Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy. 相似文献
Summary We synthesized the m-maleimidobenzoyl derivative of digoxigenin-3-0-succinate (through a p-phenylenediamine bridge) as a hapten derivative directed towards coupling to sulfhydryl groups of -galactosidase. Prepared enzyme conjugate had about 97% of the enzyme labeled with the hapten derivative while retaining full enzyme activity. The enzyme immunoassay for digoxin we prepared showed a maximum sensitivity of 30 pg per assay (c.v.=3%) with minimal cross-reaction with digotoxin (3.8%). Our method for hapten conjugation to -galactosidase is highly efficient and is simple and easily replicated. 相似文献
In this paper we examine the role of top management in relation to the diversified operations of a company and the meaning of “strategic planning” for these entities. We briefly examine two general approaches to generation of growth: conglomeration (portfolio management) and synergistic growth. We argue that the second is preferable. We then challenge the universally popluar notion that growth is the appropriate objective for a business entity. We propose the concept of “development” as a better alternative. We offer the case of Armco's Latin American Division (known as ALAD) as an illustration of the kind of thinking that emerges when development is taken as the corporate objective. We present a five-phase strategy that combines the notions of synergistic growth and corporate development in a systemic framework. 相似文献
zirconia-based nanostructured coatings were deposited on AA2024 to improve the corrosion resistance properties. Three different nanostructured coatings, namely, zirconia-benzotriazole, zirconia-alumina-benzotriazole, and zirconia-yttria-benzotriazole, were applied on AA2024 via a sol-gel method using the dip-coating technique. Next, the coatings were annealed at 150℃ after each dipping period. The phases and morphologies of the coatings were investigated using grazing incidence X-ray diffraction (GIXRD), Fourier transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FESEM), and atomic force microscopy (AFM). The corrosion properties were evaluated using electrochemical methods, including polarization and electrochemical impedance techniques in 3.5wt% NaCl solution. The obtained results confirm the formation of homogeneous and crack free zirconia-benzotriazole-based nanostructured coatings. The average roughness values for zirconia-benzotriazole, zirconia-alumina-benzotriazole, and zirconia-yttria-benzotriazole nanostructured coatings were 30, 8, and 6 nm, respectively. The presence of alumina as a stabilizer on zirconia coating was found to have a beneficial impact on the stability of the corrosion resistance for different immersion times. In fact, the addition of alumina resulted in the dominance of the healing behavior in competition with the corrosion process of zirconia-benzotriazole nanostructured coating. 相似文献
The perennial Medicago sativa cv. Gabès is widely grown on saline soils in Tunisian oases. Morphological and physiological analyses of two populations (Mareth and Gannouch) were conducted in order to study the effect of salinity and gamma radiation (350 Gy) interaction on two populations of this species. It has been shown that the two irradiated populations of Medicago sativa are fairly tolerant to salt at growth phase compared to the non-irradiated. Exposure to gamma irradiation (350 Gy), alone or in combination with salt stress, increased significantly (p<0.001) shoot number, stem height and chlorophyll b pigment especially for the Gannouch population, while no change occurred for the Mareth population. The presence of salt to 9g/l affected significantly the root biomass and induced a reduction of shoot development of both control and irradiated alfalfa populations. For all treatments, plants of two populations remained able to produce and to allocate dry matter to the different organs. The survey of Na+ / K+ ratio showed that the growth of the aerial organs of two non-irradiated populations was at least determined by a selectivity in favour of the K+ ions (r2 = 0.97 and r2 = 0.59 for Mareth and Gannouch irradiated populations, respectively). However, the rather weak correlation detected for the irradiated populations, particularly for the irradiated Gannouch, seems to be the consequence of the effect of irradiation that improved potassium availability, essential element for growth and development. Results also showed that the two irradiated populations, especially the Mareth, accumulated Na+ ions in its photosynthetic organs. This accumulation was associated with an improvement of foliar water content at a level of salinity arrounding 5g/l. Such a mechanism reflects probably an inclusive behaviour of the plants and a good aptitude to use the dominant ions (Na+) for the osmotic adjustment. However, the non-irradiated populations are unable to adjust their internal osmotic potential. Consequently, irradiated plants have probably adapted to the osmotic stress by either closing their stomata or increasing the osmotic pressure of the leaf cells. 相似文献
Over the last decade, there has been an exponential growth of services over the Internet. Services such as online gaming are gaining popularity, whereas, Voice over Internet (VoIP) has been well established. Storage, management and processing of data have moved away from the devices to the cloud. Quality of experience (QoE) defined as the user’s perception of service quality is utilized in different technologies, services and products for improving end user satisfaction and provides quality of service (QoS) according to their demands. In this paper, we describe the utilization of QoE in different technologies, services and products for improving end user satisfaction. Specifically, we present the latest developments in QoE in multimedia services, network management, VoIP, web development, games and cloud computing. Finally, we discuss the current research, solutions and present open issues of future research in QoE.
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ~25% of the familial risk in this disease, have now been identified. 相似文献