Immer im kreis und kein schritt zuriick: Die EU zwischen externer Demokratiefórderung und interner Konsolidierung

"Dem Anschein nach ist nicht viel geschehen: Das Europäische Parlament hat im Juni 2008 eine Stellungnahme zu der Mitteilung der Europäischen Kommission über die Erweiterungspolitik abgegeben. Durch diesen Beschluss wird der Lauf der Dinge nicht verändert, zumal das Europäische Parlament im Hinblick auf die Erweiterung der Europäischen Union nur über eingeschränkte Eingriffs- und Steuerungsmöglichkeiten verfügt. Dennoch lohnt es sich, das Dokument aufmerksam zu lesen. Besser als jede andere europäische Institution hat das Parlament das Ohr an der Basis der europäischen Bevölkerung und drückt die Stimmungen und Wünsche aus, die den Bürgern Europas zu eigen sind."(...

FOXA1 repression is associated with loss of BRCA1 and increased promoter methylation and chromatin silencing in breast cancer

FOXA1 expression correlates with the breast cancer luminal subtype and patient survival. RNA and protein analysis of a panel of breast cancer cell lines revealed that BRCA1 deficiency is associated with the downregulation of FOXA1 expression. Knockdown of BRCA1 resulted in the downregulation of FOXA1 expression and enhancement of FOXA1 promoter methylation in MCF-7 breast cancer cells, whereas the reconstitution of BRCA1 in Brca1-deficent mouse mammary epithelial cells (MMECs) promoted Foxa1 expression and methylation. These data suggest that BRCA1 suppresses FOXA1 hypermethylation and silencing. Consistently, the treatment of MMECs with the DNA methylation inhibitor 5-aza-2'-deoxycitydine induced Foxa1 mRNA expression. Furthermore, treatment with GSK126, an inhibitor of EZH2 methyltransferase activity, induced FOXA1 expression in BRCA1-deficient but not in BRCA1-reconstituted MMECs. Likewise, the depletion of EZH2 by small interfering RNA enhanced FOXA1 mRNA expression. Chromatin immunoprecipitation (ChIP) analysis demonstrated that BRCA1, EZH2, DNA methyltransferases (DNMT)1/3a/3b and H3K27me3 are recruited to the endogenous FOXA1 promoter, further supporting the hypothesis that these proteins interact to modulate FOXA1 methylation and repression. Further co-immunoprecipitation and ChIP analysis showed that both BRCA1 and DNMT3b form complexes with EZH2 but not with each other, consistent with the notion that BRCA1 binds to EZH2 and negatively regulates its methyltransferase activity. We also found that EZH2 promotes and BRCA1 impairs the deposit of the gene silencing histone mark H3K27me3 on the FOXA1 promoter. These associations were validated in a familial breast cancer patient cohort. Integrated analysis of the global gene methylation and expression profiles of a set of 33 familial breast tumours revealed that FOXA1 promoter methylation is inversely correlated with the transcriptional expression of FOXA1 and that BRCA1 mutation breast cancer is significantly associated with FOXA1 methylation and downregulation of FOXA1 expression, providing physiological evidence to our findings that FOXA1 expression is regulated by methylation and chromatin silencing and that BRCA1 maintains FOXA1 expression through suppressing FOXA1 gene methylation in breast cancer.Oncogene advance online publication, 22 December 2014; doi:10.1038/onc.2014.421.published_or_final_versio

Vitamin D3 suppresses morphological evolution of the cribriform cancerous phenotype

