miR171 belongs to a highly conserved and ubiquitously expressed micro RNA gene family across species that play a critical role in controlling plant growth and development through the regulation of the miR171-SCL(scare...miR171 belongs to a highly conserved and ubiquitously expressed micro RNA gene family across species that play a critical role in controlling plant growth and development through the regulation of the miR171-SCL(scarecrow-like proteins)module.There is limited research available on the evolutionary relationship and functional diversification of miR171 members.In this study,we identified eight miR171 genes in the mulberry genome by bioinformatics analysis that were subsequently used to compare the evolutionary levels and explore abiotic stress mechanisms mediated by mno-miR171s(Morus notabilis miR171s).The results of phylogenetic analysis showed that the mature mno-miR171 sequences have strong sequence conservation,but their critical sites also exhibit high variation leading to functional diversification.Through quantitative real-time PCR,the expression profile of each mno-miR171 was analyzed under different stress treatments.All mno-miR171s,apart from mnomiR171h,were found to be significantly up-regulated under salt and drought stress conditions.The target genes of mno-miR171a namely,Morus020885 and Morus011800,were predicted and verified using the plural RNA method.5-rapid amplification of complementary DNA ends assays further to reveal that the target genes could be degraded by mno-miR171a post-transcriptionally.Overexpression of mno-miR171a in Arabidopsis improved the percentage of seed germination when the seeds were grown in NaCl-and mannitol-containing media.Transgenic plants were observed to grow better under drought conditions.The expression of various stress genes was significantly higher in transgenic plants than in wild type,except ERF11.Taken together,our study confirmed that mno-miR171a enhanced plant resistance to adverse stress environments via the regulation of the SCL targets.展开更多
Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significant...Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significantly expanded treatment options for NSCLC patients.These alterations include MET exon 14 skipping mutations(MET exon 14 skipping),MET gene amplifications,MET point mutations(primarily kinase domain mutations),and MET protein overexpression.Accurate identification of these alterations and appropriate selection of patient populations and targeted therapies are essential for improving clinical outcomes.The East China Lung Cancer Group,Youth Committee(ECLUNG YOUNG,Yangtze River Delta Lung Cancer Cooperation Group)has synthesized insights from China’s innovative drug development landscape and clinical practice to formulate an expert consensus on the diagnosis and treatment of NSCLC patients with MET alterations.This consensus addresses key areas,such as optimal testing timing,testing methods,testing strategies,quality control measures,and treatment approaches.By offering standardized recommendations,this guidance aims to streamline diagnostic and therapeutic processes and enhance clinical decision-making for NSCLC with MET alterations.展开更多
The phytohormone abscisic acid(ABA)plays pivotal roles in triggering stomatal closure and facilitating adaptation of plants to drought stress.Hydrogen sulfide(H2S),a small signaling gas molecule,is involved in ABA-dep...The phytohormone abscisic acid(ABA)plays pivotal roles in triggering stomatal closure and facilitating adaptation of plants to drought stress.Hydrogen sulfide(H2S),a small signaling gas molecule,is involved in ABA-dependent stomatal closure.However,how H2S regulates ABA signaling remains largely unclear.Here,we show that ABA induces the production of H2S catalyzed by L-CYSTEINE DESULFHYDRASE1(DES1)in guard cells,and H2S in turn positively regulates ABA signaling through persulfidation of Open Stomata 1(OST1)/SNF1-RELATED PROTEIN KINASE2.6(SnRK2.6).Two cysteine(Cys)sites,Cys131 and Cys137,which are exposed on the surface of SnRK2.6 and close to the activation loop,were identified to be persulfidated,which promotes the activity of SnRK2.6 and its interaction with ABA response element-binding factor 2(ABF2),a transcription factor acting downstream of ABA signaling.When Cys131,Cys137,or both residues in SnRK2.6 were substituted with serine(S),H2S_induced SnRK2_6 activity and SnRK2.6-ABF2 interaction were partially(SnRK2.6c131s and SnRK2.6c137S)or completely(SnRK2.6c131sc137S)compromised.Introduction of SnRK2.6c131s,SnRK2.6c137S,or SnRK2.6c131sc137S into the ost1-3 mutant could not rescue the mutant phenotype:less sensitivity to ABA-and H2S-induced stomatal closure and Ca2+influx as well as increased water loss and decreased drought tolerance.Taken together,our study reveals a novel post-translational regulatory mechanism of ABA signaling whereby H2S persulfidates SnRK2.6 to promote ABA signaling and ABA-induced stomatal closure.展开更多
