Design of new oxazaphosphorine anticancer drugs

The oxazaphosphorines including cyclophosphamide (CPA, Cytoxan, or Neosar), ifosfamide (IFO, Ifex) and trofosfamide (Ixoten) represent an important group of therapeutic agents due to their substantial antitumor and immunomodulating activity. However, several intrinsic limitations have been uncounted during the clinical use of these oxazaphosphorines, including substantial pharmacokinetic variability, resistance and severe host toxicity. To circumvent these problems, new oxazaphosphorines derivatives have been designed and evaluated with an attempt to improve the selectivity and response with reduced host toxicity. These include mafosfamide (NSC 345842), glufosfamide (D19575, β-Dglucosylisophosphoramide mustard), S-(-)-bromofosfamide (CBM-11), NSC 612567 (aldophosphamide perhydrothiazine) and NSC 613060 (aldophosphamide thiazolidine). Mafosfamide is an oxazaphosphorine analog that is a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxy-CPA. Glufosfamide is IFO derivative in which the isophosphoramide mustard, the alkylating metabolite of IFO, is glycosidically linked to a β-D-glucose molecule. Phase II studies of glufosfamide in the treatment of pancreatic cancer, non-small cell lung cancer (NCSLC), and recurrent glioblastoma multiform (GBM) have recently completed and Phase III trials are ongoing, while Phase I studies of intrathecal mafosfamide have recently completed for the treatment of meningeal malignancy secondary to leukemia, lymphoma, or solid tumors. S-(-)- bromofosfamide is a bromine-substituted IFO analog being evaluated in a few Phase I clinical trials. The synthesis and development of novel oxazaphosphorine analogs with favourable pharmacokinetic and pharmacodynamic properties still constitutes a great challenge for medicinal chemists and cancer pharmacologists.

SEPS1 protects RAW264.7 cells from pharmacological ER stress agent-induced apoptosis

Selenoprotein S (SEPS1) is a novel endoplasmic reticulum (ER) resident protein and it is known to play an important role in production of inflammatory cytokines. Here, we show evidence that SEPS1 is stimulated by pharmacological ER stress agents in RAW264.7 macrophages as well as other cell types. Overexpression studies reveal a protective action of SEPS1 in macrophages against ER stress-induced cytotoxicity and apoptosis, resulting in promoting cell survival during ER stress. The protective action of SEPS1 is largely dependent on ER stress-mediated cell death signal with less effect on non-ER stress component cell death signals. Conversely, suppression of SEPS1 in macrophages results in sensitization of cells to ER stress-induced cell death. These findings suggest that SEPS1 could be a new ER stress-dependent survival factor that protects macrophage against ER stress-induced cellular dysfunction.

Smart cluster bombs - control of multi-agent systems for military applications

This paper introduces an aggregation algorithm for airborne swarming guided weapon systems, which can aggregate munitions into a given shape while reaching the surface. The algorithm uses an artificial force based controller to navigate the members of the swarm into the desired geographical position and evenly distribute them inside the shape. Inter-member repulsion forces are used to avoid collisions among members, which is crucial for a weapon deployment system. Moreover, a lower bound for the release height was obtained which guarantee convergence of the complete weapon system into the target area. The proposed swarming guided weapon system was tested using computer simulations.

Secure mobile agent-based e-negotiation for on-line trading

Electronic negotiation (e-negotiation) is a major activity in e-Commerce applications. Agent-based e-negotiation has recently received increasing attention. However, agent-based electronic negotiation suffers from a number of security attacks. In this paper, we present a mobile agent-based e-commerce framework. We also propose a security protocol that protects the information exchanged between the mobile agents during e- negotiations. We reason the correctness of the proposed security protocol in the presence of various security threats. The reasoning shows that the protocol maintains privacy, non- repudiation, authenticity, anonymity, and strong integrity of exchanged information.

Information sharing between heterogeneous uncertain reasoning models in a multi-agent environment : a case study

The issue of information sharing and exchanging is one of the most important issues in the areas of artificial intelligence and knowledge-based systems (KBSs), or even in the broader areas of computer and information technology. This paper deals with a special case of this issue by carrying out a case study of information sharing between two well-known heterogeneous uncertain reasoning models: the certainty factor model and the subjective Bayesian method. More precisely, this paper discovers a family of exactly isomorphic transformations between these two uncertain reasoning models. More interestingly, among isomorphic transformation functions in this family, different ones can handle different degrees to which a domain expert is positive or negative when performing such a transformation task. The direct motivation of the investigation lies in a realistic consideration. In the past, expert systems exploited mainly these two models to deal with uncertainties. In other words, a lot of stand-alone expert systems which use the two uncertain reasoning models are available. If there is a reasonable transformation mechanism between these two uncertain reasoning models, we can use the Internet to couple these pre-existing expert systems together so that the integrated systems are able to exchange and share useful information with each other, thereby improving their performance through cooperation. Also, the issue of transformation between heterogeneous uncertain reasoning models is significant in the research area of multi-agent systems because different agents in a multi-agent system could employ different expert systems with heterogeneous uncertain reasonings for their action selections and the information sharing and exchanging is unavoidable between different agents. In addition, we make clear the relationship between the certainty factor model and probability theory.

A study of train group operation multi-agent model oriented RITS

In this paper, aiming at describing interrelationships and communication mechanisms among agents based on a multi-agent framework of Railway Intelligent Transportation System (RITS), we construct the model about stations and trains in the system, which is called Agent-Oriented G-Net Train Group Operation Model (AGNTOM). The framework degrades the complexity of computation and makes the distribution of simulation system easy in design. The simulated experiments prove that the model provides an effective approach for dealing with communication problems in the system.

