Brain metastasis (BM) is a major cause of mortality in small-cell lung cancer (SCLC) patients; however, the molecular pathway of SCLC BM remains largely unknown because of a lack of investigation. Here we screen the levels of some candidate-soluble factors in the serum of SCLC patients and find that SCLC patients with high levels of placental growth factor (PLGF) are prone to BM. Using in vitro blood-brain barrier model, we show that PLGF derived from SCLC cells triggers vascular endothelial growth factor receptor-1-Rho-extracellular regulated protein kinase 1/2 signaling axis activation, results in disassembly of tight junction in brain endothelial cells and promotes SCLC cell transendothelial migration. Furthermore, the downregulation of PLGF suppresses SCLC cell metastasis to the brain in an experimental BM model. These data suggest that PLGF is a potential signature of SCLC BM and a prospective therapeutic target for SCLC BM.
The prediction of a forming limit diagram (FLD) for aluminium alloy sheet using finite element analysis without implementing pre-defined geometrical imperfections or material imperfections is studied. The limit strains of the FLD are determined by applying a new proposed localization criterion in the dome stretching test. The elements just outside the necking area, where their major and minor principal strains have no simultaneous change after localized necking happens, are chosen as the reference elements for measurement of limit strains. Simulations are carried out for various strain paths ranging from balanced biaxial stretching to uniaxial stretching. The predicted FLD of AA 5182-O is compared with an experimentally determined FLD and very good agreement is achieved. It is demonstrated that FLDs can be predicted by the finite element method without requiring any assumed geometric or material imperfections in the numerical model.
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