Helicobacter pylori(H.pylori)gamma-glutamyl transpeptidase(GGT)is a bacterial virulence factor that converts glutamine into glutamate and ammonia,and converts glutathione into glutamate and cysteinylglycine.H.pylori G...Helicobacter pylori(H.pylori)gamma-glutamyl transpeptidase(GGT)is a bacterial virulence factor that converts glutamine into glutamate and ammonia,and converts glutathione into glutamate and cysteinylglycine.H.pylori GGT causes glutamine and glutathione consumption in the host cells,ammonia production and reactive oxygen species generation.These products induce cell-cycle arrest,apoptosis,and necrosis in gastric epithelial cells.H.pylori GGT may also inhibit apoptosis and induce gastric epithelial cell proliferation through the induction of cyclooxygenase-2,epidermal growth factor-related peptides,inducible nitric oxide synthase and interleukin-8.H.pylori GGT induces immune tolerance through the inhibition of T cell-mediated immunity and dendritic cell differentiation.The effect of GGT on H.pylori colonization and gastric persistence are also discussed.展开更多
Helicobacter pylori(H.pylori)produce an enzyme known asγ-glutamyl transpeptidase(HpGGT)that is highly conserved and common to all strains.HpGGT has been gaining increasing attention as an important virulence factor o...Helicobacter pylori(H.pylori)produce an enzyme known asγ-glutamyl transpeptidase(HpGGT)that is highly conserved and common to all strains.HpGGT has been gaining increasing attention as an important virulence factor of the bacterium,having been demonstrated to be an important colonization factor in several animal models and has also recently been strongly associated with the development of peptic ulcer disease.From the results of various independent researcher groups,it is clear that HpGGT acts through several pathways to damage gastric epithelial cells including the induction of apoptosis and cell cycle arrest,production of reactive oxygen species leading to DNA damage,promotion of inflammation by increasing cyclooxygenase-2 and interleukin-8 expression,and upregulation of heparin-binding epidermal growth factor-like growth factor resulting in cell survival and proliferation.In addition,the potential role of HpGGT in promoting gastric carcinogenesis will also be discussed in this review.Apart from affecting the gastric epithelium,HpGGT also has immunomodulatory actions on host immune cells where it displays an antiproliferative effect on T cells by inducing cell cycle arrest and also works with other H.pylori virulence factors to skew dendritic cells towards a tolerogenic phenotype,possibly contributing to the persistence of the pathogen in the gastric mucosa.展开更多
Objective Antibodies targeting programmed cell death protein 1(PD-1)have become the mainstay of treatment for chemotherapy-refractory gastric cancer,characterized by high levels of programmed cell death ligand-1(PDL-1...Objective Antibodies targeting programmed cell death protein 1(PD-1)have become the mainstay of treatment for chemotherapy-refractory gastric cancer,characterized by high levels of programmed cell death ligand-1(PDL-1)expression.However,the routine clinical implementation of PDL-1 testing is currently limited by the lack of robust detection methods.In this regard,the role of plasmaγ-glutamyl transpeptidase(GGT),an N-terminal nucleophilic hydrolase,as an independent predictor of the efficacy of anti-PD-1 therapy remains unknown.In this study,we aimed to assessed the prognostic role of changes in plasma GGT levels(6 weeks vs.baseline)in patients with advanced gastric cancer treated with anti-PD-1 immunotherapy.Methods We retrospectively analyzed data from 57 patients with gastric cancer treated with anti-PD-1 antibodies(camrelizumab,sintilimab,nivolumab,tislelizumab,and toripalimab)at the Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China,from July 2018 to February 2021.Results We found that after 6 weeks of treatment,there were significant differences between responders and non-responders with respect to plasma GGT levels(P<0.001).Multivariate logistic regression analysis revealed that the continuous value of the 6-week difference in GGT levels(OR=1.437,95%CI=1.116-1.849,P=0.005)and 6-week difference in GGT≥0 or<0(OR=53.675,95%CI=6.379-451.669,P<0.001)were independent predictors of disease control.Survival analysis indicated that a reduction in plasma GGT6 levels during treatment was significantly associated with a favorable progression-free survival(PFS)and overall survival(P<0.001).Consistently,univariate and multivariate Cox regression analyses revealed that a reduction in plasma GGT6 levels during treatment was an independent predictor of PFS(HR=1.033,95%CI=1.013-1.053,P=0.001).Conclusion Alterations in plasma GGT levels during treatment can be used as a predictor of disease progression and survival in patients with advanced gastric cancer undergoing treatment with anti-PD-1 antibodies.展开更多
