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
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
AIM:To evaluate the association of nonalcoholic fatty liver disease(NAFLD)with acute ischemic stroke severity and in-hospital outcome.METHODS:We prospectively studied all patients who were admitted in our Department w...AIM:To evaluate the association of nonalcoholic fatty liver disease(NAFLD)with acute ischemic stroke severity and in-hospital outcome.METHODS:We prospectively studied all patients who were admitted in our Department with acute ischemic stroke between September 2010 and August 2012(n=415;39.5%males,mean age 78.8±6.6 years).The severity of stroke was assessed with the National Institutes of Health Stroke Scale(NIHSS)score at admission.NALFD was defined as serum alanine aminotransferase and/or aspartate aminotransferase levels above the upper limit of normal in the absence of other causes of elevated aminotransferases levels[chronic hepatitis B or C,drug toxicity,increased alcohol consumption(】21 and】14 drinks per week in men and women,respectively),cholestatic diseases or rhabdomyolysis].The outcome was assessed with the modified Rankin scale(mRS)score at discharge and in-hospital mortality.Adverse outcome was defined as mRS score at discharge≥2.Dependency at discharge was defined as mRS score between 2 to 5.RESULTS:NAFLD was present in 7.7%of the study population.Patients with NAFLD had lower serum high-density lipoprotein cholesterol and higher triglyceride levels than patients without NAFLD(P【0.05 for both comparisons).Demographic data,the prevalence of other cardiovascular risk factors and the prevalence of established CVD did not differ between the two groups.At admission,the NIHSS score did not differ between patients with and without NAFLD(6.3±6.4and 8.8±9.6,respectively;P=NS).At discharge,the mRS score did not differ between the two groups(1.9±2.2 and 2.6±2.2 in patients with and without NAFLD,respectively;P=NS).Rates of dependency at discharge were also similar in patients with and without NAFLD(36.8%and 55.0%,respectively;P=NS)as were the rates of adverse outcome(42.9%and58.6%,respectively;P=NS).In-hospital mortality rates also did not differ between the 2 groups(8.0%and 7.0%in patients with and without NAFLD,respectively;P=NS).CONCLUSION:The presence of NAFLD in patients admitted for acute ischemic stroke does not appear to be associated with more severe stroke or with worse in-hospital outcome.展开更多
Unique physiopathological characteristics of tumor tissues impose obstacles to the sufficient penetration of traditional nanomedicines,resulting in undesirable drug delivery efficacy and therapeutic outcomes.Here,we c...Unique physiopathological characteristics of tumor tissues impose obstacles to the sufficient penetration of traditional nanomedicines,resulting in undesirable drug delivery efficacy and therapeutic outcomes.Here,we constructed TRAIL-[NDHCPT]^(GAC),a synergistic hydroxycamptothecin(HCPT)and tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)protein co-loaded disk-shaped nanocarrier withγ-glutamyl transpeptidase responsiveness.When the novel nanodisks extravasated into the tumor interstitium,theγ-glutamyl transpeptidase overexpressed on the tumor cell membranes cleaved theγ-glutamyl portions of the nanodisk surface to produce positively charged amino groups.As a result,the cationic nanodisks possessed stronger tumor infiltration ability through transcytosis than anionic nanodisks.HCPT and TRAIL exerted synergistic antitumor effects with better overall therapeutic efficacy.This TRAIL-[ND-HCPT]^(GAC)system performed significantly better than free HCPT and remarkably prolonged the survival of breast tumor-bearing mice with no significant toxicity.展开更多
A γ-glutamyl transpeptidase （isopeptidase） has been purified 580-fold to homogeneity from the midgut of keratinophagous larvae of Hofmannophila pseudospretella. The enzyme is a single polypeptide of molecular mass ...A γ-glutamyl transpeptidase （isopeptidase） has been purified 580-fold to homogeneity from the midgut of keratinophagous larvae of Hofmannophila pseudospretella. The enzyme is a single polypeptide of molecular mass 80 kDa. The enzyme was identified by its hydrolytic activity against the synthetic substrate, γ-glutamyl-AMC, its molecular mass and inhibition profile compared to other γ-glutamyl transpeptidases. The enzyme is low or absent from most other insect digestive systems apart from other keratinophagous lepidopteran larvae and predatory carabids. While isopepfide bonds are present in high levels of the proteins in the diet of keratinophages, their presence in the diet of predatory beetles has not been established.展开更多
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.
