currently being tested in a phase 1/2 study in pts with either relapsed or refractory (R/R) AML. We have previously reported FLZ activity in primary refractory AML (4); herein, we provide additional scientific rationale supporting the investigation of FLZ in this patient population. The recommended Phase 2 dose (RP2D) of FLZ identified in an ongoing Phase 1/2 study is 500 ng/kg/day administered as a 7 -day/week continuous infusion. Pts receive a lead-in dose during week (W) 1, followed by 500 ng/kg/day during W2-4 of Cycle 1, and a 4-day on/3-day off schedule for Cycle 2 and beyond. Disease status was assessed by modified IWG criteria; bone marrow (BM) samples were collected to investigate biomarkers, including CD123 receptor density (RD), and gene expression profiling using the NanoString PanCancer IO 360™ panel, which measures the expression of 770 genes, including 14 immune cell types and 32 immuno-oncology biological signatures. Gene expression comparisons are presented at fold change (FC) and a t-test was used for statistical analysis. Fifty pts with R/R AML received FLZ at the RP2D. Thirty (60%) pts had primary refractory AML: 24 failed ≥2 induction attempts and 6 recurred after remission of &lt;6 months (median duration of remission 32 [range: 29-45] days). This population was heavily pretreated (median 4 previous lines of therapy [range 2-9]), with 40% (12/30) having secondary AML and most having non-favorable cytogenetic risk (60% adverse and 23% intermediate by ELN 2017 risk category). Compared to relapsed pts, those with primary refractory disease had greater CD123 expression on AML blasts (11277±3246 vs 6254±1779 sites/cell), with baseline BM samples showing higher inflammatory chemokine signature scores (1.7x increase, p=0.018), and an enhanced interferon gamma (IFNγ) signaling gene expression score (1.85x increase, p=0.014), a signature associated with resistance to cytotoxic chemotherapy (2). Among 28 primary refractory pts evaluable for disease assessment, FLZ complete remission (CR) rate was 32.1% (3 CR, 3 CRh, 3 CRi). Four pts (1 CR, 1CRh, and 2 CRi) subsequently underwent allogeneic hematopoietic stem cell transplantation. For comparison, the expected CR rate to conventional salvage therapy in this population was calculated as &lt;10%, estimated based on historical response rates of pts subjected to similar numbers and types of salvage therapies (1, 5). Pts with CR showed higher CD123 RD compared to pts with no response (15186.5 vs 10836.8 sites/cell). FLZ anti-leukemic activity (&gt;30% decrease in BM blasts) was associated with increased baseline immune gene signatures, including significantly higher IFNγ scores (1.8 FC, p=0.0212; AUROC=0.74), and an increased tumor inflammation signature (TIS) score (1.658 FC, p=0.00827, AUROC=0.847 compared to non-responders. FLZ was well tolerated, with no increased cytokine release syndrome events in primary refractory pts (30% G1, 67% G2, 3% G3) compared to relapse pts (26% G1, 58% G2, 16% G3), notwithstanding the increased CD123 RD in the former. In conclusion, we show that FLZ elicits clinical response in heavily treated patients with poor response rates to primary therapy. We also show that increased IFNγ signaling gene expression scores in baseline BM appears to associate with response to FLZ therapy. Enrollment has been expanded to further define FLZ's activity specifically in pts with primary refractory AML, and candidate biomarkers to enable identification of pts more likely to respond to FLZ. Estey E, et al. Blood (1996), 88 (2) 756Vadakekolathu J, et al. Blood (2017) 130:3942Vergez F, et al. Haematologica (2011), 96(12):1792-8Uy GL, et al. Blood (2018) 132:764Duong V, et al. Leukemia (2013),13(6):711-5 Disclosures Uy: Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Aldoss:Agios: Consultancy, Honoraria; AUTO1: Consultancy; Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses. Foster:Bellicum Pharmaceuticals, Inc: Research Funding; Daiichi Sankyo: Consultancy; MacroGenics: Research Funding; Celgene: Research Funding. Sallman:Celgene: Research Funding, Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Jazz: Research Funding; Novartis: Speakers Bureau; Abbvie: Speakers Bureau. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Stemline: Consultancy; Pfizer: Consultancy; Jazz: Speakers Bureau; Incyte: Research Funding. Rizzieri:AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; Stemline: Research Funding. Advani:Amgen: Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy. Emadi:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Genentech: Consultancy, Honoraria; KinaRx: Membership on an entity's Board of Directors or advisory committees, Other: Co-Founder and Scientific Advisor, Patents & Royalties; Jazz Pharmaceuticals: Research Funding. Wieduwilt:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Reata Pharmaceuticals: Equity Ownership. