The lung is one of the primary target organs of hydrogen sulfide(H2S),as exposure to H2S can cause acute lung injury(ALI)and pulmonary edema.Dexamethasone(Dex)exerts a protective effect on ALI caused by exposure to to...The lung is one of the primary target organs of hydrogen sulfide(H2S),as exposure to H2S can cause acute lung injury(ALI)and pulmonary edema.Dexamethasone(Dex)exerts a protective effect on ALI caused by exposure to toxic gases and is commonly used in the clinic;however,the underlying mechanisms remain elusive,and the dose is unclear.Methods:In vivo experiments:divided C57BL6 mice into 6 groups at random,12 in each group.The mice were exposed to H2S for 3 h and 5 or 50 mg/kg Dex pretreated before exposure,sacrificed 12 h later.The morphological changes of HE staining and the ultrastructural changes of lungs under transmission electron microscopy were evaluated.The wet/dry ratio of lung tissue was measured.Bronchial alveolar lavage fluid(BALF)protein content and lung permeability index were detected.The expression of AQP5 protein was measured by immunohistochemistry and Western Blot(WB).In vitro experiments:divided human lung adenocarcinoma cell line A549 into 4 groups.1μmol/L dexamethasone was added to pre-incubation.The WB analyzed the protein of p-ERK1/2,p-JNK,and p-p38 in MAPK pathway after 1 h of NaHS exposure;six hours after NaHS exposure,the AQP5 protein was measured by WB.Results:Dex treatment could significantly attenuate the H2S-induced destruction to the alveolar wall,increase the wet-to-dry weight ratio and decrease pulmonary permeability index,with high-dose dexamethasone seemingly functioning better.Additionally,our previous studies showed that aquaporin 5(AQP 5),a critical protein that regulates water flux,decreased both in a mouse and cell model following the exposure to H2S.This study indicates that tThe decrease in AQP 5 can be alleviated by Dex treatment.Additionally,the mitogen activated protein kinase(MAPK)pathway may be involved in the protective effects of Dex in ALI caused by exposure to H2S since H2Sinduced MAPK activation could be inhibited by Dex.Conclusion:The present results indicate that AQP 5 may be considered a therapeutic target for Dex in H2S or other hazardous gases-induced ALI.展开更多
Objective: To develop and validate a radiomics prediction model for individualized prediction of perineural invasion(PNI) in colorectal cancer(CRC).Methods: After computed tomography(CT) radiomics features ext...Objective: To develop and validate a radiomics prediction model for individualized prediction of perineural invasion(PNI) in colorectal cancer(CRC).Methods: After computed tomography(CT) radiomics features extraction, a radiomics signature was constructed in derivation cohort(346 CRC patients). A prediction model was developed to integrate the radiomics signature and clinical candidate predictors [age, sex, tumor location, and carcinoembryonic antigen(CEA) level]. Apparent prediction performance was assessed. After internal validation, independent temporal validation(separate from the cohort used to build the model) was then conducted in 217 CRC patients. The final model was converted to an easy-to-use nomogram.Results: The developed radiomics nomogram that integrated the radiomics signature and CEA level showed good calibration and discrimination performance [Harrell's concordance index(c-index): 0.817; 95% confidence interval(95% CI): 0.811–0.823]. Application of the nomogram in validation cohort gave a comparable calibration and discrimination(c-index: 0.803; 95% CI: 0.794–0.812).Conclusions: Integrating the radiomics signature and CEA level into a radiomics prediction model enables easy and effective risk assessment of PNI in CRC. This stratification of patients according to their PNI status may provide a basis for individualized auxiliary treatment.展开更多
