Objective: Primary resistance to trastuzumab frequently occurs in human epidermal growth factor receptor 2(HER2)-positive(+) breast cancer patients and remains a clinical challenge. Pyrotinib is a novel tyrosine kinas...Objective: Primary resistance to trastuzumab frequently occurs in human epidermal growth factor receptor 2(HER2)-positive(+) breast cancer patients and remains a clinical challenge. Pyrotinib is a novel tyrosine kinase inhibitor that has shown efficacy in the treatment of HER2+ breast cancer. However, the efficacy of pyrotinib in HER2+ breast cancer with primary trastuzumab resistance is unknown.Methods: HER2+ breast cancer cells sensitive or primarily resistant to trastuzumab were treated with trastuzumab, pyrotinib, or the combination. Cell proliferation, migration, invasion, and HER2 downstream signal pathways were analyzed. The effects of pyrotinib plus trastuzumab and pertuzumab plus trastuzumab were compared in breast cancer cells in vitro and a xenograft mouse model with primary resistance to trastuzumab.Results: Pyrotinib had a therapeutic effect on trastuzumab-sensitive HER2+ breast cancer cells by inhibiting phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT) and rat sarcoma virus(RAS)/rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)/extracellular-signal regulated kinase(ERK)pathways. In primary trastuzumab-resistant cells, pyrotinib inhibited cell growth, migration, invasion, and HER2 downstream pathways, whereas trastuzumab had no effects. The combination with trastuzumab did not show increased effects compared with pyrotinib alone. Compared with pertuzumab plus trastuzumab, pyrotinib plus trastuzumab was more effective in inhibiting cell proliferation and HER2 downstream pathways in breast cancer cells and tumor growth in a trastuzumab-resistant HER2+ breast cancer xenograft model.Conclusions: Pyrotinib-containing treatments exhibited anti-cancer effects in HER2+ breast cancer cells sensitive and with primary resistance to trastuzumab. Notably, pyrotinib plus trastuzumab was more effective than trastuzumab plus pertuzumab in inhibiting tumor growth and HER2 downstream pathways in HER2+ breast cancer with primary resistance to trastuzumab. These findings support clinical testing of the therapeutic efficacy of dual anti-HER2 treatment combining an intracellular small molecule with an extracellular antibody.展开更多
To uncover the effects of segregation and precipitation on grain refinement of metals under severe plastic deformation,high-pressure-torsion(HPT)processing is performed on three binary Al-(Si,Mg,and Cu)alloys with dif...To uncover the effects of segregation and precipitation on grain refinement of metals under severe plastic deformation,high-pressure-torsion(HPT)processing is performed on three binary Al-(Si,Mg,and Cu)alloys with different stability and segregation characteristics.Atom probe tomography analysis reveals that HPT processing induces significant decomposition of Al-1 at%Si and Al-1 at%Cu alloys with coarse Si particles and fine Al_(2) Cu(θ)precipitates formed,but no decomposition of Al-1 at%Mg alloy,with dislocations segregated with Si,Cu,and Mg,and grain boundaries(GBs)only segregated with Cu and Mg.The GB segregation of Cu is stronger than that of Mg and Si,with Cu excess in the range of 1.5-7.0 atoms/nm2,Mg excess in the range of 0-4.0 atoms/nm^(2),but no Si excess.Interestingly,some GBs without Mg segregation develop a Mg-depletion zone along a single side.All evidences demonstrate that GB segregation and precipitation are responsible for HPT-induced grain refinement of Al-1Mg and Al-1Cu alloys but coarsening of the Al-1Si alloy.Engineering solute distribution is of significance in controlling the ultrafine grain of the Al alloys.展开更多
Ambient coarse particles （diameter 1.8-10 μm）, fine particles （diameter 0.1-1.8 μm）, and ultrafine particles （diameter 〈 0.1 μm） in the atmosphere of the city of Shanghai were sampled during the summer of 20...Ambient coarse particles （diameter 1.8-10 μm）, fine particles （diameter 0.1-1.8 μm）, and ultrafine particles （diameter 〈 0.1 μm） in the atmosphere of the city of Shanghai were sampled during the summer of 2008 （from Aug 27 to Sep 08）. Microscopic characterization of the particles was investigated by scanning electron microscopy coupled with energy dispersive X-ray spectroscopy （SEM/EDX）. Mass concentrations of Si, P, S, Cl, K, Ca, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, As, Se, Br, Rb, Sr, and Pb in the size-resolved particles were quantified by using synchrotron radiation X-ray fluorescence （SRXRF）. Source apportionment of the chemical elements was analyzed by means of an enrichment factor method. Our results showed that the average mass concentrations of coarse particles, fine particles and ultrafine particles in the summer air were 9.38 ± 2.18, 8.82 ± 3.52, and 2.02 ± 0.41 μg/m3, respectively. The mass percentage of the fine particles accounted for 