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- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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- Smith, LK, et al.
(författare)
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Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAFV600 melanoma
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 1100-
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Tidskriftsartikel (refereegranskat)abstract
- Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.
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| 7. |
- Sopha, B. M., et al.
(författare)
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Simulating long-term performance of regional distribution centers in archipelagic logistics systems
- 2021
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Ingår i: Maritime Economics & Logistics. - : Springer Science and Business Media LLC. - 1479-2931 .- 1479-294X. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Indonesia has reevaluated its archipelagic logistics system to implement a strategic shift from a point-to-point network to a hub-and-spoke network, with a plan to establish seven new regional distribution centers (RDCs). To supplement the previous qualitative assessment of the plan and to potentially justify continuing with its implementation, this paper aims to evaluate the prospective long-term performance of the planned RDCs within a hub-and-spoke (HS) network. The chosen methodology for this analysis is a hybrid of optimization and simulation, using an agent-based modeling and simulation platform that incorporates a geographic information system (GIS) element to provide a realistic geographical context. This constitutes a relatively novel innovation in logistics research. Experiments were developed to estimate the logistics performance of the hub-and-spoke network and planned RDCs, as well as to identify potential problems such as bottlenecks at the RDCs and the relative (in)efficiency of the selected multimodal transport. Transport costs, inventory costs, and the order backlog of RDCs are evaluated based on the average results from 100 replications. Outcomes from the model are validated against empirical data on Indonesia's logistics costs from the World Bank. Model results indicate that the hub-and-spoke network performs better than the point-to-point network when it comes to transportation costs. Since this is found to be the dominant element of total logistics costs, appropriate modal choice and route optimization are, therefore, critical to reducing logistics costs. The planned RDCs are found to have significant imbalance in their loadings, which is likely to produce bottlenecks. The paper concludes that a planned move to a hub-and spoke system is appropriate and that the planned investment in the RDCs is therefore justified. However, there is a need to streamline the predicted loadings at the RDCs to avoid bottlenecks. Our results suggest that the government should reopen the case and reevaluate the locations and coverage of each RDC. More generically, it is concluded that the application of hybrid optimization and simulation using agent-based modeling and simulation is feasible and the methodological approach adopted herein is generalizable to other archipelagic logistics systems.
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