Induced pluripotent stem cells (iPSCs) resemble embryonic stem cells (ESCs) in morphol- ogy, gene expression and in vitro differentiation, raising new hope for personalized clinical therapy. While many efforts hav...Induced pluripotent stem cells (iPSCs) resemble embryonic stem cells (ESCs) in morphol- ogy, gene expression and in vitro differentiation, raising new hope for personalized clinical therapy. While many efforts have been made to improve reprogramming efficiency, significant problems such as genomic instability of iPSCs need to be addressed before clinical therapy. In this study, we try to figure out the real genomic state of iPSCs and their DNA damage response to ionizing radiation (IR). We found that iPSC line 3FB4-1 had lower DNA damage repair ability than mouse embryonic fibroblast (MEF) cells, from which 3FB4-11ine was derived. After the introduction of DNA damage by IR, the number of 7-H2AX loci in 3FB4-1 increased modestly compared to a large increase seen in MEF, albeit both significantly (P 〈 0.01). In addition, whole-genome sequencing analysis showed that after IR, 3FB4-1 possessed more point mutations than MEF and the point mutations spread all over chromosomes. These observations provide evidence that iPSCs are more sensitive to ionizing radiation and their relatively low DNA damage repair capacity may account for their high radiosensitivity. The compromised DNA damage repair capacity of iPSCs should be considered when used in clinical therapy.展开更多
DNA methylation plays an essential role in mammalian development[1].However,how DNA methylation is inherited between generations and if there is family-specific DNA methylation pattern remains to be elucidated[2].In t...DNA methylation plays an essential role in mammalian development[1].However,how DNA methylation is inherited between generations and if there is family-specific DNA methylation pattern remains to be elucidated[2].In this study,we collect male blood samples including a big pedigree of the descendants of an ancient Chinese empire and samples from different haplogroups to study their whole genome DNA methylation pattern.We find 115 male family-specific methylation sites from three families.The difference of whole genome DNA methylation pattern correlates展开更多
Background:Induced pluripotent stem cells(iPSCs)and embryonic stem cells(ESCs)share many common features,including similar morphology,gene expression and in vitro differentiation profiles.However,genomic stability is ...Background:Induced pluripotent stem cells(iPSCs)and embryonic stem cells(ESCs)share many common features,including similar morphology,gene expression and in vitro differentiation profiles.However,genomic stability is much lower in iPSCs than in ESCs.In the current study,we examined whether changes in DNA damage repair in iPSCs are responsible for their greater tendency towards mutagenesis.Methods:Mouse iPSCs,ESCs and embryonic fibroblasts were exposed to ionizing radiation(4 Gy)to introduce dou-ble-strand DNA breaks.At 4 h later,fidelity of DNA damage repair was assessed using whole-genome re-sequencing.We also analyzed genomic stability in mice derived from iPSCs versus ESCs.Results:In comparison to ESCs and embryonic fibroblasts,iPSCs had lower DNA damage repair capacity,more somatic mutations and short indels after irradiation.iPSCs showed greater non-homologous end joining DNA repair and less homologous recombination DNA repair.Mice derived from iPSCs had lower DNA damage repair capacity than ESC-derived mice as well as C57 control mice.Conclusions:The relatively low genomic stability of iPSCs and their high rate of tumorigenesis in vivo appear to be due,at least in part,to low fidelity of DNA damage repair.展开更多
Histone methylation is a kind of important epigenetic modification which occurs on the lysine residue or arginine residue of histone tails(Zhang and Reinberg,2001).It takes part in multiple biological processes,incl...Histone methylation is a kind of important epigenetic modification which occurs on the lysine residue or arginine residue of histone tails(Zhang and Reinberg,2001).It takes part in multiple biological processes,including gene expression,genomic stability,stem cell maturity,genetic imprinting,mitosis and development(Fischle et al.,2005).展开更多
基金supported by the Science and Technology Plan Project of Jiangsu Province(Grant No.BL2014088)the Program of Changshu Science and Technology Bureau(Grant No.CS201813)+1 种基金Suzhou Medical and Health Science and Technology Innovation Project(Grant No.SKJY2021007)Suzhou Gusu Health Talent Project(Grant No.GSWS2022101).
