Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models.

PURPOSE: ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1%-2% of cases. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single-agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data have suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. EXPERIMENTAL DESIGN: We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin, and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient-derived xenografts (PDX). RESULTS: Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX, lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth. CONCLUSIONS: In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.

Extreme climate projections under representative concentration pathways in the Lower Songkhram River Basin, Thailand.

This paper aims to assess changes in the extreme climate indices of the Lower Songkhram River Basin of Thailand under Representative Concentration Pathways (RCPs) scenarios. A linear scaling method was used to correct climate data bias in three Regional Climate Models (RCMs) under RCP 4.5 and RCP 8.5 scenarios. Thereafter, extreme climate indices related to temperature and rainfall were analysed for the wet and dry seasons in upstream and downstream areas of the basin. A total of 14 climate indices were analysed for three time periods: the 2030s (2020-2044), 2055s (2045-2069), and 2080s (2070-2094) and compared with the baseline climate from 1980‒2004. The results show that considerable variability is expected in the extreme climate of the basin in future. The average annual and monthly maximum and minimum temperature is projected to increase, with a lesser increase in the near future and higher in the far future. Heat events (TXx, TXn) are projected to increase while the cold events (TNx, TNn) are projected to decrease in both dry and wet seasons upstream and downstream of the basin. The future average annual rainfall in the basin is projected to decrease under RCP 4.5 and RCP 8.5 scenarios for all three periods. However, the variability in average monthly rainfall is expected to increase in the dry season (Jan-May) and decrease in the wet (Aug-Dec). The most intense rainfall in one day (RX1Day) and five consecutive days (RX5Day) in the wet season is observed to increase in future, with a higher increase in the near future and a lower increase in the far future. The very heavy rainfall days (R20) (the number of days receiving more than 20 mm/day in the basin) are observed to decrease in both wet and dry seasons under RCP 4.5 and RCP 8.5 scenarios in both locations. The results of this study will be helpful for the planning and management of natural resources as well as disaster risk reduction in the Lower Songkhram River Basin.

Biological Role of MYCN in Medulloblastoma: Novel Therapeutic Opportunities and Challenges Ahead.

The constitutive and dysregulated expression of the transcription factor MYCN has a central role in the pathogenesis of the paediatric brain tumour medulloblastoma, with an increased expression of this oncogene correlating with a worse prognosis. Consequently, the genomic and functional alterations of MYCN represent a major therapeutic target to attenuate tumour growth in medulloblastoma. This review will provide a comprehensive synopsis of the biological role of MYCN and its family components, their interaction with distinct signalling pathways, and the implications of this network in medulloblastoma development. We will then summarise the current toolbox for targeting MYCN and highlight novel therapeutic avenues that have the potential to results in better-tailored clinical treatments.

Designing topographically textured microparticles for induction and modulation of osteogenesis in mesenchymal stem cell engineering.

Mesenchymal stem cells are the focus of intense research in bone development and regeneration. The potential of microparticles as modulating moieties of osteogenic response by utilizing their architectural features is demonstrated herein. Topographically textured microparticles of varying microscale features are produced by exploiting phase-separation of a readily soluble sacrificial component from polylactic acid. The influence of varying topographical features on primary human mesenchymal stem cell attachment, proliferation and markers of osteogenesis is investigated. In the absence of osteoinductive supplements, cells cultured on textured microparticles exhibit notably increased expression of osteogenic markers relative to conventional smooth microparticles. They also exhibit varying morphological, attachment and proliferation responses. Significantly altered gene expression and metabolic profiles are observed, with varying histological characteristics in vivo. This study highlights how tailoring topographical design offers cell-instructive 3D microenvironments which allow manipulation of stem cell fate by eliciting the desired downstream response without use of exogenous osteoinductive factors.