Yeast screens identify the RNA polymerase II CTD and SPT5 as relevant targets of BRCA1 interaction.

BRCA1 has been implicated in numerous DNA repair pathways that maintain genome integrity, however the function responsible for its tumor suppressor activity in breast cancer remains obscure. To identify the most highly conserved of the many BRCA1 functions, we screened the evolutionarily distant eukaryote Saccharomyces cerevisiae for mutants that suppressed the G1 checkpoint arrest and lethality induced following heterologous BRCA1 expression. A genome-wide screen in the diploid deletion collection combined with a screen of ionizing radiation sensitive gene deletions identified mutants that permit growth in the presence of BRCA1. These genes delineate a metabolic mRNA pathway that temporally links transcription elongation (SPT4, SPT5, CTK1, DEF1) to nucleopore-mediated mRNA export (ASM4, MLP1, MLP2, NUP2, NUP53, NUP120, NUP133, NUP170, NUP188, POM34) and cytoplasmic mRNA decay at P-bodies (CCR4, DHH1). Strikingly, BRCA1 interacted with the phosphorylated RNA polymerase II (RNAPII) carboxy terminal domain (P-CTD), phosphorylated in the pattern specified by the CTDK-I kinase, to induce DEF1-dependent cleavage and accumulation of a RNAPII fragment containing the P-CTD. Significantly, breast cancer associated BRCT domain defects in BRCA1 that suppressed P-CTD cleavage and lethality in yeast also suppressed the physical interaction of BRCA1 with human SPT5 in breast epithelial cells, thus confirming SPT5 as a relevant target of BRCA1 interaction. Furthermore, enhanced P-CTD cleavage was observed in both yeast and human breast cells following UV-irradiation indicating a conserved eukaryotic damage response. Moreover, P-CTD cleavage in breast epithelial cells was BRCA1-dependent since damage-induced P-CTD cleavage was only observed in the mutant BRCA1 cell line HCC1937 following ectopic expression of wild type BRCA1. Finally, BRCA1, SPT5 and hyperphosphorylated RPB1 form a complex that was rapidly degraded following MMS treatment in wild type but not BRCA1 mutant breast cells. These results extend the mechanistic links between BRCA1 and transcriptional consequences in response to DNA damage and suggest an important role for RNAPII P-CTD cleavage in BRCA1-mediated cancer suppression.

Unesp Ciência, 2015, ano 6, número 66

Revista elaborada pela Assessoria de Comunicação e Imprensa da Reitoria da UNESP

Y-90-Ibritumomab Tiuxetan (Zevalin (R)) Consolidation of First Remission In Advanced-Stage Follicular Non-Hodgkin's Lymphoma: Updated Results After a Median Follow-up of 66.2 Months From the International, Randomized, Phase III First-Line Indolent Trial (FIT) In 414 Patients

The FIT trial was conducted to evaluate the safety and efficacy of 90Y-ibritumomab tiuxetan (0.4 mCi/kg; maximum dose 32 mCi) when used as consolidation of first complete or partial remission in patients with previously untreated, advanced-stage follicular lymphoma (FL). Patients were randomly assigned to either 90Y-ibritumomab treatment (n = 207) or observation (n = 202) within 3 months (mo) of completing initial induction therapy (chemotherapy only: 86%; rituximab in combination with chemotherapy: 14%). Response status prior to randomization did not differ between the groups: 52% complete response (CR)/CR unconfirmed (CRu) to induction therapy and 48% partial response (PR) in the 90Y-ibritumomab arm vs 53% CR/CRu and 44% PR in the control arm. The primary endpoint was progression-free survival (PFS) of the intent-to-treat (ITT) population. Results from the first extended follow-up after a median of 3.5 years revealed a significant improvement in PFS from the time of randomization with 90Y-ibritumomab consolidation compared with control (36.5 vs 13.3 mo, respectively; P < 0.0001; Morschhauser et al. JCO. 2008; 26:5156-5164). Here we report a median follow-up of 66.2 mo (5.5 years). Five-year PFS was 47% in the 90Y-ibritumomab group and 29% in the control group (hazard ratio (HR) = 0.51, 95% CI 0.39-0.65; P < 0.0001). Median PFS in the 90Y-ibritumomab group was 49 mo vs 14 mo in the control group. In patients achieving a CR/CRu after induction, 5-year PFS was 57% in the 90Y-ibritumomab group, and the median had not yet been reached at 92 months, compared with a 43% 5-year PFS in the control group and a median of 31 mo (HR = 0.61, 95% CI 0.42-0.89). For patients in PR after induction, the 5-year PFS was 38% in the 90Y-ibritumomab group with a median PFS of 30 mo vs 14% in the control group with a median PFS of 6 mo (HR = 0.38, 95% CI 0.27-0.53). Patients who had received rituximab as part of induction treatment had a 5-year PFS of 64% in the 90Y-ibritumomab group and 48% in the control group (HR = 0.66, 95% CI 0.30-1.47). For all patients, time to next treatment (as calculated from the date of randomization) differed significantly between both groups; median not reached at 99 mo in the 90Y-ibritumomab group vs 35 mo in the control group (P < 0.0001). The majority of patients received rituximab-containing regimens when treated after progression (63/82 [77%] in the 90Y-ibritumomab group and 102/122 [84%] in the control group). Overall response rate to second-line treatment was 79% in the 90Y-ibritumomab group (57% CR/CRu and 22% PR) vs 78% in the control arm (59% CR/CRu, 19% PR). Five-year overall survival was not significantly different between the groups; 93% and 89% in the 90Y-ibritumomab and control groups, respectively (P = 0.561). To date, 40 patients have died; 18 in the 90Y-ibritumomab group and 22 in the control group. Secondary malignancies were diagnosed in 16 patients in the 90Y-ibritumomab arm vs 9 patients in the control arm (P = 0.19). There were 6 (3%) cases of myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) in the 90Y-ibritumomab arm vs 1 MDS in the control arm (P = 0.063). In conclusion, this extended follow-up of the FIT trial confirms the benefit of 90Y-ibritumomab consolidation with a nearly 3 year advantage in median PFS. A significant 5-year PFS improvement was confirmed for patients with a CR/CRu or a PR after induction. Effective rescue treatment with rituximab-containing regimens may explain the observed no difference in overall survival between both patient groups who were - for the greater part - rituximab-naïve.

