Citations

Abstract IL-17 is known to play important roles in immune and inflammatory disease, such as in asthma, but its functions in allergic airway inflammation are still controversial, and the molecular mechanisms mediating these functions remain unclear. Increased production of eosinophils in bone marrow and their emergence in the airway have been linked to the onset and progression of allergic asthma. In this study, we investigated the effects of exogenous IL-17 on allergic airway inflammation and explored the underlying molecular mechanisms through eosinophil generation. Exogenous IL-17 significantly attenuated the features of allergic inflammation induced by ovalbumin in mice. It inhibited eosinophil differentiation both in vivo and in vitro, accompanied by down-regulated expression of CC chemokine receptor 3, GATA binding protein 1 (GATA-1), and GATA binding protein 2 (GATA-2), as well as reduced formation of common myeloid progenitors and eosinophil progenitors, but without influencing eosinophil apoptosis. IL-17 also significantly decreased the number of eosinophils in IL-5–transgenic mice, although it notably increased the levels of IL-3, IL-5, and granulocyte/macrophage colony–stimulating factor. In addition, IL-17 had little effect on secretion of the inflammatory cytokines by eosinophils. Neutralization of endogenous IL-17 significantly augmented eosinophil recruitment in the airways. Together, these findings suggest that exogenous IL-17 protects against allergic airway inflammation, most likely through inhibition of the eosinophil differentiation in bone marrow.

Abstract Poly (ADP-ribose) polymerase (PARP) plays an important role in several DNA repair processes, and previous studies with various PARP inhibitors have demonstrated robust enhancement of sensitivity to temozolomide (TMZ) chemotherapy in pre-clinical models of glioblastoma multiforme (GBM). The focus of this study was to evaluate the antitumor effects of a novel PARP inhibitor, BMN 673, as a single agent and in combination with TMZ in the established U251 glioma cell line, neurosphere cultures from the primary Mayo GBM xenograft line GBM12, and TMZ-resistant cells derived from either line (U251TMZ, GBM12TMZ(MGMT high) and GBM12TMZ(MGMT low)). In a biochemical assay of PARP inhibition, BMN 673 potently suppressed poly-ADP-ribosylation of cellular proteins at concentrations of 3 nM following hydrogen peroxide treatment of U251 cells. Single agent treatment had modest anti-tumor activity with 30 nM BMN 673 reducing absorbance in a CyQUANT cell proliferation assay relative to control treatment in both U251 and U251TMZ cells (Table 1). BMN 673 co-treatment also enhanced the efficacy of TMZ in both U251-derivative lines at a clinically relevant concentration of TMZ. Similarly, treatment with BMN673 alone or in combination with TMZ inhibited primary neurosphere formation in all three GBM12 models. Notably, the addition BMN 673 clearly re-sensitized both resistant GBM12 sub-lines to relatively low concentrations of TMZ. Consistent with a mechanism involving disruption of DNA repair, combined treatment with BMN 673 and TMZ resulted in robust activation of ATM-mediated KAP1 phosphorylation (Ser824) and ATR-mediated Chk1 phosphorylation (Ser345) as compared to TMZ or BMN 673 alone 24 hours after treatment. In conclusion, BMN673 is a promising PARP inhibitor with high potency and cytotoxicity in vitro against both TMZ sensitive and TMZ resistant GBM cells. Table 1 - In vitro antitumor effects of TMZ combined with BMN673 TMZ, microM 0 nM BMN673 30 nM BMN673 CyQUANT U251 Relative absorbance Relative absorbance 0 1.00 0.58 30 0.80 0.30 U251TMZ 0 1.00 0.69 30 1.02 0.21 Primary Neurosphere Assay GBM12 Relative Count Relative Count 0 1.00 0.66 5 0.32 0 10 0.01 0 GBM12TMZ (MGMT high) 0 1.00 0.32 5 1.11 0.02 10 1.04 0.01 GBM12TMZ (MGMT low) 0 1.00 0.25 5 0.86 0.03 10 0.75 0 Citation Format: Sani H. Kizilbash, Ryo Kawashima, Shiv Gupta, Ann C. Mladek, Yuqiao Shen, Jann N. Sarkaria. BMN 673 potentiates efficacy of temozolomide in sensitive and resistant glioblastoma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2067. doi:10.1158/1538-7445.AM2013-2067

Abstract Background There is increasing evidence for specific cellular changes in the stomach of patients with diabetic ( DG ) and idiopathic ( IG ) gastroparesis. The most significant findings are loss of interstitial cells of Cajal ( ICC ), neuronal abnormalities, and an immune cellular infiltrate. Studies done in diabetic mice have shown a cytoprotective effect of CD 206+ M2 macrophages. To quantify overall immune cellular infiltrate, identify macrophage populations, and quantify CD 206+ and i NOS + cells. To investigate associations between cellular phenotypes and ICC . Methods Full thickness gastric body biopsies were obtained from non‐diabetic controls (C), diabetic controls ( DC ), DG , and IG patients. Sections were labeled for CD 45, CD 206, Kit, i NOS , and putative human macrophage markers ( HAM 56, CD 68, and EMR 1). Immunoreactive cells were quantified from the circular muscle layer. Key Results Significantly fewer ICC were detected in DG and IG tissues, but there were no differences in the numbers of cells immunoreactive for other markers between patient groups. There was a significant correlation between the number of CD 206+ cells and ICC in DG and DC patients, but not in C and IG and a significant correlation between i NOS + cells and ICC in the DC group, but not the other groups. CD 68 and HAM 56 reliably labeled the same cell populations, but EMR 1 labeled other cell types. Conclusions & Inferences Depletion of ICC and correlation with changes in CD 206+ cell numbers in DC and DG patients suggests that in humans, like mice, CD 206+ macrophages may play a cytoprotective role in diabetes. These findings may lead to novel therapeutic options, targeting alternatively activated macrophages.