21 research outputs found
The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies
Insulinâlike growth factors (IGFs) and insulinâlike growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the crossâsectional associations of these exposures with circulating concentrations of IGFs (IGFâI and IGFâII) and IGFBPs (IGFBPâ1, IGFBPâ2 and IGFBPâ3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22â89âyears from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBPâ1 and IGFBPâ2 and lower concentrations of IGFâI, IGFâII and IGFBPâ3. Higher body mass index was associated with lower concentrations of IGFBPâ1 and IGFBPâ2. Taller height was associated with higher concentrations of IGFâI and IGFBPâ3 and lower concentrations of IGFBPâ1. Smokers had higher concentrations of IGFBPâ1 and IGFBPâ2 and lower concentrations of IGFBPâ3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGFâII and lower concentrations of IGFâI and IGFBPâ2. African Americans had lower concentrations of IGFâII, IGFBPâ1, IGFBPâ2 and IGFBPâ3 and Hispanics had lower IGFâI, IGFâII and IGFBPâ3 than nonâHispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk
Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials
An amendment to this paper has been published and can be accessed via the original article
Factor VII mutant V154G models a zymogen-like form of factor VIIa.
Proteolytic cleavage of the peptide bond between Arg(152) and Ile(153) converts the procoagulant protein Factor VII (FVII) to an activated two-chain form (FVIIa). The formation of a salt bridge between Ile(153) and Asp(343) drives the conversion of FVIIa from being zymogen-like to the active form. In the present paper, we describe the novel FVII mutant V154G (Val(154)-->Gly mutation; residue 17 in the chymotrypsin numbering system), found in three FVII-deficient patients, which models a zymogen-like form of FVIIa. Recombinant V154G FVIIa, although normally cleaved, shows markedly reduced activity towards peptidyl substrate and undetectable activity towards macromolecular substrates. Susceptibility of Ile(153) to chemical modification, in either the presence or the absence of tissue factor (TF), suggests that the reduced V154G FVIIa activity is caused by impaired salt-bridge formation, thus resulting in a zymogen-like FVIIa form. The TF-mediated protection from chemical modification of V154A indicated that Gly(154) is responsible for this peculiar feature, and suggests that this region, proximal to the heavy chain N-terminus, is directly involved in the conversion of FVII into FVIIa. V154G FVII was exploited to study the FVII-TF interaction, together with three additional FVII variants that were expressed to serve as models for different FVII forms. The comparison of binding affinities of full-length TF after relipidation in L-alpha-phosphatidylcholine for the zymogen FVII (Arg(152)-->Gln, K (d)=1.04+/-0.27 nM), inactive FVIIa (Ser(344)-->Ala, K (d)=0.27+/-0.06 nM) and a zymogen-like FVIIa (V154G, K (d)=1.15+/-0.16 nM) supports the hypothesis that preferential binding of TF to active FVIIa is insufficient to drive the 10(5)-fold enhancement of FVIIa activity. In addition, the inability of V154G FVIIa to accommodate an inhibitor in the active site, indicating an improperly shaped specificity pocket, would explain the low activity of the zymogen-like form of FVIIa, which is predominant in the absence of TF