Une nouvelle génération d’immunothérapies ciblant la voie CD39/CD73/adénosine pour favoriser la réponse immunitaire anti-tumorale

International audienceNo abstract availabl

Functional and Timing Implications of Transient Faults in Critical Systems

International audienceEmbedded systems in critical domains, such as automotive, aviation, space domains, are often required to guarantee both functional and temporal correctness. Considering transient faults, fault analysis and mitigation approaches are implemented at various levels of the system design, in order to maintain the functional correctness. However, transient faults and their mitigation methods have a timing impact, which can affect the temporal correctness of the system. In this work, we expose the functional and the timing implications of transient faults for critical systems. More precisely, we initially highlight the timing effect of transient faults occurring in the combinational and sequential logic of a processor. Furthermore, we propose a full stack vulnerability analysis that drives the design of selective hardware-based mitigation for real-time applications. Last, we study the timing impact of software-based reliability mitigation methods applied in a COTS GPU, using a fault tolerant middleware

Functional and Timing Implications of Transient Faults in Critical Systems

International audienceEmbedded systems in critical domains, such as automotive, aviation, space domains, are often required to guarantee both functional and temporal correctness. Considering transient faults, fault analysis and mitigation approaches are implemented at various levels of the system design, in order to maintain the functional correctness. However, transient faults and their mitigation methods have a timing impact, which can affect the temporal correctness of the system. In this work, we expose the functional and the timing implications of transient faults for critical systems. More precisely, we initially highlight the timing effect of transient faults occurring in the combinational and sequential logic of a processor. Furthermore, we propose a full stack vulnerability analysis that drives the design of selective hardware-based mitigation for real-time applications. Last, we study the timing impact of software-based reliability mitigation methods applied in a COTS GPU, using a fault tolerant middleware

Functional and Timing Implications of Transient Faults in Critical Systems

International audienceEmbedded systems in critical domains, such as automotive, aviation, space domains, are often required to guarantee both functional and temporal correctness. Considering transient faults, fault analysis and mitigation approaches are implemented at various levels of the system design, in order to maintain the functional correctness. However, transient faults and their mitigation methods have a timing impact, which can affect the temporal correctness of the system. In this work, we expose the functional and the timing implications of transient faults for critical systems. More precisely, we initially highlight the timing effect of transient faults occurring in the combinational and sequential logic of a processor. Furthermore, we propose a full stack vulnerability analysis that drives the design of selective hardware-based mitigation for real-time applications. Last, we study the timing impact of software-based reliability mitigation methods applied in a COTS GPU, using a fault tolerant middleware

TLR3 and Rig-like receptor on myeloid dendritic cells and Rig-like receptor on human NK cells are both mandatory for production of IFN-gamma in response to double-stranded RNA.

Cross-talk between NK cells and dendritic cells (DCs) is critical for the potent therapeutic response to dsRNA, but the receptors involved remained controversial. We show in this paper that two dsRNAs, polyadenylic-polyuridylic acid and polyinosinic-polycytidylic acid [poly(I:C)], similarly engaged human TLR3, whereas only poly(I:C) triggered human RIG-I and MDA5. Both dsRNA enhanced NK cell activation within PBMCs but only poly(I:C) induced IFN-gamma. Although myeloid DCs (mDCs) were required for NK cell activation, induction of cytolytic potential and IFN-gamma production did not require contact with mDCs but was dependent on type I IFN and IL-12, respectively. Poly(I:C) but not polyadenylic-polyuridylic acid synergized with mDC-derived IL-12 for IFN-gamma production by acting directly on NK cells. Finally, the requirement of both TLR3 and Rig-like receptor (RLR) on mDCs and RLRs but not TLR3 on NK cells for IFN-gamma production was demonstrated using TLR3- and Cardif-deficient mice and human RIG-I-specific activator. Thus, we report the requirement of cotriggering TLR3 and RLR on mDCs and RLRs on NK cells for a pathogen product to induce potent innate cell activation

PARP inhibitors and radiation potentiate liver cell death in vitro. Do hepatocellular carcinomas have an achilles’ heel?

International audienc

Cohort Creation and Visualization Using Graph Model in the PREDIMED Health Data Warehouse

International audienceGrenoble Alpes University Hospital (CHUGA) is currently deploying a health data warehouse called PREDIMED [1], a platform designed to integrate and analyze for research, education and institutional management the data of patients treated at CHUGA. PREDIMED contains healthcare data, administrative data and, potentially, data from external databases. PREDIMED is hosted by the CHUGA Information Systems Department and benefits from its strict security rules. CHUGA’s institutional project PREDIMED aims to collaborate with similar projects in France and worldwide. In this paper, we present how the data model defined to implement PREDIMED at CHUGA is useful for medical experts to interactively build a cohort of patients and to visualize this cohort

Blocking Antibodies Targeting the CD39/CD73 Immunosuppressive Pathway Unleash Immune Responses in Combination Cancer Therapies

Summary: Immune checkpoint inhibitors have revolutionized cancer treatment. However, many cancers are resistant to ICIs, and the targeting of additional inhibitory signals is crucial for limiting tumor evasion. The production of adenosine via the sequential activity of CD39 and CD73 ectoenzymes participates to the generation of an immunosuppressive tumor microenvironment. In order to disrupt the adenosine pathway, we generated two antibodies, IPH5201 and IPH5301, targeting human membrane-associated and soluble forms of CD39 and CD73, respectively, and efficiently blocking the hydrolysis of immunogenic ATP into immunosuppressive adenosine. These antibodies promoted antitumor immunity by stimulating dendritic cells and macrophages and by restoring the activation of T cells isolated from cancer patients. In a human CD39 knockin mouse preclinical model, IPH5201 increased the anti-tumor activity of the ATP-inducing chemotherapeutic drug oxaliplatin. These results support the use of anti-CD39 and anti-CD73 monoclonal antibodies and their combination with immune checkpoint inhibitors and chemotherapies in cancer. : The production of adenosine via CD39 and CD73 ectoenzymes participates in an immunosuppressive tumor microenvironment. Perrot et al. generated two antibodies, IPH5201 and IPH5301, targeting human CD39 and CD73, respectively. In vitro and in vivo data support the use of anti-CD39 and anti-CD73 mAbs in combination cancer therapies. Keywords: CD39, CD73, cancer immunotherapies, therapeutic antibodies, adenosine pathway, tumor micro-environment, immunosuppressio