Measurements of cosmic microwave background (CMB) polarization may reveal the presence of a background of gravitational waves produced during cosmic inflation, providing thus a test of inflationary ...models. The Q&U Bolometric Interferometer for Cosmology (QUBIC) is an experiment designed to measure the CMB polarization. It is based on the novel concept of bolometric interferometry, which combines the sensitivity of bolometric detectors with the properties of beam synthesis and control of calibration offered by interferometers. To modulate and extract the input polarized signal of the CMB, QUBIC exploits Stokes polarimetry based on a rotating half-wave plate (HWP). In this work, we illustrate the design of the QUBIC instrument, focusing on the polarization modulation system, and we present preliminary results of beam calibrations and the performance of the HWP rotator at 300 K.
Le mot « Gouvernement » est consacré pour la première fois par la Constitution de frimaire an VIII en lieu et place du mot « Exécutif » des constitutions révolutionnaires. Pour cette raison ...essentielle qu’il exerce un volontarisme juridique (initiative de la loi et pouvoir réglementaire au profit des consuls) que les révolutionnaires avaient tendance à dénier à l’Exécutif au profit d’un Législatif élu et représentatif. L’historiographie – surtout celle des juristes – en a longtemps inféré une relecture critique de la Révolution : une sorte de nihilisme gouvernemental révolutionnaire aurait produit par contre-coup, en 1799, une hypertrophie gouvernementale. Elle aurait été en quelque sorte nécessaire : la relecture de la Révolution porte en creux la condamnation des troisième et quatrième Républiques au profit de la cinquième République (l’organe exécutif inféodant l’organe législatif). Or les débats constitutionnels de la Révolution témoignent d’un souci constant d’établir « la force du gouvernement » par le truchement de l’administration. Elle concourt à l’uniformisation de la nation : elle fait tenir les hommes entre eux sous l’impulsion d’un centre qui dirige une administration générale. À ce titre, le gouvernement est loin d’avoir été un impensé du constitutionnalisme révolutionnaire. À la condition, comme le souhaitaient les révolutionnaires eux-mêmes, de considérer l’administration comme un objet constitutionnel.
LA FORCE DU GOUVERNEMENT BIGOT, Grégoire
Annales historiques de la Révolution française,
2017
389
Journal Article
Recenzirano
Le mot « Gouvernement » est consacré pour la première fois par la Constitution de frimaire an VIII en lieu et place du mot « Exécutif » des constitutions révolutionnaires. Pour cette raison ...essentielle qu’il exerce un volontarisme juridique (initiative de la loi et pouvoir réglementaire au profit des consuls) que les révolutionnaires avaient tendance à dénier à l’Exécutif au profit d’un Législatif élu et représentatif. L’historiographie – surtout celle des juristes – en a longtemps inféré une relecture critique de la Révolution : une sorte de nihilisme gouvernemental révolutionnaire aurait produit par contre-coup, en 1799, une hypertrophie gouvernementale. Elle aurait été en quelque sorte nécessaire : la relecture de la Révolution porte en creux la condamnation des troisième et quatrième Républiques au profit de la cinquième République (l’organe exécutif inféodant l’organe législatif). Or les débats constitutionnels de la Révolution témoignent d’un souci constant d’établir « la force du gouvernement » par le truchement de l’administration. Elle concourt à l’uniformisation de la nation : elle fait tenir les hommes entre eux sous l’impulsion d’un centre qui dirige une administration générale. À ce titre, le gouvernement est loin d’avoir été un impensé du constitutionnalisme révolutionnaire. À la condition, comme le souhaitaient les révolutionnaires eux-mêmes, de considérer l’administration comme un objet constitutionnel.
The word « Government » was formally established for the first time by the Constitution of Frimaire Year VIII to replace the term « Executive » used in the Revolutionary constitutions. Precisely because of this change, it possessed a legal voluntarism – the initiative of the law and a regulatory power assigned to the Consuls – that the Revolutionaries had been inclined to deny to the Executive, entrusting these, rather, to an elected and representative Legislature. The historiography, above all that of legal specialists, has long concluded that this change in attitude and practice represented a critical reevaluation of the Revolution – a kind of revolutionary governmental nihilism that would have produced, by a reaction in 1799, an excess of governmental power. It was in a sense necessary : the re-interpretation of the Revolution implied a condemnation of the Third, Fourth, and Fifth Republics, compared less favorably to the Fifth Republic. Yet the constitutional debates of the Revolution reveal a persistent concern to inaugurate « the power of government » with the aid of the administration. This contributed to the uniformity of the Nation : it controlled men under the impulse of centralizing power of a general administration. In this sense, the « government » was very much a part of the constitutional thinking of the revolutionaries ; indeed, the revolutionaries aimed to make administration an integral part of constitutionalism.
