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5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent for breast cancer. However, acquired chemoresistance leads to a loss of its efficacy; methods to reverse are urgently needed. Some studies have shown that pyrotinib, an ErbB receptor tyrosine kinase inhibitor, is effective against HER2+ breast cancer. However, whether pyrotinib sensitizes 5-FU-resistant breast cancer cells to 5-FU is unknown. We hypothesized that the combination of pyrotinib and 5-FU would show synergistic antitumor activity, and pyrotinib could reverse 5-FU resistance in HER2+ breast cancer cells in vitro and in vivo. Our data showed that pyrotinib inhibited the growth of 5-FU-resistant SKBR-3/FU and MDA-MB-453/FU cell lines and the parental cell lines. 5-FU remarkably suppressed the growth of SKBR-3 and MAD-MB-453 cells. However, SKBR-3/FU and MAD-MB-453/FU cells showed resistance to 5-FU. A combination of pyrotinib and 5-FU resulted in the synergistic inhibition of the growth of the 5-FU-resistant SKBR-3/FU and MDA-MB-453/FU cell lines and the parental cell lines. Pyrotinib decreased significantly the IC50 values of 5-FU and the thymidylate synthase (TS) mRNA expression levels in the 5-FU-resistant SKBR-3/FU and MDA-MB-453/FU cell lines and the parental cell lines and increased significantly the intracellular concentration of 5-FU in SKBR-3/FU and MDA-MB-453/FU cells. In addition, pyrotinib reduced the ABCG2 mRNA and protein expression levels in SKBR-3/FU and MDA-MB-453/FU cells and downregulated the protein expression levels of pAKT, pHER2, and pHER4 in all four cell lines. After TS or ABCG2 in 5-FU-resistant breast cancer cells was knocked down, the sensitivity of SKBR-3/FU and MDA-MB-453/FU cells to 5-FU was restored. Moreover, in vivo experiments demonstrated that pyrotinib in combination with 5-FU more effectively inhibited SKBR-3/FU tumor growth than either pyrotinib or 5-FU alone. In conclusion, our findings suggest that pyrotinib could restore sensitivity of 5-FU-resistant HER2+ breast cancer cells to 5-FU through downregulating the expression levels of TS and ABCG2.

Small farms are the mainstay of maize production in China. Its productivity is relatively low despite large farm inputs and the associated environmental footprints. Here, we studied public–private partnership (PPP) model for sustainable intensification of maize production to achieve co‐benefits of food security and environmental sustainability. The PPP model enabled the development of an effective partnership by bringing complementary skills, knowledge, proprietary products and technologies, and resources of public research community and private enterprises to create a new, operational maize farming system in China. We conducted on‐farm research with farmer participation in four major maize‐growing regions spanning temperate to sub‐tropical zones in China for 2 years. The PPP model achieved 78.7% of maize yield potential compared with 61.8% realized in smallholder farm (SHF) (11.0 Mg ha−1 vs. 8.6 Mg ha−1). Overall, environmental externalities of PPP were up to 32.7% lower than that of SHF, depending on the region studied. PPP significantly reduced reactive nitrogen losses by 31.3%–35.5% compared with SHF in both years. There was no significant difference between PPP and SHF for greenhouse gas emission in 2018, but it was significantly lower in PPP (19%) compared to SHF in 2019. Similarly, PPP significantly reduced soil acidification potential (by 10.1%–42.2%) and eutrophication of waterbodies (21.5%) in comparison to SHF. Overall, the net ecosystem economic budget increased 277 USD ha−1 with PPP. The PPP model provides new insights into improving food security and ecosystem and economic budget. As a logical progression to our research, future work should focus on (a) the reasons for the persistence of inter‐regional yield gap in PPP model and (b) to gain a better understanding of socioeconomic drivers critical for successful PPP in different maize‐growing regions.