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.
文摘AIM:To evaluate the association of nonalcoholic fatty liver disease(NAFLD)with acute ischemic stroke severity and in-hospital outcome.METHODS:We prospectively studied all patients who were admitted in our Department with acute ischemic stroke between September 2010 and August 2012(n=415;39.5%males,mean age 78.8±6.6 years).The severity of stroke was assessed with the National Institutes of Health Stroke Scale(NIHSS)score at admission.NALFD was defined as serum alanine aminotransferase and/or aspartate aminotransferase levels above the upper limit of normal in the absence of other causes of elevated aminotransferases levels[chronic hepatitis B or C,drug toxicity,increased alcohol consumption(】21 and】14 drinks per week in men and women,respectively),cholestatic diseases or rhabdomyolysis].The outcome was assessed with the modified Rankin scale(mRS)score at discharge and in-hospital mortality.Adverse outcome was defined as mRS score at discharge≥2.Dependency at discharge was defined as mRS score between 2 to 5.RESULTS:NAFLD was present in 7.7%of the study population.Patients with NAFLD had lower serum high-density lipoprotein cholesterol and higher triglyceride levels than patients without NAFLD(P【0.05 for both comparisons).Demographic data,the prevalence of other cardiovascular risk factors and the prevalence of established CVD did not differ between the two groups.At admission,the NIHSS score did not differ between patients with and without NAFLD(6.3±6.4and 8.8±9.6,respectively;P=NS).At discharge,the mRS score did not differ between the two groups(1.9±2.2 and 2.6±2.2 in patients with and without NAFLD,respectively;P=NS).Rates of dependency at discharge were also similar in patients with and without NAFLD(36.8%and 55.0%,respectively;P=NS)as were the rates of adverse outcome(42.9%and58.6%,respectively;P=NS).In-hospital mortality rates also did not differ between the 2 groups(8.0%and 7.0%in patients with and without NAFLD,respectively;P=NS).CONCLUSION:The presence of NAFLD in patients admitted for acute ischemic stroke does not appear to be associated with more severe stroke or with worse in-hospital outcome.
基金The Regional Innovation and Development Joint Fund(No.U20A20411)the National Science Fund for Excellent Young Scholars(No.82022070)provided funding for this work。
文摘Unique physiopathological characteristics of tumor tissues impose obstacles to the sufficient penetration of traditional nanomedicines,resulting in undesirable drug delivery efficacy and therapeutic outcomes.Here,we constructed TRAIL-[NDHCPT]^(GAC),a synergistic hydroxycamptothecin(HCPT)and tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)protein co-loaded disk-shaped nanocarrier withγ-glutamyl transpeptidase responsiveness.When the novel nanodisks extravasated into the tumor interstitium,theγ-glutamyl transpeptidase overexpressed on the tumor cell membranes cleaved theγ-glutamyl portions of the nanodisk surface to produce positively charged amino groups.As a result,the cationic nanodisks possessed stronger tumor infiltration ability through transcytosis than anionic nanodisks.HCPT and TRAIL exerted synergistic antitumor effects with better overall therapeutic efficacy.This TRAIL-[ND-HCPT]^(GAC)system performed significantly better than free HCPT and remarkably prolonged the survival of breast tumor-bearing mice with no significant toxicity.
文摘A γ-glutamyl transpeptidase （isopeptidase） has been purified 580-fold to homogeneity from the midgut of keratinophagous larvae of Hofmannophila pseudospretella. The enzyme is a single polypeptide of molecular mass 80 kDa. The enzyme was identified by its hydrolytic activity against the synthetic substrate, γ-glutamyl-AMC, its molecular mass and inhibition profile compared to other γ-glutamyl transpeptidases. The enzyme is low or absent from most other insect digestive systems apart from other keratinophagous lepidopteran larvae and predatory carabids. While isopepfide bonds are present in high levels of the proteins in the diet of keratinophages, their presence in the diet of predatory beetles has not been established.