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Church:NanoString Technologies, Inc.: Employment, Equity Ownership. Rettig:WashU: Patents & Royalties: Patent Application 16/401,950. Arellano:Gilead: Consultancy. Löwenberg:Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Frame Pharmaceuticals: Equity Ownership; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; CELYAD: Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherland: Membership on an entity's Board of Directors or advisory committees; Hoffman-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees. Ravandi:Selvita: Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding. Muth:MacroGenics, Inc.: Employment, Equity Ownership. Tran:MacroGenics: Employment. Timmeny:MacroGenics, Inc.: Employment, Other: Stock Ownership. Topp:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Guo:Macrogenics: Employment. Zhao:MacroGenics, Inc.: Employment. Wigginton:MacroGenics, Inc.: Employment, Equity Ownership; Western Oncolytics: Other: clinical advisory board. Bonvini:MacroGenics, Inc.: Employment, Equity Ownership. Rutella:NanoString Technologies, Inc.: Research Funding; MacroGenics, Inc.: Research Funding. Walter:Seattle Genetics: Research Funding; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy; Kite Pharma: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy. Davidson-Moncada:MacroGenics, Inc.: Employment, Equity Ownership. DiPersio:Amphivena Therapeutics: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Macrogenics: Research Funding, Speakers Bureau; Magenta Therapeutics: Equity Ownership; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Consultancy.

Angiogenesis plays a crucial role in the proliferation, invasion and metastasis of cancer cells. Unlike conventional chemotherapy, anti-angiogenesis drugs inhibit the formation of new blood vessels, reduce the nutrition and oxygen supply to the tumour, thus halting disease progression. In the last fifteen years, Food and Drug Administration of the United States has approved more than ten anti-cancer drugs of this group, namely the monoclonal antibody bevacizumab and small molecules drugs such as temsirolimus, sunitinib, axitinib and sorafenib. Other anti-angiogenesis agents are currently undergoing clinical trials. In addition to treating cancer, these agents have also potential applications in the treatment of complications related to angiogenesis in diabetes, arthritis, psoriasis and collagen-related diseases. Keywords Anti-angiogenesis, angiogenesis, cancer, metastasis, treatment. 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Dans un système constitutionnel fondé sur la souveraineté de la nation, le pouvoir constituant fait figure de phénomène ambivalent, difficilement analysable en termes juridiques. Par définition réfractaire à tout encadrement impératif, le pouvoir suprême au sein de l’Etat n’en doit pas moins revêtir une forme organisée pour exprimer une volonté normative. Les acteurs de la Révolution française agissent aux confins du droit, tirant profit des ressources de la philosophie politique et de l’histoire pour établir une constitution, principe fondamental du système juridique qu’ils cherchent à établir. Ils se dotent d’outils pour parvenir à leurs fins : le concept de « convention nationale » en est un, auréolé du succès des réalisations américaines. Plutôt qu’à une transposition institutionnelle, les révolutionnaires français procèdent à une adaptation. En devenant « extraordinaire », la représentation constituante qu’ils conceptualisent perd son caractère révolutionnaire pour devenir pleinement juridique. Elle offre une alternative à l’insurrection. Un tel processus présente cependant un revers. Ce pouvoir, en accédant à l’existence investi de l’exercice de la souveraineté, est dégagé de toutes contraintes juridiques autres que celles qui découlent de son organisation. Ces contraintes pèsent sur ses membres, exacerbant les tensions qui déchirent un corps collectif doté des pouvoirs les plus étendus. Les dérives sanglantes qui frappent la Convention nationale ne sont pas inéluctables ; elles découlent de l’exploitation politique des failles inhérentes au fonctionnement d’une représentation souveraine dont les membres ne doivent jouir d’aucun privilège
In a constitutional system founded on the sovereignty of the nation, constituent power is an ambivalent phenomenon, difficult to analyse in juridical terms. By definition resistant to mandatory regulation, the supreme power in the state must necessarily take a form which enables it to express a normative will. The actors of the French Revolution push the confines of the law, taking advantage of the resources of political philosophy and history to establish a constitution, fundamental principle of the juridical system they seek to institute. They create tools to achieve their ends: the concept of “national convention” being one, taking inspiration from the success of American achievements. Rather than an institutionnal transposition, the French revolutionaries proceed with an adaptation. By becoming “extraordinary”, the constituent representation which they conceptualize losses its revolutionary character to become fully juridical. It offers an alternative to the insurrection. By coming into existence invested with the capacity to exercise sovereignty, this power is released from all legal constraints other than those arising as a result of its organization. The process, however, is two-sided, and internally produced constraints weigh on its members, exacerbating tensions thar tear a collective body endowed with the broadest powers. The bloody excesses that strike the National Convention are not inevitable. They arise from political exploitation of flaws inherent to the organization of a sovereign representation whose members must not have any privilege

