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BACKGROUND: Sorafenib is the most widely used systematic therapy drug for treating unresectable hepatocellular carcinoma (HCC) but showed dissatisfactory efficacy in clinical applications. OBJECTIVE: We conducted a combinational quantitative small-molecule high-throughput screening (qHTS) to identify potential candidates to enhance the treatment effectiveness of sorafenib. METHODS: First, using a Hep3B human HCC cell line, 7051 approved drugs and bioactive compounds were screened, then the primary hits were tested with/ without 0.5μM sorafenib respectively, the compound has the half maximal inhibitory concentration (IC(50)) shift value greater than 1.5 was thought to have the synergistic effect with sorafenib. Furthermore, the MEK inhibitor PD198306 was selected for the further mechanistic study. RESULTS: 12 effective compounds were identified, including kinase inhibitors targeting MEK, AURKB, CAMK, ROCK2, BRAF, PI3K, AKT and EGFR, as well as a μ-opioid receptor agonist and a L-type calcium channel blocker. The mechanistic research of the combination of sorafenib plus PD198306 showed that the two compounds synergistically inhibited MEK-ERK and mTORC1–4EBP1, and induced apoptosis in HCC cells, which can be attributed to the transcriptional and posttranslational regulation of MCL-1 and BIM. CONCLUSION: Small-molecule qHTS identifies MEK inhibitor PD1938306 as a potent sorafenib enhancer, together with several novel combination strategies that are valuable for further studies.

We investigate how firms and markets adapt to trademark protection, an extensively used but under-examined form of IP protection to address asymmetric information, by exploring a historical precedent: China's trademark law of 1923. Exploiting unique, newly digitized firm-employee and firm-agent datasets from Shanghai in 1872-1941, we show that the trademark law, established as an unanticipated and Western-disapproved response to end foreign privileges in China, shaped firm dynamics and relationships on all sides of trade-mark conflicts. Western firms with greater dependence on trademark protection grew and raised brand investment, while Japanese businesses, most frequently accused of counterfeiting, contracted despite attempts to build their own brands. The trademark law also fostered relationships with domestic intermediaries, both within and outside the boundaries of Western firms, and the growth of the Chinese intermediary sector. At the market level, the trademark law did not reduce competition or raise brand prices, leading to a coexistence of trademarks and competitive markets and ultimately gains in consumer welfare. A comparison with previous attempts by foreign powers-such as extraterritorial rights and bilateral treaties-shows that the alternative institutions were broadly unsuccessful. *Omnia Juncta in Uno ("All Joined in One") was the Latin motto on the municipal seal of the Shanghai International Settlement (1843-1941) and signified the joint governance of foreign powers in the settlement.