51.47% in the total mass of PM10, indicating that fine particles are the major component in the Shanghai ambient particles. SEM/EDX results showed that the coarse particles were dominated by minerals, fine particles by soot aggregates and fly ashes, and ultrafine particles by soot particles and unidentified particles. SRXRF results demonstrated that crustal elements were mainly distributed in the coarse particles, while heavy metals were in higher proportions in the fine particles. Source apportionment revealed that Si, K, Ca, Fe, Mn, Rb, and Sr were from crustal sources, and S, Cl, Cu, Zn, As, Se, Br, and Pb from anthropogenic sources. Levels of P, V, Cr, and Ni in particles might be contributed from multi-sources, and need further investigation.展开更多
To investigate the dynamic characteristics of total suspended solids (TSS) and their particle-bound heavy metals in a first flush, the runoff sampling together with its flow rate measuring was conducted for three rain...To investigate the dynamic characteristics of total suspended solids (TSS) and their particle-bound heavy metals in a first flush, the runoff sampling together with its flow rate measuring was conducted for three rainfall events at outfalls of highway in Shanghai from June to September 2007. Field samples were analyzed to determine the concentrations of TSS and particle-bound heavy metals, such as Zn, Pb, and Cu. Results show that the wash off behavior of TSS under varying runoff rate condition can be explained by different antecedent dry weather period (ADWP). Contribution of fine fraction (<45 μm) to TSS was generally higher than that of coarse fraction (>45 μm). When the runoff flow increased obviously, a significant contribution of the coarse fraction was observed for a certain rainfall events with long antecedent dry weather condition. The changes of total metals concentration and particle-bound metal concentrations were strongly dependent on the TSS variation. TSS was generally well correlated with most particulate-bound heavy metals. Of the heavy metals, the concentration of Zn was found considerably high and that of Pb was significantly low at North Zhongshan 2 Road, in Shanghai, China, but they are still within the range reported in the literature. Fluctuation of heavy metal contents in the coarse fraction during a first flush period was more significant compared with that in the fine fraction. The results will assist in the development of effective control strategies to minimize heavy metals and solids in highway runoff.展开更多
Polish wheat (Triticum polonicum) is a unique tetraploid wheat species characterized by an elongated outer glume. The genetic control of the long-glume trait by a single semi-dominant locus, P1 (from Polish wheat), wa...Polish wheat (Triticum polonicum) is a unique tetraploid wheat species characterized by an elongated outer glume. The genetic control of the long-glume trait by a single semi-dominant locus, P1 (from Polish wheat), was established more than 100 years ago, but the underlying causal gene and molecular nature remain elusive. Here, we report the isolation of VRT-A2, encoding an SVP-clade MADS-box transcription factor, as the P1 candidate gene. Genetic evidence suggests that in T. polonicum, a naturally occurring sequence rearrangement in the intron-1 region of VRT-A2 leads to ectopic expression of VRT-A2 in floral organs where the long-glume phenotype appears. Interestingly, we found that the intron-1 region is a key ON/OFF molecular switch for VRT-A2 expression, not only because it recruits transcriptional repressors, but also because it confers intron-mediated transcriptional enhancement. Genotypic analyses using wheat accessions indicated that the P1 locus is likely derived from a single natural mutation in tetraploid wheat, which was subsequently inherited by hexaploid T. petropavlovskyi. Taken together, our findings highlight the promoter-proximal intron variation as a molecular basis for phenotypic differentiation, and thus species formation in Triticum plants.展开更多
A sounding rocket experiment undertaken by the Chinese Meridian Project from a low latitude station on Hainan Island(19.5°N,109.1°E),China,measured the DC electric field during 05:45-05:52 LT on April 5,2013...A sounding rocket experiment undertaken by the Chinese Meridian Project from a low latitude station on Hainan Island(19.5°N,109.1°E),China,measured the DC electric field during 05:45-05:52 LT on April 5,2013.The data observed using a set of electric field double probes,as part of the rocket's scientific payload,revealed the special profile of how the vectors of the DC electric field vary with altitude between 130 and 190 km.During the experiment,the vertical electric field was downward,and the maximum vertical electric field was nearly 5.1 mV/m near the altitude of 176 km.The zonal electric field was eastward and slightly less than 0.6 mV/m.The plasma drift velocity was estimated from the E×B motion,and the zonal drift velocity was eastward and of the order of 100 m/s.The zonal wind velocity was also estimated using the drift velocity near the maximum density height in the F1-region,and it was found to be nearly 120 m/s.This work constituted the first in situ measurement of the DC electric field conducted within the Fl-region(between 130 and 190 km) in the East Asian Sector.展开更多
