| 1. |
- Smith, HW, et al.
(författare)
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An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2901-
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.
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| 14. |
- Ghaddar, N, et al.
(författare)
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The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 4651-
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Tidskriftsartikel (refereegranskat)abstract
- The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.
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| 17. |
- Liang, S, et al.
(författare)
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Polysome-profiling in small tissue samples
- 2018
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Ingår i: Nucleic acids research. - : Oxford University Press (OUP). - 1362-4962 .- 0305-1048. ; 46:1, s. e3-
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Tidskriftsartikel (refereegranskat)
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| 21. |
- Ristau, J, et al.
(författare)
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RITA requires eIF2α-dependent modulation of mRNA translation for its anti-cancer activity
- 2019
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 10:11, s. 845-
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Tidskriftsartikel (refereegranskat)abstract
- Tumor protein 53 (p53, encoded by the TP53 gene) is a key tumor suppressor regulating cell fates in response to internal and external stresses. As TP53 is mutated or silenced in a majority of tumors, reactivation of p53 by small molecules represents a promising strategy in cancer therapeutics. One such agent is RITA (reactivation of p53 and induction of tumor cell apoptosis), which restores p53 expression in cells with hyperactive HDM2 and induces apoptosis. Yet, mechanisms underlying the anticancer activity of RITA are incompletely understood. Here we show that RITA suppresses mRNA translation independently of p53 by inducing eIF2α phosphorylation. Surprisingly, reactivation of p53 following RITA treatment is critically dependent on eIF2α phosphorylation. Moreover, inhibition of eIF2α phosphorylation attenuates pro-apoptotic and anti-neoplastic effects of RITA, while inducing phosphorylation of eIF2α enhances the anticancer activity of RITA. Collectively, these findings demonstrate that the translational machinery plays a major role in determining the antineoplastic activity of RITA, and suggest that combining p53 activators and translation modulators may be beneficial.
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| 23. |
- van de Hoef, Sebastian, et al.
(författare)
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A predictive framework for dynamic heavy-duty vehicle platoon coordination
- 2019
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Ingår i: ACM Transactions on Cyber-Physical Systems. - : Association for Computing Machinery. - 2378-962X .- 2378-9638. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- This article describes a system to facilitate dynamic en route formation of heavy-duty vehicle platoons with the goal of reducing fuel consumption. Safe vehicle platooning is a maturing technology that leverages modern sensor, control, and communication technology to automatically regulate the inter-vehicle distances. Truck platooning has been shown to reduce fuel consumption through slipstreaming by up to 10% under realistic highway-driving conditions. To further benefit from this technology, a platoon coordinator is proposed, which interfaces with fleet management systems and suggests how platoons can be formed in a fuel-efficient manner over a large region. The coordinator frequently updates the plans to react to newly available information. This way, it requires a minimum of customization with respect to the logistic operations.We discuss the system architecture in detail and introduce important underlying methodological foundations. Plans are derived in computationally tractable stages optimizing fuel savings from platooning. The effectiveness of this approach is verified in a simulation study. It shows that the coordinated platooning system can improve over spontaneously occurring platooning even under the presence of disturbances. A real demonstrator has also been developed. We present data from an experiment in which three vehicles were coordinated to form a platoon on public highways under normal traffic conditions. It demonstrates the feasibility of coordinated en route platoon formation with current communication and on-board technology. Simulations and experiments support that the proposed system is technically feasible and a potential solution to the problem of using vehicle platooning in an operational context.
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| 24. |
- van de Hoef, Sebastian, et al.
(författare)
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Computing Feasible Vehicle Platooning Opportunities for Transport Assignments
- 2016
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Ingår i: IFAC PAPERSONLINE. - : Elsevier BV. - 2405-8963. ; , s. 43-48
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Konferensbidrag (refereegranskat)abstract
- Vehicle platooning facilitates the partial automation of vehicles and can significantly reduce fuel consumption. Mobile mummification infrastructure makes it possible to dynamically coordinate the formation of platoons en route. We consider a centralized system that provides trucks with routes and speed profiles allowing them to dynamically form platoons during their journeys. For this to work, all possible pairs of vehicles that can platoon based on their location, destination, and other constraints have to be identified. The presented approach scales well to large vehicle fleets and realistic road networks by extracting features from the transport assignments of the vehicles and rules out a majority of possible pairs based on these features only. Merely a small number of remaining pairs are considered in depth by a complete and computationally expensive algorithm. This algorithm conclusively decides if platooning is possible for a pair based on the complete data associated with the two vehicles. We derive appropriate features for the problem and demonstrate the effectiveness of the approach in a simulation example.
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| 25. |
- van de Hoef, Sebastian, et al.