Distribución y rangos preferenciales de temperatura y salinidad de los recursos pelágicos deurante el otoño de 1998. Crucero BIC Humboldt 9803-05 de Tumbes a Tacna

Describe la distribución, concentración y rangos preferenciales de temperatura y salinidad de los principales recursos pelágicos: anchoveta, sardina, jurel y caballa; y adicionalmente de la samasa por el significativo nivel de abundancia determinado durante el Crucero (otoño 1998). Para la distribución y concentración se utilizó una ecosonda científica SIMRAD EK 500 con frecuencias de 38 y 120 kHz en un rango de detección de 3,5 a 400 m de profundidad, distribuidos en nueve capas de integración. Para el muestreo acústico se utilizó una grilla sistemática paralela con una separación de 12 mn entre transectos; se realizaron en total 391 lances de pesca de arrastre pelágico para la comprobación de ecorregistros (BIC Humboldt y lanchas). Las áreas de distribución de cada recurso se determinaron mediante un programa de software de interpolación de datos. Para la determinación de los rangos preferenciales de temperatura y salinidad se utilizó un CTD y botellas Niskin hasta los 300 m de profundidad. Los análisis se realizaron a bordo por el método de inducción.

Le corps, lieu de l'expérience des limites? Réflexions à partir de la littérature chrétienne antique (Ascension d'Esaïe 6 et Recconnaissances II,61-66, en écho à 2 Co 12,1-11)

(Résumé de l'ouvrage) Dans cet ouvrage réunissant théologiens et philosophes, le corps contemporain est pensé par rapport à ce qui l'excède, ce qui le met en scène, ce qui le reprend, ce qui le transforme aujourd'hui. Dans une première partie, l'ouvrage propose des éclairages sur le corps à partir de ce qui met en question sa vision strictement rationnelle. Puis, trois auteurs évoquent les différentes manières dont la Bible, la philosophie et la littérature contemporaine mettent en scène les corps. Dans une troisième partie, sont abordées des questions plus spécifiquement reliées à la tradition catholique, au christianisme primitif et à la pratique de l'ascèse. Enfin, quatre contributions explorent le défi posé par la déréalisation du corps dans nos sociétés d'aujourd'hui, avec, pour clore l'ensemble, une réflexion sur le dualisme qui traverse le questionnement sur le corps.

Le Livre des cent ballades [par JEAN DE WERCHIN, PHILIPPE D'ARTOIS, JEAN BOUCICAUT et JEAN DE CRESEQUES], avec les réponses de « REGNAUT DE TRIE » (fol. 60), « CHAMBRILLART » (fol. 61), « monseigneur DE TOURAINE », « LYONET DE COISMES » (fol. 62), « monseigneur DE BERRY » (fol. 63), « JAQUET D'ORLIENS », « TIGNONVILLE » (fol. 64), « JEHAIN DE MALLY » (fol. 65), « YVRY », « BERTHICOURT » (fol. 66), « monseigneur DE LA TRIMOULLE » (fol. 67).

Commençant par : « Une fois pieça chevauchoie Entre Pont de Cé et Angiers... » et finissant par : « Tant seulement doit en son cuer choisir En ciel un Dieu, en terre une deesse » .

Ala ciudad. Periódico de la Cámara de Comercio de Bogotá. Edición: 66

Gestión del conocimiento