Interploidy hybridization between hexaploid and tetraploid genotypes occurred repeatedly during genomic introgression events throughout wheat evolution,and is commonly employed in wheat breeding programs.Hexaploid whe...Interploidy hybridization between hexaploid and tetraploid genotypes occurred repeatedly during genomic introgression events throughout wheat evolution,and is commonly employed in wheat breeding programs.Hexaploid wheat usually serves as maternal parent because the reciprocal cross generates progeny with severe defects and poor seed germination,but the underlying mechanism is poorly understood.Here,we performed detailed analysis of phenotypic variation in endosperm between two interploidy reciprocal crosses arising from tetraploid(Triticum durum,AABB)and hexaploid wheat(Triticum aestivum,AABBDD).In the paternal‐versus the maternal‐excess cross,the timing of endosperm cellularization was delayed and starch granule accumulation in the endosperm was repressed,causing reduced germination percentage.The expression profiles of genes involved in nutrient metabolism differed strongly between these endosperm types.Furthermore,expression patterns of parental alleles were dramatically disturbed in interploidy versus intraploidy crosses,leading to increased number of imprinted genes.The endosperm‐specific TaLFL2 showed a paternally imprinted expression pattern in interploidy crosses partially due to allele‐specific DNA methylation.Paternal TaLFL2 binds to and represses a nutrient accumulation regulator TaNAC019,leading to reduced storage protein and starch accumulation during endosperm development in paternal‐excess cross,as confirmed by interploidy crosses between tetraploid wild‐type and clustered regularly interspaced palindromic repeats(CRISPR)–CRISPR‐associated protein 9 generated hexaploid mutants.These findings reveal a contribution of genomic imprinting to paternal‐excess interploidy hybridization barriers during wheat evolution history and explains why experienced breeders preferentially exploit maternal‐excess interploidy crosses in wheat breeding programs.展开更多
基金supported by the National Natural Science Foundation of China (No. 82072914)the Special Foundation for Taishan Scholars and the Fundamental Research Funds for the Central Universities (No. 2022JC009)。
文摘Objective: Primary resistance to trastuzumab frequently occurs in human epidermal growth factor receptor 2(HER2)-positive(+) breast cancer patients and remains a clinical challenge. Pyrotinib is a novel tyrosine kinase inhibitor that has shown efficacy in the treatment of HER2+ breast cancer. However, the efficacy of pyrotinib in HER2+ breast cancer with primary trastuzumab resistance is unknown.Methods: HER2+ breast cancer cells sensitive or primarily resistant to trastuzumab were treated with trastuzumab, pyrotinib, or the combination. Cell proliferation, migration, invasion, and HER2 downstream signal pathways were analyzed. The effects of pyrotinib plus trastuzumab and pertuzumab plus trastuzumab were compared in breast cancer cells in vitro and a xenograft mouse model with primary resistance to trastuzumab.Results: Pyrotinib had a therapeutic effect on trastuzumab-sensitive HER2+ breast cancer cells by inhibiting phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT) and rat sarcoma virus(RAS)/rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)/extracellular-signal regulated kinase(ERK)pathways. In primary trastuzumab-resistant cells, pyrotinib inhibited cell growth, migration, invasion, and HER2 downstream pathways, whereas trastuzumab had no effects. The combination with trastuzumab did not show increased effects compared with pyrotinib alone. Compared with pertuzumab plus trastuzumab, pyrotinib plus trastuzumab was more effective in inhibiting cell proliferation and HER2 downstream pathways in breast cancer cells and tumor growth in a trastuzumab-resistant HER2+ breast cancer xenograft model.Conclusions: Pyrotinib-containing treatments exhibited anti-cancer effects in HER2+ breast cancer cells sensitive and with primary resistance to trastuzumab. Notably, pyrotinib plus trastuzumab was more effective than trastuzumab plus pertuzumab in inhibiting tumor growth and HER2 downstream pathways in HER2+ breast cancer with primary resistance to trastuzumab. These findings support clinical testing of the therapeutic efficacy of dual anti-HER2 treatment combining an intracellular small molecule with an extracellular antibody.
基金support of the National Natural Science Foundation of China(No.51571120).
