Summary:The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease.Understanding the dysregulated human immune ...Summary:The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease.Understanding the dysregulated human immune responses in the fatal subjects is critical for management of COVID-19 patients and the pandemic.In this study,we examined the immune cell compositions in the lung tissues and hilar lymph nodes using immunohistochemistry on 6 deceased COVID-19 patients and 4 focal organizing pneumonia(FOP)patients who underwent lung surgery and served as controls.We found a dominant presence of macrophages and a general deficiency of T cells and B cells in the lung tissues from deceased COVID-19 patients.In contrast to the FOP patients,Tfh cells and germinal center formation were largely absent in the draining hilar lymph nodes in the deceased COVID-19 patients.This was correlated with reduced IgM and IgG levels compared to convalescent COVID-19 patients.In summary,our data highlight a defect of germinal center structure in deceased COVID-19 patients leading to an impaired humoral immunity.Understanding the mechanisms of this deficiency will be one of the key points for the management of this epidemic.展开更多
BACKGROUND Primary liver cancer includes three subtypes:Hepatocellular carcinoma(HCC),intrahepatic cholangiocarcinoma(CCA),and combined hepatocellular carcinoma.Patients with primary liver cancer experienced poor prog...BACKGROUND Primary liver cancer includes three subtypes:Hepatocellular carcinoma(HCC),intrahepatic cholangiocarcinoma(CCA),and combined hepatocellular carcinoma.Patients with primary liver cancer experienced poor prognosis and high mortality,so early detection of liver cancer and improved management of metastases are both key strategies to reduce the death toll from liver cancer.Prostate-specific membrane antigen(PSMA)expression in the tumor-associated neovasculature of nonprostate malignancies including liver cancer has been reported recently,but conclusive evidence of PSMA expression based on the pathological type of liver cancer remains limited.AIM To study the expression of PSMA in HCC,CCA,and liver cirrhosis.METHODS A total of 446 formalin-fixed paraffin-embedded(FFPE)liver tumor and liver cirrhosis tissue samples were obtained retrospectively from the Pathology Department of Tongji Hospital.Immunohistochemistry was used to detect PSMA expression in these 446 FFPE liver biopsy specimens(213 HCC,203 CCA,and 30 liver cirrhosis).The tumor compartment and the associated neovascular endothelium were separately analyzed.PSMA expression was examined by two certified pathologists,and the final results were presented in a 4-point scoring system(0-3 points).Correlation between PSMA expression and clinicopathological information was also assessed.RESULTS PSMA was expressed primarily in the neovascular endothelium associated with tumors.The positive rate of PSMA staining in HCC was significantly higher than that in CCA(86.8%vs 79.3%;P=0.001)but was only 6.6%in liver cirrhosis(P=0.000).HCC cases had more 3-score PSMA staining than CCA had(89/213,41.8%vs 35/203,17.2%;P=0.001).PSMA expression correlated positively with the stage and grade of HCC and CCA.In both liver cancer subtypes,there were more PSMA+cases in stages III–V diseases than in stages I and II.High staining intensity of PSMA was more frequently observed in liver cancers at high grade and advanced stage.There was no significant association of PSMA expression with sex,age,region,α-fetoprotein,hepatitis B surface antigen,or tumor size in both tumor subtypes.CONCLUSION Neovascular PSMA may be a promising marker to differentiate HCC from liver cirrhosis and a prognostic marker for anti-tumor angiogenesis therapy for HCC.展开更多
The molecular mechanisms underlying the development of intrahepatic cholangiocarcinoma(ICC)are not clear yet.In this study,we investigated the involvement of Notch1 in the development of ICC.The cDNA microarray analys...The molecular mechanisms underlying the development of intrahepatic cholangiocarcinoma(ICC)are not clear yet.In this study,we investigated the involvement of Notch1 in the development of ICC.The cDNA microarray analysis showed that Notch1 expression was higher in ICC tissues than in normal biliary epithelial cells.Stable transfection of Notchl receptor intracellular domain(NICD1)by hydrodynamic tail vein injection induced ICC formation in mice.Western blotting confirmed that Notchl signaling was activated in human ICC cell lines and mouse ICC tissues.Silencing Notchl with specific short interfering RNA(siRNA)inhibited the proliferation of ICC cells.Flow cytometry and Western blotting indicated that apoptosis was induced in Notchl-silenced ICC cells compared with controls.Additionally,Notchl silencing was associated with the inhibition of hairy and enhancer of split-1(Hes1)and activation of the phosphatase and tensin homolog(PTEN)/p53 pathway.Taken together,these data suggest that Notchl drives ICC formation and proliferation;downregulation of Notchl induces apoptosis in ICC cells;Notchl signaling may serve as a novel therapeutic target for the treatment of ICC.展开更多
