The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current ca...Show moreThe dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1−PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses. Show less
This dissertation presents a description and analysis of the Mandarin particle yě ‘also’. It provides a comprehensive syntactic and semantic treatment of three different manifestations of yě,... Show moreThis dissertation presents a description and analysis of the Mandarin particle yě ‘also’. It provides a comprehensive syntactic and semantic treatment of three different manifestations of yě, namely, Additive yě, which is similar to English also, Parametric/Scalar yě, which we find in ‘no matter’ and even/even if contexts, and, finally, Modal yě, basically a concessivity marker. Additive, Parametric/Scalar and Modal yě are different in interpretation and require different licensing conditions. Additive yě can only be licensed if an antecedent can be retrieved from the context: the antecedent must be explicitly asserted or otherwise present in the active context and it must have the same argumentative orientation as the host sentence. Parametric/scalar yě can only be licensed if scalarity is marked in the sentence. Finally, as a concessivity marker, Modal yě presupposes the existence of a concessive proposition as an alternative. Pragmatically, the use of Modal yě results in a polite, indirect, tactful or less absolute reading of the host sentence. The syntactic properties of the different manifestations of yě are explored vis à vis Butler's modal hierarchy and Cinque’s adverb hierarchy. We conclude that there are two positions of yě in the syntactic structure, one in CP and the other in IP. Show less
The vehicle routing problem is a classical combinatorial optimization problem. This work is about a variant of the vehicle routing problem with dynamically changing orders and time windows. In real... Show moreThe vehicle routing problem is a classical combinatorial optimization problem. This work is about a variant of the vehicle routing problem with dynamically changing orders and time windows. In real-world applications often the demands change during operation time. New orders occur and others are canceled. In this case new schedules need to be generated on-the-fly. Online optimization algorithms for dynamical vehicle routing address this problem but so far they do not consider time windows. Moreover, to match the scenarios found in real-world problems adaptations of benchmarks are required. In this paper, a practical problem is modeled based on the procedure of daily routing of a delivery company. New orders by customers are introduced dynamically during the working day and need to be integrated into the schedule. A multiple ant colony algorithm combined with powerful local search procedures is proposed to solve the dynamic vehicle routing problem with time windows. The performance is tested on a new benchmark based on simulations of a working day. The problems are taken from Solomon’s benchmarks but a certain percentage of the orders are only revealed to the algorithm during operation time. Different versions of the MACS algorithm are tested and a high performing variant is identified. Finally, the algorithm is tested in situ: In a field study, the algorithm schedules a fleet of cars for a surveillance company. We compare the performance of the algorithm to that of the procedure used by the company and we summarize insights gained from the implementation of the real-world study. The results show that the multiple ant colony algorithm can get a much better solution on the academic benchmark problem and also can be integrated in a real-world environment. Show less
With the rapid development of electronic commerce, logistics management has become more and more important in the procedure of supply chain management. The goal of logistics management is to... Show moreWith the rapid development of electronic commerce, logistics management has become more and more important in the procedure of supply chain management. The goal of logistics management is to satisfy the demands of customers while minimizing the use of resources of the whole process in logistics management from the point of origin to the point of consumption. The logistics management technology has been widely used in the field of engineering and contributes to reducing the total logistics cost. In this thesis, we focus on algorithms based on nature-inspired paradigms to solve dynamic logistics management problems. Results show that the proposed multiple ant system algorithm and the multi-objective cooperative particle swarm algorithm are able to produce good solutions for the vehicle routing problems and inventory routing problems not only in theory but also in practice. Show less
Yang, Z.; Emmerich, Michael T.M.; Bäck, T.H.W.; Kok, J.N. 2016
This article studies a tri-objective formulation of the inventory routing problem, extending the recently studied bi-objective formulation. As compared to distance cost and inventory cost, which... Show moreThis article studies a tri-objective formulation of the inventory routing problem, extending the recently studied bi-objective formulation. As compared to distance cost and inventory cost, which were discussed in previous work, it also considers stockout cost as a third objective. Demand is modeled as a Poisson random variable. State-of-the-art evolutionary multi-objective optimization algorithms and a new method based on swarm intelligence are used to compute approximation of the 3-D Pareto front. A benchmark previously used in bi-objective inventory routing is extended by incorporating a stochastic demand model with an expected value that equals the average demand of the original benchmark. The results provide insights into the shape of the optimal trade-off surface. Based on this the dependences between different objectives are clarified and discussed. Moreover, the performances of the four different algorithmic methods are compared and due to the consistency in the results, it can be concluded that a near optimal approximation to the Pareto front can be found for problems of practically relevant size. Show less
Yang, Z.; Osta, J.P. van; Veen, B. van; Krevelen, R. van; Stam, A.; Kok, J.N.; ... ; Emmerich, M.T.M. 2016
The vehicle routing problem is a classical combinatorial optimization problem. This work is about a variant of the vehicle routing problem with dynamically changing orders and time windows. In... Show moreThe vehicle routing problem is a classical combinatorial optimization problem. This work is about a variant of the vehicle routing problem with dynamically changing orders and time windows. In real-world applications often the demands change during operation time. New orders occur and others are canceled. In this case new schedules need to be generated on-the-fly. Online optimization algorithms for dynamical vehicle routing address this problem but so far they do not consider time windows. Moreover, to match the scenarios found in real-world problems adaptations of benchmarks are required. In this paper, a practical problem is modeled based on the procedure of daily routing of a delivery company. New orders by customers are introduced dynamically during the working day and need to be integrated into the schedule. A multiple ant colony algorithm combined with powerful local search procedures is proposed to solve the dynamic vehicle routing problem with time windows. The performance is tested on a new benchmark based on simulations of a working day. The problems are taken from Solomon's benchmarks but a certain percentage of the orders are only revealed to the algorithm during operation time. Different versions of the MACS algorithm are tested and a high performing variant is identified. Finally, the algorithm is tested in situ: In a field study, the algorithm schedules a fleet of cars for a surveillance company. We compare the performance of the algorithm to that of the procedure used by the company and we summarize insights gained from the implementation of the real-world study. The results show that the multiple ant colony algorithm can get a much better solution on the academic benchmark problem and also can be integrated in a real-world environment. Show less
