Institut de Recherche sur la Renaissance l'Age Classique et les Lumières

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Abstract Abstract 297 Background. Current models of cancer progression are based on evolution and clonal selection i.e. evolution of tumour cells inducing expansion of cells that acquire genetic lesions over time, related to ongoing mechanisms of genomic instability. An initiating event may be followed by gene mutation, copy number alteration (CNA) or copy neutral loss of heterozygosity (CN-LOH) that drive tumor progression and emergence of mechanisms of resistance to drugs. WM is a lymphoproliferative disorder characterized by bone marrow (BM) infiltration of lymphoplasmacytic cells that secrete monoclonal IgM antibody. The clinical course is characterized either by an indolent or smoldering status or a symptomatic profile that needs chemotherapy to control the progression of tumour cells. The majority of patients (pts)evolved from indolent to symptomatic, and the mechanisms of progression of WM are not fully understood to date. We hypothesized that we could gain insights into clonal evolution underlying disease progression of WM on a paired serial analysis of WM samples using genome wide SNPa, that allow both the detection of LOH and CNA. Method. BM samples of 19 untreated pts with WM (12 males, mean age: 67 years, 11 symptomatic pts) were analysed. All patients had Genome-Wide Human SNP Array 6.0 (Affymetrix chips) on at least two sequential tumor samples > 6 months apart (42 samples from 19 patients with two to three points). Tumoral DNA was extracted following CD19 B cells selection. Paired samples (tumor/normal T lymphocytes) were used as an intra-individual reference to identify germline polymorphisms. Size, position and location of genes were identified with UCSC Genome Browser HG18 assembly, LOH and CNA using genotyping console 3.02 software (Affymetrix). FISH analysis was performed to detect deletion 6q; 13q14, 11q22, TP53, trisomy 4 and 12 chromosomal aberrations using Vysis probes. P53 and MYD88 mutation were analyzed by sanger sequencing. Results. At initial sampling, SNPa detected a total of 76 CNA genetic aberrations (range 0 – 24 per genome) including 22 gains and 54 losses; 85% of patients had MYD88 L265P mutation. During the follow-up of all indolent WM that remained indolent, we haven't observed any new genetic aberrations, gain or loss (either CNA or CN-LOH) (n=8, mean follow-up: 63 months, range: 16–107 months). Among the 11 remaining patients (mean follow-up: 44.2 months, range: 7–92 months), a clonal evolution was observed in 6 cases. Three of them were symptomatic and acquired CNA or CN-LOH during clinical evolution: one case with acquisition of several CN-LOH, including one at 3p22 involving MYD88 locus associated to a mutation, one case with an additional deletion 7q31 which was observed in a patient with a chromothripsis at diagnosis, one case with emergence of subclonal del17p. The two remaining patients evolved from smoldering to symptomatic with a major variation in CNA number. Finally, loss of CNAs displayed at diagnosis was observed in one patient after chemotherapy and during indolent follow-up. In 5 cases, no detectable CNA changes were identified between the initial and subsequent sample at relapse. Conclusion. Our results using high resolution SNP array support the hypothesis that a symptomatic WM disease will favour genetic clonal evolution of tumor cells. In our study, 3 distinct genotypic patterns were observed: (i) absence of genomic variation in stable smoldering WM disease or in symptomatic relapsed patient. (ii) unstable genotype in symptomatic or asymptomatic patients switching to symptomatic suggesting high risk tumors that are less stable and more prone to change with time. (iii) loss of abnormalities suggesting that chemotherapy eradicated the dominant clone or that a genetically distinct relapsed clone has emerged. This study refines our understanding of the dynamic genetic changes in progressive WM. Further confirmation of the role of some candidate genes is underway. Disclosures: No relevant conflicts of interest to declare.