Née à partir des convulsions qui secouèrent le monde atlantique à la fin du XVIIIe siècle, la Gironde développa son républicanisme à partir de la matrice américaine. Dans leur combat abolitionniste et dans leurs regards critiques sur les systèmes politiques anglo-saxons, les futurs chefs girondins construisirent les soubassements de la constitution qu'ils eurent à charge de rédiger sous la Convention. À partir de 1792 en effet, une fois la monarchie abattue et la république mise en place, les girondins furent contraints à transformer leurs réflexions en innovation. Autorité judiciaire, pouvoir exécutif et pouvoir législatif durent être entièrement refondus. Les enseignements tirés de l'échec de la Constitution de septembre 1791 et de leur lecture des constitutions anglaise et américaine furent déterminants dans cette refondation. Plus encore, les girondins se distinguèrent par une pensée constitutionnelle tout à fait originale, un constitutionnalisme dynamique articulé autour de la notion de progrès, reposant sur un système éducatif et un droit inaltérable à changer de constitution afin de l'adapter au changement social. Ce constitutionnalisme dynamique voulait surmonter l'impossibilité de créer une constitution parfaite en permettant aux générations futures, définitivement débarrassées des préjugés de l'Ancien Régime, de modifier la constitution. Cependant, si les girondins avaient à cœur de faire persévérer leurs idéaux républicains dans le temps, ils souhaitaient étendre ces idéaux dans l'espace, au-delà des frontières françaises. D'où les plans grandioses d'une républicanisation de l'ordre international qui, mal exécutés, scellèrent leur sort
Born during the great upheaval which had shaken the whole Atlantic world at the end of the 18th century, the Gironde built its republicanism from the American matrix. During the fight for the abolition of slavery and through their critical views on Anglo-American political systems, the future Girondins chiefs elaborated the foundation of the constitution that they had to write under the Convention. Actually, in 1792, with the monarchy definitively down and the republic established, the Girondins were compelled to materialise their previous reflections. Judicial authority, legislative and executive branches, needed to be entirely rebuilt. The failure and fall of the 1791 Constitution and also their considerations on American and English constitutions were decisive for this rebuilding. Moreover, the Girondins must be distinguished for their original constitutionnal thought: a dynamic constitutionalism coherent with the concept of progress, based on an educational system and an imperishable right to change the constitution to adapt it to social change. This dynamic constitutionalism aimed to avoid the impossibility to create in one shot the perfect constitution. The next generations, totally free from the Old Regime prejudices, would have been able to improve the constitution. However, while the Girondins wanted to assure the endurance of their republican ideas for the years to come, they also wanted to expend these ideas through the world, beyond the French borders. This is the reason why they had elaborated a great design to republicanize the International relationships. A design which, clumsily executed, was, for the Girondins, the first step to the guillotine

La recherche a pour but d'étudier le processus politique qui conduit à la marginalisation et la défaite du courant modéré pendant la Révolution française, Elle voudrait le faire en travaillant sur le mouvement feuillant à la Législative, en le considérant comme un élément décisif pour comprendre l'effondrement du nouveau régime tel qui avait été conçu par la Constituante, Cette recherche voudrait esquisser une interprétation des dynamiques révolutionnaires pendant la monarchie constitutionnelle pour comprendre pourquoi le mouvement modéré et constitutionnel a perdu sa propre légitimité, révolutionnaire et pourquoi il a été dépassé par le processus révolutionnaire, La thèse que je voudrais démontrer est que, convaincu que la Constitution de 1791 était la fin de la Révolution, le mouvement feuillant n'a pas traduit sa volonté de défense de la légalité par une action et une pensée cohérente en mesure de les fusionner avec la légitimité révolutionnaire, qui progressivement a été conquise par le mouvement jacobin, Pour le dire autrement, face à l'activisme jacobin, les modérés n'ont pas su élaborer un discours feuillant efficace qui pût s'opposer à l'hégémonie politique de leurs adversaires