Post-translational modifications (PTMs) regulate the activity of SNF1-RELATED PROTEIN KINASE2.6 (SnRK2.6), including phosphorylation and persulfidation. Here, we report how persulfidations and phosphorylations of SnRK...Post-translational modifications (PTMs) regulate the activity of SNF1-RELATED PROTEIN KINASE2.6 (SnRK2.6), including phosphorylation and persulfidation. Here, we report how persulfidations and phosphorylations of SnRK2.6 influence each other. The persulfidation of cysteine C131/C137 altered SnRK2.6 structure, resulted in serine S175 residue more close to aspartic acid D140, who belong to ATP-γ-phosphate proton acceptor may effectively improve the transfer efficiency of phosphate groups to S175, thus persulfidation enhanced the phosphorylation level of S175. S267 and C137 were predicted to lie in close proximity on the protein surface. The phosphorylation status of S267 positively regulated the persulfidation level at C137. Tests of responses of dephosphorylated and depersulfidated mutants to ABA and the H2S-donor NaHS during stomatal closure, water loss, gas-exchange, Ca2+ influx and drought stress revealed that S175/S267-associated phosphorylation and C131/137-associated persulfidation are essential for SnRK2.6 function in vivo. Taken together, we propose a mechanistic model in which certain phosphorylations facilitate persulfidation, which changes SnRK2.6 structure and increases its activity.展开更多
The BRAF gene is an important signaling molecule in human cells that is involved in the regulation of cell growth,differentiation,and survival.When the BRAF gene mutates,it can lead to abnormal activation of the signa...The BRAF gene is an important signaling molecule in human cells that is involved in the regulation of cell growth,differentiation,and survival.When the BRAF gene mutates,it can lead to abnormal activation of the signaling pathway,which promotes cell proliferation,inhibits cell apoptosis,and ultimately contributes to the occurrence and development of cancer.BRAF mutations are widely present in various cancers,including malignant melanoma,thyroid cancer,colorectal cancer,non-small cell lung cancer,and hairy cell leukemia,among others.BRAF is an important target for the treatment of various solid tumors,and targeted combination therapies,represented by BRAF inhibitors,have become one of the main treatment modalities for a variety of BRAF-mutation-positive solid tumors.展开更多
Background:Durvalumab after chemoradiotherapy(CRT)failed to bring survival benefits to patients with epidermal growth factor receptor(EGFR)mutations in PACIFIC study(evaluating durvalumab in patients with stage Ⅲ,unr...Background:Durvalumab after chemoradiotherapy(CRT)failed to bring survival benefits to patients with epidermal growth factor receptor(EGFR)mutations in PACIFIC study(evaluating durvalumab in patients with stage Ⅲ,unresectable NSCLC who did not have disease progression after concurrent chemoradiotherapy).We aimed to explore whether locally advanced inoperable patients with EGFR mutations benefit from tyrosine kinase inhibitors(TKIs)and the optimal treatment regimen.Methods:We searched the PubMed,Embase,the Cochrane Central Register of Controlled Trials,and ClinicalTrials.gov databases from inception to December 31,2022 and performed a meta-analysis based on a Bayesian framework,with progression-free survival(PFS)and overall survival(OS)as the primary endpoints.Results:A total of 1156 patients were identified in 16 studies that included 6 treatment measures,including CRT,CRT followed by durvalumab(CRT-Durva),TKI monotherapy,radiotherapy combined with TKI(RT-TKI),CRT combined with TKI(CRT-TKI),and TKI combined with durvalumab(TKI-Durva).The PFS of patients treated with TKI-containing regimens was significantly longer than that of patients treated with TKI-free regimens(hazard ratio[HR]=0.37,95%confidence interval[CI],0.20–0.66).The PFS of TKI monotherapy was significantly longer than that of CRT(HR=0.66,95%CI,0.50–0.87)but shorter than RT-TKI(HR=1.78,95%CI,1.17–2.67).Furthermore,the PFS of RT-TKI or CRT-TKI were both significantly longer than that of CRT or CRT-Durva.RT-TKI ranked first in the Bayesian ranking,with the longest OS(60.8 months,95%CI=37.2–84.3 months)and the longest PFS(21.5 months,95%CI,15.4–27.5 months)in integrated analysis.Conclusions:For unresectable stage III EGFR mutant NSCLC,RT and TKI are both essential.Based on the current evidence,RT-TKI brings a superior survival advantage,while CRT-TKI needs further estimation.Large randomized clinical trials are urgently needed to explore the appropriate application sequences of TKI,radiotherapy,and chemotherapy.展开更多