Objective Clinical immunohistochemistry plays an increasingly important role in pathologic diagnosis. We investigated the usefulness of an immunohistochemical panel of glypican-3 (GPC3), hepatocyte paraffin antigen-1 ...Objective Clinical immunohistochemistry plays an increasingly important role in pathologic diagnosis. We investigated the usefulness of an immunohistochemical panel of glypican-3 (GPC3), hepatocyte paraffin antigen-1 (HepPar-1), arginase-1 (Arg-1), cytokeratin-19 (CK19), and human epithelial membrane antigen (EMA) for the differential diagnosis of liver tumors. Methods Two hundred and thirty-five immunohistochemical sections of hepatocellular carcinoma (HCC;120 cases), intrahepatic cholangiocarcinoma (ICC;50 cases), combined hepatocellular and cholangiocarcinoma (CHC;17 cases), metastatic adenocarcinoma (20 cases), and benign liver lesions (28 cases) were obtained from the Department of Pathology at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. The sensitivity and specificity of the combined biomarkers GPC3/HepPar-1/Arg-1/CK19/EMA for the differential diagnosis of HCC, ICC, and CHC were calculated and analyzed retrospectively. Results The combined biomarkers GPC3+/CK19– had the highest specificity (98.3%) for diagnosing HCC, with a sensitivity of 60.0%. The specificity of GPC3–/HepPar-1–/Arg-1–/CK19+/EMA+ for diagnosing ICC was 93.0%, with a sensitivity of 76.0%. The specificity of GPC3+/HepPar-1+/Arg-1+/CK19+/EMA+ for diagnosing CHC was 95.9%, with a sensitivity of 52.9%. Conclusion The combined biomarkers GPC3/HepPar-1/Arg-1/CK19/EMA greatly improved the specificity of liver tumor diagnosis. We believe that clinical pathological work could improve the original determination of liver nodules.展开更多
We designed and synthesized a series of 2-thioxo-4-thiazolidinone derivatives and evaluated them on peroxisome proliferator activated receptor γ(PPARγ) binding activities.Through the biological assays,compounds 18...We designed and synthesized a series of 2-thioxo-4-thiazolidinone derivatives and evaluated them on peroxisome proliferator activated receptor γ(PPARγ) binding activities.Through the biological assays,compounds 18 and 38 were highlighted with K_i values of 12.15 nmol/Land 14.46 nmol/L,respectively.Then structure-activity relationship(SAR) was analyzed to screen privileged structural modifications.Moreover,molecular fitting of these compounds onto the approved drug Rosightazone in the PPARγligand binding domain was performed to elucidate the SAR and explore potential receptor-ligand interactions.These results demonstrate that the 2-thioxo-4-thiazolidinones can be considered as new promising molecular probes with excellent binding activities to PPARγ.展开更多
Hilar cholangiocarcinoma,first described by Klatskin in 1965,is a relatively rare tumor arising from the bile ducts.The histomorphological features of hilar cholangiocarcinoma are identical with other extra-and intra-h...Hilar cholangiocarcinoma,first described by Klatskin in 1965,is a relatively rare tumor arising from the bile ducts.The histomorphological features of hilar cholangiocarcinoma are identical with other extra-and intra-hepatic bile duct carcinomas.The most common disease associated with cholangiocarcinoma is primary sclerosing cholangitis.The development of cholangiocar-cinoma is a multistep process associated with several mutations in oncogenes and tumor-suppressor genes.Based on macroscopic appearance,three distinct subtypes have been described:sclerosing,nodular,and papillary.Microscopically,more than 95%of tumors are adenocar-cinomas.Hilar cholangiocarcinoma is a slowly growing tumor and tends to spread longitudinally along the bile ducts with neural,perineural,and subepithelial extension.Lymph node invasion can be found in 30%–50%patients at the time of diagnosis,but blood-born metastases are rare and usually occur at late stages.展开更多
基金The study was funded by grants from the Special R&D Program of Ministry of Science and Technology(No.2019YFC1316203)Ministry of Science and Technology(No.2020YFC0844700)Clinical Foundation of Tongji Hospital(No.XXGZBDYJ010).
