Anaplastic lymphoma kinase (ALK) inhibitor response in neuroblastoma is highly correlated with ALK mutation status, ALK mRNA and protein levels

Background In pediatric neuroblastoma (NBL), high anaplastic lymphoma kinase (ALK) levels appear to be correlated with an unfavorable prognosis, regardless of ALK mutation status. This suggests a therapeutic role for ALK inhibitors in NBL patients. We examined the correlation between levels of ALK, phosphorylated ALK (pALK) and downstream signaling proteins and response to ALK inhibition in a large panel of both ALK mutated and wild type (WT) NBL cell lines. Methods We measured protein levels by western blot and ALK inhibitor sensitivity (TAE684) by viability assays in 19 NBL cell lines of which 6 had a point mutation and 4 an amplification of the ALK gene. Results ALK 220 kDa (p=0.01) and ALK 140 kDa (p= 0.03) protein levels were higher in ALK mutant than WT cell lines. Response to ALK inhibition was significantly correlated with ALK protein levels (p<0.01). ALK mutant cell lines (n=4) were 14,9 fold (p<0,01) more sensitive to ALK inhibition than eight WT cell lines. Conclusion NBL cell lines often express ALK at high levels and are responsive to ALK inhibitors. Mutated cell lines express ALK at higher levels, which may define their superior response to ALK inhibition

In search of the authentic nation: landscape and national identity in Canada and Switzerland

While the study of nationalism and national identity has flourished in the last decade, little attention has been devoted to the conditions under which natural environments acquire significance in definitions of nationhood. This article examines the identity-forming role of landscape depictions in two polyethnic nation-states: Canada and Switzerland. Two types of geographical national identity are identified. The first – what we call the ‘nationalisation of nature’– portrays zarticular landscapes as expressions of national authenticity. The second pattern – what we refer to as the ‘naturalisation of the nation’– rests upon a notion of geographical determinism that depicts specific landscapes as forces capable of determining national identity. The authors offer two reasons why the second pattern came to prevail in the cases under consideration: (1) the affinity between wild landscape and the Romantic ideal of pure, rugged nature, and (2) a divergence between the nationalist ideal of ethnic homogeneity and the polyethnic composition of the two societies under consideration

Verification of genes differentially expressed in neuroblastoma tumours: a study of potential tumour suppressor genes

<p>Abstract</p> <p>Background</p> <p>One of the most striking features of the childhood malignancy neuroblastoma (NB) is its clinical heterogeneity. Although there is a great need for better clinical and biological markers to distinguish between tumours with different severity and to improve treatment, no clear-cut prognostic factors have been found. Also, no major NB tumour suppressor genes have been identified.</p> <p>Methods</p> <p>In this study we performed expression analysis by quantitative real-time PCR (QPCR) on primary NB tumours divided into two groups, of favourable and unfavourable outcome respectively. Candidate genes were selected on basis of lower expression in unfavourable tumour types compared to favourables in our microarray expression analysis. Selected genes were studied in two steps: (1) using TaqMan Low Density Arrays (TLDA) targeting 89 genes on a set of 12 NB tumour samples, and (2) 12 genes were selected from the TLDA analysis for verification using individual TaqMan assays in a new set of 13 NB tumour samples.</p> <p>Results</p> <p>By TLDA analysis, 81 out of 87 genes were found to be significantly differentially expressed between groups, of which 14 have previously been reported as having an altered gene expression in NB. In the second verification round, seven out of 12 transcripts showed significantly lower expression in unfavourable NB tumours, <it>ATBF1</it>, <it>CACNA2D3</it>, <it>CNTNAP2</it>, <it>FUSIP1</it>, <it>GNB1</it>, <it>SLC35E2</it>, and <it>TFAP2B</it>. The gene that showed the highest fold change in the TLDA analysis, <it>POU4F2</it>, was investigated for epigenetic changes (CpG methylation) and mutations in order to explore the cause of the differential expression. Moreover, the fragile site gene <it>CNTNAP2 </it>that showed the largest fold change in verification group 2 was investigated for structural aberrations by copy number analysis. However, the analyses of <it>POU4F2 </it>and <it>CNTNAP2 </it>showed no genetic alterations that could explain a lower expression in unfavourable NB tumours.</p> <p>Conclusion</p> <p>Through two steps of verification, seven transcripts were found to significantly discriminate between favourable and unfavourable NB tumours. Four of the transcripts, <it>CACNA2D3</it>, <it>GNB1</it>, <it>SLC35E2</it>, and <it>TFAP2B</it>, have been observed in previous microarray studies, and are in this study independently verified. Our results suggest these transcripts to be markers of malignancy, which could have a potential usefulness in the clinic.</p

International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee

Neuroblastoma serves as a paradigm for utilising tumour genomic data for determining patient prognosis and treatment allocation. However, before the establishment of the International Neuroblastoma Risk Group (INRG) Task Force in 2004, international consensus on markers, methodology, and data interpretation did not exist, compromising the reliability of decisive genetic markers and inhibiting translational research efforts. The objectives of the INRG Biology Committee were to identify highly prognostic genetic aberrations to be included in the new INRG risk classification schema and to develop precise definitions, decisive biomarkers, and technique standardisation. The review of the INRG database (n=8800 patients) by the INRG Task Force finally enabled the identification of the most significant neuroblastoma biomarkers. In addition, the Biology Committee compared the standard operating procedures of different cooperative groups to arrive at international consensus for methodology, nomenclature, and future directions. Consensus was reached to include MYCN status, 11q23 allelic status, and ploidy in the INRG classification system on the basis of an evidence-based review of the INRG database. Standardised operating procedures for analysing these genetic factors were adopted, and criteria for proper nomenclature were developed. Neuroblastoma treatment planning is highly dependant on tumour cell genomic features, and it is likely that a comprehensive panel of DNA-based biomarkers will be used in future risk assignment algorithms applying genome-wide techniques. Consensus on methodology and interpretation is essential for uniform INRG classification and will greatly facilitate international and cooperative clinical and translational research studies

