Gastric cancer(GC)is a prevalent and devastating disease with a poor prognosis.The lack of biomarkers for early detection and effective targeted therapeutics for GC patients represents two major challenges.Through iso...Gastric cancer(GC)is a prevalent and devastating disease with a poor prognosis.The lack of biomarkers for early detection and effective targeted therapeutics for GC patients represents two major challenges.Through isobaric tags for relative and absolute quantitation(iTRAQ)coupled with liquid chromatography-tandem mass spectrometry(LC-MS/MS)phosphoproteomic analysis of 14 GC and gastric epithelial cell lines,we discovered the discoidin domain receptor tyrosine kinase 1(DDR1)as a top potential drug target out of 40 tyrosine kinases detected along with over 1000 phosphoproteins profiled.The DDR1 protein and mRNA levels were upregulated in GC cells concurrent with DDR1 gene amplification.Immunohistochemistry staining of more than 200 clinical samples revealed that DDR1 was overexpressed in approximately 41%and 48%of the intestinal and diffuse types of GC cases,respectively,compared with only 3.5%in normal tissues.Higher DDR1 expression was associated with poor prognosis.In cellular models,DDR1 overexpression led to accelerated proliferation,invasion,and malignant transformation,putatively via inhibition of the Hippo pathway and consequent activation of YAP-TEAD target gene expression.Notably,DDR1-overexpressing GC cells exhibited high vulnerability to selective DDR1 inhibitors.The present study provides preclinical support for the application of DDR1-selective inhibitors in DDR1-overexpressing GC.展开更多
The mixed-valent Pb3Rh7O15 undergoes a Verwey-type transition at Tv≈180K, below which the development of Rh3＋3＋/Rh4＋4＋ charge order induces an abrupt conductor-to-insulator transition in resistivity. Here we inve...The mixed-valent Pb3Rh7O15 undergoes a Verwey-type transition at Tv≈180K, below which the development of Rh3＋3＋/Rh4＋4＋ charge order induces an abrupt conductor-to-insulator transition in resistivity. Here we investigate the effect of pressure on the Verwey-type transition of Pb3Rh7O15 by measuring its electrical resistivity under hydrostatic pressures up to 8GPa with a cubic anvil cell apparatus. We find that the application of high pressure can suppress the Verwey-type transition around 3GPa, above which a metallic state is realized at temperatures below ～70K, suggesting the melting of charge order by pressure. Interestingly, the low-temperature metallic region shrinks gradually upon further increasing pressure and disappears completely at P〉7GPa, which indicates that the charge carriers in Pb3Rh7O15 undergo a reentrant localization under higher pressures. We have constructed a temperature-pressure phase diagram for Pb3Rh7O15 and compared to that of Fe3O4, showing an archetype Verwey transition.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.32170738)the National Medical Research Council of Singapore(Grant No.NMRC/CBRG/0013/2012).
文摘Gastric cancer(GC)is a prevalent and devastating disease with a poor prognosis.The lack of biomarkers for early detection and effective targeted therapeutics for GC patients represents two major challenges.Through isobaric tags for relative and absolute quantitation(iTRAQ)coupled with liquid chromatography-tandem mass spectrometry(LC-MS/MS)phosphoproteomic analysis of 14 GC and gastric epithelial cell lines,we discovered the discoidin domain receptor tyrosine kinase 1(DDR1)as a top potential drug target out of 40 tyrosine kinases detected along with over 1000 phosphoproteins profiled.The DDR1 protein and mRNA levels were upregulated in GC cells concurrent with DDR1 gene amplification.Immunohistochemistry staining of more than 200 clinical samples revealed that DDR1 was overexpressed in approximately 41%and 48%of the intestinal and diffuse types of GC cases,respectively,compared with only 3.5%in normal tissues.Higher DDR1 expression was associated with poor prognosis.In cellular models,DDR1 overexpression led to accelerated proliferation,invasion,and malignant transformation,putatively via inhibition of the Hippo pathway and consequent activation of YAP-TEAD target gene expression.Notably,DDR1-overexpressing GC cells exhibited high vulnerability to selective DDR1 inhibitors.The present study provides preclinical support for the application of DDR1-selective inhibitors in DDR1-overexpressing GC.
基金Supported by the"Shi-Pei Ji Hua",the National Science Foundation of China under Grant Nos 51402019 and 11574377the Beijing Natural Science Foundation under Grant No 2152011+5 种基金the National Basic Research Program of China under Grants No2014CB921500the Strategic Priority Research ProgramKey Research Program of Frontier Sciences of the Chinese Academy of Sciences under Grant Nos XDB07020100 and QYZDB-SSW-SLH013the U.S.Department of Energy,Office of Science,Basic Energy Sciences,Materials Sciences and Engineering Divisionthe CEMNSF MRSEC under Grant No DMR-1420451
文摘The mixed-valent Pb3Rh7O15 undergoes a Verwey-type transition at Tv≈180K, below which the development of Rh3＋3＋/Rh4＋4＋ charge order induces an abrupt conductor-to-insulator transition in resistivity. Here we investigate the effect of pressure on the Verwey-type transition of Pb3Rh7O15 by measuring its electrical resistivity under hydrostatic pressures up to 8GPa with a cubic anvil cell apparatus. We find that the application of high pressure can suppress the Verwey-type transition around 3GPa, above which a metallic state is realized at temperatures below ～70K, suggesting the melting of charge order by pressure. Interestingly, the low-temperature metallic region shrinks gradually upon further increasing pressure and disappears completely at P〉7GPa, which indicates that the charge carriers in Pb3Rh7O15 undergo a reentrant localization under higher pressures. We have constructed a temperature-pressure phase diagram for Pb3Rh7O15 and compared to that of Fe3O4, showing an archetype Verwey transition.