文摘Summary:The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease.Understanding the dysregulated human immune responses in the fatal subjects is critical for management of COVID-19 patients and the pandemic.In this study,we examined the immune cell compositions in the lung tissues and hilar lymph nodes using immunohistochemistry on 6 deceased COVID-19 patients and 4 focal organizing pneumonia(FOP)patients who underwent lung surgery and served as controls.We found a dominant presence of macrophages and a general deficiency of T cells and B cells in the lung tissues from deceased COVID-19 patients.In contrast to the FOP patients,Tfh cells and germinal center formation were largely absent in the draining hilar lymph nodes in the deceased COVID-19 patients.This was correlated with reduced IgM and IgG levels compared to convalescent COVID-19 patients.In summary,our data highlight a defect of germinal center structure in deceased COVID-19 patients leading to an impaired humoral immunity.Understanding the mechanisms of this deficiency will be one of the key points for the management of this epidemic.
基金National Natural Science Foundation of China,No.81873903,No.81671718,No.91959119 and No.81271600Natural Science Foundation of Hubei Province in China,No.2016CFB687.
文摘BACKGROUND Primary liver cancer includes three subtypes:Hepatocellular carcinoma(HCC),intrahepatic cholangiocarcinoma(CCA),and combined hepatocellular carcinoma.Patients with primary liver cancer experienced poor prognosis and high mortality,so early detection of liver cancer and improved management of metastases are both key strategies to reduce the death toll from liver cancer.Prostate-specific membrane antigen(PSMA)expression in the tumor-associated neovasculature of nonprostate malignancies including liver cancer has been reported recently,but conclusive evidence of PSMA expression based on the pathological type of liver cancer remains limited.AIM To study the expression of PSMA in HCC,CCA,and liver cirrhosis.METHODS A total of 446 formalin-fixed paraffin-embedded(FFPE)liver tumor and liver cirrhosis tissue samples were obtained retrospectively from the Pathology Department of Tongji Hospital.Immunohistochemistry was used to detect PSMA expression in these 446 FFPE liver biopsy specimens(213 HCC,203 CCA,and 30 liver cirrhosis).The tumor compartment and the associated neovascular endothelium were separately analyzed.PSMA expression was examined by two certified pathologists,and the final results were presented in a 4-point scoring system(0-3 points).Correlation between PSMA expression and clinicopathological information was also assessed.RESULTS PSMA was expressed primarily in the neovascular endothelium associated with tumors.The positive rate of PSMA staining in HCC was significantly higher than that in CCA(86.8%vs 79.3%;P=0.001)but was only 6.6%in liver cirrhosis(P=0.000).HCC cases had more 3-score PSMA staining than CCA had(89/213,41.8%vs 35/203,17.2%;P=0.001).PSMA expression correlated positively with the stage and grade of HCC and CCA.In both liver cancer subtypes,there were more PSMA+cases in stages III–V diseases than in stages I and II.High staining intensity of PSMA was more frequently observed in liver cancers at high grade and advanced stage.There was no significant association of PSMA expression with sex,age,region,α-fetoprotein,hepatitis B surface antigen,or tumor size in both tumor subtypes.CONCLUSION Neovascular PSMA may be a promising marker to differentiate HCC from liver cirrhosis and a prognostic marker for anti-tumor angiogenesis therapy for HCC.
