Algorithmically Reconstructed Molecular Pathways as the New Generation of Prognostic Molecular Biomarkers in Human Solid Cancers.

Individual gene expression and molecular pathway activation profiles were shown to be effective biomarkers in many cancers. Here, we used the human interactome model to algorithmically build 7470 molecular pathways centered around individual gene products. We assessed their associations with tumor type and survival in comparison with the previous generation of molecular pathway biomarkers (3022 "classical" pathways) and with the RNA transcripts or proteomic profiles of individual genes, for 8141 and 1117 samples, respectively. For all analytes in RNA and proteomic data, respectively, we found a total of 7441 and 7343 potential biomarker associations for gene-centric pathways, 3020 and 2950 for classical pathways, and 24,349 and 6742 for individual genes. Overall, the percentage of RNA biomarkers was statistically significantly higher for both types of pathways than for individual genes (p < 0.05). In turn, both types of pathways showed comparable performance. The percentage of cancer-type-specific biomarkers was comparable between proteomic and transcriptomic levels, but the proportion of survival biomarkers was dramatically lower for proteomic data. Thus, we conclude that pathway activation level is the advanced type of biomarker for RNA and proteomic data, and momentary algorithmic computer building of pathways is a new credible alternative to time-consuming hypothesis-driven manual pathway curation and reconstruction.

Distinct Traits of Structural and Regulatory Evolutional Conservation of Human Genes with Specific Focus on Major Cancer Molecular Pathways.

The evolution of protein-coding genes has both structural and regulatory components. The first can be assessed by measuring the ratio of non-synonymous to synonymous nucleotide substitutions. The second component can be measured as the normalized proportion of transposable elements that are used as regulatory elements. For the first time, we characterized in parallel the regulatory and structural evolutionary profiles for 10,890 human genes and 2972 molecular pathways. We observed a ~0.1 correlation between the structural and regulatory metrics at the gene level, which appeared much higher (~0.4) at the pathway level. We deposited the data in the publicly available database RetroSpect. We also analyzed the evolutionary dynamics of six cancer pathways of two major axes: Notch/WNT/Hedgehog and AKT/mTOR/EGFR. The Hedgehog pathway had both components slower, whereas the Akt pathway had clearly accelerated structural evolution. In particular, the major hub nodes Akt and beta-catenin showed both components strongly decreased, whereas two major regulators of Akt TCL1 and CTMP had outstandingly high evolutionary rates. We also noticed structural conservation of serine/threonine kinases and the genes related to guanosine metabolism in cancer signaling: GPCRs, G proteins, and small regulatory GTPases (Src, Rac, Ras); however, this was compensated by the accelerated regulatory evolution.

Evaluation of the Behavior of Carbon Short Fiber Reinforced Concrete (CSFRC) Based on a Multi-Sensory Experimental Investigation and a Numerical Multiscale Approach.

Carbon fiber reinforcement used in concrete has become a remarkable alternative to steel fibers. Admixing short fibers to fresh concrete and processing the material with a 3D printer leads to an orientation of fibers and a material with high uniaxial strength properties, which offers an economic use of fibers. To investigate its mechanical behavior, the material is subjected to flexural and tensional tests, combining several measuring techniques. Numerical analysis complements this research. Computed tomography is used with several post-processing algorithms for separating matrix and fibers. This helps to validate fiber alignment and serves as input data for numerical analysis with representative volume elements concatenating real fiber position and orientation with the three-dimensional stress tensor. Flexural and uniaxial tensional tests are performed combining multiple measuring techniques. Next to conventional displacement and strain measuring methods, sound emission analysis, in terms of quantitative event analysis and amplitude appraisal, and also high-resolution digital image correlation accompany the tests. Due to the electrical conductibility of carbon fibers, the material's resistivity could be measured during testing. All sensors detect the material's degradation behavior comparably, showing a strain-hardening effect, which results from multiple, yet locally restricted and distributed, microcracks arising in combination with plastic deformation.