ABSTRACT
To determine a reasonable control strategy for deep buried soft rock roadways, a study on deformation and failure characteristics was carried out. The Weibull distribution damage variable was introduced to construct a damage-softening model considering the lateral deformation of the rock mass, and the functional relationship between the model parameters F0 and m and the confining pressure were discussed. The nonlinear fitting method was used to correct the model parameters. Using the model, the failure characteristics of deep buried soft rock roadways were analyzed. A comprehensive and step-by-step joint support control strategy was proposed based on the numerical simulation results. The research results showed that the damage-softening model curve established could genuinely reflect the whole process of mudstone failure. The apparent stress concentration phenomenon occurred in the surrounding rock. The surrounding rock deformation showed that roadway floors had larger plastic failure areas than sides and vaults. The plastic failure depth could reach 2.45 m. After a comprehensive and step-by-step joint support control strategy was adopted, the deformation rate of the roadway at the section was less than 0.1 mm/d. The optimized support scheme can effectively improve the stability of the roadway.
ABSTRACT
Melanoma is a particularly virulent human cancer, due to its resistance to conventional treatments and high frequency of metastasis. Melanomas contain a fraction of cells, the melanoma-initiating cells (MICs), responsible for tumor propagation and relapse. Identification of the molecular pathways supporting MICs is, therefore, vital for the development of targeted treatments. One factor produced by melanoma cells and their microenvironment, insulin-like growth factor-1 (IGF- 1), is linked to epithelial-mesenchymal transition (EMT) and stemness features in several cancers.We evaluated the effect of IGF-1 on the phenotype and chemoresistance of B16-F10 cells. IGF-1 inhibition in these cells prevented malignant cell proliferation, migration and invasion, and lung colony formation in immunodeficient mice. IGF-1 downregulation also markedly inhibited EMT, with low levels of ZEB1 and mesenchymal markers (N-cadherin, CD44, CD29, CD105) associated with high levels of E-cadherin and MITF, the major regulator of melanocyte differentiation. IGF-1 inhibition greatly reduced stemness features, including the expression of key stem markers (SOX2, Oct-3/4, CD24 and CD133), and the functional characteristics of MICs (melanosphere formation, aldehyde dehydrogenase activity, side population). These features were associated with a high degree of sensitivity to mitoxantrone treatment.In this study, we deciphered new connections between IGF-1 and stemness features and identified IGF-1 as instrumental for maintaining the MIC phenotype. The IGF1/IGF1-R nexus could be targeted for the development of more efficient anti-melanoma treatments. Blocking the IGF-1 pathway would improve the immune response, decrease the metastatic potential of tumor cells and sensitize melanoma cells to conventional treatments.
Subject(s)
Biomarkers, Tumor/metabolism , Cell Proliferation , Epithelial-Mesenchymal Transition , Insulin-Like Growth Factor I/metabolism , Melanoma, Experimental/metabolism , Neoplastic Stem Cells/metabolism , Skin Neoplasms/metabolism , Animals , Antineoplastic Agents/pharmacology , Biomarkers, Tumor/genetics , Cell Line, Tumor , Cell Movement , Drug Resistance, Neoplasm , Epithelial-Mesenchymal Transition/drug effects , Female , Insulin-Like Growth Factor I/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Melanoma, Experimental/drug therapy , Melanoma, Experimental/genetics , Melanoma, Experimental/secondary , Mice, Inbred C57BL , Mitoxantrone/pharmacology , Neoplasm Invasiveness , Neoplastic Stem Cells/pathology , Neoplastic Stem Cells/radiation effects , Signal Transduction , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Time Factors , Transfection , Tumor MicroenvironmentABSTRACT
Modified melanoma B16 cells inhibited in their IGF-1 expression (B16MOD), on the contrary to the IGF-1 fully expressed parental wild-type (B16WT) counterpart, were shown to stimulate humoral as well as cellular immune responses. Among humoral components, the neutralizing and complement-fixing antibodies of IgM and essentially IgG2 (a+b) isotypes exhibited in vitro and in vivo effects upon tumour growth, while the IgG1 antibody isotype promoted enhanced tumour proliferation. As for the cellular immunity, it was found that the T CD8(+) lymphocyte subpopulation remained the main potent and long lasting immune active effector regulating tumour growth.
