Background:Epidermal growth factor receptor(EGFR) mutations,including a known exon 19 deletion(19 del) and exon 21 L858 R point mutation(L858R mutation),are strong predictors of the response to EGFR tyrosine kinase in...Background:Epidermal growth factor receptor(EGFR) mutations,including a known exon 19 deletion(19 del) and exon 21 L858 R point mutation(L858R mutation),are strong predictors of the response to EGFR tyrosine kinase inhibitor(EGFR-TKI) treatment in lung adenocarcinoma.However,whether patients carrying EGFR 19 del and L858 R mutations exhibit different responsiveness to EGFR-TKls and what are the potential mechanism for this difference remain controversial.This study aimed to investigate the clinical outcomes of EGFR-TKI treatment in patients with EGFR 19 del and L858 R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes.Methods:Of 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858 R mutations,532 received EGFR-TKI treatment and were included in this study.EGFR 19 del and L858 R mutations were detected by using denaturing high-performance liquid chromatography(DHPLC).T790 M mutation,which is a common resistant mutation on exon 20 of EGFR,was detected by amplification refractory mutation system(ARMS).Next-generation sequencing(NGS) was used to explore the genetic heterogeneity of tumors with EGFR 19 del and L858 R mutations.Results:Of the 532 patients,319(60.0%) had EGFR 19 del,and 213(40.0%) had L858 R mutations.The patients with EGFR 19 del presented a significantly higher overall response rate(ORR) for EGFR-TKI treatment(55.2%vs.43.7%,P = 0.017) and had a longer progression-free survival(PFS) after first-line EGFR-TKI treatment(14.4 vs.11.4 months,P = 0.034) compared with those with L858 R mutations.However,no statistically significant difference in overall survival(OS) was observed between the two groups of patients.T790 M mutation status was analyzed in 88 patients before EGFR-TKI treatment and 134 after EGFR-TKI treatment,and there was no significant difference in the co-existence of T790 M mutation with EGFR 19 del and L858 R mutations before EGFR-TKI treatment(5.6%vs.8.8%,P = 0.554)or after treatment(24.4%vs.35.4%,P = 0.176).In addition,24 patie展开更多
The next-generation hybrid seed technology enables the successful production of sortable hybrid seeds from genic male sterile(GMS)lines and maintainers;however,it requires multiple laborious and complicated steps.Here...The next-generation hybrid seed technology enables the successful production of sortable hybrid seeds from genic male sterile(GMS)lines and maintainers;however,it requires multiple laborious and complicated steps.Here,we designed a simple next-generation hybrid seed production strategy that takes advantage of the CRISPR/Cas9 technology to create a Manipulated GMS Maintainer(MGM)system via a single transformation.Under this schema,the maize male fertility gene ZmMS26 was nullified by removal of its fifth exon using the CRISPR/Cas9 system on a vector,and a second vector carrying a functional ZmMS26 cDNA was co-transformed to restore fertility.The second vector also contains a male gametophyte inactivation gene(ZmAA1)encoding maizeα-amylase driven by the pollen-specific promoter PG47 and an endosperm fluorescent marker(DsRED)driven by the barley endosperm aleurone-specific promoter Ltp2.The derived single-copy hemizygous MGM lines bore a mutated MS26 gene,leading to complete male sterility but normal vegetative growth and grain yield.The MGM system could prevent genetic transmission of the MGM elements via male gametophytes,providing an efficient method for sorting maintainer seeds labeled by DsRED.This strategy can be extended to any GMS gene and to hybrid crops other than maize.展开更多
INTRODUCTIONThe liver is one of the organs,which have potentialregenerative capability in mammalian animal.The study of the canine model indicated that theliver could regenerate to original size after 70%hepatectomy i...INTRODUCTIONThe liver is one of the organs,which have potentialregenerative capability in mammalian animal.The study of the canine model indicated that theliver could regenerate to original size after 70%hepatectomy in only two weeks.So it is a hotresearch topic for the cellular and molecularmechanism of liver regeneration.展开更多
The neuronal microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in the brains of individuals with Alzheimer＇s disease and related neurodegenerative disord...The neuronal microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in the brains of individuals with Alzheimer＇s disease and related neurodegenerative disorders. The adult human brain expresses six isoforms of tau generated by alternative splicing of exons 2, 3, and 10 of its pre-mRNA. Exon 10 encodes the second microtubule-binding repeat of tau. Its alternative splicing produces tau isoforms with either three or four microtubule-binding repeats, termed 3R-tau and 4R- tau. In the normal adult human brain, the level of 3R-tau is approximately equal to that of 4R-tau. Several silent and intronic mutations of the tau gene associated with FTDP-17T （frontotemporal dementia with Parkinsonism linked to chromosome 17 and specifically characterized by tau pathology） only disrupt exon 10 splicing, but do not influence the primary sequence of the tau protein. Thus, abnormal exon 10 splicing is sufficient to cause neurodegeneration and dementia. Here, we review the regulation of tau exon 10 splicing by cis-elements and trans-factors and summarize all the mutations associated with FTDP-17T and related tauopathies. The findings suggest that correction of exon 10 splicing may be a potential target for tau exon 10 splicing-related tauopathies.展开更多