This research aims to study the political transition which led to the marginalisation and defeat of the moderate movement during the French Revolution. This will be achieved by focusing on the Feuillant movement at the Legislative Assembly, believing it to be an essential component in understanding the collapse of the new regime, which had been created by the Constituent Assembly. This research aims to outline an interpretation of the revolutionary dynamics during the Constitutional Monarchy in order to understand why the constitutional and moderate movement lost its own revolutionary legitimacy and was overtaken by the revolutionary evolution, The theory I would Iike to put forward is that, convinced that the 1791 Constitution marked the end of the Revolution, the Feuillant movement failed to translate the defence of legality into thought and action coherent enough to unite them with the revolutionary legitimacy, which was being gradually won over by the Jacobin movement

Le Comité des décrets (21 novembre-3 brumaire an IV) doit son existence au besoin de la Constituante d'un organe intermédiaire par rapport au pouvoir exécutif pour surveiller le bon envoi des décrets aux corps administratifs, face aux nombreuses pétitions des municipalités sur les retards de promulgation. Plusieurs compétences se dégagent au cours des 5 années, procédant par accumulation, intégration, transfert ou regroupement d'attributions. Un 1er groupe de compétences en fait un intervenant dans les processus d'exécution, promulgation, impression et publicité de la loi jusqu'à être un de ceux qui concourront au « Bulletin des lois ». Un 2e groupe de compétences naît de l'autorisation particulière de correspondre avec les corps administratifs en département. Sous la Législative, il assure, par délégation du corps législatif, la correspondance avec la Haute Cour de la Nation à Orléans et la rédaction des actes d'accusation. Sous la Convention, son réseau de correspondance contribue au rappel des suppléants des députés démissionnaires, absents ou morts, attribution qui amène le comité à participer à la recherche des députés hors-la-loi. 3e groupe de compétences, la correction des décrets, importante pour que la loi reste conforme au texte adopté, tout au long des étapes de son élaboration, l'installe au cœur des Archives nationales. Très vite cette attribution se centre sur la vérification des décrets d'aliénation des biens nationaux. La fonction l'amène à récupérer les fonctions des Archives nationales sous la Convention thermidorienne et à mettre en application la loi du 7 messidor an II sur le triage des archives domaniales, judiciaires et historiques
The Comittee's decrees, created November 21, 1789 and removed the 3 brumaire IV at the point where the National Convention, owes its existence to the need of the constituent Assembly to have an intermediary body from the Executive to monitor the proper shipment of its decrees to the administrative body, facing the many petitions of municipalities on delays in promulgation. Several competencies emerge over 5 years by accumulating, integration, transfer or grouping of powers. A first group of skills makes an intervener in the execution process, promulgation, printing and advertising of the Act to be one of those who will compete in the Bulletin of the laws. A second group of powers arises from special permission to correspond with the administrative body in the Department. Under the legislation, it shall, by delegation of the legislative body, correspondance with the High Court of the Nation in Orléans and the drafting of indictments. Under the Convention, its network of correspondance is updated contribution under the recall of alternates of the resigning members, absent or dead assignment that brings the Comitee to participe in finding the outlaw members. Third group of skills, correction of the decrees, important to ensure that the Act remains the same throughout the stages of its development, installs it in the heart of the National Archives. Very quickly this assignment focuses on the verification of the decrees of national property disposition. This function leads him to recover the functions of the National Archives under the Thermidor Convention and to implement the law of 7 messidor II on the triage of Crown, judicial and historical archives

