Le paratexte, trente ans après

Over the past three decades since the publication of Gérard Genette’s Seuils (1987), studies on paratext have spread in different disciplines and in several literary fields. To mark the thirtieth anniversary of the emergence of this pioneering work, an international conference held in Bologna and host many researchers questioning the relevance of the paratext. The thematic dossier of the current issue focuses on both the implications drawn from Seuils and its reception in our current literary and media landscape. The aim is to detect some advancements, differences and connections, on the one hand, between the subcategories indicated in the text and, on the other hand, between the research strands that researchers have developed. This article, which accounts for the dossier’s introduction, sets the theoretical basis of our research and summarizes the following articles.Pendant les trois décennies qui se sont écoulées depuis la publication de Seuils (1987) de Gérard Genette, les études sur le paratexte se sont multipliées dans des disciplines très différentes et dans plusieurs champs littéraires. Pour couronner le trentième anniversaire de la publication de cet ouvrage pionnier, un colloque international a été organisé à Bologne, pendant lequel de nombreux chercheurs se sont interrogés sur l’actualité des études sur le paratexte. Le dossier thématique qui en constitue l’issue comporte une réflexion aussi bien sur les implications découlant des théories de Seuils que sur sa réception dans les domaines littéraires et médiatiques. Il y est question de détecter les évolutions, les distances et les connexions entre les sous-catégories indiquées dans l’essai d’une part et, d’autre part, entre les directions de recherche assumées par les chercheurs. Le présent article, qui constitue l’introduction au dossier, définit les bases théoriques de la recherche et synthétise les développements des articles qui le suivent

Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET

<p>Abstract</p> <p>Background</p> <p>Primary and secondary drug resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GISTs) has led to a pressing need for new therapeutic strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT, while RAD001 (everolimus) inhibits mTOR. We report a preclinical study on drug combinations in a xenograft model of GIST in which effects on tumor dimensions and metabolic activity were assessed by small animal PET imaging.</p> <p>Methods</p> <p>Rag2-/-; γcommon -/- male mice were injected s.c. into the right leg with GIST 882. The animals were randomized into 6 groups of 6 animals each for different treatment regimens: No therapy (control), imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, everolimus (10 mg/kg/d.) by oral gavage, everolimus (10 mg/kg/d.) + imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75 mg/kg/d.) by oral gavage, nilotinib (75 mg/kg/d.) + imatinib (150 mg/kg b.i.d) by oral gavage for 6 days, then once/day for another 7 days. Tumor growth control was evaluated by measuring tumor volume (cm³). Small animal PET (GE Explore tomography) was used to evaluate tumor metabolism and performed in one animal per group at base-line then after 4 and 13 days of treatment.</p> <p>Results</p> <p>After a median latency time of 31 days, tumors grew in all animals (volume 0,06-0,15 cm³) and the treatments began at day 38 after cell injection. Tumor volume control (cm3) after 13 days of treatment was > 0.5 for imatinib alone and nilotinib alone, and < 0.5 for the 2 combinations of drugs and for everolimus alone. The baseline FDG uptake was positive in all animals. FDG/SUV/TBR was strongly reduced over time by everolimus both as a single agent and in combination with imatinib respectively: 3.1 vs. 2.3 vs. 1.9 and 2.5 vs 2.3 vs 0.</p> <p>Conclusions</p> <p>As single agents, all drugs showed an anti-tumor effect in GIST xenografts but everolimus was superior. The everolimus plus imatinib combination appeared to be the most active regimen both in terms of inhibiting tumor growth and tumor metabolism. The integration of everolimus in GIST treatment merits further investigation.</p

2010a): Real Business Cycles with Cournot Competition and Endogenous Entry

Abstract We introduce Cournot competition and endogenous entry in an otherwise neoclassical macroeconomic framework. First, we develop a model with exogenous savings à la Solow describing the dynamic path of business creation. Then, we develop a model à la Ramsey describing the dynamic interaction of consumption and business creation. Our models are able to explain why markups vary countercylically and pro…ts are procyclical. The analysis of permanent and temporary technology and preference shocks and of the second moments suggests that our model can outperform the Real Business Cycle framework in many dimensions. We are grateful t

SDHA Loss-of-Function Mutations in KIT-PDGFRA Wild-Type Gastrointestinal Stromal Tumors Identified by Massively Parallel Sequencing

Approximately 10%-15% of gastrointestinal stromal tumors (GISTs) in adults do not harbor any mutation in the KIT or PDGFRA genes (ie, KIT/PDGFRA wild-type GISTs). Recently, mutations in SDHB and SDHC (which encode succinate dehydrogenase subunits B and C, respectively) but not in SDHA and SDHD (which encode subunits A and D, respectively) were identified in KIT/PDGFRA wild-type GISTs. To search for novel pathogenic mutations, we sequenced the tumor transcriptome of two young adult patients who developed sporadic KIT/PDGFRA wild-type GISTs by using a massively parallel sequencing approach. The only variants identified as disease related by computational analysis were in SDHA. One patient carried the homozygous nonsense mutation p.Ser384X, the other patient was a compound heterozygote harboring a p.Arg31X nonsense mutation and a p.Arg589Trp missense mutation. The heterozygous nonsense mutations in both patients were present in germline DNA isolated from peripheral blood. Protein structure analysis indicates that all three mutations lead to functional inactivation of the protein. This is the first report, to our knowle dge, that identifies SDHA inactivation as a common oncogenic event in GISTs that lack a mutation in KIT and PDGFRA