Investigations into both the pathophysiology and therapeutic targets in muscle dystrophies have been hampered by the limited proliferative capacity of human myoblasts. Isolation of reliable and ...stable immortalized cell lines from patient biopsies is a powerful tool for investigating pathological mechanisms, including those associated with muscle aging, and for developing innovative gene-based, cell-based or pharmacological biotherapies.
Using transduction with both telomerase-expressing and cyclin-dependent kinase 4-expressing vectors, we were able to generate a battery of immortalized human muscle stem-cell lines from patients with various neuromuscular disorders.
The immortalized human cell lines from patients with Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, congenital muscular dystrophy, and limb-girdle muscular dystrophy type 2B had greatly increased proliferative capacity, and maintained their potential to differentiate both in vitro and in vivo after transplantation into regenerating muscle of immunodeficient mice.
Dystrophic cellular models are required as a supplement to animal models to assess cellular mechanisms, such as signaling defects, or to perform high-throughput screening for therapeutic molecules. These investigations have been conducted for many years on cells derived from animals, and would greatly benefit from having human cell models with prolonged proliferative capacity. Furthermore, the possibility to assess in vivo the regenerative capacity of these cells extends their potential use. The innovative cellular tools derived from several different neuromuscular diseases as described in this report will allow investigation of the pathophysiology of these disorders and assessment of new therapeutic strategies.
Abstract
Background: Molecular alterations involving FGFR family genes (FGFR 1-4) are emerging driver events in a variety of solid tumors, mainly represented by urothelial carcinoma (UC) and ...intrahepatic cholangiocarcinoma (CC). Several tyrosine kinase inhibitors (TKI) are in clinical development to counteract FGFR-driven diseases, being especially active against activating gene mutations and rearrangements. Progression on these targeted agents eventually appears and the understanding of molecular mechanisms of resistance is crucial to develop novel strategies.
Methods: In the MATCH-R prospective study (NCT02517892), patients with unresectable or metastatic cancer are included upon acquired resistance to targeted therapies or immunotherapy, defined as progressive disease after complete/partial response or stable disease for six months. Serial blood samples are collected and tumor biopsy is performed upon progression. Targeted NGS, CGH, WES and RNAseq are performed on the tissue samples. PDX models and patient-derived cell lines are developed to fully investigate the underlying mechanisms of resistance. Only patients receiving TKI for FGFR-mutated or -rearranged tumors were included (i.e. FGFRamplifications were excluded) in the analysis.
Results: From June 2015 to November 2018, 113 patients treated with a TKI were included in the MATCH-R study, of which 17 (15%) had received an FGFR inhibitor. Tumor types and corresponding molecular aberrations were as follows: 8 CC (n=6 FGFR2-rearranged, n=1 FGFR2:C383R, n=1 FGFR3:S249C), 7 UC (n=5 FGFR3:S249C, n=1 FGFR3:R248C, n=1 FGFR3:Y373C), 1 breast (FGFR3-rearranged) and 1 ovarian (FGFR2-rearranged) cancers. Evaluable tumor biopsies were taken upon progression to treatment with erdafitinib (n=12), pemigatinib (INCB54828) (n=3) or TAS-120 (n=4). Two patients underwent multiple biopsies as progressing on sequential FGFR inhibitors. Resistance mechanisms consisted of polyclonal secondary mutations (n=5), bypass pathways activation (n=3) and the remaining nine cases are still under investigation. PDX models/patient-derived cell lines were obtained in eight cases and extensively characterized in three. Adaptive treatment with novel FGFR TKI or combinatorial strategies aiming to block the bypass pathways allowed to restore sensitivity in both cell lines (readouts: IC50 and Western Blots) and PDX (readout: median tumor growth). Novel mutations potentially implicated in resistance to FGFR TKI were characterized by infecting Ba/F3 cells with respective lentiviral vectors, as well as the inhibitory potential of the differential FGFR inhibitors.
Conclusions: Novel mechanisms of resistance to FGFR inhibitors in solid tumors were identified and consequent treatment strategies allowed to regain sensitivity in both patient-derived cell lines and PDX. Updated results will be presented at the Meeting.
Citation Format: Francesco Facchinetti, Rastislav Bahleda, Antoine Hollebecque, Yohann Loriot, Gonzalo Recondo, Ludovic Bigot, Ken A. Olaussen, Gilles Vassal, Stefan Michiels, Rosa L. Frias, Justine Galissant, Tony Sourisseau, Claudio Nicotra, Maud Ngo-Camus, Linda Mahjoubi, Ludovic Lacroix, Etienne Rouleau, Catherine Richon, Aurélie Abou-Lovergne, Olivier Deas, Nathalie Auger, Thierry De Baere, Frederic Deschamps, Eric Solary, Jean-Yves Scoazec, Eric Angevin, Alexander Eggermont, Fabrice André, Benjamin Besse, Jean-Paul Thiery, Jean-Charles Soria, Christophe Massard, Luc Friboulet. Mechanisms of acquired resistance to FGFR inhibitors in molecularly-selected solid tumors: A prospective cohort from the MATCH-R study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 318.
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