Strategies for kinome profiling in cancer and potential clinical applications: chemical proteomics and array-based methods

Kinases are key enzymes involved in deregulated signal transduction associated with cancer development and progression. The advent of personalized medicine drives the development of new diagnostic tools for patient stratification and therapy selection Ginsburg and Willard (Transl Res 154:277-287, 2009). Since deregulation of kinase-mediated signal transduction is implied in tumorigenesis, the analysis of all kinases (the kinome) active in a particular tumor may yield tumor-specific information on aberrant cell signalling pathways. Tumor tissue kinase activity profiles may correlate with response to therapy and therefore may be used for future therapy selection. In this Trend paper we describe peptide array and mass spectrometry-based technologies and new developments for kinome profiling, and we present an outlook towards future implementation of therapy selection based on kinome profiling in clinical practice.     

Synthesis and Characterization of 1-Iminopropan-2-one and 2-Iminobutan-3-one Compounds,RC(O)C(NR')R

Metal catalyzed reduction of the carbonyl group in pyridyl-ketones as well as of the imine group in α-diimines have been subject of extensive study^1–5. In contrast to the formation which at present is available concerning the complex formation of α-diimines with metals^6–10, only little is known about the complex forming properties of the -C(O)C(NR)-system which is present in pyridylketones^11–14.     

Phase transitions in self-dual generalizations of the Baxter–Wu model

We study two types of generalized Baxter–Wu models, by means of transfer-matrix and Monte Carlo techniques. The first generalization allows for different couplings in the up- and down-triangles, and the second generalization is to a q-state spin model with three-spin interactions. Both generalizations lead to self-dual models, so that the probable locations of the phase transitions follow. Our numerical analysis confirms that phase transitions occur at the self-dual points. For both generalizations of the Baxter–Wu model, the phase transitions appear to be discontinuous.     

1‐allyloxy‐2‐hydroxy‐propyl‐starch: Synthesis and characterization

New reactive unsaturated starch derivatives, 1‐allyloxy‐2‐hydroxy‐propyl‐starches (AHP‐starches), were synthesized by the reaction of waxy maize starch (WMS) and amylose‐enriched maize starch (AEMS) with allyl glycidyl ether in a heterogeneous alkaline suspension containing NaOH and Na₂SO₄. The degree of substitution (DS) was determined by ¹H NMR spectroscopy, and a DS of 0.20 ± 0.01 was found for both AHP‐WMS and AHP‐AEMS, respectively. The AHP derivatives of WMS and AEMS were further characterized with ¹H and ¹³C NMR. It was shown that the AHP substitution was located on the C‐6 hydroxyl group of the glucose residues in the starch. The substitution pattern of the AHP groups along the polymer chain was randomly clustered, as determined by enzymatic digestion using pullulanase, α‐amylase, and amyloglucosidase, followed by matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry analysis of the digestion products. With X‐ray diffraction and scanning electron microscopy, no changes in the granular morphology and crystallinity between the unmodified starches and AHP‐starches were detected. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2734–2744, 2007     

Bond-strengthening in staphylococcal adhesion to hydrophilic and hydrophobic surfaces using atomic force microscopy

Time-dependent bacterial adhesion forces of four strains of Staphylococcus epidermidis to hydrophobic and hydrophilic surfaces were investigated. Initial adhesion forces differed significantly between the two surfaces and hovered around -0.4 nN. No unambiguous effect of substratum surface hydrophobicity on initial adhesion forces for the four different S. epidermidis strains was observed. Over time, strengthening of the adhesion forces was virtually absent on hydrophobic dimethyldichlorosilane (DDS)-coated glass, although in a few cases multiple adhesion peaks developed in the retract curves. Bond-strengthening on hydrophilic glass occurred within 5-35 s to maximum adhesion forces of -1.9 +/- 0.7 nN and was concurrent with the development of multiple adhesion peaks upon retract. Poisson analysis of the multiple adhesion peaks allowed separation of contributions of hydrogen bonding from other nonspecific interaction forces and revealed a force contribution of -0.8 nN for hydrogen bonding and +0.3 nN for other nonspecific interaction forces. Time-dependent bacterial adhesion forces were comparable for all four staphylococcal strains. It is concluded that, on DDS-coated glass, the hydrophobic effect causes instantaneous adhesion, while strengthening of the bonds on hydrophilic glass is dominated by noninstantaneous hydrogen bond formation.     

Catalytic and Mechanistic Insights of the Low‐Temperature Selective Oxidation of Methane over Cu‐Promoted Fe‐ZSM‐5

The partial oxidation of methane to methanol presents one of the most challenging targets in catalysis. Although this is the focus of much research, until recently, approaches had proceeded at low catalytic rates (<10 h^?1), not resulted in a closed catalytic cycle, or were unable to produce methanol with a reasonable selectivity. Recent research has demonstrated, however, that a system composed of an iron‐ and copper‐containing zeolite is able to catalytically convert methane to methanol with turnover frequencies (TOFs) of over 14 000 h^?1 by using H₂O₂ as terminal oxidant. However, the precise roles of the catalyst and the full mechanistic cycle remain unclear. We hereby report a systematic study of the kinetic parameters and mechanistic features of the process, and present a reaction network consisting of the activation of methane, the formation of an activated hydroperoxy species, and the by‐production of hydroxyl radicals. The catalytic system in question results in a low‐energy methane activation route, and allows selective C₁‐oxidation to proceed under intrinsically mild reaction conditions.     

Sensitive and selective bioanalytical assay for the determination of dobutamine in rat plasma samples

Summary Dobutamine is one of the synthetic catecholamines acting directly onβ ₁-receptors. For the analysis of dobutamine in rat plasma samples, a selective and sensitive liquid chromatographic method is described. After a simple liquid-liquid extraction, separation of the analyte was performed using a reversed-phase ion-pair system with an octyl modified silica column. The solute was detected by fluorescence detection, applying an excitation wavelength of 285nm and an emission wavelength of 313nm. The (im)possibilities of the application of the normally used assays for the isolation, concentration and quantitation of catecholamines are discussed. By the addition of a minimum amount of modifier to the mobile phase, the selectivity of the system was increased significantly. With this method the detection limit is 9ng/ml in 0.2ml plasma samples. The application of the method is shown in rat plasma samples by measuring the concentration-time curves to establish plasma level-effect relationships for this drug.     

The family of topological Hall effects for electrons in skyrmion crystals

Hall effects of electrons can be produced by an external magnetic field, spin–orbit coupling or a topologically non-trivial spin texture. The topological Hall effect (THE) – caused by the latter – is commonly observed in magnetic skyrmion crystals. Here, we show analogies of the THE to the conventional Hall effect (HE), the anomalous Hall effect (AHE), and the spin Hall effect (SHE). In the limit of strong coupling between conduction electron spins and the local magnetic texture the THE can be described by means of a fictitious, “emergent” magnetic field. In this sense the THE can be mapped onto the HE caused by an external magnetic field. Due to complete alignment of electron spin and magnetic texture, the transverse charge conductivity is linked to a transverse spin conductivity. They are disconnected for weak coupling of electron spin and magnetic texture; the THE is then related to the AHE. The topological equivalent to the SHE can be found in antiferromagnetic skyrmion crystals. We substantiate our claims by calculations of the edge states for a finite sample. These states reveal in which situation the topological analogue to a quantized HE, quantized AHE, and quantized SHE can be found.