Dans un système constitutionnel fondé sur la souveraineté de la nation, le pouvoir constituant fait figure de phénomène ambivalent, difficilement analysable en termes juridiques. Par définition réfractaire à tout encadrement impératif, le pouvoir suprême au sein de l’Etat n’en doit pas moins revêtir une forme organisée pour exprimer une volonté normative. Les acteurs de la Révolution française agissent aux confins du droit, tirant profit des ressources de la philosophie politique et de l’histoire pour établir une constitution, principe fondamental du système juridique qu’ils cherchent à établir. Ils se dotent d’outils pour parvenir à leurs fins : le concept de « convention nationale » en est un, auréolé du succès des réalisations américaines. Plutôt qu’à une transposition institutionnelle, les révolutionnaires français procèdent à une adaptation. En devenant « extraordinaire », la représentation constituante qu’ils conceptualisent perd son caractère révolutionnaire pour devenir pleinement juridique. Elle offre une alternative à l’insurrection. Un tel processus présente cependant un revers. Ce pouvoir, en accédant à l’existence investi de l’exercice de la souveraineté, est dégagé de toutes contraintes juridiques autres que celles qui découlent de son organisation. Ces contraintes pèsent sur ses membres, exacerbant les tensions qui déchirent un corps collectif doté des pouvoirs les plus étendus. Les dérives sanglantes qui frappent la Convention nationale ne sont pas inéluctables ; elles découlent de l’exploitation politique des failles inhérentes au fonctionnement d’une représentation souveraine dont les membres ne doivent jouir d’aucun privilège
In a constitutional system founded on the sovereignty of the nation, constituent power is an ambivalent phenomenon, difficult to analyse in juridical terms. By definition resistant to mandatory regulation, the supreme power in the state must necessarily take a form which enables it to express a normative will. The actors of the French Revolution push the confines of the law, taking advantage of the resources of political philosophy and history to establish a constitution, fundamental principle of the juridical system they seek to institute. They create tools to achieve their ends: the concept of “national convention” being one, taking inspiration from the success of American achievements. Rather than an institutionnal transposition, the French revolutionaries proceed with an adaptation. By becoming “extraordinary”, the constituent representation which they conceptualize losses its revolutionary character to become fully juridical. It offers an alternative to the insurrection. By coming into existence invested with the capacity to exercise sovereignty, this power is released from all legal constraints other than those arising as a result of its organization. The process, however, is two-sided, and internally produced constraints weigh on its members, exacerbating tensions thar tear a collective body endowed with the broadest powers. The bloody excesses that strike the National Convention are not inevitable. They arise from political exploitation of flaws inherent to the organization of a sovereign representation whose members must not have any privilege

Abstract John Frost, a London attorney and Solicitor to the Lottery in the Stamp Office, had been a founder member of the Society for Constitutional Information and one of the most active campaigners for parliamentary reform in the early 1780s. When the reform campaign reawoke in 1792, he was active again—accompanying Tom Paine in his dramatic escape to France in September, and at the end of November presenting, with Joel Barlow, the SCI’s address to the National Convention of the newly declared French republic.1 Between those two events, however, he had returned to London and committed an indiscretion which would result, the following year, in his trial and imprisonment. On 6 November 1792, Frost attended the annual dinner of an agricultural society in a room above the Percy Coffee House, at the corner of Rathbone Place and Percy Street, just north of Oxford Street. At the end of a bibulous evening he went downstairs, intending to walk through the public coffee room to reach the street.

Abstract With the storming of the Tuileries palace on August 10, 1792, what remained of the tattered French monarchy was destroyed. Shortly thereafter, in early September, as Prussian and Austrian troops marching in step with French émigrés bore down on the nation’s capital, Parisian sans-culottes invaded the city’s prisons, massacring upward of eleven hundred suspected opponents of the Revolution, including over two hundred priests. Pleased with this purging—for which they were publicly congratulated by the directing municipal authority, the Paris commune—many of these same men then rushed to the aid of the struggling French army, which made its famous stand at Valmy on September 20, halting the counterrevolutionary armies to the cry of Vive la Nation. Consecrated in blood, the newly elected National Convention voted on the very next day to establish a republic, the first in a series of genuinely revolutionary decrees that broke definitively with France’s past. In November, it vowed fraternal assistance to all peoples seeking to recover their liberty, and in the following months it gave alarming credence to these words by declaring war on Great Britain, the Dutch Republic, and Spain. Fighting for “freedom” without, the National Convention battled “tyranny” within, decreeing the guilt of Louis XVI in early January and sending him to the guillotine shortly thereafter.