High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy

We investigated whether the occurrence of veno-occlusive disease of the liver (VOD) may be associated with individual variations in the pharmacokinetics of high-dose cyclophosphamide. Patients received single or multiple courses of cyclophosphamide (1000 or 1500 mg m−2 day−1), thiotepa (80 or 120 mg m−2 day−1) and carboplatin (265–400 mg m−2 day−1) (CTC) for 4 consecutive days. The area under the plasma concentration–time curves (AUCs) were calculated for cyclophosphamide and its activated metabolites 4-hydroxycyclophosphamide and phosphoramide mustard based on multiple blood samples. Possible relationships between the AUCs and the occurrence of VOD were studied. A total of 59 patients (115 courses) were included. Four patients experienced VOD after a second CTC course. The first-course AUC of 4-hydroxycyclophosphamide (P=0.003) but not of phosphoramide mustard (P=0.101) appeared to be predictive of the occurrence of VOD after multiple courses. High exposures to bioactivated cyclophosphamide may lead to increased organ toxicity

Role of Sphingomyelin Synthase in Controlling the Antimicrobial Activity of Neutrophils against Cryptococcus neoformans

The key host cellular pathway(s) necessary to control the infection caused by inhalation of the environmental fungal pathogen Cryptococcus neoformans are still largely unknown. Here we have identified that the sphingolipid pathway in neutrophils is required for them to exert their killing activity on the fungus. In particular, using both pharmacological and genetic approaches, we show that inhibition of sphingomyelin synthase (SMS) activity profoundly impairs the killing ability of neutrophils by preventing the extracellular release of an antifungal factor(s). We next found that inhibition of protein kinase D (PKD), which controls vesicular sorting and secretion and is regulated by diacylglycerol (DAG) produced by SMS, totally blocks the extracellular killing activity of neutrophils against C. neoformans. The expression of SMS genes, SMS activity and the levels of the lipids regulated by SMS (namely sphingomyelin (SM) and DAG) are up-regulated during neutrophil differentiation. Finally, tissue imaging of lungs infected with C. neoformans using matrix-assisted laser desorption-ionization mass spectrometry (MALDI-MS), revealed that specific SM species are associated with neutrophil infiltration at the site of the infection. This study establishes a key role for SMS in the regulation of the killing activity of neutrophils against C. neoformans through a DAG-PKD dependent mechanism, and provides, for the first time, new insights into the protective role of host sphingolipids against a fungal infection

Semantics of agent-based service delegation and alignment

In this paper we concentrate on conceptual modeling and semantics of service delegation and alignment in information systems. In delegation, a source company wishes to hand over parts of its functionality together with related responsibilities to a supplying party. From the side of the outsourcer the search for a suitable supplier mostly will be a manual process with all the consequences of a long time to market, as well as trial and error before a good fit is obtained between both related parties. This paper addresses an agent-based solution for improving this match-making process in B2B markets. Part of the match-making process will be the alignment of business processes on the side of the outsourcer as well on the side of the supplier. We will provide a formal means to ensure that the delegation relationship, determined by a ruling service level agreement (SLA), satisfies specific correctness criteria. These correctness criteria are defined in terms of consistency and completeness between the delegated operation and the associated operation offered by the supplier. Our correctness criterion will concern mappings between an existing delegator schema and an existing supplier schema, and will address both semantical and ontological aspects pertaining to delegation and alignment. Agent-based delegation together with formal specifications can prove their value in the process of constructing delegation contracts. Our analysis will be performed within the modeling framework based on the UML/OCL formalism. The concepts we discussed in this paper are illustrated by an example of companies delegating billing services to Billing Service Providers.</p