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121.
VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche 总被引:4,自引:0,他引:4
Kaplan RN Riba RD Zacharoulis S Bramley AH Vincent L Costa C MacDonald DD Jin DK Shido K Kerns SA Zhu Z Hicklin D Wu Y Port JL Altorki N Port ER Ruggero D Shmelkov SV Jensen KK Rafii S Lyden D 《Nature》2005,438(7069):820-827
The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread. 相似文献
122.
Although it is widely accepted that most galaxies have supermassive black holes at their centres, concrete proof has proved elusive. Sagittarius A* (Sgr A*), an extremely compact radio source at the centre of our Galaxy, is the best candidate for proof, because it is the closest. Previous very-long-baseline interferometry observations (at 7 mm wavelength) reported that Sgr A* is approximately 2 astronomical units (au) in size, but this is still larger than the 'shadow' (a remarkably dim inner region encircled by a bright ring) that should arise from general relativistic effects near the event horizon of the black hole. Moreover, the measured size is wavelength dependent. Here we report a radio image of Sgr A* at a wavelength of 3.5 mm, demonstrating that its size is approximately 1 au. When combined with the lower limit on its mass, the lower limit on the mass density is 6.5 x 10(21)M(o) pc(-3) (where M(o) is the solar mass), which provides strong evidence that Sgr A* is a supermassive black hole. The power-law relationship between wavelength and intrinsic size (size proportional, variantwavelength(1.09)) explicitly rules out explanations other than those emission models with stratified structure, which predict a smaller emitting region observed at a shorter radio wavelength. 相似文献
123.
Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome 总被引:20,自引:0,他引:20
Amiel J Laudier B Attié-Bitach T Trang H de Pontual L Gener B Trochet D Etchevers H Ray P Simonneau M Vekemans M Munnich A Gaultier C Lyonnet S 《Nature genetics》2003,33(4):459-461
Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. This core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system (ANS) including Hirschsprung disease and tumors of neural-crest derivatives such as ganglioneuromas and neuroblastomas. In mice, the development of ANS reflex circuits is dependent on the paired-like homeobox gene Phox2b. Thus, we regarded its human ortholog, PHOX2B, as a candidate gene in CCHS. We found heterozygous de novo mutations in PHOX2B in 18 of 29 individuals with CCHS. Most mutations consisted of 5-9 alanine expansions within a 20-residue polyalanine tract probably resulting from non-homologous recombination. We show that PHOX2B is expressed in both the central and the peripheral ANS during human embryonic development. Our data support an essential role of PHOX2B in the normal patterning of the autonomous ventilation system and, more generally, of the ANS in humans. 相似文献
124.
125.
Wan-Bang Lo R. A. Jungmann J. S. Schweppe B. S. Berlin M. Grover 《Cellular and molecular life sciences : CMLS》1973,29(3):280-282
Zusammenfassung Das elektrophoretische Muster von Histonen und sauren Zellkernproteinen von Hühnerembryonen und deren primären und sekundären Fibroblastzellen wurde qualitativ und quantitativ verglichen. Die Zellkernproteine der verschiedenen Zelltypen erwiesen sich qualitativ als identisch, die relative quantitative Verteilung der Kernproteine war jedoch leicht verschieden. 相似文献
126.
Janoueix-Lerosey I Lequin D Brugières L Ribeiro A de Pontual L Combaret V Raynal V Puisieux A Schleiermacher G Pierron G Valteau-Couanet D Frebourg T Michon J Lyonnet S Amiel J Delattre O 《Nature》2008,455(7215):967-970
Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood. It usually occurs sporadically but familial cases are observed, with a subset of cases occurring in association with congenital malformations of the neural crest being linked to germline mutations of the PHOX2B gene. Here we conducted genome-wide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumour DNAs we identified somatic mutations of the ALK kinase domain that mainly clustered in two hotspots. Germline mutations were observed in two neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wild-type ALK, led to a marked decrease of cell proliferation. Altogether, these data identify ALK as a critical player in neuroblastoma development that may hence represent a very attractive therapeutic target in this disease that is still frequently fatal with current treatments. 相似文献
127.
n-heptane pool fire and industrial alcohol pool fire in a ceiling vented compartment were studied experimentally. The parameters including mass loss rate and rate of gas temperature rise were investigated. The results suggest that the rate of gas temperature rise, whose varia- tions were highly coincident with those of the mass loss rate, minimized at the moment of extinction. The correlation of the rate of average nondimensional temperature rise with mass loss rate was established. It was found that the rate of average nondimensional temperature rise may be correlated with mass loss rate via the gas heat absorption coefficient which was found to be a quadratic function of the nondimensional heat release rate for the ceiling vented compartment under study. The present study may be of practical use for estimation of the time-dependent changes in mass loss rate from the gas temperature curves. 相似文献
128.
Viré E Brenner C Deplus R Blanchon L Fraga M Didelot C Morey L Van Eynde A Bernard D Vanderwinden JM Bollen M Esteller M Di Croce L de Launoit Y Fuks F 《Nature》2006,439(7078):871-874
The establishment and maintenance of epigenetic gene silencing is fundamental to cell determination and function. The essential epigenetic systems involved in heritable repression of gene activity are the Polycomb group (PcG) proteins and the DNA methylation systems. Here we show that the corresponding silencing pathways are mechanistically linked. We find that the PcG protein EZH2 (Enhancer of Zeste homolog 2) interacts-within the context of the Polycomb repressive complexes 2 and 3 (PRC2/3)-with DNA methyltransferases (DNMTs) and associates with DNMT activity in vivo. Chromatin immunoprecipitations indicate that binding of DNMTs to several EZH2-repressed genes depends on the presence of EZH2. Furthermore, we show by bisulphite genomic sequencing that EZH2 is required for DNA methylation of EZH2-target promoters. Our results suggest that EZH2 serves as a recruitment platform for DNA methyltransferases, thus highlighting a previously unrecognized direct connection between two key epigenetic repression systems. 相似文献
129.
Organic–inorganic hybrid solar cells based on poly(3-hexylthiophene) and electrospun TiO2 nano bers were fabricated by solution process.The ef ciency of the device was improved by modifying CdS nanoparticles on the surface of TiO2 by electrochemical method.The CdS layer can lead to the increase of both open circuit voltage and short circuit current of the device,which are attributed to enhanced exciton dissociation and light absorption and suppressed carrier recombination by CdS at the heterojunction.However,too thick CdS layer led to increased series resistance and decreased ef ciency of the device.Therefore,the optimum condition of the CdS deposition was obtained,which increased the power conversion ef ciency of the device for about 50%.Our results indicate that the surface modi cation on the inorganic semiconductor layer is an effect way to improve the performance of the hybrid solar cells. 相似文献