A multivariate modeling framework to quantify immune checkpoint context-dependent stimulation on T cells.

Cells receive, and adjust to, various stimuli, which function as part of complex microenvironments forming their "context". The possibility that a given context impacts the response to a given stimulus defines "context-dependency" and it explains large parts of the functional variability of physiopathological and pharmacological stimuli. Currently, there is no framework to analyze and quantify context-dependency over multiple contexts and cellular response outputs.

The Dendritic Cell Receptor DNGR-1 Promotes the Development of Atherosclerosis in Mice.

Rationale: Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. However, the molecular links between necrosis and the development of atherosclerosis are not completely understood. Clec9a (C-type lectin receptor) or DNGR-1 (dendritic cell NK lectin group receptor-1) is preferentially expressed by the CD8α subset of dendritic cells (CD8α DCs) and is involved in sensing necrotic cells.

SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies.

Purpose: The CD38 cell surface antigen is expressed in diverse hematologic malignancies including multiple myeloma, B-cell non-Hodgkin lymphoma (NHL), B-cell chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), and T-cell ALL. Here, we assessed the antitumor activity of the anti-CD38 antibody SAR650984.

Experimental Design: Activity of SAR650984 was examined on lymphoma, leukemia and multiple myeloma cell lines, primary multiple myeloma samples, and multiple myeloma xenograft models in immunodeficient mice.

Group X secreted phospholipase A2 limits the development of atherosclerosis in LDL receptor-null mice.

Objective: Several secreted phospholipases A2 (sPLA2s), including group IIA, III, V, and X, have been linked to the development of atherosclerosis, which led to the clinical testing of A-002 (varespladib), a broad sPLA2 inhibitor for the treatment of coronary artery disease. Group X sPLA2 (PLA2G10) has the most potent hydrolyzing activity toward phosphatidylcholine and is believed to play a proatherogenic role.

Methods And Results: Here, we show that Ldlr(-/-) mice reconstituted with bone marrow from mouse group X-deficient mice (Pla2g10(-/-)) unexpectedly display a doubling of plaque size compared with Pla2g10(+/+) chimeric mice.

Srf-dependent paracrine signals produced by myofibers control satellite cell-mediated skeletal muscle hypertrophy.

Adult skeletal muscles adapt their fiber size to workload. We show that serum response factor (Srf) is required for satellite cell-mediated hypertrophic muscle growth. Deletion of Srf from myofibers and not satellite cells blunts overload-induced hypertrophy, and impairs satellite cell proliferation and recruitment to pre-existing fibers.

Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets.

Chronic inflammation drives the development of atherosclerosis, and adaptive immunity is deeply involved in this process. Initial studies attributed a pathogenic role to T cells in atherosclerosis, mainly owing to the proatherogenic role of the T-helper (T(H))-1 cell subset, whereas the influence of T(H)2 and T(H)17 subsets is still debated. Today we know that T regulatory cells play a critical role in the protection against atherosclerotic lesion development and inflammation.

Premature aging in skeletal muscle lacking serum response factor.

Aging is associated with a progressive loss of muscle mass, increased adiposity and fibrosis that leads to sarcopenia. At the molecular level, muscle aging is known to alter the expression of a variety of genes but very little is known about the molecular effectors involved. SRF (Serum Response Factor) is a crucial transcription factor for muscle-specific gene expression and for post-natal skeletal muscle growth.

New role for serum response factor in postnatal skeletal muscle growth and regeneration via the interleukin 4 and insulin-like growth factor 1 pathways.

Serum response factor (SRF) is a crucial transcriptional factor for muscle-specific gene expression. We investigated SRF function in adult skeletal muscles, using mice with a postmitotic myofiber-targeted disruption of the SRF gene. Mutant mice displayed severe skeletal muscle mass reductions due to a postnatal muscle growth defect resulting in highly hypotrophic adult myofibers.