Objectives:The current treatment options and therapeutic targets for triple-negative breast cancer(TNBC),an aggressive subtype of breast cancer(BrCA),are limited.This study aimed to identify novel biomarkers and trans...Objectives:The current treatment options and therapeutic targets for triple-negative breast cancer(TNBC),an aggressive subtype of breast cancer(BrCA),are limited.This study aimed to identify novel biomarkers and transcriptional regulatory networks(TRN)inherent in TNBC samples.Methods:We analyzed pan-cancer BrCA datasets from The Cancer Genome Atlas(TCGA)to compare triple-positive breast cancer(TPBC)with TNBC.TRN algorithms and virtual inference of protein-enriched regulon(VIPER)were used to identify master regulators and their target genes.Utilizing TNBC cells(MDA-MB-231 and MDA-MB-468),we validated the relationship of nuclear factor erythroid 2-like 3(NFE2L3)and basic helix-loop-helix family member E 40(BHLHE40)by performing a luciferase assay.The expression levels of these targets were measured after transfections with plasmid and siRNA via qRT-PCR and western blots.The effect of these genes on cell proliferation and migration was studied using phenotypic assays.Results:Using computational approaches,we identified NFE2L3 as a master regulator with BHLHE40 as its target gene.NFE2L3 protein binds to the promoter region of BHLHE40 and regulates its transcriptional activity.Additionally,silencing and overexpressing NFE2L3 and BHLHE40 in TNBC cell lines MDA-MB-231 and MDA-MB-468 showed that NFE2L3 directly regulates BHLHE40 at both transcriptional and translational levels.We found that BHLHE40 requires NFE2L3 for cell proliferation and migration in TNBC.Conclusion:These findings underscore the significance of NFE2L3 and BHLHE40 in TNBC,highlighting NFE2L3’s role in regulating the oncogenic activity of BHLHE40 in TNBC cells.展开更多
The big underground powerhouse cavern of the China Baihetan hydropower plant is 438m long,34m wide,and 88.7m high.It is cut by a weak interlayer shear zone and its high sidewall poses a huge stability problem.This pap...The big underground powerhouse cavern of the China Baihetan hydropower plant is 438m long,34m wide,and 88.7m high.It is cut by a weak interlayer shear zone and its high sidewall poses a huge stability problem.This paper reports our successful solution of this problem through numerical simulations and a replacement-tunnel scheme in the detailed design stage and close site monitoring in the excavation stage.Particularly,in the detail design stage,mechanical parameters of the shear zone were carefully determined through laboratory experiments and site tests.Then,deformation of the surrounding rocks and the shear zone under high in situ stress conditions was predicted using 3 Dimensional Distinct Element Code(3DEC).Subsequently,a replacement-tunnel scheme was proposed for the treatment on the shear zone to prevent severe unloading relaxation of surrounding rocks.In the construction period,excavation responses were closely monitored on deformations of surrounding rocks and the shear zone.The effect of local cracking in the replacement tunnels on sidewall stability was evaluated using the strength reduction method.These monitoring results were compared with the predicted numerical simulation in the detailed design stage.It is found that the shear zone greatly modified the deformation mode of the cavern surrounding rocks.Without any treatment,rock mass deformation on the downstream sidewall was larger than 125mm and the shearing deformation of the shear zone was 60–70 mm.These preset replacement tunnels can reduce not only the unloading and relaxation of rock masses but also the maximum shearing deformation of the shear zone by 10–20 mm.The predictions by numerical simulation were in good agreement with the monitoring results.The proposed tunnel-replacement scheme can not only restrain the shear zone deformation but also enhance the safety of surrounding rocks and concrete tunnels.This design procedure offers a good reference for interaction between a big underground cavern and a weak layer zone in the future.展开更多
文摘Objectives:The current treatment options and therapeutic targets for triple-negative breast cancer(TNBC),an aggressive subtype of breast cancer(BrCA),are limited.This study aimed to identify novel biomarkers and transcriptional regulatory networks(TRN)inherent in TNBC samples.Methods:We analyzed pan-cancer BrCA datasets from The Cancer Genome Atlas(TCGA)to compare triple-positive breast cancer(TPBC)with TNBC.TRN algorithms and virtual inference of protein-enriched regulon(VIPER)were used to identify master regulators and their target genes.Utilizing TNBC cells(MDA-MB-231 and MDA-MB-468),we validated the relationship of nuclear factor erythroid 2-like 3(NFE2L3)and basic helix-loop-helix family member E 40(BHLHE40)by performing a luciferase assay.The expression levels of these targets were measured after transfections with plasmid and siRNA via qRT-PCR and western blots.The effect of these genes on cell proliferation and migration was studied using phenotypic assays.Results:Using computational approaches,we identified NFE2L3 as a master regulator with BHLHE40 as its target gene.NFE2L3 protein binds to the promoter region of BHLHE40 and regulates its transcriptional activity.Additionally,silencing and overexpressing NFE2L3 and BHLHE40 in TNBC cell lines MDA-MB-231 and MDA-MB-468 showed that NFE2L3 directly regulates BHLHE40 at both transcriptional and translational levels.We found that BHLHE40 requires NFE2L3 for cell proliferation and migration in TNBC.Conclusion:These findings underscore the significance of NFE2L3 and BHLHE40 in TNBC,highlighting NFE2L3’s role in regulating the oncogenic activity of BHLHE40 in TNBC cells.
基金Program of China Three Gorges Corporation,Grant/Award Number:BHT 0679-1。
文摘The big underground powerhouse cavern of the China Baihetan hydropower plant is 438m long,34m wide,and 88.7m high.It is cut by a weak interlayer shear zone and its high sidewall poses a huge stability problem.This paper reports our successful solution of this problem through numerical simulations and a replacement-tunnel scheme in the detailed design stage and close site monitoring in the excavation stage.Particularly,in the detail design stage,mechanical parameters of the shear zone were carefully determined through laboratory experiments and site tests.Then,deformation of the surrounding rocks and the shear zone under high in situ stress conditions was predicted using 3 Dimensional Distinct Element Code(3DEC).Subsequently,a replacement-tunnel scheme was proposed for the treatment on the shear zone to prevent severe unloading relaxation of surrounding rocks.In the construction period,excavation responses were closely monitored on deformations of surrounding rocks and the shear zone.The effect of local cracking in the replacement tunnels on sidewall stability was evaluated using the strength reduction method.These monitoring results were compared with the predicted numerical simulation in the detailed design stage.It is found that the shear zone greatly modified the deformation mode of the cavern surrounding rocks.Without any treatment,rock mass deformation on the downstream sidewall was larger than 125mm and the shearing deformation of the shear zone was 60–70 mm.These preset replacement tunnels can reduce not only the unloading and relaxation of rock masses but also the maximum shearing deformation of the shear zone by 10–20 mm.The predictions by numerical simulation were in good agreement with the monitoring results.The proposed tunnel-replacement scheme can not only restrain the shear zone deformation but also enhance the safety of surrounding rocks and concrete tunnels.This design procedure offers a good reference for interaction between a big underground cavern and a weak layer zone in the future.
