Hypoxic gene regulation and oncogenic pathways in neuroblastoma

Neuroblastoma patients show remarkable clinical heterogeneity, with courses ranging from spontaneous regression to fatal tumor progression despite intense multi-modal treatment. Previous studies have shown that hypoxia pushes neuroblastoma cells towards a more immature phenotype, which correlates to aggressive disease. Here we define a role for the hypoxia inducible factor-2α in neuroblastoma tumor progression. While HIF-1α was transiently stabilized at hypoxia (1% oxygen), HIF-2α was induced and regulated HIF-specific target genes, such as VEGF, at later time points. Furthermore, HIF-2α was stabilized and transcriptionally active in cells grown at physiological oxygen levels (5% O2). Subsequent microarray analysis showed that HIF-2α induced genes, previously identified as hypoxia regulated, at this physiological oxygen level. Several of these genes have been implicated in tumorigenic processes and correlated to adverse patient outcome in various tumor forms. Indeed, siRNA mediated knock-down of HIF-2α in neuroblastoma cells significantly reduced xenograft tumor growth, as compared to siHIF1-α treated or wild-type cells. Moreover, immunohistochemical analyses of a large neuroblastoma tumor material arranged in a tissue microarray showed that HIF-2α expression correlated to VEGF, and that high HIF-2α levels was predictive of poor patient prognosis. Prognostic markers of neuroblastoma patient adverse prognosis include amplification of the MYCN oncogene and an undifferentiated morphology. While these features discriminate high- from low-risk patients with precision, identification of poor outcome low- and intermediate-risk patients is more challenging. We analyze two large neuroblastoma microarray data sets by using a priori-defined gene expression signatures. The results show that differential overexpression of Myc transcriptional targets and low expression of genes involved in sympathetic neuronal differentiation predict relapse and death from disease. This was evident not only for high-risk patients, but also was robust in identifying groups of poor prognosis patients otherwise judged to be at low- or intermediate-risk for adverse outcome. These data suggest that pathway-specific gene expression profiling might be useful in the clinic to adjust treatment strategies for children with neuroblastoma

Proceedings of the XIII Spanish Conference on Programming and Computer Languages (PROLE 2013)

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Leftist, Jewish, and Canadian Identities Voiced in the Repertoire of the Toronto Jewish Folk Choir, 1939-1959

This article focuses on a twenty-year period of the Toronto Jewish Folk Choir, during which the ensemble was conducted by Emil Gartner. Considering historical contexts, including political pressures and social frameworks, the author shows how repertoire choices were linked to overlapping patterns of identity, notably the choir as a voice for progressive political ideas, as a Jewish community group, and as a player in the emerging multicultural Canadian fabric

Just, Speedy, and Inexpensive or Just Speedy and Inexpensive - Mandatory Alternative Dispute Resolution in the Western District of Missouri

This Comment will address five questions which may arise as challenges to the Western District of Missouri\u27s implementation of its ADR program. First, is the experimental program designed by the court likely to be predictive? That is, will the program be able to tell us whether cost and delay are being reduced by the ADR program? Second, is the program as implemented likely to reduce cost and delay? Third, does the Western District of Missouri have authority to impose mandatory ADR on litigants? Fourth, is the provision for mandatory ADR constitutionally sound? And fifth, assuming affirmative answers to these questions, does the General Order of the Western District of Missouri promote policy concerns

The effects of live Streptococcus pneumoniae and tumor necrosis factor-α on neutrophil oxidative burst and β2-integrin expression

ObjectiveTo study the effects of TNF-α and live Streptococcus pneumoniae on human neutrophil oxidative burst and β2-integrin expression using flow cytometry.MethodsSix clinical isolates of S. pneumoniae (serotypes 3, 19A, 22F, 6A, 33P and 9N) from patients with bacteremic pneumonia or upper respiratory tract infections were studied. Whole blood was incubated either alone, with TNF-α or with S. pneumoniae or with both TNF-α and pneumococci at a ratio of one neutrophil per 1–5 bacteria. After 30 min of incubation, the tubes were put into ice, fixed and analysed.ResultsS. pneumoniae caused an increase in oxidative burst but not greater than that caused by TNF-α alone. When whole blood was preincubated with TNF-α for 30 min before the addition of pneumococci, a further increase in the oxidative burst response was seen. The variation in CD 11b expression was not significant. Both S. pneumoniae and TNF-α caused increases in CD18 expression. The addition of TNF-α directly with the bacteria caused no further increase, but preincubation of blood with TNF-α 30 min before the addition of the bacteria caused a significant increase in CD18 expression.ConclusionsLive S. pneumoniae stimulates polymorphonuclear leukocytes to produce an oxidative burst and increases expression of CD18, and these effects are enhanced by TNF-α