Background and Aims:Microvascular invasion(MVI)is a major risk factor for the early recurrence of hepatocel-lular carcinoma(HCC)and it seriously worsens the prog-nosis.Accurate preoperative evaluation of the presence ...Background and Aims:Microvascular invasion(MVI)is a major risk factor for the early recurrence of hepatocel-lular carcinoma(HCC)and it seriously worsens the prog-nosis.Accurate preoperative evaluation of the presence of MVI could greatly benefit the treatment management and prognosis prediction of HCC patients.The study aim was to evaluate the diagnostic performance of the apparent dif-fusion coefficient(ADC),a quantitative parameter for the preoperative diagnosis MVI in HCC patients.Methods:Original articles about diffusion-weighted imaging(DWI)and/or intravoxel incoherent motion(IVIM)conducted on a 3.0 or 1.5 Tesla magnetic resonance imaging(MRI)system indexed through January 17,2021were collected from MED-LINE/PubMed,Web of Science,EMBASE,and the Cochrane Library.Methodological quality was evaluated using Quality Assessment of Diagnostic Accuracy Studies 2(QUADAS-2).The pooled sensitivity,specificity,and summary area un-der the receiver operating characteristic curve(AUROC)were calculated,and meta-regression analysis was per-formed using a bivariate random effects model through a meta-analysis.Results:Nine original articles with a total of 988 HCCs were included.Most studies had low bias risk and minimal applicability concerns.The pooled sensitivity,specificity and AUROC of the ADC value were 73%,70%,and 0.78,respectively.The time interval between the index test and the reference standard was identified as a pos-sible source of heterogeneity by subgroup meta-regression analysis.Conclusions:Meta-analysis showed that the ADC value had moderate accuracy for predicting MVI in HCC.The time interval accounted for the heterogeneity.展开更多
基金supported by the Natural Science Foundation of Hebei Province(Grant No.C2019406113)Hebei Provincial Department of Education(Grant No.QN2020236)Chengde Medical College Youth Foundation(Grant No.201913)。
文摘miR171 belongs to a highly conserved and ubiquitously expressed micro RNA gene family across species that play a critical role in controlling plant growth and development through the regulation of the miR171-SCL(scarecrow-like proteins)module.There is limited research available on the evolutionary relationship and functional diversification of miR171 members.In this study,we identified eight miR171 genes in the mulberry genome by bioinformatics analysis that were subsequently used to compare the evolutionary levels and explore abiotic stress mechanisms mediated by mno-miR171s(Morus notabilis miR171s).The results of phylogenetic analysis showed that the mature mno-miR171 sequences have strong sequence conservation,but their critical sites also exhibit high variation leading to functional diversification.Through quantitative real-time PCR,the expression profile of each mno-miR171 was analyzed under different stress treatments.All mno-miR171s,apart from mnomiR171h,were found to be significantly up-regulated under salt and drought stress conditions.The target genes of mno-miR171a namely,Morus020885 and Morus011800,were predicted and verified using the plural RNA method.5-rapid amplification of complementary DNA ends assays further to reveal that the target genes could be degraded by mno-miR171a post-transcriptionally.Overexpression of mno-miR171a in Arabidopsis improved the percentage of seed germination when the seeds were grown in NaCl-and mannitol-containing media.Transgenic plants were observed to grow better under drought conditions.The expression of various stress genes was significantly higher in transgenic plants than in wild type,except ERF11.Taken together,our study confirmed that mno-miR171a enhanced plant resistance to adverse stress environments via the regulation of the SCL targets.
文摘Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significantly expanded treatment options for NSCLC patients.These alterations include MET exon 14 skipping mutations(MET exon 14 skipping),MET gene amplifications,MET point mutations(primarily kinase domain mutations),and MET protein overexpression.Accurate identification of these alterations and appropriate selection of patient populations and targeted therapies are essential for improving clinical outcomes.The East China Lung Cancer Group,Youth Committee(ECLUNG YOUNG,Yangtze River Delta Lung Cancer Cooperation Group)has synthesized insights from China’s innovative drug development landscape and clinical practice to formulate an expert consensus on the diagnosis and treatment of NSCLC patients with MET alterations.This consensus addresses key areas,such as optimal testing timing,testing methods,testing strategies,quality control measures,and treatment approaches.By offering standardized recommendations,this guidance aims to streamline diagnostic and therapeutic processes and enhance clinical decision-making for NSCLC with MET alterations.
