Particle swarm optimization for the Steiner tree in graph and delay-constrained multicast routing problems

This paper presents the first investigation on applying a particle swarm optimization (PSO) algorithm to both the Steiner tree problem and the delay constrained multicast routing problem. Steiner tree problems, being the underlining models of many applications, have received significant research attention within the meta-heuristics community. The literature on the application of meta-heuristics to multicast routing problems is less extensive but includes several promising approaches. Many interesting research issues still remain to be investigated, for example, the inclusion of different constraints, such as delay bounds, when finding multicast trees with minimum cost. In this paper, we develop a novel PSO algorithm based on the jumping PSO (JPSO) algorithm recently developed by Moreno-Perez et al. (Proc. of the 7th Metaheuristics International Conference, 2007), and also propose two novel local search heuristics within our JPSO framework. A path replacement operator has been used in particle moves to improve the positions of the particle with regard to the structure of the tree. We test the performance of our JPSO algorithm, and the effect of the integrated local search heuristics by an extensive set of experiments on multicast routing benchmark problems and Steiner tree problems from the OR library. The experimental results show the superior performance of the proposed JPSO algorithm over a number of other state-of-the-art approaches

High resolution crystal structure of the human PDK1 catalytic domain defines the regulatory phosphopeptide docking site

3-phosphoinositide dependent protein kinase-1 (PDK1) plays a key role in regulating signalling pathways by activating AGC kinases such as PKB/Akt and S6K. Here we describe the 2.0 Å crystal structure of the PDK1 kinase domain in complex with ATP. The structure defines the hydrophobic pocket termed the ‘PIF-pocket’, which plays a key role in mediating the interaction and phosphorylation of certain substrates such as S6K1. Phosphorylation of S6K1 at its C-terminal PIF-pocket-interacting motif promotes the binding of S6K1 with PDK1. In the PDK1 structure, this pocket is occupied by a crystallographic contact with another molecule of PDK1. Interestingly, close to the PIF-pocket in PDK1, there is an ordered sulfate ion, interacting tightly with four surrounding side chains. The roles of these residues were investigated through a combination of site-directed mutagenesis and kinetic studies, the results of which confirm that this region of PDK1 represents a phosphate-dependent docking site. We discuss the possibility that an analogous phosphate-binding regulatory motif may participate in the activation of other AGC kinases. Furthermore, the structure of PDK1 provides a scaffold for the design of specific PDK1 inhibitors

Genetic and expression analysis of MET, MACC1 and HGF in metastatic colorectal cancer: Response to Met inhibition in patient xenografts and pathological correlations

PURPOSE: We determined the gene copy numbers for MET, for its transcriptional activator MACC1 and for its ligand hepatocyte growth factor (HGF) in liver metastases from colorectal carcinoma (mCRC). We correlated copy numbers with mRNA levels and explored whether gain and/or overexpression of MET and MACC1 predict response to anti-Met therapies. Finally, we assessed whether their genomic or transcriptional deregulation correlates with pathologic and molecular parameters of aggressive disease. EXPERIMENTAL DESIGN: One hundred three mCRCs were analyzed. Copy numbers and mRNA were determined by quantitative PCR (qPCR). Thirty nine samples were implanted and expanded in NOD (nonobese diabetic)/SCID (severe combined immunodeficient) mice to generate cohorts that were treated with the Met inhibitor JNJ-38877605. In silico analysis of MACC1 targets relied on genome-wide mapping of promoter regions and on expression data from two CRC datasets. RESULTS: No focal, high-grade amplifications of MET, MACC1, or HGF were detected. Chromosome 7 polysomy and gain of the p-arm were observed in 21% and 8% of cases, respectively, and significantly correlated with higher expression of both Met and MACC1. Met inhibition in patient-derived xenografts did not modify tumor growth. Copy number gain and overexpression of MACC1 correlated with unfavorable pathologic features better than overexpression of Met. Bioinformatic analysis of putative MACC1 targets identified elements besides Met, whose overexpression cosegregated with aggressive forms of colorectal cancer. CONCLUSIONS: Experiments in patient-derived xenografts suggest that mCRCs do not rely on Met genomic gain and/or overexpression for growth. On the basis of pathologic correlations and bioinformatic analysis, MACC1 could contribute to CRC progression through mechanisms other than or additional to Met transcriptional upregulation