Abstract Aim The evolutionary drivers of hyperdiversity in tropical rain forests are complex and multifaceted. We used the pantropical Xylopia (Annonaceae) genus to address the diversification of rain forest lineages through time, across different regions, and into novel non-rain forest habitats with a comparative phylogenetic approach. Location Global (pantropical) Methods We generated a time-calibrated phylogeny of Xylopia using hybrid capture sequence data, including 88% (168/191 spp.) of species within the genus. Diversification analyses were conducted to test for the presence of rate heterogeneity (BAMM, ClaDS, CoMET) and environmental-dependent (RPANDA), geographic-dependent, and habitat dependent (GeoHiSSE) diversification in Xylopia . Results Significant diversification rate heterogeneity was detected along the backbone of the core Xylopia clade, leading to near synchronous radiations across tropical regions globally in the Miocene, with higher diversification rates in Africa, Central America, and Madagascar, and lower rates in Australia + New Guinea. Transitions from rain forest to subhumid habitats led to lower diversification rates, whereas transitions to ultramafic habitats lead to higher rates. Regional diversification models indicate sea-level changes as an important driver for Asian, Australian, Pacific, and Neotropical clades and regional temperature changes as the main diversification driver for an African clade of Xylopia . Main conclusions Our study shows that despite synchronous radiations across regions, different regional environmental drivers have affected the diversification of Xylopia across tropical regions globally. A noteworthy example includes radiations of all five Malagasy clades c. 7 Ma coinciding with the establishment of heavy seasonal rainfall linked with the Indian monsoon. The diversification dynamics of rain forests are complex and heterogenous, with different clade-dependent and region-dependent environmental drivers.

Abstract Abstract 1307 Background. Mutation of MYD88 gene has recently been identified in activated B-cell like diffuse B-cell lymphoma, and enhanced JAK STAT and NF-kB signalling pathways. Whole exome sequencing study in Waldenstrom macroglobulinemia (WM) suggested a high frequency of MYD88 L265P mutation in WM. Although the genetic background is not fully deciphered in WM, the role of NF-kB and JAK STAT pathways has been demonstrated in WM; which underlying mechanisms of deregulation remain to be elucidated. We aimed to analyze MYD88 mutation in exon 5 and to characterize the clinical significance of this genetic alteration in 67 WM. Method. 67 patients (42 males, 25 females) diagnosed with WM were included in this study, along with 9 patients with chronic lymphocytic leukemia (CLL), 4 multiple myeloma (MM) and 9 marginal zone lymphoma (MZL) were also studied. Patients were untreated at time of BM collection and gave informed consent prior to research sampling. Clinical features, immunophenotypic markers using flow cytometry (Matutes score panel, CD38, CD138, CD27, CD80), conventional cytogenetic, FISH and SNP array data (n = 46) were analysed. B cells from bone marrow and T cells from blood were isolated respectively using B cell isolation kit and Pan T isolation kit (Myltenyi Biotech). For DNA sequencing of exon 5 of MYD88, the exon 5 of MYD88 gene was amplified from genomic DNA by PCR. The purified PCR products were directly sequenced in both directions using BigDye® Terminator Cycle Sequencing Kit (Applied Biosystems, CA, USA) and analyzed on the Applied Biosystems 3130xl Genetic Analyzer. Data were analyzed with SeqScape software version 2.5 (Applied Biosystems). Results. MYD88 L265P mutation (MYDmut) was observed in 79% of patients, including homozygous mutation in two patients (3%). MYD88 mutation was not identified in T lymphocytes isolated from 4 WM patients that confirmed MYD88 mutation was acquired in the tumoral cells. We haven't observed any other mutation on exon 5. We then sought for other mechanisms of MYD88 gene alteration, such as copy number alteration (CNA) and copy neutral –loss of heterozygosity (CN-LOH) also considered as an acquired UPD (uniparental disomy) at MYD88 locus. We found an UPD at MYD88 locus in solely one patient (2%), and haven't identified any deletion at 3p22. On the contrary, we observed a gain on chromosome 3 at 3p22 locus (including MYD88 gene) in 7/57 (12%) patients. Taking together, we identified alteration of the MYD88 locus in 85% of patients with WM, by either gain-of-function mutation (79%) or CNA (12%). Interestingly, we found gain on chromosome 3 more frequently in the MYDwildgroup than in the MYDmutgroup (p=0.02). Twenty one percent of the patients with WM had no mutation of MYD (MYDwild), and were characterized with a female predominance, a splenomegaly, gain of chromosome 3 and CD27 expression. We did not observed difference in terms of survival according to the MYD88 mutation status. MYD88 mutation was not related to deletion 6q, gain of 4, deletion 11q, deletion 17p, deletion 13q14 in our study. Interestingly, deletion 7q, a frequent cytogenetic aberration in marginal zone lymphoma, was rare in our series (4/57; 7%) and was independent of MYD88 mutation status (2 in the MYDwild and 2 in the MYDmut) (p=ns). No MYD88 L265P mutation was observed in CLL and MM. In MZL, 1/9 patient without M monoclonal component had a MYDL265p mutation. Conclusion. These results confirm a high frequency of MYD88 L265P mutation in WM that may become a useful biomarker for diagnostic in WM and may help better understand the physiopathogeny of WM. Disclosures: No relevant conflicts of interest to declare.

