Levels of DNA methylation vary at CpG sites across the BRCA1 promoter, and differ according to triple negative and "BRCA-like" status, in both blood and tumour DNA

Triple negative breast cancer is typically an aggressive and difficult to treat subtype. It is often associated with loss of function of the BRCA1 gene, either through mutation, loss of heterozygosity or methylation. This study aimed to measure methylation of the BRCA1 gene promoter at individual CpG sites in blood, tumour and normal breast tissue, to assess whether levels were correlated between different tissues, and with triple negative receptor status, histopathological scoring for BRCA-like features and BRCA1 protein expression. Blood DNA methylation levels were significantly correlated with tumour methylation at 9 of 11 CpG sites examined (p<0.0007). The levels of tumour DNA methylation were significantly higher in triple negative tumours, and in tumours with high BRCA-like histopathological scores (10 of 11 CpG sites; p<0.01 and p<0.007 respectively). Similar results were observed in blood DNA (6 of 11 CpG sites; p<0.03 and 7 of 11 CpG sites; p<0.02 respectively). This study provides insight into the pattern of CpG methylation across the BRCA1 promoter, and supports previous studies suggesting that tumours with BRCA1 promoter methylation have similar features to those with BRCA1 mutations, and therefore may be suitable for the same targeted therapies

Silyl Hydrides of Tantalum Supported by Cyclopentadienyl-imido Ligand Sets: Syntheses, X-ray, NMR, and DFT Studies

Reactions of the imido complex Cp(ArN)Ta(PMe 3) 2 (1, Ar = 2,6-diisopropylphenyl) with silanes afford the silyl hydrides Cp(ArN)Ta(PMe 3)(H)(SiR nCl 3-n) (2b-e) and Cp(ArN)Ta(PMe 3)(H)(SiPhMeH) (2a) as the first kinetic products. However, the hydride compounds Cp(ArN)Ta(PMe 3)(H)(SiR nCl 3-n) are metastable and, first, rearrange in the presence of phosphine to the chlorides Cp(ArN)Ta(PMe 3)(Cl)(SiHR nCl 2-n) (5) and then decompose to Cp(ArN)Ta(PMe 3)(Cl)(H) (4) and eventually to Cp(ArN)Ta(PMe 3)Cl 2 (3). Complexes with a smaller Ar' substituent at nitrogen (Ar′ = 2,6-dimethylphenyl) react faster, as do more Lewis acidic silanes. The occurrence of interligand hypervalent interactions in the tantalum complexes Cp(ArN)Ta(PMe 3)(H)(SiR nCl 3-n) has been revealed by X-ray structure analysis, DFT calculations, and the experimental determination of the sign of the coupling constant J(Si-H). The J(Si-H) was found to be negative for Cp(ArN)Ta(PMe 3)(H)(SiMe nCl 3-n) (J(Si-H) = -40 Hz for n = 1; J(Si-H) = -50 Hz for n = 0), indicative of the presence of Si-H bonding, but positive for Cp(ArN)Ta(PMe 3)(H)(SiMeHPh) (J(Si-H) = +14 Hz), suggesting the absence of direct Si-H interactions. A DFT study of the mechanism of silane coupling with the model imido complex Cp(MeN)Ta(PMe 3) 2 established the feasibility of the direct addition of silanes HSiMe nCl 3-n (n = 1-3) to the imido group to give the adduct Cp(MeN{→SiR 3-H})Ta(PMe 3) 2, as previously found in the related niobium chemistry. © 2008 American Chemical Society

Non-innocent behaviour of imido ligands in the reactions of silanes with half-sandwich imido complexes of Nb and V: a silane/imido coupling route to compounds with nonclassical Si--H interactions.

Reactions of imido complexes [M(Cp)(=NR')(PR''3)2] (M=V, Nb) with silanes afford a plethora of products, depending on the nature of the metal, substitution at silicon and nitrogen and the steric properties of the phosphine. The main products are [M(Cp)(=NR')(PR3)(H)(SiRnCl3-n)] (M=V, Nb; R'=2,6-diisopropylphenyl (Ar), 2,6-dimethylphenyl (Ar')), [Nb(Cp)(=NR')(PR''3)(H)(SiPhR2)] (R2=MeH, H2), [Nb(Cp)(==NR')(PR''3)(Cl)(SiHRnCl2-n)] and [Nb(Cp)(eta 3-N(R)SiR2--H...)(PR''3)(Cl)]. Complexes with the smaller Ar' substituent at nitrogen react faster, as do more acidic silanes. Bulkier groups at silicon and phosphorus slow down the reaction substantially. Kinetic NMR experiments supported by DFT calculations reveal an associative mechanism going via an intermediate N-silane adduct [Nb(Cp){=N(--&gt;SiHClR2)R'}(PR''3)2] bearing a penta-coordinate silicon centre, which then rearranges into the final products through a Si--H or Si--Cl bond activation process. DFT calculations show that this imido-silane adduct is additionally stabilized by a Si--HM agostic interaction. Si--H activation is kinetically preferred even when Si--Cl activation affords thermodynamically more stable products. The niobium complexes [NbCp(=NAr)(PMe3)(H)(SiR2Cl)] (R=Ph, Cl) are classical according to X-ray studies, but DFT calculations suggest the presence of interligand hypervalent interactions (IHI) in the model complex [Nb(Cp) (==NMe)(PMe3)(H)(SiMe2Cl)]. The extent of Si--H activation in the beta-Si--HM agostic complexes [Cp{eta 3-N(R')SiR2--H}M(PR''3)(Cl)] (R''=PMe3, PMe2Ph) primarily depends on the identity of the ligand trans to the Si--H bond. A trans phosphine leads to a stronger Si--H bond, manifested by a larger J(Si--H) coupling constant. The Si--H activation diminishes slightly when a less basic phosphine is employed, consistent with decreased back-donation from the metal

Measurement of the total photoabsorption cross section on a proton in the energy range 600–1500 MeV at the GRAAL

The total photoabsorption cross section on a free proton was measured at the GRAAL facility in the energy range Eγ = 600−1500MeV.The large-aperture LAGRANγE detector and a liquid hydrogen target were used in the experiment performed with a back-scattered Compton gamma beam. To improve the accuracy, two alternative methods were employed. First, a subtraction method of using emptytarget measurements allowed the cross section σtot to be evaluated directly because of a low level of the electromagnetic background. Second, an algorithm for evaluating σtot on the basis of summing the dominating partial cross sections was developed. Experimental results obtained for σtot by the two methods are compared with existing data