文摘The lung is one of the primary target organs of hydrogen sulfide(H2S),as exposure to H2S can cause acute lung injury(ALI)and pulmonary edema.Dexamethasone(Dex)exerts a protective effect on ALI caused by exposure to toxic gases and is commonly used in the clinic;however,the underlying mechanisms remain elusive,and the dose is unclear.Methods:In vivo experiments:divided C57BL6 mice into 6 groups at random,12 in each group.The mice were exposed to H2S for 3 h and 5 or 50 mg/kg Dex pretreated before exposure,sacrificed 12 h later.The morphological changes of HE staining and the ultrastructural changes of lungs under transmission electron microscopy were evaluated.The wet/dry ratio of lung tissue was measured.Bronchial alveolar lavage fluid(BALF)protein content and lung permeability index were detected.The expression of AQP5 protein was measured by immunohistochemistry and Western Blot(WB).In vitro experiments:divided human lung adenocarcinoma cell line A549 into 4 groups.1μmol/L dexamethasone was added to pre-incubation.The WB analyzed the protein of p-ERK1/2,p-JNK,and p-p38 in MAPK pathway after 1 h of NaHS exposure;six hours after NaHS exposure,the AQP5 protein was measured by WB.Results:Dex treatment could significantly attenuate the H2S-induced destruction to the alveolar wall,increase the wet-to-dry weight ratio and decrease pulmonary permeability index,with high-dose dexamethasone seemingly functioning better.Additionally,our previous studies showed that aquaporin 5(AQP 5),a critical protein that regulates water flux,decreased both in a mouse and cell model following the exposure to H2S.This study indicates that tThe decrease in AQP 5 can be alleviated by Dex treatment.Additionally,the mitogen activated protein kinase(MAPK)pathway may be involved in the protective effects of Dex in ALI caused by exposure to H2S since H2Sinduced MAPK activation could be inhibited by Dex.Conclusion:The present results indicate that AQP 5 may be considered a therapeutic target for Dex in H2S or other hazardous gases-induced ALI.
基金supported by the National Key Research and Development Program of China (No. 2017YFC1309100)the National Natural Scientific Foundation of China (No. 81771912, 81701782 and 81601469)
文摘Objective: To develop and validate a radiomics prediction model for individualized prediction of perineural invasion(PNI) in colorectal cancer(CRC).Methods: After computed tomography(CT) radiomics features extraction, a radiomics signature was constructed in derivation cohort(346 CRC patients). A prediction model was developed to integrate the radiomics signature and clinical candidate predictors [age, sex, tumor location, and carcinoembryonic antigen(CEA) level]. Apparent prediction performance was assessed. After internal validation, independent temporal validation(separate from the cohort used to build the model) was then conducted in 217 CRC patients. The final model was converted to an easy-to-use nomogram.Results: The developed radiomics nomogram that integrated the radiomics signature and CEA level showed good calibration and discrimination performance [Harrell's concordance index(c-index): 0.817; 95% confidence interval(95% CI): 0.811–0.823]. Application of the nomogram in validation cohort gave a comparable calibration and discrimination(c-index: 0.803; 95% CI: 0.794–0.812).Conclusions: Integrating the radiomics signature and CEA level into a radiomics prediction model enables easy and effective risk assessment of PNI in CRC. This stratification of patients according to their PNI status may provide a basis for individualized auxiliary treatment.
