Cargo Routing Research Articles

Abstract LB-240: Mechanism-based enhancement of ErbB2-targeted delivery of chemotherapeutics encapsulated in Trastuzumab-conjugated polymeric nanocarriers

Abstract ErbB2-driven breast cancers account for 20-25% of Breast Cancer patients screened in the USA. The humanized monoclonal antibody, Trastuzumab (Herceptin™), in combination with chemotherapy is the current standard of treatment. However, newer agents to overcome challenges associated with de novo and acquired resistance to Trastuzumab therapy, are being explored. The HSP90 inhibitor, 17-allylaminodemethoxygeldanamycin (17-AAG), which recently completed phase II clinical trials, is an example. Despite the potent anti-cancer activity of 17-AAG, toxicities associated with current formulations remain a concern. Strategies for 17-AAG-encapsulation into biocompatible nanoparticle formulations (polymeric micelles, liposomes, nanoalbumins and dendrimers) are being pursued as an alternative. We have described nanogels composed of cross-linked polyanion and poly(ethylene glycol), PEG shell, which can be surface-functionalized with targeting ligands/antibodies for overexpressed cell-surface receptors, as novel polymeric nanocarriers for targeted delivery of anti-cancer agents. However, the slow endocytosis and rapid recycling of ErbB2-receptor, limits the efficacy of uptake of the targeted nanocarrier cargo. Since HSP90 inhibition can enhance the internalization and lysosomal routing of ErbB2 receptor, we hypothesize that, HSP90 inhibitors such as 17-AAG, can increase the efficiency of ErbB2-targeted delivery of nano-encapsulated drug cargo. We report our studies describing the preparation, characterization, endocytic uptake and anti-cancer activity of 17-AAG and Doxorubicin co-encapsulated in nanogels against ErbB2-overexpressing breast cancer models. 17-AAG and Doxorubicin were loaded into the cross-linked core of the nanogels at high total loading capacities. The drug-loaded nanogels had potent cytotoxic activity against ErbB2-overexpressing breast cancer cell lines, with 17-AAG potentiating the activity of Doxorubicin. Confocal immunofluorescence microscopy confirmed that the drug-loaded nanogels are efficiently internalized via the endocytic pathway. Analysis of ErbB2 degradation confirmed efficient 17-AAG release from nanogels with activities comparable to free 17-AAG. As proof-of-principle, we also demonstrate that the HSP90 inhibitors indeed facilitate the internalization of ErbB2-targeted nanogels into cancer cells. These studies demonstrate that nanogels could therefore serve as novel nanocarriers for synergistic combinations of 17-AAG with chemotherapeutics, providing an opportunity to overcome solubility issues associated with 17-AAG. Most importantly, we suggest a mechanism-based strategy to achieve the full potential of ErbB2-targeted delivery of chemotherapeutic payloads, by HSP90-inhibition-facilitated ErbB2-internalization and lysosomal routing of the nanogel cargo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-240. doi:1538-7445.AM2012-LB-240

Dynamic routing of time-sensitive air cargo using real-time information

The route planning of time-sensitive air-cargo is becoming more important with the growing air-network congestion and delays. We consider a freight forwarder’s routing of a time-sensitive air-cargo in the presence of real-time and historical information regarding flight availability, departure delays and travel times. A departure delay estimation model is developed to account for real-time information inaccuracy. A novel Markov decision model is formulated and solved with online backward induction. Through synthetic experiments and case studies, we demonstrate that dynamic routing with real-time information can improve delivery reliability and reduce expected cost.

