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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. β-Catenin (CTNNB1)-mutated HCC represents 30% of cases of the disease with no precision therapeutics available. Using chemical libraries derived from clinical multi-kinase inhibitor (KI) scaffolds, we screened HCC organoids to identify WNTinib, a KI with exquisite selectivity in CTNNB1-mutated human and murine models, including patient samples. Multiomic and target engagement analyses, combined with rescue experiments and in vitro and in vivo efficacy studies, revealed that WNTinib is superior to clinical KIs and inhibits KIT/mitogen-activated protein kinase (MAPK) signaling at multiple nodes. Moreover, we demonstrate that reduced engagement on BRAF and p38α kinases by WNTinib relative to several multi-KIs is necessary to avoid compensatory feedback signaling-providing a durable and selective transcriptional repression of mutant β-catenin/Wnt targets through nuclear translocation of the EZH2 transcriptional repressor. Our studies uncover a previously unknown mechanism to harness the KIT/MAPK/EZH2 pathway to potently and selectively antagonize CTNNB1-mutant HCC with an unprecedented wide therapeutic index.

In the past, the studies on the operation characteristics of urban vehicles were mostly aimed at single type of vehicles, which was difficult to reflect the differences and comparative characteristics between current taxis and online ride-hailing. In order to accurately analyze the operation efficiency and spatial-temporal changes of urban operating vehicles, the GPS trajectory data of taxis and online car-hailing in Xiamen and Baidu Interest Point (POI) data are taken as the research objects. On the basis of constructing the operation characteristic index system, the weighted time capacity utilization index is introduced, and the operation efficiency and spatial-temporal changes of two types of operating vehicles at different time points, different administrative regions and different functional areas are compared. The results show that the two types of vehicles have obvious and unbalanced daily change trends, but the proportion of orders in different administrative areas and different functional areas is roughly the same. The operation intensity of taxis is significantly higher than that of online ride-hailing, but the service scope of online ride-hailing is much larger than that of taxis. The weighted time capacity utilization rate of taxis is significantly related to the ratio of GDP and taxi number in the administrative area. Therefore, the planning and management of taxis and online car-hailing should be strengthened in Tongan District and other economically underdeveloped areas. The research results can provide reference and data support for the supervision and scientific services of traditional taxis and online car-hailing. [ABSTRACT FROM AUTHOR]

Body channel communication (BCC) which uses the human body as the communication channel has shown better energy efficiency and security compared with air channel communication. This article presents a simple, stable, and high transfer rate BCC technique using Manchester encoding, capacitive termination, and digital signal transfer operation. Manchester encoding is used to realize the spectrum migration of the baseband signal, and digital signal transmission simplifies system design and improves signal stability. The chip is fabricated in 65-nm technology. The experimental results show that the proposed transceiver achieved the highest data rates of 60 Mbps and the measured RX sensitivity is -64dBm. And the chip is also used to set up a multi-sensor nodes communication system to realize the data interaction between one hub and eight slave sensors utilizing the human body as the communication medium.

This study was to investigate the potential molecular mechanisms underlying the Cathepsin S (CTSS) silencing induced apoptosis of Hepatocellular Carcinoma (HCC) cells with lentivirus-mediated RNA interference. Real-time quantitative PCR and western blot assay were performed to detect the mRNA and protein expression of CTSS, respectively, in 13 HCC cell lines with different metastatic potentials. Results showed MHCC97-H cells had the highest CTSS expression. Therefore, MHCC97-H cells were used in following experiments. Then, lentivirus-mediated RNAi was employed to silence CTSS expression (shCTSS). Annexin V/FITC staining showed NF-κB was activated in shCTSS cells treated with conditioned medium from shCTSS-PAR2 cells. This implies a probable positive correlation between PAR2 and CTSS. In addition, results demonstrated CTSS induced apoptosis of HCC cells and increased their chemosensitivity via regulating NF-κB and activating cleaved caspase-3. Our results indicate that CTSS silencing by lentivirus mediated RNAi can significantly induce apoptosis and chemosensitivity of MHCC97-H cells. This provides an attractive anti-cancer strategy and a novel strategy for the treatment of human HCC.