基金supported by grants from the National Natural Sciences Foundation Key Program(No.81330062)Education Ministry Innovative Research Team Program(No.IRT13003)+1 种基金Peking University-Tsinghua University Joint Center for Life Sciences Clinical Investigator,National High Technology Research and Development Program 863(No.SS2015AA020403)Beijing Technology Project(No.Z141100000214013)
文摘Background:Epidermal growth factor receptor(EGFR) mutations,including a known exon 19 deletion(19 del) and exon 21 L858 R point mutation(L858R mutation),are strong predictors of the response to EGFR tyrosine kinase inhibitor(EGFR-TKI) treatment in lung adenocarcinoma.However,whether patients carrying EGFR 19 del and L858 R mutations exhibit different responsiveness to EGFR-TKls and what are the potential mechanism for this difference remain controversial.This study aimed to investigate the clinical outcomes of EGFR-TKI treatment in patients with EGFR 19 del and L858 R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes.Methods:Of 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858 R mutations,532 received EGFR-TKI treatment and were included in this study.EGFR 19 del and L858 R mutations were detected by using denaturing high-performance liquid chromatography(DHPLC).T790 M mutation,which is a common resistant mutation on exon 20 of EGFR,was detected by amplification refractory mutation system(ARMS).Next-generation sequencing(NGS) was used to explore the genetic heterogeneity of tumors with EGFR 19 del and L858 R mutations.Results:Of the 532 patients,319(60.0%) had EGFR 19 del,and 213(40.0%) had L858 R mutations.The patients with EGFR 19 del presented a significantly higher overall response rate(ORR) for EGFR-TKI treatment(55.2%vs.43.7%,P = 0.017) and had a longer progression-free survival(PFS) after first-line EGFR-TKI treatment(14.4 vs.11.4 months,P = 0.034) compared with those with L858 R mutations.However,no statistically significant difference in overall survival(OS) was observed between the two groups of patients.T790 M mutation status was analyzed in 88 patients before EGFR-TKI treatment and 134 after EGFR-TKI treatment,and there was no significant difference in the co-existence of T790 M mutation with EGFR 19 del and L858 R mutations before EGFR-TKI treatment(5.6%vs.8.8%,P = 0.554)or after treatment(24.4%vs.35.4%,P = 0.176).In addition,24 patie
基金supported by grants from Beijing Municipal Science and Technology(Major Program D171100007717001)the National Major Project of Developing New GM Crops(2019ZX08010-003)+1 种基金the Agricultural Science and Technology Innovation Program of Chinese Academy of Agricultural Sciences,the National Science Foundation of China(no.31771808&31361140364)the China National Modern Corn Industry Tech no logy System.
文摘The next-generation hybrid seed technology enables the successful production of sortable hybrid seeds from genic male sterile(GMS)lines and maintainers;however,it requires multiple laborious and complicated steps.Here,we designed a simple next-generation hybrid seed production strategy that takes advantage of the CRISPR/Cas9 technology to create a Manipulated GMS Maintainer(MGM)system via a single transformation.Under this schema,the maize male fertility gene ZmMS26 was nullified by removal of its fifth exon using the CRISPR/Cas9 system on a vector,and a second vector carrying a functional ZmMS26 cDNA was co-transformed to restore fertility.The second vector also contains a male gametophyte inactivation gene(ZmAA1)encoding maizeα-amylase driven by the pollen-specific promoter PG47 and an endosperm fluorescent marker(DsRED)driven by the barley endosperm aleurone-specific promoter Ltp2.The derived single-copy hemizygous MGM lines bore a mutated MS26 gene,leading to complete male sterility but normal vegetative growth and grain yield.The MGM system could prevent genetic transmission of the MGM elements via male gametophytes,providing an efficient method for sorting maintainer seeds labeled by DsRED.This strategy can be extended to any GMS gene and to hybrid crops other than maize.
文摘INTRODUCTIONThe liver is one of the organs,which have potentialregenerative capability in mammalian animal.The study of the canine model indicated that theliver could regenerate to original size after 70%hepatectomy in only two weeks.So it is a hotresearch topic for the cellular and molecularmechanism of liver regeneration.
基金supported by Nantong UniversityNew York State Institute for Basic Research in Developmental Disabilities+3 种基金by grants from the National Natural Science Foundation of China(81030059 and 81170317)the Basic Research Program of Education Department of Jiangsu Province,China(10KJA310040)the U.S.Alzheimer’s Association(Grant IIRG-10-173154)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)of China
文摘The neuronal microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in the brains of individuals with Alzheimer＇s disease and related neurodegenerative disorders. The adult human brain expresses six isoforms of tau generated by alternative splicing of exons 2, 3, and 10 of its pre-mRNA. Exon 10 encodes the second microtubule-binding repeat of tau. Its alternative splicing produces tau isoforms with either three or four microtubule-binding repeats, termed 3R-tau and 4R- tau. In the normal adult human brain, the level of 3R-tau is approximately equal to that of 4R-tau. Several silent and intronic mutations of the tau gene associated with FTDP-17T （frontotemporal dementia with Parkinsonism linked to chromosome 17 and specifically characterized by tau pathology） only disrupt exon 10 splicing, but do not influence the primary sequence of the tau protein. Thus, abnormal exon 10 splicing is sufficient to cause neurodegeneration and dementia. Here, we review the regulation of tau exon 10 splicing by cis-elements and trans-factors and summarize all the mutations associated with FTDP-17T and related tauopathies. The findings suggest that correction of exon 10 splicing may be a potential target for tau exon 10 splicing-related tauopathies.