Bâtisseuse de Babylone et d’autres cités, guerrière, impératrice et amante, Sémiramis inspira aux auteurs de l’Antiquité de nombreux récits contrastés de ses faits et gestes. Les Pères de l’Église, dont Saint Augustin, l’associaient à la cité de Babylone et, en prolongement, à la tour de Babel. Le présent article explore quelques facettes de la figure de Sémiramis telle qu’elle s’est recomposée dans des textes européens de la fin du Moyen Âge et de la première modernité, et d’étudier les représentations contrastées qui en découlèrent dans la littérature anglaise, grâce au matériau qui circulait dans les dictionnaires et les traductions. Il en ressort une figure plurielle, lieu d’interaction des traditions mythologique et biblique, qui invite à une exploration et réévaluation des codes de représentation de la femme et de l’homme.

Contrairement à ce qu’on pourrait imaginer, le type du « méchant » français, assassin, traître ou prédateur sexuel, est rarement représenté par les dramaturges élisabéthains sous un jour comique voire grotesque ou absurde. Au terme d’une recherche menée en marge du projet de base de données Allusions to France and the French in English Drama to 1642, un nombre fort réduit de cas ont été identifiés, dans des pièces de Greene, Lodge, Marston, ou dans des textes anonymes. Par ailleurs, les « méchants » français (les français sont méchants par définition puisqu’ennemis des Anglais―ainsi en est-il des pièces historiques) et les français comiques mais pas particulièrement méchants, abondent dans le théâtre de l’époque, y compris chez Shakespeare. Les personnages principaux que sont Pedro dans The Wounds of Civil War de Lodge et Jaques dans James IV de Greene sont traités différemment par les deux dramaturges. L’un s’enfuit, terrifié à la vue du visage de sa victime, le consul romain Caius Marius. L¹autre prend la fuite après avoir tenté, sans succès, de tuer la femme du roi, abandonnant son patron Ateukin, le vrai “méchant” de la pièce, à son destin, et jure de rentrer en France pour ne pas être pendu dans un pays étranger. Un troisième personnage d’une petite pièce de Marston complète cette courte liste. L’Italie et l’Espagne fourniraient aux dramaturges anglais dans les premières décennies du XVIIe siècle beaucoup plus de matière, dans la comédie comme dans la tragédie.

L e temps est pass o l'on pensait que d'un arrire-fond habilement dcrit, dans toute l'exhaustivit ncessaire la dmonstration, pouvait merger par une espce d'osmose jamais clairement dfinie une oeuvre, un concept, une thorie.Dans une telle optique, on parvient tout au plus une juxtaposition de donnes historiques et d'une oeuvre ou d'une pense, sur un mode plus intuitif que raisonn.Le temps est pass, mais les habitudes scolastiques demeurent parfois, revtues d'habits neufs.L'invocation d'un air du temps ou la multiplication de donnes matrielles cense sceller la vrit conduisent des impasses pistmologiques.La tentation est alors grande de refuser, dans certaines disciplines, tout regard sur l'extrieur de leurs objets, comme si une histoire de la littrature, de la philosophie, ou de l'conomie pouvait gagner tre totalement indpendante des tournants et des dmarcations qui ont lieu dans le reste des domaines de la pense ou des structures de la vie humaine.On se rend assez vite compte que ce qui est alors gagn en autonomie se traduit par une large perte d'intelligibilit.C'est pourquoi la notion de contexte a progressivement occup une place centrale dans l'analyse historique.Que ce soit en histoire politique, conomique, intellectuelle ou littraire, elle parat permettre de situer un vnement, un changement ou une production esthtique dans son environnement temporel, social et culturel.Comprendre le contexte, c'est alors saisir les conditions

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Cet article propose de mettre au jour le lien qui régit l’espace et le sujet dans le Manuscrit trouvé à Saragosse. Partant du postulat que, dans cette œuvre, le lieu semble constitutif de l’être, qu’il le conditionne jusque dans son identité la plus intime par l’influence des mœurs, de la filiation ou encore du climat, il semble intéressant d’interroger ce qu’est l’homme pour Potocki, indépendamment de son espace. Le lecteur est en effet le témoin privilégié d’une expérience sur l’humain menée à travers la Sierra Morena comme « laboratoire ontologique », dont il s’agit d’analyser les résultats.