文摘To uncover the effects of segregation and precipitation on grain refinement of metals under severe plastic deformation,high-pressure-torsion(HPT)processing is performed on three binary Al-(Si,Mg,and Cu)alloys with different stability and segregation characteristics.Atom probe tomography analysis reveals that HPT processing induces significant decomposition of Al-1 at%Si and Al-1 at%Cu alloys with coarse Si particles and fine Al_(2) Cu(θ)precipitates formed,but no decomposition of Al-1 at%Mg alloy,with dislocations segregated with Si,Cu,and Mg,and grain boundaries(GBs)only segregated with Cu and Mg.The GB segregation of Cu is stronger than that of Mg and Si,with Cu excess in the range of 1.5-7.0 atoms/nm2,Mg excess in the range of 0-4.0 atoms/nm^(2),but no Si excess.Interestingly,some GBs without Mg segregation develop a Mg-depletion zone along a single side.All evidences demonstrate that GB segregation and precipitation are responsible for HPT-induced grain refinement of Al-1Mg and Al-1Cu alloys but coarsening of the Al-1Si alloy.Engineering solute distribution is of significance in controlling the ultrafine grain of the Al alloys.
基金supported by the National Natural Science Foundation of China (No. 10775094, 40973072,41073073)the Shanghai Pujiang Talent Program,the Shanghai Committee of Science and Technology (No.10JC1405500)+1 种基金the Innovation Program of Shanghai Municipal Education Commission (No. 11ZZ80)the Shanghai Leading Academic Discipline Project (No.S30109)
文摘Ambient coarse particles （diameter 1.8-10 μm）, fine particles （diameter 0.1-1.8 μm）, and ultrafine particles （diameter 〈 0.1 μm） in the atmosphere of the city of Shanghai were sampled during the summer of 2008 （from Aug 27 to Sep 08）. Microscopic characterization of the particles was investigated by scanning electron microscopy coupled with energy dispersive X-ray spectroscopy （SEM/EDX）. Mass concentrations of Si, P, S, Cl, K, Ca, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, As, Se, Br, Rb, Sr, and Pb in the size-resolved particles were quantified by using synchrotron radiation X-ray fluorescence （SRXRF）. Source apportionment of the chemical elements was analyzed by means of an enrichment factor method. Our results showed that the average mass concentrations of coarse particles, fine particles and ultrafine particles in the summer air were 9.38 ± 2.18, 8.82 ± 3.52, and 2.02 ± 0.41 μg/m3, respectively. The mass percentage of the fine particles accounted for 51.47% in the total mass of PM10, indicating that fine particles are the major component in the Shanghai ambient particles. SEM/EDX results showed that the coarse particles were dominated by minerals, fine particles by soot aggregates and fly ashes, and ultrafine particles by soot particles and unidentified particles. SRXRF results demonstrated that crustal elements were mainly distributed in the coarse particles, while heavy metals were in higher proportions in the fine particles. Source apportionment revealed that Si, K, Ca, Fe, Mn, Rb, and Sr were from crustal sources, and S, Cl, Cu, Zn, As, Se, Br, and Pb from anthropogenic sources. Levels of P, V, Cr, and Ni in particles might be contributed from multi-sources, and need further investigation.
基金Project supported by the National Key Technology R&D Program of China (No. 2006BAK13B04)the Expo Shanghai Sci-Tech Program of Science and Technology Commission of Shanghai (No.06dz05808)the Natural Science Foundation of Jiangxi Province(No. 2007GZH839), China
文摘To investigate the dynamic characteristics of total suspended solids (TSS) and their particle-bound heavy metals in a first flush, the runoff sampling together with its flow rate measuring was conducted for three rainfall events at outfalls of highway in Shanghai from June to September 2007. Field samples were analyzed to determine the concentrations of TSS and particle-bound heavy metals, such as Zn, Pb, and Cu. Results show that the wash off behavior of TSS under varying runoff rate condition can be explained by different antecedent dry weather period (ADWP). Contribution of fine fraction (<45 μm) to TSS was generally higher than that of coarse fraction (>45 μm). When the runoff flow increased obviously, a significant contribution of the coarse fraction was observed for a certain rainfall events with long antecedent dry weather condition. The changes of total metals concentration and particle-bound metal concentrations were strongly dependent on the TSS variation. TSS was generally well correlated with most particulate-bound heavy metals. Of the heavy metals, the concentration of Zn was found considerably high and that of Pb was significantly low at North Zhongshan 2 Road, in Shanghai, China, but they are still within the range reported in the literature. Fluctuation of heavy metal contents in the coarse fraction during a first flush period was more significant compared with that in the fine fraction. The results will assist in the development of effective control strategies to minimize heavy metals and solids in highway runoff.