基金the National Natural Science Foundation of China(NSFC 31700445,31400246)Shaanxi Province Natural Science Foundation of China(2018JM3017,2018JQ3020)China Postdoctoral Science Foundation(2018M641022).
文摘The phytohormone abscisic acid(ABA)plays pivotal roles in triggering stomatal closure and facilitating adaptation of plants to drought stress.Hydrogen sulfide(H2S),a small signaling gas molecule,is involved in ABA-dependent stomatal closure.However,how H2S regulates ABA signaling remains largely unclear.Here,we show that ABA induces the production of H2S catalyzed by L-CYSTEINE DESULFHYDRASE1(DES1)in guard cells,and H2S in turn positively regulates ABA signaling through persulfidation of Open Stomata 1(OST1)/SNF1-RELATED PROTEIN KINASE2.6(SnRK2.6).Two cysteine(Cys)sites,Cys131 and Cys137,which are exposed on the surface of SnRK2.6 and close to the activation loop,were identified to be persulfidated,which promotes the activity of SnRK2.6 and its interaction with ABA response element-binding factor 2(ABF2),a transcription factor acting downstream of ABA signaling.When Cys131,Cys137,or both residues in SnRK2.6 were substituted with serine(S),H2S_induced SnRK2_6 activity and SnRK2.6-ABF2 interaction were partially(SnRK2.6c131s and SnRK2.6c137S)or completely(SnRK2.6c131sc137S)compromised.Introduction of SnRK2.6c131s,SnRK2.6c137S,or SnRK2.6c131sc137S into the ost1-3 mutant could not rescue the mutant phenotype:less sensitivity to ABA-and H2S-induced stomatal closure and Ca2+influx as well as increased water loss and decreased drought tolerance.Taken together,our study reveals a novel post-translational regulatory mechanism of ABA signaling whereby H2S persulfidates SnRK2.6 to promote ABA signaling and ABA-induced stomatal closure.
基金This work was supported by the Shaanxi Province Natural Science Foundation of China(2021JZ-14)the National Natural Science Foundation of China(NSFC 31700445)the China Postdoctoral Science Foundation(2018M641022)。
文摘Post-translational modifications (PTMs) regulate the activity of SNF1-RELATED PROTEIN KINASE2.6 (SnRK2.6), including phosphorylation and persulfidation. Here, we report how persulfidations and phosphorylations of SnRK2.6 influence each other. The persulfidation of cysteine C131/C137 altered SnRK2.6 structure, resulted in serine S175 residue more close to aspartic acid D140, who belong to ATP-γ-phosphate proton acceptor may effectively improve the transfer efficiency of phosphate groups to S175, thus persulfidation enhanced the phosphorylation level of S175. S267 and C137 were predicted to lie in close proximity on the protein surface. The phosphorylation status of S267 positively regulated the persulfidation level at C137. Tests of responses of dephosphorylated and depersulfidated mutants to ABA and the H2S-donor NaHS during stomatal closure, water loss, gas-exchange, Ca2+ influx and drought stress revealed that S175/S267-associated phosphorylation and C131/137-associated persulfidation are essential for SnRK2.6 function in vivo. Taken together, we propose a mechanistic model in which certain phosphorylations facilitate persulfidation, which changes SnRK2.6 structure and increases its activity.
基金supported by the Natural Science Foundation of China(grant number 82002456)China Postdoctoral Science Foundation(grant number 2022M723207)+10 种基金the Medical Scientific Research Foundation of Zhejiang Province,China(grant number 2023KY666)Zhejiang Traditional Chinese Medicine Science Fund Project(grant number 2024ZL372)Qiantang Cross Fund Project(grant number 2023-16)National Natural Science Foundation of China of Zhejiang Cancer Hospital Cultivation Project(grant number PY2023006)the Medical Scientific Research Foundation of Zhejiang Province,China(grant number 2024KY812)the Natural Science Foundation of Zhejiang Province(grant number LQ24H160036)Beijing Health Technologies Promotion Program[grant number BHTPP2022041]Peking University Clinical Scientist Training Program and the Fundamental Research Funds for the Central Universities[grant number BMU2024PYJH010]Science Foundation of Peking University Cancer Hospital[grant number PY202333]the Beijing Natural Science Foundation[grant number 7232248]Beijing Hospitals Authority Youth Programme[grant number QML20231902].
