Cooperativity of imprinted genes inactivated by acquired chromosome 20q deletions

Large regions of recurrent genomic loss are common in cancers; however, with a few well-characterized exceptions, how they contribute to tumor pathogenesis remains largely obscure. Here we identified primate-restricted imprinting of a gene cluster on chromosome 20 in the region commonly deleted in chronic myeloid malignancies. We showed that a single heterozygous 20q deletion consistently resulted in the complete loss of expression of the imprinted genes L3MBTL1 and SGK2, indicative of a pathogenetic role for loss of the active paternally inherited locus. Concomitant loss of both L3MBTL1 and SGK2 dysregulated erythropoiesis and megakaryopoiesis, 2 lineages commonly affected in chronic myeloid malignancies, with distinct consequences in each lineage. We demonstrated that L3MBTL1 and SGK2 collaborated in the transcriptional regulation of MYC by influencing different aspects of chromatin structure. L3MBTL1 is known to regulate nucleosomal compaction, and we here showed that SGK2 inactivated BRG1, a key ATP-dependent helicase within the SWI/SNF complex that regulates nucleosomal positioning. These results demonstrate a link between an imprinted gene cluster and malignancy, reveal a new pathogenetic mechanism associated with acquired regions of genomic loss, and underline the complex molecular and cellular consequences of "simple" cancer-associated chromosome deletions.

Revised response criteria for polycythemia vera and essential thrombocythemia:an ELN and IWG-MRT consensus project

Standardized response criteria to interpret and compare clinical trials are needed for approval of new therapeutic agents by regulatory agencies. The European LeukemiaNet (ELN) response criteria for essential thrombocythemia (ET) and polycythemia vera (PV) issued in 2009 have been widely adopted as end points in a number of recent clinical trials. However, evidence exists that they do not predict response or provide clinically relevant measures of benefit for the patients. This article presents revised recommendations for assessing response in ET and PV provided by a working group established by ELN and International Working Group-Myeloproliferative Neoplasms Research and Treatment. New definitions of complete and partial remission incorporate clinical, hematological, and histological response assessments that include a standardized symptom assessment form and consider absence of disease progression and vascular events. We anticipate that these criteria will be adopted widely to facilitate the development of new and more effective therapies for ET and PV.

The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis

BACKGROUND: Anemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35-54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.

RESULTS: Thirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.

CONCLUSIONS: Concomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted (ClinicalTrials.gov identifier, NCT00934544; July 6, 2009).

Les mécanismes de l'interprétation dans la chanson populaire (d'expression francophone) proposition d'une méthode d'analyse

Pour montrer comment s'articulent les mécanismes de l'interprétation dans la chanson populaire, nous nous sommes inspirée [inspirés] de travaux de sociologues qui se sont penchés sur la chanson depuis une vingtaine d'années (Authelain, Buxton, Calvet, Giroux, Hennion, Frith, Middleton) ou sur le marché des biens symboliques (Bourdieu), ainsi que de la sémiologie musicale de Jean-Jacques Nattiez. Comme lui, nous avons identifié un processus poïétique, un niveau neutre et un processus esthésique dans la pratique de la chanson, processus qui se dédoublent dans la chanson populaire selon le point d'ancrage de l'analyse: la partition (la trace, constituant un premier"niveau neutre") puis la chanson interprétée (ou résultat musical, qui constitue un second"niveau neutre"). Nous avons par la suite identifié les différents lieux où entre en jeu l'interprétation: chez les exécutants (musiciens et interprètes) qui actualisent la partition, produisant ainsi la chanson interprétée; dans le processus de production/promotion, où s'élaborent l'image de marque de l'artiste et les discours promotionnels; chez le public où l'interprétation apparaît aussi sous ses deux facettes, c'est-à-dire l'exécution possible par les auditeurs/spectateurs, mais surtout la lecture que propose le discours critique. Un exemple précis, l'album D'instinct (1995) de l'auteur/compositeur/interprète Richard Séguin, nous a permis de mettre à l'épreuve ce modèle ainsi qu'une méthode d'analyse qui permet à la fois de se pencher sur une chanson et sur la chanson. Dans un premier temps, nous avons analysé une chanson à partir de la partition puis de la chanson interprétée (sous forme de chanson, d'album, de vidéoclip et de spectacle), sans tenir compte des discours que l'on tient sur cette chanson. Dans un deuxième temps, notre attention s'est portée sur la chanson, analysant l'objet"chanson" transformé par les discours, puis les discours eux-mêmes. Ces analyses nous ont permis de nous pencher sur l'interprétation, d'abord comme exécution (de la partition), et surtout comme lecture, puis de schématiser le réseau des discours, promotionnels et critiques, qui circulent entre l'artiste (et sa musique) et l'auditeur/spectateur. Notre recherche s'intéresse ainsi de façon nouvelle à la chanson populaire et la méthode d'analyse que nous proposons permet de tenir compte de la spécificité de son objet: une approche multidisciplinaire s'imposait pour étudier un phénomène pluridimensionnel comme la chanson. Aussi, les résultats de nos analyses confirment que le modèle et la méthode sont opératoires, mais surtout, ils laissent entrevoir de nombreuses possibilités d'analyses nouvelles d'une/de la chanson, analyses qui permettraient d'en saisir le caractère stylistique, les qualités esthétiques, etc. et même, il nous semble qu'ils pourraient s'avérer tout aussi opératoires appliqués à d'autres corpus."--Résumé abrégé par UMI

O trabalho autobiográfico de Louise Bourgeois e o discurso autobiográfico filosófico

O trabalho denominado como autobiográfico é diverso na sua forma, podendo ser uma manifestação de cariz artístico, literário ou filosófico. A presente dissertação procura investigar as particularidades da forma autobiográfica, os objectivos do autor perante a sua obra e a sua recepção no campo público. Para tal, traz-se para análise: a obra escultórica de Louise Bourgeois para chegar a um entendimento sobre a forma artística da autobiografia; os Cadernos do Subterrâneo de Fiódor Dostoiévski que é exemplo controverso de uma obra autobiográfica literária; e as Confissões de Jean- Jacques Rousseau e Santo Agostinho que nos permitem experienciar uma obra autobiográfica com preocupações características de uma investigação filosófica. Pretende-se compreender a autobiografia na sua generalidade, tanto do ponto de vista do autor como do seu receptor.