Development of cribriform morphology (CM) heralds malignant change in human colon but lack of mechanistic understanding hampers preventive therapy. This study investigated CM pathobiology in three-dimensional (3D) Caco-2 culture models of colorectal glandular architecture, assessed translational relevance and tested effects of 1,25(OH)2D3,theactive form of vitamin D. CM evolution was driven by oncogenic perturbation of the apical polarity (AP) complex comprising PTEN, CDC42 and PRKCZ (phosphatase and tensin homolog, cell division cycle 42 and protein kinase C zeta). Suppression of AP genes initiated a spatiotemporal cascade of mitotic spindle misorientation, apical membrane misalignment and aberrant epithelial configuration. Collectively, these events promoted “Swiss cheese-like” cribriform morphology (CM) comprising multiple abnormal “back to back” lumens surrounded by atypical stratified epithelium, in 3D colorectal gland models. Intestinal cancer driven purely by PTEN-deficiency in transgenic mice developed CM and in human CRC, CM associated with PTEN and PRKCZ readouts. Treatment of PTEN-deficient 3D cultures with 1,25(OH)2D3 upregulated PTEN, rapidly activated CDC42 and PRKCZ, corrected mitotic spindle alignment and suppressed CM development. Conversely, mutationally-activated KRAS blocked1,25(OH)2D3 rescue of glandular architecture. We conclude that 1,25(OH)2D3 upregulates AP signalling to reverse CM in a KRAS wild type (wt), clinically predictive CRC model system. Vitamin D could be developed as therapy to suppress inception or progression of a subset of colorectal tumors

The characterisation of the transcriptional regulation of FOXC1 by BRCA1 and its role in the oncogenesis of basal-like breast cancer

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Immer im kreis und kein schritt zuriick: Die EU zwischen externer Demokratiefórderung und interner Konsolidierung

"Dem Anschein nach ist nicht viel geschehen: Das Europäische Parlament hat im Juni 2008 eine Stellungnahme zu der Mitteilung der Europäischen Kommission über die Erweiterungspolitik abgegeben. Durch diesen Beschluss wird der Lauf der Dinge nicht verändert, zumal das Europäische Parlament im Hinblick auf die Erweiterung der Europäischen Union nur über eingeschränkte Eingriffs- und Steuerungsmöglichkeiten verfügt. Dennoch lohnt es sich, das Dokument aufmerksam zu lesen. Besser als jede andere europäische Institution hat das Parlament das Ohr an der Basis der europäischen Bevölkerung und drückt die Stimmungen und Wünsche aus, die den Bürgern Europas zu eigen sind."(...

The influence of zinc on properties of common cements

W pracy omówiono wyniki badań dotyczących wpływu cynku na właściwości cementów. Celem artykułu było wyjaśnienie niektórych ważnych problemów związanych ze zwiększonym dodatkiem cynku, a także różnic wynikających z dodawania związków cynku bezpośrednio do cementu oraz do zestawu surowcowego do produkcji klinkieru portlandzkiego. Omówiono także wpływ cynkano-glinianów wapnia, które powstają w klinkierze ze zwiększoną zawartością cynku w składzie surowcowym, na właściwości cementów. Przedstawiono również opis ostatnich badań dotyczących granicznej zawartości cynku (dodawanego wraz z surowcami), po przekroczeniu której następuje gwałtowne pogorszenie właściwości cementu.In the paper the results of recent studies of the zinc influence on cement properties are presented. The aim of this work was clarification of some important issues associated with higher zinc content, and also the explanation of the differences, which result from the way of zinc introduction i.e. addition of zinc compounds directly to cement and to the raw mix to Portland clinker production. The influence of zinc phases, which form in clinker with higher zinc content in raw mix, on cement properties was also discussed. Description of recent studies concerning the limit zinc content (added with raw materials), which exceeding causes rapid deterioration of cement properties

The influence of the usage of secondary fuels for Portland clinker production on the emission value of heavy metals from cement and concrete

Abstract The influence of secondary fuels components used for Portland clinker production on emission value of heavy metals is presented in this paper. Analyses and studies of hazardous substances emission (heavy metals) from cements and concretes were conducted according to standards developed by Technical Committee CEN TC 351. The contents of following heavy metals were analyzed: Cr, Zn, Cd, Pb, Co, Ni, Mn, Cu, Sr, Ba and P in secondary fuels used by cement industry in Poland for Portland clinker production. Total heavy metal contents in cements and their leaching from cements CEM I were studied. Leaching of heavy metals from CEM I-based concretes to environment was also determined. Obtained tests results allow to conclude that changes in technology of cement clinker production leading to the usage of waste materials and secondary fuels does not cause an increase in heavy metals emission in level, which requires qualifying cement as material, which has to be regularly controlled for harmfulness on man and natural environment.</jats:p