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R406, an Orally Available Spleen Tyrosine Kinase Inhibitor Blocks Fc Receptor Signaling and Reduces Immune Complex-Mediated Inflammation
TLDR
A first-inhuman study is reported showing that R406 is orally bioavailable, achieving exposures capable of inhibiting Syk-dependent IgE-mediated basophil activation and showing R406 potential for modulating Syk activity in human disease.
NFATx, a novel member of the nuclear factor of activated T cells family that is expressed predominantly in the thymus
TLDR
The expression pattern of NFATx, together with its functional activity, strongly suggests thatNFATx plays a role in the regulation of gene expression in T cells and immature thymocytes.
Quantitative measurement of mast cell degranulation using a novel flow cytometric annexin-V binding assay.
TLDR
The annexin-V binding assay represents a powerful new flow cytometric method to monitor mast cell degranulation for functional analysis and was blocked by phosphatidylserine containing liposomes, consistent with specific binding to this membrane lipid.
The granulocyte-macrophage colony-stimulating factor promoter cis-acting element CLE0 mediates induction signals in T cells and is recognized by factors related to AP1 and NFAT.
TLDR
The presence of CLE0-like elements in the promoters of interleukin-3 (IL-3), IL-4, IL-5, GM-CSF, and NFAT sites in the IL-2 promoter suggests that the factors detected, or related factors that recognize these sites, may account for the coordinate induction of these genes during T-cell activation.
Inhibition of spleen tyrosine kinase prevents mast cell activation and airway hyperresponsiveness.
TLDR
A functional role for Syk is delineated in the development of mast cell- and IgE-mediated AHR and airway inflammation, and these results indicate that inhibition of Syk may be a target in the treatment of allergic asthma.
Syk activation in dendritic cells is essential for airway hyperresponsiveness and inflammation.
TLDR
It is demonstrated that Syk inhibition prevents allergen-induced AHR and airway inflammation after systemic sensitization and challenge, at least in part through alteration of DC function.
A spleen tyrosine kinase inhibitor reduces the severity of established glomerulonephritis.
TLDR
Results suggest that Syk is an important therapeutic target for the treatment of glomerulonephritis, and in vitro, R406 downregulated MCP-1 production from mesangial cells and macrophages stimulated with aggregated IgG.
A Novel E3 Ubiquitin Ligase TRAC-1 Positively Regulates T Cell Activation
TLDR
The results of in vitro biochemical studies indicate that TRAC-1 can stimulate the formation of both K48- and K63-linked polyubiquitin chains and therefore could potentially activate both degradative and regulatory ubiquitin-dependent pathways.
Developmental toxicity associated with receptor tyrosine kinase Ret inhibition in reproductive toxicity testing.
TLDR
A dose-dependent increase in malformations, including renal and ureteric agenesis and a specific major vessel anomaly, retroesophageal right subclavian artery, was observed in both the rat and rabbit as R788 proved to be a potent inhibitor of Ret kinase.
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