Alteration of the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, due to actue gastrointestinal tosicity of doxorubicin

Purpose Combination of COL-3, a matrix metalloproteinase inhibitor, and doxorubicin (DOX) might be a promising anticancer regimen. The present study was to examine the potential pharmacokinetic interactions and toxicity profile following their coadministration in rats.
Methods Normal rats were treated with single agent or different combinations with oral or intravenous COL-3 and DOX, and the bile-duct cannulated (BDC) rats received oral COL-3 plus DOX. In a separate disposition study, the effects of DOX on the biliary, urinary, and fecal excretion of COL-3 were examined. In addition, the effects of DOX on in vitro protein binding, metabolism, and transport of COL-3 across Caco-2 monolayers were investigated.
Results COL-3 did not affect the pharmacokinetics of DOX in rats. However, treatment with DOX significantly decreased the oral absorption, and prolonged the elimination, of COL-3 in the normal rats, but not in the BDC rats. DOX did not alter the biliary and urinary excretion of COL-3, but significantly decreased the fecal excretion of COL-3. DOX significantly enhanced the basolateral to apical flux of COL-3 across Caco-2 monolayers, but had no apparent effects on the protein binding and metabolism of COL-3. The combination of DOX with oral COL-3 did not significantly (p > 0.05) increase the acute diarrhea score and intestinal damage compared to rats receiving DOX alone.
Conclusions These results indicated that DOX altered the oral absorption and elimination of COL-3, largely resulting from gastrointestinal toxicity caused by biliary excretion of DOX. Further studies are required to explore the efficacy and optimized dosage regimen of this promising combination.

A logical framework for knowledge sharing in multi-agent systems

The issue of knowledge sharing has been an important topic in multi-agent research. Knowledge sharing leads to that agents analyze, judge and synthesize the told information so as to make agents’ own knowledge. To match these applications, this paper builds a logical framework for knowledge sharing among agents. We develop a multimodal logic for reasoning about both agents’ knowledge and told information. For formalizing the relationship between knowledge and told information, we present a framework of semantics, with respect to which a sound and complete proof theory is given.

An agent-based intelligent system for information gathering from world wide web environment

To use the vast amount of information efficiently and effectively from Web sites is very important for making informed decisions. There are, however, still many problems that need to be overcome in the information gathering research arena to enable the delivery of relevant information required by users. In this paper, an information gathering system is develop by means of multiple agents to solve those problems. We employed some ideas of Gaia's methodology and an open agent architecture to analyze and design the system. The system consists of a query preprocessing agent, information retrieval agent, information filtering agent, and information management agent. The filtering agent is trained with categorized documents and can provide users with the necessary information. The experimental results show that all agents in the system can work cooperatively to retrieve relevant information from the World Wide Web environment.

An agent-based framework for petroleum information services from distributed heterogeneous data resources

For making good decisions in the area of petroleum production, it is becoming a big problem how to timely gather sufficient and correct information, which may be stored in databases, data files, or on the World Wide Web. In this paper, Gaia methodology and Open Agent Architecture were employed to contribute a framework to solve above problem. The framework consists of three levels, namely, role mode, agent type, and agent instance. The model with five roles is analyzed. Four agent types are designed Six agent instances are developed for constructing the system of petroleum information services. The experimental results show that all agents in the system can work cooperatively to organize and retrieve relevant petroleum information. The successful implementation of the framework shows that agent-based technology can significantly facilitate the construction of complex systems in distributed heterogeneous data resource environment.

A ring-based architectural model for middle agents in agent-based system

In agent-based systems, the performance of middle agents not only relies on the matchmaking algorithms employed by them, but also the architecture that organizes them with suitable organizational structure and coordination mechanism. In this paper, we contribute a framework and develop a couple of middle agents with logical ring organizational structure to match requester agents with service provider agents. The middle agent is of the features of proliferation and self-cancellation according to the sensory input from its environment. The token-based coordination mechanism of middle agents is designed. Two kinds of middle agents, namely, host and duplicate, are designed for promoting the scalability and robustness of agent-based systems. We demonstrate the potentials of the architecture by case study.

Supporting knowledge management infrastructure : a multi-agent approach

Knowledge management has by now exerted a large influence over industrial practice. We propose a multi-agent based system to provide infrastructure service to meet various requirements of knowledge management in view of the complex nature of the task, i.e., covering science and technologies across different disciplines. The paper discusses the use of a multi-agent system to support the knowledge management infrastructure. It will also discuss the design rational and implementation details as well as an application to the problem of feature extraction in weather prediction.

A scalable and robust framework for agent-based heterogeneous database operation

How to operate database efficiently and unfailingly in agent-based heterogeneous data source environment is becoming a big problem. In this paper, we contribute a framework and develop a couple of agent-oriented matchmakers with logical ring organization structure to match task agents' requests with middleware agents of databases. The middleware agent is a wrapper of a specific database and is run on the same server with the database management system. The matchmaker is of the features of proliferation and self-cancellation according to the sensory input from its environment. The ring-based coordination mechanism of matchmakers is designed. Two kinds of matchmakers, namely, host and duplicate, are designed for improving the scalability and robustness of agent-based system. The middleware agents are improved for satisfying the framework. We demonstrate the potentials of the framework by case study and present theoretical and empirical evidence that our approach is scalable and robust.