Eisai Inc.

Macrophage inflammatory protein-1 (MIP-1), MIP-1α (CCL3) and MIP-1β (CCL4) are chemokines crucial for immune responses towards infection and inflammation. Both MIP-1α and MIP-1β form high-molecular-weight aggregates. Our crystal structures reveal that MIP-1 aggregation is a polymerization process and human MIP-1α and MIP-1β form rod-shaped, double-helical polymers. Biophysical analyses and mathematical modelling show that MIP-1 reversibly forms a polydisperse distribution of rod-shaped polymers in solution. Polymerization buries receptor-binding sites of MIP-1α, thus depolymerization mutations enhance MIP-1α to arrest monocytes onto activated human endothelium. However, same depolymerization mutations render MIP-1α ineffective in mouse peritoneal cell recruitment. Mathematical modelling reveals that, for a long-range chemotaxis of MIP-1, polymerization could protect MIP-1 from proteases that selectively degrade monomeric MIP-1. Insulin-degrading enzyme (IDE) is identified as such a protease and decreased expression of IDE leads to elevated MIP-1 levels in microglial cells. Our structural and proteomic studies offer a molecular basis for selective degradation of MIP-1. The regulated MIP-1 polymerization and selective inactivation of MIP-1 monomers by IDE could aid in controlling the MIP-1 chemotactic gradient for immune surveillance.

Aim: To evaluate the effect of topically administered bevacizumab (Avastin) on experimental corneal neovascularisation in rats. Methods: Silver nitrate sticks (75% silver nitrate, 25% potassium nitrate) were used to perform chemical cauterisation on the corneas of 16 eyes from 16 male Long Evans rats. For the following 7 days, the 10 eyes in the treatment group were instilled with bevacizumab 4 mg/ml drops twice daily, whereas the 6 eyes in the control group received placebo (normal saline drops twice daily). Digital photographs of the cornea were analysed to determine the area of cornea covered by neovascularisation as a percentage of the total corneal area. Results: In the bevacizumab-treated eyes, neovascularisation covered, on average, 38.2% (15.5%) (mean (SD)) of the corneal surface compared with 63.5% (5.0%) in the control group (p,0.02, Mann-Whitney U test). Conclusion: Topically administered bevacizumab (Avastin) at a concentration of 4 mg/ml limits corneal neovascularisation following chemical injury in the male Long Evans rat model.

Purpose: Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC).Experimental Design: Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review.Results: Lenvatinib ORR was 36% [95% confidence interval (CI), 24%-49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%-89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9-3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0-not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction.Conclusions: Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications.

Interleukin 9 (IL-9) is a γ c -family cytokine that is highly produced by T-helper 9 (Th9) cells and regulates a range of immune responses, including allergic inflammation. Here we show that IL-2-JAK3-STAT5 signaling is required for Th9 differentiation, with critical STAT5 binding sites in the Il9 (the gene encoding IL-9) promoter. IL-2 also inhibited B cell lymphoma 6 (BCL6) expression, and overexpression of BCL6 impaired Th9 differentiation. In contrast, IL-21 induced BCL6 and diminished IL-9 expression in wild-type but not Bcl6 −/− cells, and Th9 differentiation was increased in Il21and Il21r −/− T cells. Interestingly, BCL6 bound in proximity to many STAT5 and STAT6 binding sites, including at the Il9 promoter. Moreover, there was increased BCL6 and decreased STAT binding at this site in cells treated with blocking antibodies to IL-2 and the IL-2 receptor, suggesting a possible BCL6-STAT5 binding competition that influences IL-9 production. BCL6 binding was also increased when cells were Th9-differentiated in the presence of IL-21. Thus, our data reveal not only direct IL-2 effects via STAT5 at the Il9 gene, but also opposing actions of IL-2 and IL-21 on BCL6 expression, with increased BCL6 expression inhibiting IL-9 production. These data suggest a model in which increasing BCL6 expression decreases efficient Th9 differentiation, indicating possible distinctive approaches for controlling this process.T cells can differentiate into an array of specialized T-helper populations, including Th1 cells, which mediate antiviral responses; Th2 cells, which mediate host defense to parasites and allergic inflammation; and Th17 cells, which are involved in inflammatory processes and diseases such as psoriasis and inflammatory bowel disease (1-5). Th9 cells are a population of cells differentiated in the presence of IL-4 and TGF-β to secrete IL-9 and mediate allergic inflammation and immunity to intestinal parasites (6-9). The IL-9 receptor consists of IL-9R and the common cytokine receptor γ chain, γ c , which is shared by the receptors for IL-2, IL-4, IL-7, IL-15, and IL-21 (10) and mutated in humans with X-linked severe combined immunodeficiency (11). IL-9R is broadly expressed, including on hematopoietic progenitors, mast cells, macrophages, dendritic cells, B cells, airway epithelial cells, immature neurons, eosinophils, natural killer T (NKT) cells, natural killer (NK) cells, Th9 cells, Th17 cells, and Treg cells (6-9, 12, 13). This distribution helps to explain diverse actions of IL-9. IL-9 increases CD4 + T-cell growth, IgE production by B cells, Treg function, Th17 differentiation, mast cell growth and survival, expression of FceR1α, production of IL-6 by mast cells, and the maturation of hematopoietic progenitor cells (8,9,13). IL-9 also induces the production of IL-8, IL-13, and eotaxin by airway smooth muscle cells and goblet cell metaplasia in airway epithelial cells (14). Recently, IL-9-producing cells have also been shown to exhibit robust antitumor immunity for melanoma (15,16).Like IL-9, IL-2 is a type ...

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1-VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1-FGFR4), platelet-derived growth factor receptor α (PDGFRα), ret proto-oncogene (RET), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine-refractory, differentiated thyroid cancer (RR-DTC)

No abstract

SUMMARY Protein Kinase D (PKD) mediates signal transduction downstream from phospholipase C and diacylglycerol (DAG). PKDs are activated by hormones and stresses in cell lines, but little is known about PKD functions, regulators and effectors in vivo. Here, we show that DKF-2, a C. elegans PKD, regulates innate immunity. Animals lacking DKF-2 are hypersensitive to killing by bacteria that are C. elegans and human pathogens. DKF-2 induces >75 mRNAs, which encode anti-microbial peptides and proteins that sustain intestinal epithelium. Induction of immune effector mRNAs by DKF-2 proceeds via PMK-1 (p38 Map-kinase)-dependent and independent pathways. TPA-1, a PKCδ homolog, regulates activation and functions of DKF-2 in vivo. DKF-2 provides a novel molecular link that couples DAG signaling to regulation of immunity. A newly-discovered intersection between DAG/TPA-1/DKF-2 and PMK-1 pathways enables integrated immune responses to multiple stimuli.