(författare)
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Coordinating Truck Platooning by Clustering Pairwise Fuel-Optimal Plans
- 2015
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Ingår i: IEEE Conference on Intelligent Transportation Systems, Proceedings, ITSC. - : IEEE conference proceedings. - 9781467365956 - 9781467365956 - 9781467365956 - 9781467365956 ; , s. 408-415
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Konferensbidrag (refereegranskat)abstract
- We consider the fuel-optimal coordination of trucks into platoons. Truck platooning is a promising technology that enables trucks to save significant amounts of fuel by driving close together and thus reducing air drag. We study how fuel-optimal speed profiles for platooning can be computed. A first-order fuel model is considered and pairwise optimal plans are derived. We formulate an optimization problem that combines these pairwise plans into an overall plan for a large number of trucks. The problem resembles a medoids clustering problem. We propose an approximation algorithm similar to the partitioning around medoids algorithm and discuss its convergence. The method is evaluated with Monte Carlo simulations. We demonstrate that the proposed algorithm can compute a plan for thousands of trucks and that significant fuel savings can be achieved.
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| 26. |
- van de Hoef, Sebastian
(författare)
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Coordination of Heavy-Duty Vehicle Platooning
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A network-wide coordination system for heavy-duty vehicle platooning with the purpose of reducing fuel consumption is developed. Road freight is by far the dominating mode for overland transport with over 60 % modal share in the OECD countries and is thus critically important for the economy. Overcoming its strong dependency on fossil fuels and manual labor as well as handling rising congestion levels are therefore important societal challenges. Heavy-duty vehicle platooning is a promising near-term automated-driving technology. It combines vehicle-to-vehicle communication and on-board automation to slipstream in a safe manner, which can reduce fuel consumption by more than 10 %. However, in order to realize these benefits in practice, a strategy is needed to form platoons in an operational context. We propose a platoon coordination system that supports the process of automatically forming platoons over large geographic areas.We develop an architecture in which fleet management systems send start locations, destinations, and arrival deadlines to a platoon coordinator. By computing desirable speed profiles and by letting the vehicles' on-board systems track them, vehicles can meet en route and form platoons. Matching vehicles into platoons and deriving suitable speed profiles is treated as an optimization problem with the objective of maximizing the overall fuel savings under the constraint that vehicles arrive in time at their destinations. By updating the speed profiles and the platoon configurations based on real-time measurements of vehicle position and platoon state, the system can accommodate new vehicles joining on the fly. Using real-time measurements also makes the system resilient to disturbances and changing operating conditions. This thesis seeks to develop the theoretical foundations of such a system and evaluate its potential to improve transport efficiency. We first explore the coordination of vehicle pairs. Fuel-optimal speed profiles are derived. The uncertainty arising from traffic is taken into account by modeling travel time distributions and considering the probability of two vehicles successfully merging. Building on this coordination algorithm for vehicle pairs, we derive algorithms for larger platoons and vehicle fleets. This results in an NP-hard combinatorial optimization problem. The problem is formulated as an integer program and results on the solution structure are derived. In order to handle realistic fleet sizes with thousands of vehicles and continental sized geographical areas under real-time operation, heuristic algorithms are developed. The speed profiles resulting from the combinatorial optimization are further improved using convex optimization. Moreover, we derive efficient algorithms to identify all pairs of vehicles that can platoon. Simulations demonstrate that the proposed algorithm is able to compute plans for thousands of vehicles. Coordinating approximately a tenth of Germany's heavy-duty vehicle traffic, platooning rates over 65 % can be achieved and fuel consumption can be reduced by over 5 %. The proposed system was implemented in a demonstrator system. This demonstrator system has been used in experiments on public roads that show the technical feasibility of en route platoon coordination.
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| 27. |
- van de Hoef, Sebastian, et al.
(författare)
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Efficient Dynamic Programming Solution to a Platoon Coordination Merge Problem With Stochastic Travel Times
- 2017
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Ingår i: IFAC-PapersOnLine. - : Elsevier. - 2405-8963. ; 50:1, s. 4228-4233
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Tidskriftsartikel (refereegranskat)abstract
- The problem of maximizing the probability of two trucks being coordinated to merge into a platoon on a highway is considered. Truck platooning is a promising technology that allows heavy vehicles to save fuel by driving with small automatically controlled inter-vehicle distances. In order to leverage the full potential of platooning, platoons can be formed dynamically en route by small adjustments to their speeds. However, in heavily used parts of the road network, travel times are subject to random disturbances originating from traffic, weather and other sources. We formulate this problem as a stochastic dynamic programming problem over a finite horizon, for which solutions can be computed using a backwards recursion. By exploiting the characteristics of the problem, we derive bounds on the set of states that have to be explored at every stage, which in turn reduces the complexity of computing the solution. Simulations suggest that the approach is applicable to realistic problem instances.
