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Receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) play crucial roles in many human malignancies. Numerous drugs have been developed against kinase center of MET or HGF-mediated activation; however, the outcomes in patients are not so promising. Increasing evidence show that MET has kinase-independent effects on tumorigenesis and dissemination, which explains the low efficacy in kinase inhibition-based strategy. VHH is the recombinant variable region of Camelid heavy-chain antibody. As a nanoscale antigen-binding unit, VHH has become an appealing drug candidate in cancer therapy. In our study, we choose a novel strategy to construct an anti-MET VHH pool against the whole ecto-domain of MET. Comparing to monoclonal antibody or single VHH, the anti-MET VHH pool strongly promotes MET degradation through Clathrin-dependent endo-lysosomal pathway. Thus, the anti-MET VHH pool not only blocks kinase activity of MET, but also reduces protein level of MET. As a consequence, anti-MET VHH pool dramatically suppresses cancer cell proliferation, viability, and colony formation in vitro, and inhibits tumorigenesis and growth in mice. Taken together, VHH pool-based strategy greatly improves MET-targeted therapeutic effects on cancer.

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Grouting is always used in mine water plugging, reinforcement, and other disaster prevention projects. The diffusion mechanism of slurry in fractured rock is affected by geological environment and slurry performance, which should be revealed and characterized better. Based on the two-phase flow diffusion theory, a slurry diffusion model considering flowing water condition was established for a blocking area of a fracture zone in one case from China. The feasibility of two-phase flow model in grouting diffusion calculation was analyzed. The diffusion model in dynamic water environment was studied, and the diffusion range varying with time in the grouting area of Zhangji Coal Mine was explored. The optimization method of multi grouting holes was put forward, and the influence of water flowing was discussed. The results show that the slurry diffusion calculated by the two-phase flow model was feasible and consistent with the experimental study. The dynamic water can change the conventional circular diffusion state of slurry, but its pattern was oval and leaf type. There were different penetration distances in directions, and typical grouting voids were made on the side and upstream. When the single-hole grouting was carried out, the predetermined value can be achieved in the height range, but it was only about 15 m on the side because of the water flowing, which cannot meet the requirements. The optimization scheme of grouting was put forward, which adopted multiple grouting holes in the long side, and grouting in different directions and periods to avoid the possible problems of multihole intersection. The rationality and effectiveness of the proposed optimization method were verified through the calculation of water yield and analysis of cement composition from the drilling core in the grouted zone. In the grouting process, the water flowing has double effects, which has a significant role in promoting and scouring along the flow direction, but there is a significant weakness in the side diffusion. It is very important to realize the rational use of the dynamic water through the optimization scheme. This study is an important basic work of grouting mechanism, and it is expected to promote the development of grouting technology and application of two-phase fluid-solid coupling theory.

The evolution characteristics of high-energy and low-energy microfracture events play an important role in the brittle failure mechanism of rock and reasonable microseismic (MS) monitoring and acoustic emission (AE) monitoring. The bimodal distribution (BMD) model is commonly used to observe the evolution characteristics of high-energy and low-energy MS events; however, its precise mechanism remains unclear. The evolution characteristics of high-energy and low-energy microfracture events are assessed in this study based on a BMD model. MS monitoring results from the No. 22517 working face of the Dongjiahe Coal Mine are studied, and AE monitoring results of a biaxial compression experiment of a granite specimen are analyzed. High-energy MS events in the No. 22517 working face are found to be generated by an increase in the failure scale of the overlying rock mass upon exiting the insufficient mining stage and entering the sufficient mining stage. The change characteristics of the high-energy AE hits are positively correlated with crack evolution characteristics in the granite specimen and negatively correlated with changes in the Gutenberg-Richter b value. A precise high-energy and low-energy AE hit evolution mechanism is analyzed based on the microscopic structure of the granite specimen. Similarities and differences between high-energy MS events and low-energy AE hits are determined based on these results. Both are found to have bimodal characteristics; an increase in the failure scale is identified as the root cause of the high-energy component. The bimodal distribution of AE hits is far less obvious than that of MS events.