Background: New therapeutic targets are needed to improve the outcomes for gastric cancer(GC) patients with advanced disease. Evasion of programmed cell death(apoptosis) is a hallmark of cancer cells and direct induct...Background: New therapeutic targets are needed to improve the outcomes for gastric cancer(GC) patients with advanced disease. Evasion of programmed cell death(apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions. Method: Here we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR(ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using(CellTiter-Glo) CTG assay in vitro. Western Blot(WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Coimmunoprecipitation(Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR(RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity. Results: The functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time-and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression.Conclusion: We identified BCL-XL as a promising therapeutic target in a subset of GC cases with high levels of BCL-XL protein expression. Functionally, we demonstrated that both selective BCL-XL inhibitors and VHL-based PROTAC BCL-XL can potently kill GC cells that are reliant on BCL-XL for survival. However, we found that BCL2L1 copy number variations(CNVs) cannot reliably predict BCL-XL expression, but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds. Taken together, our study pinpointed BCL-XL as potential druggable target for specific subsets of GC.展开更多
Aging increases the risks of various diseases and the vulnerability to death.Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases.This study demonstrates that extrace...Aging increases the risks of various diseases and the vulnerability to death.Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases.This study demonstrates that extracellular vesicles from human urine-derived stem cells(USC-EVs)efficiently inhibit cellular senescence in vitro and in vivo.The intravenous injection of USC-EVs improves cognitive function,increases physical fitness and bone quality,and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice.The anti-aging effects of USC-EVs are not obviously affected by the USC donors’ages,genders,or health status.Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase(PLAU)and tissue inhibitor of metalloproteinases 1(TIMP1).These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases,cyclin-dependent kinase inhibitor 2A(P16INK4a),and cyclin-dependent kinase inhibitor 1A(P21cip1).These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.展开更多
To the Editor:Accumulating evidence has shown that gut microbiota–host interactions play vital roles in human health and disease.However,the dynamic equilibria between microbes and their hosts limit the utility of si...To the Editor:Accumulating evidence has shown that gut microbiota–host interactions play vital roles in human health and disease.However,the dynamic equilibria between microbes and their hosts limit the utility of single strains or microbial signatures as markers for disease risk prediction and outcome assessment.[1]Analysis of changes in the gut microenvironment using multi-omics approaches has now become routine.[2]In inflammatory bowel disease,and especially during the acute phase,a significant shift in the gut microenvironment occurs within 2 weeks.Therefore,effective strategies to obtain fecal samples every 2 to 3 days are needed.However,challenges in specimen storage,transport,and handling limit long-term sampling ability.The microbial composition of fecal samples stored at room temperature for>24 h is significantly altered.Storage of fecal specimens at−80°C immediately after evacuation is standard procedure but is impractical in real-life situations.An alternative is a storage at−20°C for up to 1 month followed by sample transport and laboratory analysis.The objective of this study was to evaluate whether the gut microenvironment in fecal specimens collected every 2 to 3 days and stored at home at−20°C for up to 1 month could be preserved.展开更多
Background and aims:Protein induced by vitamin K absence or antagonist II(PIVKA-II)is a well-accepted biomarker for diagnosing hepatocellular carcinoma(HCC).Although nonspecific increase of PIVKA-II has been reported,...Background and aims:Protein induced by vitamin K absence or antagonist II(PIVKA-II)is a well-accepted biomarker for diagnosing hepatocellular carcinoma(HCC).Although nonspecific increase of PIVKA-II has been reported,real-world evidence remains scarce.Based on real-world data,this study aimed to comprehensively describe the use of PIVKA-II at a hepatobiliary and pancreatic disease center and to assess its utility for the initial screening of HCC or other hepatobiliary–pancreatic malignancies.Methods:This real-world retrospective study is based on the PIVKA-II results of 16,215 individuals and other relevant laboratory test(alpha-fetoprotein[AFP],carbohydrate antigen 19-9[CA19-9],liver function,blood coagulation indicators,hepatitis B virus,and hepatitis C virus).However,only the first PIVKA-II results of 7809 eligible individuals were included.Between-group comparisons,correlation analysis,and receiver operating characteristic curve analysis were performed.Results:PIVKA-II results were abnormal in patients with HCC(55.9%),biliary carcinoma(BC,13.4%),gastroin-testinal and pancreatic cancer(6.3%),and benign diseases(23.5%)as well as in healthy individuals(0.92%).The area under the curve of PIVKA-II for detecting malignancies was 0.7754(0.7620–0.7688),whereas that for detecting HCC was 0.7509(0.7357–0.7662).Stratifying the PIVKA-II values or combining PIVKA-II with AFP or CA19-9 helped improve the diagnostic performance of PIVKA-II for HCC.PIVKA-II values were significantly positively correlated with AST in patients with HCC and with bilirubin in patients with BC.Conclusions:This study determined the role of PIVKA-II in malignancy screening at hepatobiliary and pancreatic disease centers.It was also noted that the diagnostic efficacy of PIVKA-II for HCC improved after combining PIVKA-II with AFP or stratifying its value.展开更多
文摘Background: New therapeutic targets are needed to improve the outcomes for gastric cancer(GC) patients with advanced disease. Evasion of programmed cell death(apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions. Method: Here we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR(ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using(CellTiter-Glo) CTG assay in vitro. Western Blot(WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Coimmunoprecipitation(Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR(RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity. Results: The functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time-and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression.Conclusion: We identified BCL-XL as a promising therapeutic target in a subset of GC cases with high levels of BCL-XL protein expression. Functionally, we demonstrated that both selective BCL-XL inhibitors and VHL-based PROTAC BCL-XL can potently kill GC cells that are reliant on BCL-XL for survival. However, we found that BCL2L1 copy number variations(CNVs) cannot reliably predict BCL-XL expression, but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds. Taken together, our study pinpointed BCL-XL as potential druggable target for specific subsets of GC.