BACKGROUND There is increasing interest in transplanting patients with hepatocellularcarcinoma (HCC) with tumors greater than 5 cm (Milan criteria).AIM To investigate possible prognostically-useful factors for liver t...BACKGROUND There is increasing interest in transplanting patients with hepatocellularcarcinoma (HCC) with tumors greater than 5 cm (Milan criteria).AIM To investigate possible prognostically-useful factors for liver transplantation inHCC patients with large tumors.METHODS In this clinical study, 50 patients with HCC who were transplanted at our LiverTransplant Center between April 2006 and August 2019 and had tumors greaterthan 6 cm maximum diameter were retrospectively analyzed. Their survival andfull clinical characteristics were examined, with respect to serum alphafetoprotein(AFP) and gamma glutamyl transpeptidase (GGT) levels. Kaplan-Meier survival estimates were used to determine overall survival and disease-freesurvival in these patients. The inclusion criterion was evidence of HCC. Exclusioncriteria were the presence of macroscopic portal vein thrombosis or metastasisand a follow-up period of less than 90 d.RESULTS Using receiver operating characteristic curve (ROC) analysis, cutoff values of AFP200 ng/mL and GGT 104 IU/L were identified and used in this study.Significantly longer overall survival (OS) and disease-free-survival (DFS) were found in patients who had lower values of either parameter, compared withhigher values. Even greater differences in survival were found when the 2parameters were combined. Two tumor size bands were identified, in searchingfor the limits of this approach with larger tumors, namely 6-10 cm and > 10 cm.Combination parameters in the 6-10 cm band reflected 5-year OS of 76.2% inpatients with low AFP plus low GGT vs 0% for all other groups. Patients withtumors greater than 10 cm, did not have low AFP plus low GGT. The mostconsistent clinical correlates for longer survival were degree of tumordifferentiation and absence of microscopic portal venous invasion.CONCLUSION Serum levels of AFP and GGT, both alone and combined, represent a simpleprognostic identifier in patients with large HCCs undergoing liver transplantation.展开更多
Photodynamic therapy(PDT),a light triggered therapeutic mode,has been recognized as an attractive treatment for oncotherapy.The phototoxicity to normal tissues during treatment limited the development of PDT owing to ...Photodynamic therapy(PDT),a light triggered therapeutic mode,has been recognized as an attractive treatment for oncotherapy.The phototoxicity to normal tissues during treatment limited the development of PDT owing to the always“on”properties of photosensitizers.Activatable photosensitizers are of great importance for improving the selectivity of PDT.Herein,we regarded the overexpressed GGT(γ-Glutamyl transpeptidase)enzyme in tumor cells as a biomarker and developed an activatable photosensitizer Cy-GGT by decorating a specific recognition moiety of GGT,L-glutamic acid,to a hemicyanine dye based on photosensitizer Cy-NH_(2).Cy-GGT was in the“off”state with negligible fluorescence and suppressed singlet oxygen generation,but it could be specifically hydrolyzed to Cy-NH_(2) in the presence of GGT,accompanied with significant fluorescence recovery and singlet oxygen generation increase under light irradiation.The in vitro and in vivo studies indicated that Cy-GGT was suitable for precise tumor imaging and could work as an efficient photosensitizer for inhibiting tumor growth.展开更多
基金Supported by Italian Ministry for University and Research(Progetto di Ricerca di Interesse Nazionale No.2009A37C8C_002,to Ricci V)Fondazione Cariplo Grant(No.2011-0485 to Ricci V)+2 种基金Second University of Naples(CIRANAD to Romano M)University of Naples "Federico Ⅱ"(Fondo d’Ateneo per la Ricercato Zarrilli R)
