Activating mutations in ALK provide a therapeutic target in neuroblastoma

Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.     

Glutamine synthetase activity in subdivisions of brain of the shark,Squalus acanthias

Summary Specific activity of glutamine synthetase inSqualus acanthias (spiny dogfish) central nervous system regions was highest in the cerebellum and lowest in the spinal cord. The levels of activity may relate to the excitability of each region by regulating the glutamate pool.Publication No. 14 from the Laboratory of Biochemical Ecology. Contribution No. 527, College of Fisheries, University of Washington. This work was supported in part by a fellowship from the national Wildlife Federation and a Pacific Fisheries Biologists' scholarship to J.T.W.     

Forecasts of inflation from var models

Why are forecasts of inflation from VAR models so much worse than their forecasts of real variables? This paper documents that relatively poor performance, and finds that the price equation of a VAR model fitted to US post-war data is poorly specified. Statistical work by other authors has found that coefficients in such price equations may not be constant. Based on specific monetary actions, two changes in monetary policy regimes are proposed. Accounting for those two shifts yields significantly more accurate forecasts and lessens the evidence of misspecification.     

Inhibition of DNA synthesis in regenerating rat liver by hydrocortisone

Résumé Dans le foie du rat en voie de régénération, la biosynthèse de DNA est inhibée au maximum par le hydrocortisone 17–19 h après l'opération. C'est pourquoi le foie en régénération est le plus sensible au hydrocortisone s'il est injecté pendant la période de la synthèse maximale de DNA.