基金This work was supported by grants from the National Natural Science Foundation of China(32072055,31991210,and 91935304).
文摘Polish wheat (Triticum polonicum) is a unique tetraploid wheat species characterized by an elongated outer glume. The genetic control of the long-glume trait by a single semi-dominant locus, P1 (from Polish wheat), was established more than 100 years ago, but the underlying causal gene and molecular nature remain elusive. Here, we report the isolation of VRT-A2, encoding an SVP-clade MADS-box transcription factor, as the P1 candidate gene. Genetic evidence suggests that in T. polonicum, a naturally occurring sequence rearrangement in the intron-1 region of VRT-A2 leads to ectopic expression of VRT-A2 in floral organs where the long-glume phenotype appears. Interestingly, we found that the intron-1 region is a key ON/OFF molecular switch for VRT-A2 expression, not only because it recruits transcriptional repressors, but also because it confers intron-mediated transcriptional enhancement. Genotypic analyses using wheat accessions indicated that the P1 locus is likely derived from a single natural mutation in tetraploid wheat, which was subsequently inherited by hexaploid T. petropavlovskyi. Taken together, our findings highlight the promoter-proximal intron variation as a molecular basis for phenotypic differentiation, and thus species formation in Triticum plants.
基金supported by the Specialized Research Fund for State Key Laboratories and National Space Science Center-135 (Sounding Rocket Project)National Natural Science Foundation of China(Grant Nos.40774081 & 2011CB811404)+2 种基金Chinese Academy of Sciences(Grant No.KZZD-EW-01-2)Chinese Academy of Science Fellowship for Young International Scientist Grant(Grant No.2010Y1GB3)Chinese Academy of Sciences-The Third World Academy of Sciences (CAS-TWAS) Fellowship for Postdoctoral and Visiting Scholar(Grant No. 201377GB0001)
文摘A sounding rocket experiment undertaken by the Chinese Meridian Project from a low latitude station on Hainan Island(19.5°N,109.1°E),China,measured the DC electric field during 05:45-05:52 LT on April 5,2013.The data observed using a set of electric field double probes,as part of the rocket's scientific payload,revealed the special profile of how the vectors of the DC electric field vary with altitude between 130 and 190 km.During the experiment,the vertical electric field was downward,and the maximum vertical electric field was nearly 5.1 mV/m near the altitude of 176 km.The zonal electric field was eastward and slightly less than 0.6 mV/m.The plasma drift velocity was estimated from the E×B motion,and the zonal drift velocity was eastward and of the order of 100 m/s.The zonal wind velocity was also estimated using the drift velocity near the maximum density height in the F1-region,and it was found to be nearly 120 m/s.This work constituted the first in situ measurement of the DC electric field conducted within the Fl-region(between 130 and 190 km) in the East Asian Sector.
基金This work was supported by the National Natural Science of China(31471479)the Chinese Universities Scientific Fund(2017TC035).
文摘Interploidy hybridization between hexaploid and tetraploid genotypes occurred repeatedly during genomic introgression events throughout wheat evolution,and is commonly employed in wheat breeding programs.Hexaploid wheat usually serves as maternal parent because the reciprocal cross generates progeny with severe defects and poor seed germination,but the underlying mechanism is poorly understood.Here,we performed detailed analysis of phenotypic variation in endosperm between two interploidy reciprocal crosses arising from tetraploid(Triticum durum,AABB)and hexaploid wheat(Triticum aestivum,AABBDD).In the paternal‐versus the maternal‐excess cross,the timing of endosperm cellularization was delayed and starch granule accumulation in the endosperm was repressed,causing reduced germination percentage.The expression profiles of genes involved in nutrient metabolism differed strongly between these endosperm types.Furthermore,expression patterns of parental alleles were dramatically disturbed in interploidy versus intraploidy crosses,leading to increased number of imprinted genes.The endosperm‐specific TaLFL2 showed a paternally imprinted expression pattern in interploidy crosses partially due to allele‐specific DNA methylation.Paternal TaLFL2 binds to and represses a nutrient accumulation regulator TaNAC019,leading to reduced storage protein and starch accumulation during endosperm development in paternal‐excess cross,as confirmed by interploidy crosses between tetraploid wild‐type and clustered regularly interspaced palindromic repeats(CRISPR)–CRISPR‐associated protein 9 generated hexaploid mutants.These findings reveal a contribution of genomic imprinting to paternal‐excess interploidy hybridization barriers during wheat evolution history and explains why experienced breeders preferentially exploit maternal‐excess interploidy crosses in wheat breeding programs.