文摘Helicobacter pylori(H.pylori)gamma-glutamyl transpeptidase(GGT)is a bacterial virulence factor that converts glutamine into glutamate and ammonia,and converts glutathione into glutamate and cysteinylglycine.H.pylori GGT causes glutamine and glutathione consumption in the host cells,ammonia production and reactive oxygen species generation.These products induce cell-cycle arrest,apoptosis,and necrosis in gastric epithelial cells.H.pylori GGT may also inhibit apoptosis and induce gastric epithelial cell proliferation through the induction of cyclooxygenase-2,epidermal growth factor-related peptides,inducible nitric oxide synthase and interleukin-8.H.pylori GGT induces immune tolerance through the inhibition of T cell-mediated immunity and dendritic cell differentiation.The effect of GGT on H.pylori colonization and gastric persistence are also discussed.
基金Supported by Singapore National Medical Research Council,No.R182000180213
文摘Helicobacter pylori(H.pylori)produce an enzyme known asγ-glutamyl transpeptidase(HpGGT)that is highly conserved and common to all strains.HpGGT has been gaining increasing attention as an important virulence factor of the bacterium,having been demonstrated to be an important colonization factor in several animal models and has also recently been strongly associated with the development of peptic ulcer disease.From the results of various independent researcher groups,it is clear that HpGGT acts through several pathways to damage gastric epithelial cells including the induction of apoptosis and cell cycle arrest,production of reactive oxygen species leading to DNA damage,promotion of inflammation by increasing cyclooxygenase-2 and interleukin-8 expression,and upregulation of heparin-binding epidermal growth factor-like growth factor resulting in cell survival and proliferation.In addition,the potential role of HpGGT in promoting gastric carcinogenesis will also be discussed in this review.Apart from affecting the gastric epithelium,HpGGT also has immunomodulatory actions on host immune cells where it displays an antiproliferative effect on T cells by inducing cell cycle arrest and also works with other H.pylori virulence factors to skew dendritic cells towards a tolerogenic phenotype,possibly contributing to the persistence of the pathogen in the gastric mucosa.
基金Supported by a grant from the Hubei and the Huazhong University of Science and Technology Undergraduate Innovation and Entrepreneurship Training Program(No.S202110487427,DYLC2021072).
文摘Objective Antibodies targeting programmed cell death protein 1(PD-1)have become the mainstay of treatment for chemotherapy-refractory gastric cancer,characterized by high levels of programmed cell death ligand-1(PDL-1)expression.However,the routine clinical implementation of PDL-1 testing is currently limited by the lack of robust detection methods.In this regard,the role of plasmaγ-glutamyl transpeptidase(GGT),an N-terminal nucleophilic hydrolase,as an independent predictor of the efficacy of anti-PD-1 therapy remains unknown.In this study,we aimed to assessed the prognostic role of changes in plasma GGT levels(6 weeks vs.baseline)in patients with advanced gastric cancer treated with anti-PD-1 immunotherapy.Methods We retrospectively analyzed data from 57 patients with gastric cancer treated with anti-PD-1 antibodies(camrelizumab,sintilimab,nivolumab,tislelizumab,and toripalimab)at the Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China,from July 2018 to February 2021.Results We found that after 6 weeks of treatment,there were significant differences between responders and non-responders with respect to plasma GGT levels(P<0.001).Multivariate logistic regression analysis revealed that the continuous value of the 6-week difference in GGT levels(OR=1.437,95%CI=1.116-1.849,P=0.005)and 6-week difference in GGT≥0 or<0(OR=53.675,95%CI=6.379-451.669,P<0.001)were independent predictors of disease control.Survival analysis indicated that a reduction in plasma GGT6 levels during treatment was significantly associated with a favorable progression-free survival(PFS)and overall survival(P<0.001).Consistently,univariate and multivariate Cox regression analyses revealed that a reduction in plasma GGT6 levels during treatment was an independent predictor of PFS(HR=1.033,95%CI=1.013-1.053,P=0.001).Conclusion Alterations in plasma GGT levels during treatment can be used as a predictor of disease progression and survival in patients with advanced gastric cancer undergoing treatment with anti-PD-1 antibodies.