基金supported by the National Natural Science Foundation of China(Grant Nos.82125023,82072504,81871822,82172501,81801395,and 82200039)the Science and Technology Innovation Program of Hunan Province(Grant Nos.2020RC4008 and 2022RC1211,China)+4 种基金the China National Postdoctoral Program for Innovative Talents(Grant No.BX2021383,China)the Central South University InnovationDriven Research Programme(Grant Nos.2023CXQD001 and 2019CX014,China)the Hunan Province Natural Science Foundation of China(Grant Nos.2023JJ10094 and 2020JJ5883)the Youth Science Foundation of Xiangya Hospital(Grant No.2022Q07,China)the Hunan Provincial Innovation Foundation for Postgraduate(Grant Nos.2021ZZTS0342 and 2022ZZTS0239,China)。
文摘Aging increases the risks of various diseases and the vulnerability to death.Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases.This study demonstrates that extracellular vesicles from human urine-derived stem cells(USC-EVs)efficiently inhibit cellular senescence in vitro and in vivo.The intravenous injection of USC-EVs improves cognitive function,increases physical fitness and bone quality,and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice.The anti-aging effects of USC-EVs are not obviously affected by the USC donors’ages,genders,or health status.Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase(PLAU)and tissue inhibitor of metalloproteinases 1(TIMP1).These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases,cyclin-dependent kinase inhibitor 2A(P16INK4a),and cyclin-dependent kinase inhibitor 1A(P21cip1).These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.
基金This work was supported by grants from the Chinese Academy of Medical Sciences Innovation Funds for Medical Sciences(Nos.2020-I2M-2-013,2021-I2M-C&T-A-001)。
文摘To the Editor:Accumulating evidence has shown that gut microbiota–host interactions play vital roles in human health and disease.However,the dynamic equilibria between microbes and their hosts limit the utility of single strains or microbial signatures as markers for disease risk prediction and outcome assessment.[1]Analysis of changes in the gut microenvironment using multi-omics approaches has now become routine.[2]In inflammatory bowel disease,and especially during the acute phase,a significant shift in the gut microenvironment occurs within 2 weeks.Therefore,effective strategies to obtain fecal samples every 2 to 3 days are needed.However,challenges in specimen storage,transport,and handling limit long-term sampling ability.The microbial composition of fecal samples stored at room temperature for>24 h is significantly altered.Storage of fecal specimens at−80°C immediately after evacuation is standard procedure but is impractical in real-life situations.An alternative is a storage at−20°C for up to 1 month followed by sample transport and laboratory analysis.The objective of this study was to evaluate whether the gut microenvironment in fecal specimens collected every 2 to 3 days and stored at home at−20°C for up to 1 month could be preserved.
基金This study was supported by Beijing Tsinghua Changgung Hospital Fund(Grant No.12022C1009).
文摘Background and aims:Protein induced by vitamin K absence or antagonist II(PIVKA-II)is a well-accepted biomarker for diagnosing hepatocellular carcinoma(HCC).Although nonspecific increase of PIVKA-II has been reported,real-world evidence remains scarce.Based on real-world data,this study aimed to comprehensively describe the use of PIVKA-II at a hepatobiliary and pancreatic disease center and to assess its utility for the initial screening of HCC or other hepatobiliary–pancreatic malignancies.Methods:This real-world retrospective study is based on the PIVKA-II results of 16,215 individuals and other relevant laboratory test(alpha-fetoprotein[AFP],carbohydrate antigen 19-9[CA19-9],liver function,blood coagulation indicators,hepatitis B virus,and hepatitis C virus).However,only the first PIVKA-II results of 7809 eligible individuals were included.Between-group comparisons,correlation analysis,and receiver operating characteristic curve analysis were performed.Results:PIVKA-II results were abnormal in patients with HCC(55.9%),biliary carcinoma(BC,13.4%),gastroin-testinal and pancreatic cancer(6.3%),and benign diseases(23.5%)as well as in healthy individuals(0.92%).The area under the curve of PIVKA-II for detecting malignancies was 0.7754(0.7620–0.7688),whereas that for detecting HCC was 0.7509(0.7357–0.7662).Stratifying the PIVKA-II values or combining PIVKA-II with AFP or CA19-9 helped improve the diagnostic performance of PIVKA-II for HCC.PIVKA-II values were significantly positively correlated with AST in patients with HCC and with bilirubin in patients with BC.Conclusions:This study determined the role of PIVKA-II in malignancy screening at hepatobiliary and pancreatic disease centers.It was also noted that the diagnostic efficacy of PIVKA-II for HCC improved after combining PIVKA-II with AFP or stratifying its value.