SDHA and SDHB mutations in KIT/PDGFRA WT gastrointestinal stromal tumors

Background: KIT/PDGFRA wild-type (WT) GISTs harbour mutations on SDHB and SDHC and, more recently, we described mutations on SDHA using massively parallel sequencing approach. We sequenced SDHA and SDHB genes in a larger series in order to validate the data. Methods: SDHA gene (1-15 exons) and SDHB gene (1-8 exons) (even not all exons in all samples) were sequenced on tumor (T) and/or peripheral blood (PB) of WT GIST patients by Sanger Sequencing method. DNA was extracted from tumor specimens by the QIAmp DNA Mini kit (Qiagen, Milan, Italy) and amplified with specific primer pairs designed to amplify exons but not SDHA pseudo-genes located on chromosomes 3 and 5. Then, PCR products were purified with the Qiaquick PCR purification kit (Qiagen, Milan, Italy) and sequenced on both strands using the Big Dye Terminator v1.1 Cycle Sequencing kit (Applied Biosystems). Sanger sequencing was performed on ABI 3730 Genetic Analyzer (Applied Biosystems). Results: SDHA gene exons were sequenced on a total of 27 WT GIST patients, in particular on T, PB and both from 12, 6 and 9 patients respectively. SDHB gene exons were sequenced on a total of 18 out of 27 patients, in particular on T, PB and both from 7, 8 and 3 patients respectively. 8 SDHA mutations were found in 5 samples (18.5%). Besides those previously identified, 5 new SDHA mutations were found in other 3 samples: one sample harboured R171C and R589Q heterozygous missense mutation in exons 5 and 13 respectively. The other one harboured G419R and E564K heterozygous missense mutations in exons 9 and 13 respectively. The third sample harboured a delCAG immediately upstream of exon 5, in heterozygosis on PB and in homozygosis on T. A SDHB heterozygous mutation (301delT) in exon 4 was found on 1 PB sample. Conclusions: the presence of SDHA mutations has been confirmed in a subgroup of WT GIST patients. All subunits of SDH complex should be sequenced on WT GIST patients in order to explore the frequency and any linkage between each other and the pathogenetic and clinical significance

Quaderni di Dipartimento Endogenous Market Structures and Labor Market Dynamics Endogenous Market Structures and Labor Market Dynamics 1

Abstract We propose a flexible prices model where endogenous market structures and search and matching frictions in the labor market interact endogenously. The interplay between firms endogenous entry, strategic interactions among producers and labor market frictions represents a strong amplification channel of technology shocks on labor market variables, and helps addressing the unemployment-volatility puzzle. Consistently with U.S. evidence, new firms create a large fraction of new jobs and grow faster than more mature firms, net firms&apos; entry is procyclical and the price mark up is countercyclical. JEL classification: E24, E32, L11

Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET.

Primary and secondary drug resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GISTs) has led to a pressing need for new therapeutic strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT, while RAD001 (everolimus) inhibits mTOR. We report a preclinical study on drug combinations in a xenograft model of GIST in which effects on tumor dimensions and metabolic activity were assessed by small animal PET imaging. METHODS: Rag2-/-; γcommon -/- male mice were injected s.c. into the right leg with GIST 882. The animals were randomized into 6 groups of 6 animals each for different treatment regimens: No therapy (control), imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, everolimus (10 mg/kg/d.) by oral gavage, everolimus (10 mg/kg/d.) + imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75 mg/kg/d.) by oral gavage, nilotinib (75 mg/kg/d.) + imatinib (150 mg/kg b.i.d) by oral gavage for 6 days, then once/day for another 7 days. Tumor growth control was evaluated by measuring tumor volume (cm3). Small animal PET (GE Explore tomography) was used to evaluate tumor metabolism and performed in one animal per group at base-line then after 4 and 13 days of treatment. RESULTS: After a median latency time of 31 days, tumors grew in all animals (volume 0,06-0,15 cm3) and the treatments began at day 38 after cell injection. Tumor volume control (cm3) after 13 days of treatment was > 0.5 for imatinib alone and nilotinib alone, and < 0.5 for the 2 combinations of drugs and for everolimus alone. The baseline FDG uptake was positive in all animals. FDG/SUV/TBR was strongly reduced over time by everolimus both as a single agent and in combination with imatinib respectively: 3.1 vs. 2.3 vs. 1.9 and 2.5 vs 2.3 vs 0. CONCLUSIONS: As single agents, all drugs showed an anti-tumor effect in GIST xenografts but everolimus was superior. The everolimus plus imatinib combination appeared to be the most active regimen both in terms of inhibiting tumor growth and tumor metabolism. The integration of everolimus in GIST treatment merits further investigatio