A New Approach for Air Cargo Network Planning

A central element of the air cargo planning process is the generation of optimal flight schedules. A flight schedule simultaneously defines the market potential of an airline and allocates its resources. The schedule design process is a difficult and time-consuming task that involves and affects virtually all business units. Because of its complexity, the process is traditionally decomposed into several steps that are executed in a sequential manner. In this paper, we present novel model formulations and solution procedures which have been developed in the course of a feasibility study for a decision support system (DSS) for a pragmatic approach to “freighter network planning” at one of the top international cargo carriers. We formulate two integrated models that combine the three planning steps: flight selection, aircraft rotation planning, and cargo routing. The aim of the schedule optimization is to maximize the network-wide profit by determining the best combination from a list of mandatory and optional flights, assigning the selected flights to aircrafts and identifying optimal cargo flows. Both model formulations are embedded in a solution procedure that builds on the column generation technique with shortest path algorithms for solving the subproblems. The applicability of the models in a DSS is demonstrated on realistic problem instances that match the requirements specified in the feasibility study.

LIM Kinase 1 and Cofilin Regulate Actin Filament Population Required for Dynamin-dependent Apical Carrier Fission from theTrans-Golgi Network

The functions of the actin cytoskeleton in post-Golgi trafficking are still poorly understood. Here, we report the role of LIM Kinase 1 (LIMK1) and its substrate cofilin in the trafficking of apical and basolateral proteins in Madin-Darby canine kidney cells. Our data indicate that LIMK1 and cofilin organize a specialized population of actin filaments at the Golgi complex that is selectively required for the emergence of an apical cargo route to the plasma membrane (PM). Quantitative pulse-chase live imaging experiments showed that overexpression of kinase-dead LIMK1 (LIMK1-KD), or of LIMK1 small interfering RNA, or of an activated cofilin mutant (cofilin S3A), selectively slowed down the exit from the trans-Golgi network (TGN) of the apical PM marker p75-green fluorescent protein (GFP) but did not interfere with the apical PM marker glycosyl phosphatidylinositol-YFP or the basolateral PM marker neural cell adhesion molecule-GFP. High-resolution live imaging experiments of carrier formation and release by the TGN and analysis of peri-Golgi actin dynamics using photoactivatable GFP suggest a scenario in which TGN-localized LIMK1-cofilin regulate a population of actin filaments required for dynamin-syndapin-cortactin-dependent generation and/or fission of precursors to p75 transporters.

Ship Scheduling and Network Design for Cargo Routing in Liner Shipping

Acommon problem faced by carriers in liner shipping is the design of their service network. Given a set of demands to be transported and a set of ports, a carrier wants to design service routes for its ships as efficiently as possible, using the underlying facilities. Furthermore, the profitability of the service routes designed depends on the paths chosen to ship the cargo. We present an integrated model, a mixed-integer linear program, to solve the ship-scheduling and the cargo-routing problems, simultaneously. The proposed model incorporates relevant constraints, such as the weekly frequency constraint on the operated routes, and emerging trends, such as the transshipment of cargo between two or more service routes. To solve the mixed-integer program, we propose algorithms that exploit the separability of the problem. More specifically, a greedy heuristic, a column generation-based algorithm, and a two-phase Benders decomposition-based algorithm are developed, and their computational efficiency in terms of the solution quality and the computational time taken is discussed. An efficient iterative search algorithm is proposed to generate schedules for ships. Computational experiments are performed on randomly generated instances simulating real life with up to 20 ports and 100 ships. Our results indicate high percentage utilization of ships' capacities and a significant number of transshipments in the final solution.

AP-2-dependent Internalization of Potassium Channel Kir2.3 Is Driven by a Novel Di-hydrophobic Signal

