Tracing cytotoxic effects of small organic Se species in human liver cells back to total cellular Se and Se metabolites.

Small selenium (Se) species play a major role in the metabolism, excretion and dietary supply of the essential trace element selenium. Human cells provide a valuable tool for investigating currently unresolved issues on the cellular mechanisms of Se toxicity and metabolism. In this study, we developed two isotope dilution inductively coupled plasma tandem-mass spectrometry based methods and applied them to human hepatoma cells (HepG2) in order to quantitatively elucidate total cellular Se concentrations and cellular Se species transformations in relation to the cytotoxic effects of four small organic Se species. Species- and incubation time-dependent results were obtained: the two major urinary excretion metabolites trimethylselenonium (TMSe) and methyl-2-acetamido-2-deoxy-1-seleno-ß-d-galactopyranoside (SeSugar 1) were taken up by the HepG2 cells in an unmodified manner and did not considerably contribute to the Se pool. In contrast, Se-methylselenocysteine (MeSeCys) and selenomethionine (SeMet) were taken up in higher amounts, they were largely incorporated by the cells (most likely into proteins) and metabolized to other small Se species. Two new metabolites of MeSeCys, namely γ-glutamyl-Se-methylselenocysteine and Se-methylselenoglutathione, were identified by means of HPLC-electrospray-ionization-Orbitrap-MS. They are certainly involved in the (de-)toxification modes of Se metabolism and require further investigation.

Exon-level expression analyses identify MYCN and NTRK1 as major determinants of alternative exon usage and robustly predict primary neuroblastoma outcome.

BACKGROUND: Using mRNA expression-derived signatures as predictors of individual patient outcome has been a goal ever since the introduction of microarrays. Here, we addressed whether analyses of tumour mRNA at the exon level can improve on the predictive power and classification accuracy of gene-based expression profiles using neuroblastoma as a model. METHODS: In a patient cohort comprising 113 primary neuroblastoma specimens expression profiling using exon-level analyses was performed to define predictive signatures using various machine-learning techniques. Alternative transcript use was calculated from relative exon expression. Validation of alternative transcripts was achieved using qPCR- and cell-based approaches. RESULTS: Both predictors derived from the gene or the exon levels resulted in prediction accuracies >80% for both event-free and overall survival and proved as independent prognostic markers in multivariate analyses. Alternative transcript use was most prominently linked to the amplification status of the MYCN oncogene, expression of the TrkA/NTRK1 neurotrophin receptor and survival. CONCLUSION: As exon level-based prediction yields comparable, but not significantly better, prediction accuracy than gene expression-based predictors, gene-based assays seem to be sufficiently precise for predicting outcome of neuroblastoma patients. However, exon-level analyses provide added knowledge by identifying alternative transcript use, which should deepen the understanding of neuroblastoma biology.

[Does migration from high and intermediate endemic regions increase the prevalence of hepatitis B infection in Germany?]. / Erhöhen Migrationen aus hohen und mittleren Endemiegebieten die Hepatitis B-Prävalenz in Deutschland? Epidemiologische Schätzung der HBsAg-Prävalenz bei verschiedenen erwachsenen Bevölkerungsgruppen.

BACKGROUND AND OBJECTIVE: Germany is one of the low endemic areas for hepatitis B. There are 7,3 million foreign citizens and 3,2 million migrants from the former USSR and Eastern Europe with German roots, the "Resettlers" (Aussiedler), who migrated to Germany mostly from countries with moderate or high HBsAg prevalence. The aim of this study was to determine the HBsAg prevalence in adult foreign citizens and resettlers compared with that among the adult German population. METHODS: Adult foreign citizens and resettlers were categorized according to their country of origin into groups with low, intermediate or high HBsAg prevalence, using data from the WHO. Statistics of the Federal Office for Statistics, the Federal Office for Administration and the Federal Ministry of the Interior were used for the demographic analysis. The number of chronic HBsAg carriers for the different population groups and the whole population was then calculated. RESULTS: 84% of the adult migrant population in Germany migrated from countries with intermediate and high HBsAg endemicity. For 2003 we calculated 503 040 HBsAg carriers in Germany. 42% of these have a migratory background, even though migrants represent only 12.7% of the whole population. The risk for chronic infection with HBsAg is 7.1 (4.8-13.2) for the resettlers and is 4.3 (3.0-8.1) times higher for foreign citizens than for the German population. CONCLUSIONS: These remarkable differences in prevalence make it important that migrants and their close contacts be vaccinated properly, pregnant women be included in screening programs and cases of chronic hepatitis B be treated adequately.