Ultimate strength

Concern for the ductile behaviour of ships and offshore structures and their structural components under ultimate conditions. Attention shall be given to the influence of fabrication imperfections and in-service damage and degradation on reserve strength

Epigenetics and the estrogen receptor

The position effect variegation in Drosophila and Schizosaccharomyces pombe, and higher-order chromatin structure regulation in yeast, is orchestrated by modifier genes of the Su(var) group, (e.g., histone deacetylases ([HDACs]), protein phosphatases) and enhancer E(Var) group (e.g., ATP [adenosine 5\u27-triphosphate]-dependent nucleosome remodeling proteins). Higher-order chromatin structure is regulated in part by covalent modification of the N-terminal histone tails of chromatin, and histone tails in turn serve as platforms for recruitment of signaling modules that include nonhistone proteins such as heterochromatin protein (HP1) and NuRD. Because the enzymes governing chromatin structure through covalent modifications of histones (acetylation, methylation, phosphorylation, ubiquitination) can also target nonhistone substrates, a mechanism is in place by which epigenetic regulatory processes can affect the function of these alternate substrates. The posttranslational modification of histones, through phosphorylation and acetylation at specific residues, alters chromatin structure in an orchestrated manner in response to specific signals and is considered the basis of a histone code. In an analogous manner, specific residues within transcription factors form a signaling module within the transcription factor to determine genetic target specificity and cellular fate. The architecture of these signaling cascades in transcription factors (SCITs) are poorly understood. The regulation of estrogen receptor (ERalpha) by enzymes that convey epigenetic signals is carefully orchestrated and is reviewed here

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

Scantling Optimization of Ship Structures Considering Fatigue at the Early Design Stage

peer reviewedABSTRACT: Fatigue aspects are leading criterion for the scantling optimization of ships structures. LBR-5 software is an integrated package which performs, at the early design stage, cost and/or weight optimization of ships structures (scantling). This software takes into account structural constraints (yielding, buckling, displacement, ultimate strength). Until now, the fatigue failure issue was not implicitly included in the optimization loop. At the early design stage, limited information and details are available. Therefore simplified methods have to be applied. LBR-5 software provides the nominal stress, so chosen procedure uses the nominal stress and the Miner’s rule. This approach requires a library of stress concentration factors for predefined typical structural details. The goal of the present work is to develop a tool for fatigue assessment that can be integrated on LBR5 optimization process, to realize global optimization taking into account the fatigue issues. Until now, the integration of the fatigue tool is not finished. Only fatigue verification on the optimized structure is possible. On the present paper, the procedure adopted is presented and a longitudinal scantling of the mid-ship section of a LNG is optimized with LBR-5. Production cost is considered as objective functions. The optimized scantling is checked by the fatigue tool. The fatigue criterion is not respected on some panels. Corrections are performed on these panels to have an optimized scantling without fatigue problems