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781.
It is well known that malignant cells circulate in the bloodstream of patients with solid tumors. However, the biological significance of circulating tumor cells (CTCs) and the clinical relevance of their detection are still debated. Besides technical issues regarding CTC-detection methods, discontinuous shedding of CTCs from established cancer deposits, genomic instability and metastatic inefficiency might underlie the conflicting results currently available. Nevertheless, technological advances and recent clinical findings are prompting researchers to dissect CTC biology further. Here, we review these recent findings, and discuss the prospects for the identification and molecular characterization of the CTC subset that is responsible for metastasis development. This would provide a formidable tool for prognosis evaluation, anticancer-drug development and, ultimately, cancer-therapy personalization. 相似文献
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The cytotoxic effect of adenylate cyclase (AC) toxin from Bordetella pertussis on host cells has been attributed to the production of supraphysiologic levels of cyclic AMP by the toxin. We have tested this hypothesis and show that at least two different mechanisms, cAMP accumulation/ATP depletion and oligomerization/pore formation, contribute, perhaps synergistically, to AC toxin-induced cytotoxicity. Wild-type (WT) AC toxin causes cell death associated with an increase in cAMP, a reduction in ATP, activation of caspases 3/7, and increased annexin V and TUNEL staining. In contrast, a non-acylated, enzymatically active, non-haemolytic form of AC toxin is able to increase cAMP, reduce ATP and elicit annexin V staining, but the decrease in ATP and the annexin staining are transient and there is minimal caspase activation, TUNEL staining and cell death. Mutant AC toxins defective in either enzymatic activity or the ability to deliver their enzymatic domain are able to kill J774 cells, without cAMP production, and with minimal caspase activation and TUNEL staining. Comparison of the potencies of WT toxin and those of mutants that only increase cAMP or only create transmembrane pores establishes that at least two mechanisms are contributory and that simply the production of cAMP is not enough to account for the cytotoxicity produced by AC toxin. 相似文献
785.
Vasseur-Godbillon C Sahu SC Domingues E Fablet C Giovannelli JL Tam TC Ho NT Ho C Marden MC Baudin-Creuza V 《The FEBS journal》2006,273(1):230-241
We have engineered a stable octameric hemoglobin (Hb) of molecular mass 129 kDa, a dimer of recombinant hemoglobin (rHb betaG83C-F41Y) tetramers joined by disulfide bonds at the beta83 position. One of the major problems with oxygen carriers based on acellular hemoglobin solutions is vasoactivity, a limitation which may be overcome by increasing the molecular size of the carrier. The oxygen equilibrium curves showed that the octameric rHb betaG83C-F41Y exhibited an increased oxygen affinity and a decreased cooperativity. The CO rebinding kinetics, auto-oxidation kinetics, and size exclusion chromatography did not show the usual dependence on protein concentration, indicating that this octamer was stable and did not dissociate easily into tetramers or dimers at low concentration. These results were corroborated by the experiments with haptoglobin showing no interaction between octameric rHb betaG83C-F41Y and haptoglobin, a plasma glycoprotein that binds the Hb dimers and permits their elimination from blood circulation. The lack of dimers could be explained if there are two disulfide bridges per octamer, which would be in agreement with the lack of reactivity of the additional cysteine residues. The kinetics of reduction of the disulfide bridge by reduced glutathione showed a rate of 1000 M(-1) x h(-1) (observed time coefficient of 1 h at 1 mM glutathione) at 25 degrees C. Under air, the cysteines are oxidized and the disulfide bridge forms spontaneously; the kinetics of the tetramer to octamer reaction displayed a bimolecular reaction of time coefficient of 2 h at 11 microM Hb and 25 degrees C. In addition, the octameric rHb betaG83C-F41Y was resistant to potential reducing agents present in fresh plasma. 相似文献
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Scippa GS Di Michele M Di Iorio A Costa A Lasserre B Chiatante D 《Annals of botany》2006,97(5):857-866
BACKGROUND AND AIMS: Plant anchorage is governed by complex, finely regulated mechanisms that occur at a morphological, architectural and anatomical level. Spanish broom (Spartium junceum) is a woody plant frequently found on slopes--a condition that affects plant anchorage. This plant grows throughout the Mediterranean area where it plays an important role in preventing landslides. Spanish broom seedlings respond promptly to slope by altering stem and root morphology. The aim of this study was to investigate the mechanisms whereby the root system of Spanish broom seedlings adapts to ensure anchorage to the ground. METHODS: Seedlings were grown in tilted and untilted pots under controlled conditions. The root apparatus was removed at different times of growth and subjected to morphological, biomechanical and molecular analyses. KEY RESULTS: In slope-grown seedlings, changes in root system morphology, pulling strength and chemical lignin content, all features related to plant anchorage in the soil, were related to seedling age. cDNA-AFLP analysis revealed changes in the expression of several genes in root systems of slope-grown plants. BLAST analysis showed that some differentially expressed genes are homologues of genes induced by environmental stresses in other plant species, and/or are involved in the production of strengthening materials. CONCLUSION: Plants use various mechanisms/strategies to respond to slope depending on their developmental stage. 相似文献
789.
