APPLICATION OF MULTICRITERIAL NUMERICAL OPTIMISATION IN GEOTECHNICAL ENGINEERING

Geotechnical constructions are sophisticated structures due to the non-linear soil behaviour and the complex soil-structure interaction, which entails great exigencies on the liable engineer during the design process. The process can be schematised as a difficult and, depending on the opportunities and skills of the processor more or less innovative, creative and heuristic search for one or a multiple of defined objectives under given boundary conditions. Wholistic approaches including numerical optimisation which support the constructing engineer in this task do not currently exist. Abstract problem formulation is not state of the art; commonly parameter studies are bounded by computational effort. Thereby potential regarding cost effectiveness, construction time, load capacity and/or serviceability are often used insufficiently. This paper describes systematic approaches for comprehensive optimisation of selected geotechnical constructions like combined pile raft foundations and quay wall structures. Several optimisation paradigms like the mono- and the multi-objective optimisation are demonstrated and their use for a more efficient design concerning various intentions is shown in example. The optimisation is implemented by using Evolutionary Algorithms. The applicability to geotechnical real world problems including nonlinearities, discontinuities and multi-modalities is shown. The routines are adapted to common problems and coupled with conventional analysis procedures as well as with numerical calculation software based on the finite element method. Numerical optimisation of geotechnical design using efficient algorithms is able to deliver highly effective solutions after investing more effort into the parameterization of the problem. Obtained results can be used for realizing different constructions near the stability limit, visualizing the sensitivity regarding the construction parameters or simply procuring more effective solutions

Mutations in the WTX - gene are found in some high-grade microsatellite instable (MSI-H) colorectal cancers

Background: Genetically, colorectal cancers (CRCs) can be subdivided into tumors with chromosomal instability (CIN) or microsatellite instability (MSI). In both types of CRCs genes that are involved in the degradation of beta-CATENIN are frequently mutated. Whereas in CIN CRCs APC (Adenomatous Polyposis Coli) is affected in most cases, high grade MSI (MSI-H) CRCs frequently display mutations in various genes, like the APC-, AXIN2- or CTNNBI (beta-CATENIN) gene itself. Recently in Wilms tumors, WTX (Wilms tumor gene on the X-chromosome) was discovered as another gene involved in the destruction of beta-CATENIN. As the WTX-gene harbors a short T(6)-microsatellite in its N-terminal coding region, we hypothesized that frameshift-mutations might occur in MSI-H CRCs in the WTX gene, thus additionally contributing to the stabilization of beta-CATENIN in human CRCs. Methods: DNA was extracted from 632 formalin-fixed, paraffin-embedded metastatic CRCs (UICCIV) and analyzed for MSI-H by investigating the stability of the highly sensitive microsatellite markers BAT25 and BAT26 applying fluorescence capillary electrophoresis (FCE). Then, in the MSI-H cases, well described mutational hot spot regions from the APC-, AXIN2- and CTNNBI genes were analyzed for genomic alterations by didesoxy-sequencing while the WTX T(6)-microsatellite was analyzed by fragment analysis. Additionally, the PCR products of T(5)-repeats were subcloned and mutations were validated using didesoxy-sequencing. Furthermore, the KRAS and the BRAF proto-oncogenes were analyzed for the most common activating mutations applying pyro-sequencing. mRNA expression of WTX from MSI-H and MSS cases and a panel of colorectal cancer cell lines was investigated using reverse transcription (RT-) PCR and FCE. Results: In our cohort of 632 metastatic CRCs (UICCIV) we identified 41 MSI-H cases (6.5%). Two of the 41 MSI-H cases (4.8%) displayed a frameshift mutation in the T(6)-repeat resulting in a T(5) sequence. Only one case, a male patient, expressed the mutated WTX gene while being wild type for all other investigated genes. Conclusion: Mutations in the WTX-gene might compromise the function of the beta-CATENIN destruction complex in only a small fraction of MSI-H CRCs thus contributing to the process of carcinogenesis