Homosexuality, politics and Pentecostal nationalism in Zambia

Building upon debates about the politics of nationalism and sexuality in post-colonial Africa, this article highlights the role of religion in shaping nationalist ideologies that seek to regulate homosexuality. It specifically focuses on Pentecostal Christianity in Zambia, where the constitutional declaration of Zambia as a Christian nation has given rise to a form of ‘Pentecostal nationalism’ in which homosexuality is considered to be a threat to the purity of the nation and is associated with the Devil. The article offers an analysis of recent Zambian public debates about homosexuality, focusing on the ways in which the ‘Christian nation’ argument is deployed, primarily in a discourse of anti-homonationalism, but also by a few recent dissident voices. The latter prevent Zambia, and Christianity, from accruing a monolithic depiction as homophobic. Showing that the Zambian case presents a mobilisation against homosexuality that is profoundly shaped by the local configuration in which Christianity defines national identity – and in which Pentecostal-Christian moral concerns and theo-political imaginations shape public debates and politics – the article nuances arguments that explain African controversies regarding homosexuality in terms of exported American culture wars, proposing an alternative reading of these controversies as emerging from conflicting visions of modernity in Africa

An Evolutionary Conserved Role for Anaplastic Lymphoma Kinase in Behavioral Responses to Ethanol

Anaplastic lymphoma kinase (Alk) is a gene expressed in the nervous system that encodes a receptor tyrosine kinase commonly known for its oncogenic function in various human cancers. We have determined that Alk is associated with altered behavioral responses to ethanol in the fruit fly Drosophila melanogaster, in mice, and in humans. Mutant flies containing transposon insertions in dAlk demonstrate increased resistance to the sedating effect of ethanol. Database analyses revealed that Alk expression levels in the brains of recombinant inbred mice are negatively correlated with ethanol-induced ataxia and ethanol consumption. We therefore tested Alk gene knockout mice and found that they sedate longer in response to high doses of ethanol and consume more ethanol than wild-type mice. Finally, sequencing of human ALK led to the discovery of four polymorphisms associated with a low level of response to ethanol, an intermediate phenotype that is predictive of future alcohol use disorders (AUDs). These results suggest that Alk plays an evolutionary conserved role in ethanol-related behaviors. Moreover, ALK may be a novel candidate gene conferring risk for AUDs as well as a potential target for pharmacological intervention

Anaplastic Lymphoma Kinase Is Required for Neurogenesis in the Developing Central Nervous System of Zebrafish

10.1371/journal.pone.0063757PLoS ONE85

Futurismo, cultura e politica

Nell’ambito della mostra “Futurismo e Futurismi”, curata da Palazzo Grassi a Venezia nel 1986, la Fondazione Giovanni Agnelli organizzò a Venezia, il 15 e 16 maggio 1986, il convegno “Futurismo, Cultura e Politica”, volto ad esplorare la dimensione politica e meta-politica del movimento e della cultura futurista, in Italia ed all’estero. Il volume raccoglie i saggi nati dalle relazioni presentate in quella occasione.- Indice #5- Introduzione di Renzo De Felice #9- Parte Prima. Gli aspetti generali del rapporto tra futurismo, cultura e politica #13- Futurismo e culture politiche in Europa: una prospettiva globale, George L. Mosse #15- Il ruolo di Marinetti nella costruzione del futurismo, Luciano De Maria #35- Il futurismo nel dibattito intellettuale italiano dalle origini al 1920, Alberto Asor Rosa #51- Futurismo e sinistra politica, Umberto Carpi #69- Macchine e rarimerletti. Alcune fonti del futurismo nell’ideologia e nella letteratura, Roberto Tessari #81- Parte Seconda. L’esperienza politica del futurismo italiano #105- II futurismo e la politica. Dal nazionalismo modernista al fascismo (1909-1920), Emilio Gentile #107- Futurismo e fascismo, Niccolò Zapponi #163- Settimelli e Carli dal futurismo al fascismo, Paolo Buchignani #179- Bottai: da intellettuale futurista a leader fascista, Giordano Bruno Guerri #223- La politica culturale del fascismo, le avanguardie e il problema del futurismo, Enrico Crispolti #249- Parte Terza. Futurismo, cultura e politica fuori d’Italia #287- Futurismo e culture politiche in Francia, Pasquale A. Jannini #289- Futurismo e rivoluzione conservatrice in Germania, Ferruccio Masini #307- Il futurismo italiano e l’avanguardia ungherese, Gianpiero Cavaglià #323- I contatti politico-culturali tra futuristi italiani e Russia, Cesare G. De Michelis #355- Il secondo futurismo russo: la dimensione politica, Halina Stephan #385- Futurismo, ultraismo e culture politiche nell’area ispanica, Jaime Brihuega #411- Futurismo, vorticismo e “mondomoderno”, William C. Wees #443- Interventi #459- Arti liberali e diritto dell’individuo in F. T. Marinetti, Leonardo Clerici #461- Futurismo e dibattito politico, Emilio R. Papa #483- Spettacolo politico e “18 BL”, Marco Verdone #48