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Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ozone (O3) exposure evokes asthma exacerbations by mechanisms that are poorly understood. We used a murine model to characterize the effects of O3 on allergic airway inflammation and hyperresponsiveness and to identify factors that might contribute to the O3-induced exacerbation of asthma. Methods: BALB/c mice were sensitized and challenged with Aspergillus fumigatus ( Af). A group of sensitized and challenged mice was exposed to 3.0 ppm of O3 for 2 h and studied 12 h later (96 h after Af challenge). Naive mice and mice exposed to O3 alone were used as controls. Bronchoalveolar lavage (BAL) cellular and cytokine content, lung function [enhanced pause (Penh)], isometric force generation by tracheal rings and gene and protein expression of Fas and FasL were assessed. Apoptosis of eosinophils was quantified by FACS. Results: In sensitized mice allergen challenge induced a significant increase of Penh and contractile force in tracheal rings that peaked 24 h after challenge and resolved by 96 h. O3 inhalation induced an exacerbation of airway hyperresponsiveness accompanied by recurrence of neutrophils and enhancement of eosinophils 96 h after allergen challenge. The combination of allergen and O3 exposure inhibited Fas and FasL gene and protein expression and eosinophil apoptosis and increased interleukin-5 (IL-5), granulocyte-macrophage-colony stimulating factor (GM-CSF) and G-CSF protein levels. Conclusions: O3 affects airway responsiveness of allergen-primed airways indirectly by increasing viability of eosinophils and eosinophil-mediated pathological changes. [ABSTRACT FROM AUTHOR]