文摘The BRAF gene is an important signaling molecule in human cells that is involved in the regulation of cell growth,differentiation,and survival.When the BRAF gene mutates,it can lead to abnormal activation of the signaling pathway,which promotes cell proliferation,inhibits cell apoptosis,and ultimately contributes to the occurrence and development of cancer.BRAF mutations are widely present in various cancers,including malignant melanoma,thyroid cancer,colorectal cancer,non-small cell lung cancer,and hairy cell leukemia,among others.BRAF is an important target for the treatment of various solid tumors,and targeted combination therapies,represented by BRAF inhibitors,have become one of the main treatment modalities for a variety of BRAF-mutation-positive solid tumors.
文摘Background:Durvalumab after chemoradiotherapy(CRT)failed to bring survival benefits to patients with epidermal growth factor receptor(EGFR)mutations in PACIFIC study(evaluating durvalumab in patients with stage Ⅲ,unresectable NSCLC who did not have disease progression after concurrent chemoradiotherapy).We aimed to explore whether locally advanced inoperable patients with EGFR mutations benefit from tyrosine kinase inhibitors(TKIs)and the optimal treatment regimen.Methods:We searched the PubMed,Embase,the Cochrane Central Register of Controlled Trials,and ClinicalTrials.gov databases from inception to December 31,2022 and performed a meta-analysis based on a Bayesian framework,with progression-free survival(PFS)and overall survival(OS)as the primary endpoints.Results:A total of 1156 patients were identified in 16 studies that included 6 treatment measures,including CRT,CRT followed by durvalumab(CRT-Durva),TKI monotherapy,radiotherapy combined with TKI(RT-TKI),CRT combined with TKI(CRT-TKI),and TKI combined with durvalumab(TKI-Durva).The PFS of patients treated with TKI-containing regimens was significantly longer than that of patients treated with TKI-free regimens(hazard ratio[HR]=0.37,95%confidence interval[CI],0.20–0.66).The PFS of TKI monotherapy was significantly longer than that of CRT(HR=0.66,95%CI,0.50–0.87)but shorter than RT-TKI(HR=1.78,95%CI,1.17–2.67).Furthermore,the PFS of RT-TKI or CRT-TKI were both significantly longer than that of CRT or CRT-Durva.RT-TKI ranked first in the Bayesian ranking,with the longest OS(60.8 months,95%CI=37.2–84.3 months)and the longest PFS(21.5 months,95%CI,15.4–27.5 months)in integrated analysis.Conclusions:For unresectable stage III EGFR mutant NSCLC,RT and TKI are both essential.Based on the current evidence,RT-TKI brings a superior survival advantage,while CRT-TKI needs further estimation.Large randomized clinical trials are urgently needed to explore the appropriate application sequences of TKI,radiotherapy,and chemotherapy.
基金The work was supported by the National Natural Science Foundation of China(Nos.82071876,61871276)Beijing Natural Science Foundation(No.7184199)+1 种基金and Heilongjiang province Science Foundation for Youths(No.QC201807)Beijing Municipal Administration of Hospitals’Youth Programme(No.QML20200108).
文摘Background and Aims:Microvascular invasion(MVI)is a major risk factor for the early recurrence of hepatocel-lular carcinoma(HCC)and it seriously worsens the prog-nosis.Accurate preoperative evaluation of the presence of MVI could greatly benefit the treatment management and prognosis prediction of HCC patients.The study aim was to evaluate the diagnostic performance of the apparent dif-fusion coefficient(ADC),a quantitative parameter for the preoperative diagnosis MVI in HCC patients.Methods:Original articles about diffusion-weighted imaging(DWI)and/or intravoxel incoherent motion(IVIM)conducted on a 3.0 or 1.5 Tesla magnetic resonance imaging(MRI)system indexed through January 17,2021were collected from MED-LINE/PubMed,Web of Science,EMBASE,and the Cochrane Library.Methodological quality was evaluated using Quality Assessment of Diagnostic Accuracy Studies 2(QUADAS-2).The pooled sensitivity,specificity,and summary area un-der the receiver operating characteristic curve(AUROC)were calculated,and meta-regression analysis was per-formed using a bivariate random effects model through a meta-analysis.Results:Nine original articles with a total of 988 HCCs were included.Most studies had low bias risk and minimal applicability concerns.The pooled sensitivity,specificity and AUROC of the ADC value were 73%,70%,and 0.78,respectively.The time interval between the index test and the reference standard was identified as a pos-sible source of heterogeneity by subgroup meta-regression analysis.Conclusions:Meta-analysis showed that the ADC value had moderate accuracy for predicting MVI in HCC.The time interval accounted for the heterogeneity.
