To evaluate whether genotyping for 18 prostate cancer founder variants is helpful in identifying high-risk individuals and for determining optimal screening regimens.
A serum PSA level was measured ...and a digital rectal examination (DRE) was performed on 2907 unaffected men aged 40-90. Three hundred and twenty-three men with an elevated PSA (≥4 ng ml⁻¹) or an abnormal DRE underwent a prostate biopsy. All men were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA and C61G), for four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395 and I157T), for one allele in NBS1 (657del5), for one allele in HOXB13 (G84E), and for nine low-risk single-nucleotide polymorphisms (SNPs).
On the basis of an elevated PSA or an abnormal DRE, prostate cancer was diagnosed in 135 of 2907 men (4.6%). In men with a CHEK2 missense mutation I157T, the cancer detection rate among men with an elevated PSA or an abnormal DRE was much higher (10.2%, P=0.0008). The cancer detection rate rose with the number of SNP risk genotypes observed from 1.2% for men with no variant to 8.6% for men who carried six or more variants (P=0.04). No single variant was helpful on its own in predicting the presence of prostate cancer, however, the combination of all rare mutations and SNPs improved predictive power (area under the curve=0.59; P=0.03).
These results suggest that testing for germline CHEK2 mutations improves the ability to predict the presence of prostate cancer in screened men, however, the clinical utility of incorporating DNA variants in the screening process is marginal.
To establish the contribution of eight founder alleles in three DNA damage repair genes (BRCA1, CHEK2 and NBS1) to prostate cancer in Poland, and to measure the impact of these variants on survival ...among patients.
Three thousand seven hundred fifty men with prostate cancer and 3956 cancer-free controls were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA, C61G), four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395, I157T), and one allele in NBS1 (657del5).
The NBS1 mutation was detected in 53 of 3750 unselected cases compared with 23 of 3956 (0.6%) controls (odds ratio (OR)=2.5; P=0.0003). A CHEK2 mutation was seen in 383 (10.2%) unselected cases and in 228 (5.8%) controls (OR=1.9; P<0.0001). Mutation of BRCA1 (three mutations combined) was not associated with the risk of prostate cancer (OR=0.9; P=0.8). In a subgroup analysis, the 4153delA mutation was associated with early-onset (age ≤ 60 years) prostate cancer (OR=20.3, P=0.004). The mean follow-up was 54 months. Mortality was significantly worse for carriers of a NBS1 mutation than for non-carriers (HR=1.85; P=0.008). The 5-year survival for men with an NBS1 mutation was 49%, compared with 72% for mutation-negative cases.
A mutation in NBS1 predisposes to aggressive prostate cancer. These data are relevant to the prospect of adapting personalised medicine to prostate cancer prevention and treatment.
Different ternary carbide phases, namely Ti3AlC2, Ti3AlC, and Ti2AlC, were successfully synthesized in a self‐sustaining regime. Direct reactions among elemental powders of titanium, aluminum, and ...carbon are strongly exothermic, and the resulting reaction products consist of binary carbides and they are partially molten. The use of TiAl, instead of elemental titanium and aluminum, significantly reduces the combustion temperature. As a result, ternary titanium aluminum carbide phases are formed. In addition, the combustion‐synthesized products are not sintered and easy to deagglomerate. Reaction conditions and X‐ray diffraction patterns of different ternary phases formed in a self‐sustaining regime are presented.
The paper is focused on application of sensitivity methods to analysis of signaling pathway models. Two basic methods are compared: local, based on standard sensitivity functions, and global, based ...on Sobol indices. Firstly, a general outline of modeling of signaling pathways by means of ordinary differential equations is briefly described. Afterwards, the methods of sensitivity analysis, known from literature, are introduced and illustrated with a simple example of a dynamical system of the second order. Subsequently, the analysis of the p53/Mdm2 regulatory module, which is a key element of any pathway involving p53 protein, is presented. The results of this analysis suggest that no single method should be chosen for investigation of any signaling pathway model but several of them should be applied to answer important questions about sources of heterogeneity in cells behavior, robustness of signaling pathways and possible molecular drug targets.
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