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The detailed molecular mechanism of action of secondgeneration BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/ threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the midnanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation.

Restoration concepts for large river systems are currently in an early stage of development. Possibilities for, and constraints of, rehabilitation—both from a process‐oriented view as well as from the nature conservation perspective—differ strongly according to the degree of anthropogenic changes. This requires precisely formulated amelioration goals. Well‐conceived and thoroughly analysed case studies are necessary to better understand reversibility, direction and time scale of changes, and the sustainability of various scenarios. It is important to plan controllable set‐ups with long‐term monitoring in the pre‐ and post‐implementation phases of restoration programmes. In order to achieve these goals, monitoring instruments have to be developed and calibrated that allow the definition and analysis of improvements. Finally, controlled restoration programmes offer the opportunity for large‐scale experiments to test overall concepts and hypotheses and have an important heuristic value to improve the understanding of river ecology in general. Copyright © 1999 John Wiley & Sons, Ltd.

The multidrug transporter P-glycoprotein is suspected of contributing to pharmacoresistance in temporal lobe epilepsy (TLE). To assess the role of functional variations in its coding gene (ABCB1) the authors genotyped 210 patients with TLE who were stratified according to their degree of drug resistance. They identified a common haplotype that when present in the homozygous state significantly increased the risk for pharmacoresistance.