Examples are given of prime Legendrian knots in the standard contact 3-space that have arbitrarily many distinct Chekanov polynomials, refuting a conjecture of Lenny Ng. These are constructed using a new "Legendrian tangle replacement" technique. This technique is then used to show that the phenomenon of multiple Chekanov polynomials is in fact quite common. Finally, building on unpublished work of Yufa and Branson, a tabulation is given of Legendrian fronts, along with their Chekanov polynomials, representing maximal ThurstonBennequin Legendrian knots for each knot type of nine or fewer crossings. These knots are paired so that the front for the mirror of any knot is obtained in a standard way by rotating the front for the knot.

No abstract

Background: 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 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 has suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. Aims: To study the preclinical activity of ALK inhibitors alone and combined with chemotherapy or idasanutlin. Methods: 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. Conclusion: 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.

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.

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.

Background: ALK activating mutations are identified in approximately 10% of newly diag-nosed neuroblastomas and ALK amplifications in a further 1-2% of cases. Lorlatinib, a third generation 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 stud-ied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data has suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. Aims: To study the preclinical activity of ALK inhibitors alone and in combination with chemotherapy or idasanutlin. Methods: We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemo-therapy (CAV: cyclophosphamide, doxorubicin and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and pa-tient derived xenografts (PDX). Results: Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only ob-served in the ALK-amplified PDX model with the highest ALK expression. In this PDX lorla-tinib combined with idasanutlin resulted in complete tumor regression and significantly de-layed tumor regrowth. Conclusion: Our study suggests that in neuroblastoma, high ALK expression could be asso-ciated with response to lorlatinib and either chemotherapy or idasanutlin. The synergy be-tween MDM2 inhibition and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.

22Mesenchymal stem cells have been the focus of intense research in bone development and regeneration. 23 We demonstrate the potential of microparticles as modulating moieties of osteogenic response by 24 utilizing their architectural features. Topographically textured microparticles of varying microscale 25 features were produced by exploiting phase-separation of a readily-soluble sacrificial component from 26 polylactic acid. The influence of varying topographical features on primary human mesenchymal stem 27 cell attachment, proliferation and markers of osteogenesis was investigated. In the absence of 28 osteoinductive supplements, cells cultured on textured microparticles exhibited notably increased 29 expression of osteogenic markers relative to conventional smooth microparticles. They also exhibited 30 varying morphological, attachment and proliferation responses. Significantly altered gene expression 31 and metabolic profiles were observed, with varying histological characteristics in vivo. This study 32 highlights how tailoring topographical design offers cell-instructive 3D microenvironments which allow 33 manipulation of stem cell fate by eliciting the desired downstream response without use of exogenous 34 osteoinductive factors. 35 Results 65 Fabrication of Textured Microparticles with Controlled Topographical Surfaces 66Fabrication of microparticles using emulsion polymerization methods is amenable to scale-up for 67 translational applications (1). Therefore, topographically textured polymer microparticles were 68 fabricated using a drug-induced phase separation emulsion-solvent extraction method to investigate their 69 ability to modulate MSCs differentiation in vitro and in vivo. Textured microparticles were produced by 70 exploiting phase separation of fusidic acid (FA) from polymers during loss of solvent from an oil-in-71 water emulsion. Fusidic acid then dissolves leaving textured surfaces ( Fig. 1A, Supplementary Fig. 72 1C). It was possible to design polymer-based microparticle systems with tunable surface features by 73 changing polymer and drug composition. Towards the aim of producing optimized microparticles for 74 bone regenerative engineering, polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA), two 75 biocompatible polymers with varying biodegradability properties and suitability for implantation (6), 76 were explored. By varying emulsion settings, microparticles with conventional smooth surfaces were 77 produced, in addition to microparticles of two morphologies: dimpled and angular ( Fig. 1B). Our studies 78 have demonstrated that both microparticle and dimple sizes were dependent on polymer concentration 79 and polymer/FA ratio (Fig. 1C-D, Supplementary Table 1 and Supplementary Fig. 1B). An increase 80 in FA content slightly increased dimple size without altering particle size ( Supplementary Fig. 81 1A,B,D). Dimpled microparticles were fabricated with different polymer/FA ratios and total 82 concentrations in the organic phase (Fig 1C and Supplementary Fig 1). S...

<p>Supplementary methods, supplementary tables, supplementary figure legends</p>