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| 28. |
- van de Hoef, Sebastian
(författare)
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Fuel-Efficient Centralized Coordination of Truck Platooning
- 2016
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The problem of how to coordinate a large fleet of trucks with given itinerary to enable fuel-efficient platooning is considered. Platooning is a promising technology that enables trucks to save significant amounts of fuel by driving close together and thus reducing air drag. A setting is considered in which a fleet of trucks is provided with transport assignments consisting of a start location, a destination, a departure time and an arrival deadline from a higher planning level. Fuel-efficient plans are computed by a centralized platoon coordinator. The plans consist of routes and speed profiles that allow trucks to reach their respective destinations by their arrival deadlines. Hereby, the trucks can meet on common parts of their routes and form platoons, resulting in a decreased fuel consumption. First, routes are computed. Then, all pairs of trucks that can potentially platoon are identified. Potential platoon pairs are identified efficiently by extracting features from the routes and processing these features. In the next step, two types of plans are computed for each vehicle: default and adapted plans. An adapted plan is such that the vehicle can meet another vehicle en route and platoon. We formulate a combinatorial optimization problem that combines these plans in order to achieve low fuel consumption. An algorithm to compute optimal solutions to this problem is developed. The optimization problem is shown to be NP-hard, which motivates us to propose a heuristic algorithm that can handle realistically sized problem instances. The resulting plans are further optimized using convex optimization. The method is evaluated with Monte Carlo simulations in a realistic setting. We demonstrate that the proposed algorithm can compute plans for thousands of trucks and that significant fuel savings can be achieved.
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| 29. |
- van de Hoef, Sebastian, et al.
(författare)
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Fuel-Efficient En Route Formation of Truck Platoons
- 2018
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Ingår i: IEEE transactions on intelligent transportation systems (Print). - : Institute of Electrical and Electronics Engineers (IEEE). - 1524-9050 .- 1558-0016. ; 19:1, s. 102-112
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Tidskriftsartikel (refereegranskat)abstract
- The problem of how to coordinate a large fleet of trucks with a given itinerary to enable fuel-efficient platooning is considered. Platooning is a promising technology that enables trucks to save significant amounts of fuel by driving close together and thus reducing air drag. A setting is considered in which each truck in a fleet is provided with a start location, a destination, a departure time, and an arrival deadline from a higher planning level. Fuel-efficient plans should be computed. The plans consist of routes and speed profiles that allow trucks to arrive by their arrival deadlines. Hereby, trucks can meet on common parts of their routes and form platoons, resulting in decreased fuel consumption. We formulate a combinatorial optimization problem that combines plans involving only two vehicles. We show that this problem is difficult to solve for large problem instances. Hence, a heuristic algorithm is proposed. The resulting plans are further optimized using convex optimization techniques. The method is evaluated with Monte Carlo simulations in a realistic setting. We demonstrate that the proposed algorithm can compute plans for thousands of trucks and that significant fuel savings can be achieved.
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| 30. |
- van de Hoef, Sebastian, et al.
(författare)
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Fuel-optimal centralized coordination of truck platooning based on shortest paths
- 2015
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Ingår i: Proceedings of the American Control Conference. - : IEEE. - 9781479986842 ; , s. 3740-3745
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Konferensbidrag (refereegranskat)abstract
- Platooning is a way to significantly reduce fuel consumption of trucks. Vehicles that drive at close inter-vehicle distance assisted by automatic controllers experience substantially lower air-drag. In this paper, we deal with the problem of coordinating the formation and the breakup of platoons in a fuel-optimal way. We formulate an optimization problem which accounts for routing, speed-dependent fuel consumption, and platooning decisions. An algorithm to obtain an approximate solution to the problem is presented. It first determines the shortest path for each truck. Then, possible platoon configurations are identified. For a certain platoon configuration the optimal speed profile is the solution to a convex program. The algorithm is illustrated by a realistic example.
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| 31. |
- van de Hoef, Sebastian, et al.
(författare)
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Spectral analysis of extended consensus algorithms for multiagent systems
- 2014
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Ingår i: Decision and Control (CDC), 2014 IEEE 53rd Annual Conference on. - 9781479977468 ; , s. 2204-2209
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Konferensbidrag (refereegranskat)abstract
- We analyze an extension of the well-known linear consensus protocol for agents moving in two dimensions, where the standard consensus feedback is multiplied with a rotation matrix. This leads to a richer family of trajectories, and if only the new feedback term is applied, periodic solutions emerge. For special configurations of the controller gains, the form of the system trajectories is given in terms of the eigenvalues and eigenvectors of the closed-loop system matrix. We characterize the resulting closed-loop trajectories for specific choices of the controller gains and of the communication graph topology. Furthermore, the control strategy is extended to agents with double integrator dynamics. It is shown that stability is achieved with sufficiently large velocity feedback. The effect of this feedback on the overall system performance is further investigated. We finally provide simulations to illustrate the theoretical results.
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