Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation.

Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL ALK(+)). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(-)), which is characterized by a worse prognosis. We found that ALCL ALK(-), in contrast to ALCL ALK(+), lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK(-), we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(-) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1).This work was supported by the SCRI-LIMCR GmbH, the “Jubiläumsfond der Österreichischen Nationalbank” (grant-no. 14856 to O.M.), R.G. was supported by grant SFB P021 from the Austrian Science Funds (FWF), L.K. was supported by grant FWF, P26011, R.M. was supported by FWF grants SFB F28 and SFB F47. S.D.T. is a Senior Lecturer supported with funding from Leukemia and Lymphoma Research.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/path.453

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Oncogenic role of miR155 in anaplastic large cell lymphoma lacking the t(2;5) translocation

Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, nonHodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosminanaplastic lymphoma tyrosine kinase (NPMALK) fusion protein (ALCL ALK+). However, little is known about the molecular features and tumour drivers in ALKnegative ALCL (ALCL ALK), which is characterized by a worse prognosis. We found that ALCL ALK, in contrast to ALCL ALK+, lymphomas display high miR155 expression. Consistent with this, we observed an inverse correlation between miR155 promoter methylation and miR155 expression in ALCL. However, no direct effect of the ALK kinase on miR155 levels was observed. Ago2 immunoprecipitation revealed miR155 as the most abundant miRNA, and enrichment of target mRNAs C/EBP and SOCS1. To investigate its function, we overexpressed miR155 in ALCL ALK+ cell lines and demonstrated reduced levels of C/EBP and SOCS1. In murine engraftment models of ALCL ALK, we showed that antimiR155 mimics are able to reduce tumour growth. This goes handinhand with increased levels of cleaved caspase3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR155 induces IL22 expression and suppresses the C/EBP target IL8. These data suggest that miR155 can act as a tumour driver in ALCL ALK and blocking miR155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1). © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.(VLID)484329

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Bionomics and distribution of the stag beetle, Lucanus cervus (L.) across Europe

1. The European stag beetle, Lucanus cervus, is thought to be widely distributed across its range, but a detailed description of its occurrence is lacking. 2. Researchers in 41 countries were contacted and information sought on various life history characteristics of the insect. Data on adult body size were collected from seven countries. 3. Habitat associations differ between the United Kingdom and mainland Europe. Larvae are most commonly associated with oak, but the duration of the larval stage and the number of instars varies by up to 100% across Europe. 4. Adult size also varies; beetles from Spain, Germany, and the Netherlands are larger than those from Belgium or the UK. In the former countries, populations are composed mainly of large individuals, while in the UK, the majority of individuals are relatively small. Allometric relations between mandible size and total body length differ in Germany compared with the rest of Europe. 5. Distribution maps of the insect, split into records pre- and post-1970, from 24 countries are presented. While these inevitably suffer from recorder bias, they indicate that in only two countries, Croatia and Slovakia, does the insect seem to be increasing in range. 6. Our data suggest that the insect may be in decline across Europe, most likely due to habitat loss, and that conservation plans need to be produced that focus on the biology of the insect in the local area