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Abstract Abstract 1288 Background. Approximately 30% of the patients who fulfil the criteria of Waldenström macroglobulinemia (WM) are diagnosed while asymptomatic, and will not require immediate therapy; these cases are called indolent WM (IWM). However, patients with a disease-related event will be considered for therapy, these cases are called symptomatic or aggressive WM (AWM). The physiopathology of these 2 groups remains unclear, and the mechanisms of progression have not been fully understood so far. We hypothesized that a gene signature that differentiates these two categories could be identified to better understand the underlying mechanisms of progression of WM. Methods. Seventeen patients diagnosed with WM (8 IWM and 9 AWM) were included in this study. We selected tumour cells from the bone marrow (BM) using mononuclear cell isolation, then B cell enrichment (B cell isolation kit, Myltenyi-Biotec, USA). The purity was confirmed by flow cytometry. Total RNA was extracted using the Trizol method. Gene expression profiling was performed using U133A arrays (Affymetrix, USA). Gene expression was normalized using the RMA algorithm. We ranked genes by fold-change of expression levels on a first series of 11 patients (5 IWM and 6 AWM) calculated with the ‘limma’ package in R. Next, we used a supervised classification to establish a gene expression profile to distinguish IWM from AWM. Therewith, we validated this profile on an independent set of 6 patients (3 IWM and 3 AWM). We then performed a pathway analysis using Ingenuity® analysis software. We confirmed gene expression deregulation with qRT-PCR on 3 candidate genes in the first series of patients. Genome-wide detection of copy number alteration and loss of heterozygosity were performed on 13 of the 17 WM cases, using the Genome-Wide Human SNP Array 6.0 (Affymetrix, USA). Finally, we investigated the functional consequences of the deregulation of these candidate genes in BCWM1 and MWCL1, both B cell lines originated from WM. Survival was studied using a colorimetric method with MTS (Promega, USA). Proliferation was analyzed using incorporation of a nucleoside analog (EdU) into DNA during active DNA synthesis (Invitrogen, USA). Results. The differential analysis has identified 82 probes, corresponding to 48 genes, significantly deregulated and capable of differentiating samples from IWM and AWM in an unsupervised classification. Moreover, with a supervised classification, this gene expression profile accurately classified 94% of the 17 WM samples, including the 6 WM of the independent validation set. The two molecular networks that appeared to play a major role in the physiopathology of IWM versus AWM were the plasma cell differentiation pathway and the AKT pathway. We have then identified 3 key genes in those 2 pathways, BACH2 and CIITA on the one hand and PTEN, respectively. We have then confirmed the deregulation of these gene expression levels by qRT-PCR in 3 IWM and 4 AWM; these 3 genes were over-expressed in IMW relatively to AMW. BACH2 is a B-cell-specific transcription factor known to be a tumour suppressor gene. It was shown that BACH2 reduces proliferation and induces cell death when over-expressed in B lymphoma tumour cells. We have thus pharmacologically over-expressed BACH2 in BCWM1 and MWCL1 and significantly reduced the proliferation and the survival of the two cell-lines. Further studies using BACH2 specific overexpression with lentiviral infection are underway, in vitro. The data will be presented at ASH. In order to further study the mechanisms of deregulation of BACH2 in IWM and AWM, we have conducted a genome wide SNP array study of 13 patients. Among those, 7 patients (4 IWM and 3 AWM) demonstrate a deletion of long arm of chromosome 6 (del6q), the most frequent chromosomal abnormality in WM. BACH2 gene is located on the 6q15 locus. Interestingly, we found that 3 out of the 3 AWM had a del6q that took in the 6q15 region, whereas 3 out of 4 of the IWM had a del6q preserving the 6q15 region. Therefore, haploinsufficiency could participate in the under-expression of BACH2 in aggressive WM; this hypothesis will be verified by using DNA qRT-PCR of BACH2. Conclusion. To the best of our knowledge, we have identified for the first time a specific gene expression signature that differentiates IWM and AWM. We have exposed several genes from this dataset, including BACH2, which is a candidate to better understand the underlying mechanisms of progression of WM. Disclosures: No relevant conflicts of interest to declare.

