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您的检索式：作者名="Haoxin FAN"
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| 1 | Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations显示文摘Various c-mesenchymal-to-epithelial transition(c-MET) inhibitors are effective in the treatment of non-small cell lung cancer;however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras(PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC_(50) values and achieved picomolar DC_(50) values and>99% of maximum degradation(D_(max)) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion.Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-MET^(Y1230H) and c-MET^(D1228N) mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations. | Pengyun Li Changkai Jia Zhiya Fan Xiaotong Hu Wenjuan Zhang Ke Liu Shiyang Sun Haoxin Guo Ning Yang Maoxiang Zhu Xiaomei Zhuang Junhai Xiao Zhibing Zheng Song Li | 2023 | Acta Pharmaceutica Sinica B2023，13，6： | 0 |
| 2 | Main environmental drivers of abundance,diversity and community structure of comammox Nitrospira in paddy soils显示文摘The recently discovered complete ammonia oxidizers comammox Nitrospira contain clades A and B that can establish an independent one-step nitrification process;however,little is known about their environmental drivers or habitat distributions in agricultural soils.Previous studies on comammox Nitrospira in paddy soils have mainly focused on small-scale samples,and there is a lack of multisite research on comammox Nitrospira in paddy soils.In this study,we conducted a survey of 36 paddy soils to understand the community structure,abundance,and diversity of comammox Nitrospira and the degree to which they are affected by environmental factors at a large scale.Comammox Nitrospira were found to be widely distributed among the paddy soils.The abundance of comammox Nitrospira clade A was mostly lower than that of clade B,whereas its diversity was mostly higher than that of clade B.Correlation analysis showed that multiple factors affected(P<0.05)the abundance of comammox Nitrospira,including soil pH,organic matter,total carbon,and total nitrogen,latitude,mean annual temperature,and mean annual precipitation.Moreover,there was a clear relationship between the comammox Nitrospira community and habitat,indicating that some amplicon sequence variants(ASVs)had a unique dominant position in specific habitats.Phylogenetic analysis showed that the ASVs of comammox Nitrospira clade A clustered with the known sequences in the paddy soils and were significantly different from the known sequences in other habitats,which may be related to the unique paddy field habitat.In contrast,comammox Nitrospira clade B showed no clear habitat dependence.These results support the wide distribution and high abundance of comammox Nitrospira in paddy soils and provide novel insights into nitrogen cycling and nutrient management in agricultural ecosystems. | Fuyun GAO Yaying LI Haoxin FAN Jiantao XUE Huaiying YAO | 2023 | Pedosphere2023，33，5： | 0 |
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