« La musique, moi, je n’en ai pas besoin pour vivre »

En 1945, à l’âge de 19 ans, Michel Ragon, écrivain autodidacte et prolétaire, quitta Nantes pour Paris dans le but précis de sortir de sa condition, ou, comme il le dira lui-même, « d’être libre ». Cette distance géographique en creusa une autre, affective, culturelle et langagière. Un jour, il reçut dans son petit appartement parisien un de ses amis qui lui dit :J’ai téléphoné chez toi. Qui était cette bonne femme avec ce drôle d’accent, qui m’a répondu ? Je croyais qu’il n’existait plus qu..

« La musique, moi, je n’en ai pas besoin pour vivre »

En 1945, à l’âge de 19 ans, Michel Ragon, écrivain autodidacte et prolétaire, quitta Nantes pour Paris dans le but précis de sortir de sa condition, ou, comme il le dira lui-même, « d’être libre ». Cette distance géographique en creusa une autre, affective, culturelle et langagière. Un jour, il reçut dans son petit appartement parisien un de ses amis qui lui dit : J’ai téléphoné chez toi. Qui était cette bonne femme avec ce drôle d’accent, qui m’a répondu ? Je croyais qu’il n’existait plus qu..

Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis

Clusterin (CLU) is a stress‐activated molecular chaperone that confers treatment resistance to taxanes when highly expressed. While CLU inhibition potentiates activity of taxanes and other anti‐cancer therapies in preclinical models, progression to treatment‐resistant disease still occurs implicating additional compensatory survival mechanisms. Taxanes are believed to selectively target cells in mitosis, a complex mechanism controlled in part by balancing antagonistic roles of Cdc25C and Wee1 in mitosis progression. Our data indicate that CLU silencing induces a constitutive activation of Cdc25C, which delays mitotic exit and hence sensitizes cancer cells to mitotic‐targeting agents such as taxanes. Unchecked Cdc25C activation leads to mitotic catastrophe and cell death unless cells up‐regulate protective mechanisms mediated through the cell cycle regulators Wee1 and Cdk1. In this study, we show that CLU silencing induces a constitutive activation of Cdc25C via the phosphatase PP2A leading to relief of negative feedback inhibition and activation of Wee1‐Cdk1 to promote survival and limit therapeutic efficacy. Simultaneous inhibition of CLU‐regulated cell cycle effector Wee1 may improve synergistic responses of biologically rational combinatorial regimens using taxanes and CLU inhibitors

La Haine de la musique

Peut-on parler de « haine de la musique », à l’instar de Pascal Quignard qui accuse la musique de compromission avec les camps de concentration nazis ? Si la radicalité stimule la pensée, la longue histoire des relations entre musique et littérature est en réalité nourrie d’amour et de haine, en somme de fascination ambivalente. À ce problème ancien, notre modernité a donné une acuité nouvelle. D’abord parce que, avec le romantisme, la consécration de l’absolu musical est loin d’être univoque. Ensuite, et selon un mouvement inverse, parce que la musique résiste au xxe siècle, quels que soient les coups portés contre sa légitimité. Les études réunies ici explorent différents territoires de cette haine — anthropologique, esthétique, sociologique. Dans son interrogation sur la musique, la littérature ne cesse de chercher une définition d’elle-même et puise une inspiration constamment renouvelée

TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells

Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8 + T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8 + T cells from the tumour parenchyma that were instead found in the fibroblast-and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-Administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-Tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFβ shapes the tumour microenvironment to restrain anti-Tumour immunity by restricting T-cell infiltration

TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.

Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8+ T cells from the tumour parenchyma that were instead found in the fibroblast- and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFβ shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration

TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells

Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8 + T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8 + T cells from the tumour parenchyma that were instead found in the fibroblast-and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-Administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-Tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFβ shapes the tumour microenvironment to restrain anti-Tumour immunity by restricting T-cell infiltration