Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

BACKGROUND The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

BACKGROUND The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

El gran juego: la guerra secreta por el control de Asia Central (1836-1919)

Durant el segle XIX i les primeres dècades del XX, Àsia Central va patir de primera mà la rivalitat entre les dues grans potències europees del moment: Anglaterra i Rússia. Aquest enfrontament va ser batejat pels seus propis participants amb el nom d'El Gran Joc. A diferència d'altres lluites històriques prèvies, el Gran Joc no es va resumir en una guerra, sinó en un cúmul d'elles, que es van succeir al llarg del temps en diferents territoris del centre del continent asiàtic i a les que van acompanyar accions diplomàtiques igualment nombroses. Tot i l'extensió del conflicte, Afganistan es va erigir com el punt clau més rellevant al voltant del qual l'Imperi rus i el britànic van desenvolupar les seves intrigues. Els dos poders europeus, amb els seus respectius objectius en ment, no van dubtar a dur a terme un dels majors desplegaments estratègics mai vist a la zona, valent-se, a més dels seus efectius, dels habitants asiàtics com peons al tauler del seu joc i marcant profundament el futur de les nacions centreasiàtiques, així com establint un precedent en la manera de fer la guerra on la victòria d'una facció sobre una altra mai estaria clara.

County Clare, une auto blindée sur le pont d'Ennis [automitrailleuse Austin, patrouille du 17ème bataillon du Royal Tank Corps, près de la caserne de la Royal Irish Constabulary à Ennis] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 57114

Improving gene annotation using peptide mass spectrometry

Annotation of protein-coding genes is a key goal of genome sequencing projects. In spite of tremendous recent advances in computational gene finding, comprehensive annotation remains a challenge. Peptide mass spectrometry is a powerful tool for researching the dynamic proteome and suggests an attractive approach to discover and validate protein-coding genes. We present algorithms to construct and efficiently search spectra against a genomic database, with no prior knowledge of encoded proteins. By searching a corpus of 18.5 million tandem mass spectra (MS/MS) from human proteomic samples, we validate 39,000 exons and 11,000 introns at the level of translation. We present translation-level evidence for novel or extended exons in 16 genes, confirm translation of 224 hypothetical proteins, and discover or confirm over 40 alternative splicing events. Polymorphisms are efficiently encoded in our database, allowing us to observe variant alleles for 308 coding SNPs. Finally, we demonstrate the use of mass spectrometry to improve automated gene prediction, adding 800 correct exons to our predictions using a simple rescoring strategy. Our results demonstrate that proteomic profiling should play a role in any genome sequencing project.

Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility

Background: Germline genetic variation is associated with the differential expression of many human genes. The phenotypic effects of this type of variation may be important when considering susceptibility to common genetic diseases. Three regions at 8q24 have recently been identified to independently confer risk of prostate cancer. Variation at 8q24 has also recently been associated with risk of breast and colorectal cancer. However, none of the risk variants map at or relatively close to known genes, with c-MYC mapping a few hundred kilobases distally. Results: This study identifies cis-regulators of germline c-MYC expression in immortalized lymphocytes of HapMap individuals. Quantitative analysis of c-MYC expression in normal prostate tissues suggests an association between overexpression and variants in Region 1 of prostate cancer risk. Somatic c-MYC overexpression correlates with prostate cancer progression and more aggressive tumor forms, which was also a pathological variable associated with Region 1. Expression profiling analysis and modeling of transcriptional regulatory networks predicts a functional association between MYC and the prostate tumor suppressor KLF6. Analysis of MYC/Myc-driven cell transformation and tumorigenesis substantiates a model in which MYC overexpression promotes transformation by down-regulating KLF6. In this model, a feedback loop through E-cadherin down-regulation causes further transactivation of c-MYC.Conclusion: This study proposes that variation at putative 8q24 cis-regulator(s) of transcription can significantly alter germline c-MYC expression levels and, thus, contribute to prostate cancer susceptibility by down-regulating the prostate tumor suppressor KLF6 gene.

Les fabricacions periodístiques del segle XX: contribució a la definició del concepte de veracitat de la informació

El concepte de veracitat és un terme que genera consens entre els estudiosos del’ètica periodística, entre els mateixos periodistes i entre l’audiència perquè hi ha una càrrega simbòlica molt important. En aquest sentit, la veracitat està molt vinculada amb la praxis periodística. El seu discurs es formula des de l’ètica i es posiciona com una valor absolut. No hiha periodisme sense veritat. Tot i amb això, aquest principi es transgredit per periodistes que s’inventen o fabriquen una història i la presenten com a verídica. Coneguts són els casos de Janet Cooke, Stephen Glass o Jayson Blair. La descoberta d’aquestes invencions ha provocatun intens debat entre els professionals de la comunicació, però quina ha estat la sevacontribució en la definició del concepte de veracitat?

Itinéraire de Bône à Constantine et marche de l'armée expéditionnaire en novembre 1836 : Sous les ordres de M. le Maréchal Clausel, avec les plans Drean, Nechmeya et Guelma / Dessiné par Ginoux ; Toulon, Lith[ographe] Imbert

Échelle(s) : [ca 1:226 000], 1 Lieue de poste [= 1,9 cm]