The localization and density of Kir2.3 channels are influenced by the balance between PDZ protein interaction at the cell surface and routing into the endocytic pathway. Here, we explore mechanisms by which the Kir2.3 channel is directed into the endocytic pathway. We found that Kir2.3 channels are constitutively internalized from the cell surface in a dynamin-dependent manner, indicative of vesicle-mediated endocytosis. The rate of Kir2.3 endocytosis was dramatically attenuated following RNA interference-mediated knockdown of either alpha adaptin (AP-2 clathrin adaptor) or clathrin heavy chain, revealing that Kir2.3 is internalized by an AP-2 clathrin-dependent mechanism. Structure-rationalized mutagenesis studies of a number of different potential AP-2 interaction motifs indicate that internalization of Kir2.3 is largely dependent on a non-canonical di-isoleucine motif (II413) embedded within the C terminus. Internalization assays using CD4-Kir2.3 chimeras demonstrate that the di-isoleucine signal acts in an autonomous and transplantable manner. Kir2.3 co-immunoprecipitates with alpha adaptin, and disruption of the di-isoleucine motif decreased interaction of the channel with AP-2. Replacement of the di-isoleucine motif with a canonical di-leucine internalization signal actually blocked Kir2.3 endocytosis. Moreover, in yeast three-hybrid studies, the Kir2.3 di-isoleucine motif does not bind the AP-2 alphaC-sigma2 hemicomplex in the way that has been recently observed for canonical di-leucine signals. Altogether, the results indicate that Kir2.3 channels are marked for clathrin-dependent internalization from the plasma membrane by a novel AP-2-dependent signal.

SafeSeaNet and traffic monitoring of ships and dangerous or polluting goods in maritime transport within the European Economic Area

The European Union (EU) has established an extensive vessel traffic monitoring and information system with a view to enhancing the safety and efficiency of maritime traffic. This new information system will be mandated in most ships and provide the EU Member States and the European Commission with various information pertaining to cargo and traffic routes. The information system requires telematic exchange of data according to defined syntax and procedures and has sanctions based on EU Law for non-compliance. The information system is first and foremost the brainchild of the EU, but is also interlinked with several international conventions pertaining to the prevention of pollution and maritime security. The information system will be mandatory within the European Economic Area and will, therefore, concern maritime traffic in most European waters ? from the North Atlantic Ocean to the Black Sea.

Simultaneous fleet assignment and cargo routing using benders decomposition

In this paper, we incorporate the cargo routing problem into fleet assignment to model the fleet assignment more accurately. An integrated model and a Benders decomposition-based approach are developed to simultaneously obtain the optimal assignment of fleet to legs and the routing of forecasted cargo demand over the network. Computational experiments show that this integrated approach converges very fast for all different test scenarios.

A Mixed-Integer Programming Approach to Air Cargo Fleet Planning

This paper deals with the mathematical programming aspects of a long range planning study done for the Flying Tiger Line, an all-cargo airline. The study addressed two strategic problems: the design of the service network and the selection and deployment of the aircraft fleet. We show how the concept of a spider graph provides a natural building block for network design and present a mixed-integer programming model that enables the planner to evaluate any network constructed from spider graphs by determining the most profitable selection of aircraft and routing of cargo.

The choice of ship size on deep-sea general cargo routes†

The introduction of unit load methods, particularly the cellular container system, has been associated with a large increase in ship size on some of the world's major general cargo routes. In this sector, ship size is determined by a set of interactions between handling performance, route length, traffic flow, itinerary, requirements for frequent and regular service, port costs and general system organization. This paper explores these relationships to identify major influences and to consider the prospects for further growth.

The veterinary service of Ethiopia

Abstract Extract Ethiopia is an agricultural and stock-raising country, some six times the size of Italy, and with climates ranging from tropical desert to temperate highlands. Until recently, its isolation was profound. A year ago Eritrea was added as a Federated State, and with it came the fine port of Massawa. A road also exists to the coast to the port of Assab, and this in future may be developed into a useful cargo route. The present railway line from Djibouti to Addis is very expensive running, as it goes over much desert country without hope of picking up freight. The people, 18,000,000 in number, are made up of many tribes, the senior being the Amharic, while the religions are mainly Coptic and Moslem. Food customs vary a little but are simple, mainly consisting of bread made from teff or dhura, called indjerra, and a highly-spiced and hot stew known as “wott.” Feast days are meat-eating days of beef, mutton, goat, and poultry in varying degrees of preparedness and in that order of value.