基金supported by Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDA01040405)National Natural Science Foundation of China(Grant No.91029024)+1 种基金National Basic Research Program of China(973 ProgramGrant No.2013CB911001)
文摘Induced pluripotent stem cells (iPSCs) resemble embryonic stem cells (ESCs) in morphol- ogy, gene expression and in vitro differentiation, raising new hope for personalized clinical therapy. While many efforts have been made to improve reprogramming efficiency, significant problems such as genomic instability of iPSCs need to be addressed before clinical therapy. In this study, we try to figure out the real genomic state of iPSCs and their DNA damage response to ionizing radiation (IR). We found that iPSC line 3FB4-1 had lower DNA damage repair ability than mouse embryonic fibroblast (MEF) cells, from which 3FB4-11ine was derived. After the introduction of DNA damage by IR, the number of 7-H2AX loci in 3FB4-1 increased modestly compared to a large increase seen in MEF, albeit both significantly (P 〈 0.01). In addition, whole-genome sequencing analysis showed that after IR, 3FB4-1 possessed more point mutations than MEF and the point mutations spread all over chromosomes. These observations provide evidence that iPSCs are more sensitive to ionizing radiation and their relatively low DNA damage repair capacity may account for their high radiosensitivity. The compromised DNA damage repair capacity of iPSCs should be considered when used in clinical therapy.
基金supported by Precision Medicine Research Program of the Chinese Academy of Sciences(KJZD-EWL14)Strategic Priority Research Program of the Chinese Academy of Sciences(XDA01040407)+2 种基金National Natural Science Foundation of China(31471395,91019024,31540033 and 31100558)National Basic Research Program of China(2012CB518302 and2013CB911001)One Hundred Person Project of the Chinese Academy of Sciences
文摘DNA methylation plays an essential role in mammalian development[1].However,how DNA methylation is inherited between generations and if there is family-specific DNA methylation pattern remains to be elucidated[2].In this study,we collect male blood samples including a big pedigree of the descendants of an ancient Chinese empire and samples from different haplogroups to study their whole genome DNA methylation pattern.We find 115 male family-specific methylation sites from three families.The difference of whole genome DNA methylation pattern correlates
基金supported by the Precision Medicine Research Program of the Chinese Academy of Sciences(KJZD-EW-L14)Strategic Priority Research Program of the Chinese Academy of Sciences(XDA01040407)+2 种基金National Natural Science Foundation of China(31471395,91019024,31540033 and 31100558)National Basic Research Program of China(973 Program,2012CB518302 and 2013CB911001)100 Talents Project.
文摘Background:Induced pluripotent stem cells(iPSCs)and embryonic stem cells(ESCs)share many common features,including similar morphology,gene expression and in vitro differentiation profiles.However,genomic stability is much lower in iPSCs than in ESCs.In the current study,we examined whether changes in DNA damage repair in iPSCs are responsible for their greater tendency towards mutagenesis.Methods:Mouse iPSCs,ESCs and embryonic fibroblasts were exposed to ionizing radiation(4 Gy)to introduce dou-ble-strand DNA breaks.At 4 h later,fidelity of DNA damage repair was assessed using whole-genome re-sequencing.We also analyzed genomic stability in mice derived from iPSCs versus ESCs.Results:In comparison to ESCs and embryonic fibroblasts,iPSCs had lower DNA damage repair capacity,more somatic mutations and short indels after irradiation.iPSCs showed greater non-homologous end joining DNA repair and less homologous recombination DNA repair.Mice derived from iPSCs had lower DNA damage repair capacity than ESC-derived mice as well as C57 control mice.Conclusions:The relatively low genomic stability of iPSCs and their high rate of tumorigenesis in vivo appear to be due,at least in part,to low fidelity of DNA damage repair.
基金supported by the National Natural Science Foundation of China(Nos.31540033 and91131002)the Precision Medicine Research Program of the Chinese Academy of Sciences(KJZD-EW-L14)+2 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020343)the National Basic Research Program of China(2013CB911001 and 2012CB518302)the National Excellent Youth Science Foundation of China(No.31222030)
文摘Histone methylation is a kind of important epigenetic modification which occurs on the lysine residue or arginine residue of histone tails(Zhang and Reinberg,2001).It takes part in multiple biological processes,including gene expression,genomic stability,stem cell maturity,genetic imprinting,mitosis and development(Fischle et al.,2005).