Spadaccini R Crescenzi O Tancredi T De Casamassimi N Saviano G Scognamiglio R Di Donato A Temussi PA 《Journal of molecular biology》2001,305(3):505-514
The sweet protein MNEI is a construct of 96 amino acid residues engineered by linking, with a Gly-Phe dipeptide, chains B and A of monellin, a sweet protein isolated from Discoreophyllum cuminsii. Here, the solution structure of MNEI was determined on the basis of 1169 nuclear Overhauser enhancement derived distance restraints and 184 dihedral angle restraints obtained from direct measurement of three-bond spin coupling constants. The identification of hydrogen bonded NH groups was obtained by a combination of H/(2)H exchange data and NH resonance temperature coefficients derived from a series of HSQC spectra in the temperature range 278-328 K. The good resolution of the structure is reflected by the Z-score of the quality checking program in WHAT IF (-0.61). The topology of MNEI, like that of natural monellin and of SCM, another single-chain monellin, is typical of the cystatin superfamily: an alpha-helix cradled into the concave side of a five-strand anti-parallel beta-sheet. The high resolution (14 restraints/residue) 3D structure of MNEI shows close similarity to the crystal structures of natural monellin and of SCM but differs from the solution structure of SCM. The structures of SCM in the crystal and in solution differ in some of the secondary structure elements, but most of all in the relative arrangement of the elements: the four main beta-strands that surround the helix in the crystal structure of SCM, are displaced far from the helix in the solution structure of SCM. These differences were attributed to the fact that SCM is a monomer in solution and a dimer in the crystal. This result is at variance with the observation that our solution structure, like that of SCM, corresponds to a monomeric state of the protein, as demonstrated by the insensitivity of HSQC spectra to extreme dilution (down to 20 microM). On the basis of the solution structure of MNEI it is possible to propose that the main glucophores are hosted on loop L34, whereas the N-terminal and C-terminal regions host two other important interaction regions, centered around segments 6-9 and 94-96. 相似文献
790.
Donato Monti Giuseppe Frachey Mauro Bassetti Anthony Haynes Glenn J. Sunley Peter M. Maitlis Andrea Cantoni Gabriele Bocelli 《Inorganica chimica acta》1995,240(1-2):485-493
The reactions of complex (C5Me5)Ir(Cl) (CO) (Me) (1a) with cyclohexylisocyanide and phosphines (L=CyNC, PHPh2, PMePh2, PMe2Ph) give the products of alkyl migratory insertion (C5Me5Ir(Cl) (COMe) (L), in toluence or tetrahydrofuran at 323 K or higher temperature. The phenyl analogue (C5Me5)Ir(Cl)(CO)(Ph) or the iodide complexes (C5Me5)Ir(I) (CO) (R) (R=Me, Ph_are not reactive under the same conditions. The reaction of (C5Me5)Ir(Cl)(CO)(Me) with PMePh2 and PMe2Ph in acetonitrile yields the chloride substitution product [(C5Me5)Ir(CO)(L)(Me)]+Cl−. Kinetic measurements for the reactions of (C5Me5)Ir(Cl)(CO)(Me) in toluene are first order in the iridium complex and exhibit a saturation dependence on the incoming donors L. Analysis of the data suggests a two-step process involving (i) rapid formation of a molecular complex [(C5Me5)Ir(Cl)(CO)(Me), (L)], in which the structure of 1a is unperturbed within the limits of spectroscopic analysis, and (ii) rate determining methyl migration. The reaction parameters are K for the pre-equilibrium step (K = 1.5 (CyNC), 7.3 (PHPh2), 7.1 (PMePh2) dm3 mol−1 at 323 K) and k2 for the slow carbon---carbon bond formation (k2 (105) = 6.9 (CyNC), 1.2 (PHPh2), 1.0 (PMePh2) s−1 at 323 K). The activation parameters for the methyl migration step in the reaction with PMePh2 obtained between 308 and 338 K, are ΔH≠ = 106±16 kJ mol−1 and ΔS≠ = − 14±5 J K−1 mol−1. The reaction of 1a with PMePh2 proceeds at similar rates in tetrahydrofuran (K = 3.7 dm3 mol−1, k2 (105) = 1.2 s−1, 323 K). The crystal structure of (C5Me5)Ir(Cl)(COMe) (PMe2Ph) has been determined by X-ray diffraction. C20H29ClOPIr: Mr = 544.1, monoclinic, P21/n, A = 8.084 (2), B = 9.030(2), C = 28.715 (3) Å, β = 91.41 (3)°, Z = 4, Dc = 1.71 g cm−3, V = 2095.5 Å3, room temperatyre, Mo K, γ = 0.71069, μ = 65.55 cm−1, F(000) = 1044, R = 0.037 for 2453 independent observed reflections. The complex shows a deformed tetrahedral coordination assuming the η5-C5Me5 molecular fragment as a single coordination site. The iridium-chlorine bond is staggered with respect to two adjacent C(ring)-methyl bonds, while the Ir---P and the Ir---COMe bonds are eclipsed with respect to C(ring)-methyl bonds. 相似文献