PIM protein family, short-lived serine/threonine kinases (PIM1, PIM2 and PIM3), are weak oncogenes but contribute to tumorigenesis as cancer targets. Thus, design of a novel pan-PIM inhibitor is still a challenge for current cancer drug discovery. Herein, we used a Naïve Bayesian model to construct the PIM network and identified Bad and Hsp90 to interact with PIMs. Then, we screened a series of candidate small-molecule compounds targeting PIMs, and subsequently synthesized a novel small-molecule compound PI003 with remarkable anti-proliferative activities in cervical cancer cells. Moreover, we found that PI003 induced apoptosis via the death-receptor and mitochondrial pathways by targeting PIMs and affecting Bad and Hsp90. Combined with microRNA microarray analyses, we demonstrated that some microRNAs such as miR-1296 and miR-1299 could affect PIM1-STAT3 pathway in PI003-induced apoptosis. Finally, we reported that PI003 had remarkable anti-tumor activity and apoptosis-inducing effect in in vivo mouse model. In conclusion, these results demonstrate that PI003, as a novel synthesized pan-PIM inhibitor, induces the death-receptor and mitochondrial apoptosis involved in microRNA regulation, and also possessed remarkable anti-tumor activity and apoptosis-inducing effect in vivo. Thus, these findings would shed light on discovering more potential new small-molecule pan-PIM inhibitors in future cervical cancer therapy.

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The channel slope in the red-bed soft rock area is prone to instability and collapse due to the influence of the channel flow movement, rainfall, weathering, and other factors. Under long-term operation conditions, the sediment stripped from the channel side wall is liable to silt along the process of water flow transportation in the channel, which seriously leads to elevation of the channel bottom, increase of channel width, and reduction of the horseway, which affect the normal water conveyance and operation safety of channels. In view of the collapse and instability of Zhetang diversion irrigation channel project in Xinjiang hydraulic project, through on-site sampling and indoor rock mechanics test, the strength mechanical parameters of slope rock samples are obtained, and the indoor rheological test is carried out, and the triaxial rheological law is obtained. Under different levels of stress, the axial creep strain accounts for more than 50% of the total axial strain, indicating that the rheological effect of sample rock is obvious. Based on the strength parameters of rock samples, a numerical model is established. The stability of red-bed soft rock channel bank slope is studied by using the strength reduction method of finite element method. The seepage field of channel slope under conventional working conditions is analyzed, and the slope stability under different operating conditions is compared and calculated. The results show that the slope stability safety factor of Zhetang diversion irrigation channel slope is 1.60 under conventional working conditions and 1.33 under check working conditions, which are greater than the recommended value in the specification.

The polymer cutoff wall offers the benefits of causing little disturbance to the dam body, being convenient and economical to construct and practical to use, and possessing good resistance to seismic shocks and cracks. It has been widely used to prevent seepage and to reinforce dikes and dams. However, the polymer cutoff wall is a concealed underground structure, and nondestructive testing methods to ensure its integrity are not yet mature. This paper describes a modal analysis of polymer cutoff wall models with different damage scenarios to investigate the feasibility of nondestructive testing of the polymer cutoff wall based on vibration theory. The dynamic characteristics of the first three natural frequencies of the wall and their mode shapes show that horizontal direction damage and centrally located partial damage have a noticeable impact on the dynamic characteristics of the wall, indicating that nondestructive testing based on vibration theory is useful to test for horizontal damage and moderate damage located centrally in the wall.