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L'inventaire aprs dcs de Michel Blavet (1700-1768), musicien ordinaire du roi Il est parfois de ces hasards heureux qui font soudainement avancer la connaissance d'un sujet pourtant bien connu.Au dtour d'une archive, notre dcouverte fortuite de l'inventaire aprs dcs du bisontin Michel Blavet (1700-1768) 1 , ainsi que de ceux de son pouse 2 et de son fils an, l'abb Jean-Louis Blavet 3 , permet aujourd'hui de jeter un clairage nouveau sur les dernires annes du plus clbre fltiste du XVIIIe sicle, et de mieux comprendre le statut auquel il tait parvenu.L'essentiel sur l'homme avait dj fait l'objet de plusieurs tudes fondamentales dont celle, pionnire, de Lionel de La Laurencie en 1912 qui avait remis en perspective sa musique au sein de la fameuse Querelle des Bouffons.Malgr un modeste catalogue compos de sept recueils pour une ou deux fltes, d'un concerto rest manuscrit et de quatre opra bouffes pour le chteau de Berny, rsidence de plaisance de son dernier protecteur, Blavet y semblait essentiellement peru, avec son Jaloux Corrig de 1752, comme l'un des premiers vritables adaptateurs franais du style Italien des Bouffons 4 .Les deux tudes que consacra ensuite le bisontin Louis Vayssier 5 en 1976 puis en 1984, ont propos une vision plus dtaille de son parcours, depuis d'humbles dbuts Besanon dans l'atelier de son pre, tourneur sur bois venu de Rennes, jusqu' son dpart pour Paris en 1723 dans la suite du duc de Lvis.Parti sur les traces domestiques laisses par le musicien, Vayssier a pu rappeler les grands traits de sa biographie bien documente par ses sources crites, que ce soient les gazettes publiques ou les tmoignages de ses contemporains.Protg du prince de Carignan (1728) puis du comte de Clermont (1732) dont il dirigea durant trente ans la musique en tant que son surintendant, Blavet avait brillamment dbut en tant que soliste au Concert Spirituel ds 1726 avant de devenir ordinaire de la musique de la chambre du roi (1738) puis premire flte l'Acadmie Royale (1740).Interprte de tous les superlatifs, on continuait, bien aprs sa mort, louer la nettet de son embouchure et sa prodigieuse virtuosit.Quoi qu'il tnt singulirement son instrument l'inverse du courant nous dit Marpurg, c'est--dire gauche, Blavet fut, de l'avis unanime, ce son inimitable qui fit tirer la flte traversire vers un rpertoire concertant, bien loign de celui, plus alanguit, auquel elle tait traditionnellement cantonne.On publia longtemps sur lui des Odes et il n'est gure de presse qui ne fut louangeuse son encontre. En marge d'un article

Historiettes can be defined as a collection of small memoirs in which Tallemant des Réaux reconstructed the reign of Henri IV and the regency of Anne d’Autriche. This collection of stories reshuffles the events reported in official Historiography, giving scandalous and private anecdotes of the more or less major figures of the time. The article reflects on the form of counterfactual history in a genre that is supposed to depict historical figures with a zest of funny, strange and picturesque details.

En 1749, Jean Monnet, entrepreneur de spectacles, tente de fonder une comédie française à Londres. Parce que le contexte politique est alors particulièrement défavorable à toute forme de diplomatie culturelle française, c’est un échec retentissant, mais circonstanciel, que l’histoire aurait pu oublier. Pourtant, cette tentative avortée alimente a posteriori une relecture historiographique qui érige Monnet en héros picaresque, dans la lignée des truculents comédiens de province dépeints par Scarron. Ses tribulations sont vues, par des historiens de la seconde moitié du XIXe siècle, comme la manifestation esthétique et politique d’un théâtre supposément populaire, authentique et «gai». L’échec de 1749 est mythifié. Les revers de fortune de l’homme de théâtre deviennent l’instrument d’un discours identitaire nostalgique, qui s’épanouit dans le contexte de montée générale des nationalismes européens.

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un de ses frres 5 , le quotidien de ce messin n Thionville chappait encore l'historien, sans doute en partie cause d'une lgende rcente selon laquelle il avait toujours rechign frquenter le notariat parisien 6 .

La tragi-comédie au tournant du siècle est un genre encore en germe, dont les frontières avec les autres genres comme la tragédie et la pastorale restent fort poreuses. Par ailleurs, des pièces tragi-comiques sont publiées sur l’ensemble du territoire français, dans les différentes provinces du pays. L’excentricité formelle de la tragi-comédie, genre aux marges de la tragédie, est-elle ainsi spécifique au théâtre provincial, en opposition avec une tragi-comédie parisienne ?

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