文摘BACKGROUND There is increasing interest in transplanting patients with hepatocellularcarcinoma (HCC) with tumors greater than 5 cm (Milan criteria).AIM To investigate possible prognostically-useful factors for liver transplantation inHCC patients with large tumors.METHODS In this clinical study, 50 patients with HCC who were transplanted at our LiverTransplant Center between April 2006 and August 2019 and had tumors greaterthan 6 cm maximum diameter were retrospectively analyzed. Their survival andfull clinical characteristics were examined, with respect to serum alphafetoprotein(AFP) and gamma glutamyl transpeptidase (GGT) levels. Kaplan-Meier survival estimates were used to determine overall survival and disease-freesurvival in these patients. The inclusion criterion was evidence of HCC. Exclusioncriteria were the presence of macroscopic portal vein thrombosis or metastasisand a follow-up period of less than 90 d.RESULTS Using receiver operating characteristic curve (ROC) analysis, cutoff values of AFP200 ng/mL and GGT 104 IU/L were identified and used in this study.Significantly longer overall survival (OS) and disease-free-survival (DFS) were found in patients who had lower values of either parameter, compared withhigher values. Even greater differences in survival were found when the 2parameters were combined. Two tumor size bands were identified, in searchingfor the limits of this approach with larger tumors, namely 6-10 cm and > 10 cm.Combination parameters in the 6-10 cm band reflected 5-year OS of 76.2% inpatients with low AFP plus low GGT vs 0% for all other groups. Patients withtumors greater than 10 cm, did not have low AFP plus low GGT. The mostconsistent clinical correlates for longer survival were degree of tumordifferentiation and absence of microscopic portal venous invasion.CONCLUSION Serum levels of AFP and GGT, both alone and combined, represent a simpleprognostic identifier in patients with large HCCs undergoing liver transplantation.
基金This work was supported by the National Natural Science Foundation of China(21925802,21878039,21822804,21808028,22022803,22078046)and the Natural Science Foundation of China-Liaoning Joint Fund(U1908202).
文摘Photodynamic therapy(PDT),a light triggered therapeutic mode,has been recognized as an attractive treatment for oncotherapy.The phototoxicity to normal tissues during treatment limited the development of PDT owing to the always“on”properties of photosensitizers.Activatable photosensitizers are of great importance for improving the selectivity of PDT.Herein,we regarded the overexpressed GGT(γ-Glutamyl transpeptidase)enzyme in tumor cells as a biomarker and developed an activatable photosensitizer Cy-GGT by decorating a specific recognition moiety of GGT,L-glutamic acid,to a hemicyanine dye based on photosensitizer Cy-NH_(2).Cy-GGT was in the“off”state with negligible fluorescence and suppressed singlet oxygen generation,but it could be specifically hydrolyzed to Cy-NH_(2) in the presence of GGT,accompanied with significant fluorescence recovery and singlet oxygen generation increase under light irradiation.The in vitro and in vivo studies indicated that Cy-GGT was suitable for precise tumor imaging and could work as an efficient photosensitizer for inhibiting tumor growth.