基金the National Natural Science Foundation of China(No.81801621,No.81572723,No.81872253).
文摘The molecular mechanisms underlying the development of intrahepatic cholangiocarcinoma(ICC)are not clear yet.In this study,we investigated the involvement of Notch1 in the development of ICC.The cDNA microarray analysis showed that Notch1 expression was higher in ICC tissues than in normal biliary epithelial cells.Stable transfection of Notchl receptor intracellular domain(NICD1)by hydrodynamic tail vein injection induced ICC formation in mice.Western blotting confirmed that Notchl signaling was activated in human ICC cell lines and mouse ICC tissues.Silencing Notchl with specific short interfering RNA(siRNA)inhibited the proliferation of ICC cells.Flow cytometry and Western blotting indicated that apoptosis was induced in Notchl-silenced ICC cells compared with controls.Additionally,Notchl silencing was associated with the inhibition of hairy and enhancer of split-1(Hes1)and activation of the phosphatase and tensin homolog(PTEN)/p53 pathway.Taken together,these data suggest that Notchl drives ICC formation and proliferation;downregulation of Notchl induces apoptosis in ICC cells;Notchl signaling may serve as a novel therapeutic target for the treatment of ICC.
基金Supported by grants from National Natural Science Foundation of China(NSFC No.81271600,81671718 and 81873903)+1 种基金the Natural Science Foundation of Hubei Province in China(No.2016CFB687)the Clinical Foundation of Tongji Hospital(No.2015C013)
文摘Objective Clinical immunohistochemistry plays an increasingly important role in pathologic diagnosis. We investigated the usefulness of an immunohistochemical panel of glypican-3 (GPC3), hepatocyte paraffin antigen-1 (HepPar-1), arginase-1 (Arg-1), cytokeratin-19 (CK19), and human epithelial membrane antigen (EMA) for the differential diagnosis of liver tumors. Methods Two hundred and thirty-five immunohistochemical sections of hepatocellular carcinoma (HCC;120 cases), intrahepatic cholangiocarcinoma (ICC;50 cases), combined hepatocellular and cholangiocarcinoma (CHC;17 cases), metastatic adenocarcinoma (20 cases), and benign liver lesions (28 cases) were obtained from the Department of Pathology at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. The sensitivity and specificity of the combined biomarkers GPC3/HepPar-1/Arg-1/CK19/EMA for the differential diagnosis of HCC, ICC, and CHC were calculated and analyzed retrospectively. Results The combined biomarkers GPC3+/CK19– had the highest specificity (98.3%) for diagnosing HCC, with a sensitivity of 60.0%. The specificity of GPC3–/HepPar-1–/Arg-1–/CK19+/EMA+ for diagnosing ICC was 93.0%, with a sensitivity of 76.0%. The specificity of GPC3+/HepPar-1+/Arg-1+/CK19+/EMA+ for diagnosing CHC was 95.9%, with a sensitivity of 52.9%. Conclusion The combined biomarkers GPC3/HepPar-1/Arg-1/CK19/EMA greatly improved the specificity of liver tumor diagnosis. We believe that clinical pathological work could improve the original determination of liver nodules.
基金supported by the National Natural Science Foundation of China(Nos.81072627,81230090 and 81222046)Shanghai Committee of Science and Technology(Nos.12431900901 and 12401900801)the Fundamental Research Funds for the Central Universities(111 Project,No.B07023)
文摘We designed and synthesized a series of 2-thioxo-4-thiazolidinone derivatives and evaluated them on peroxisome proliferator activated receptor γ(PPARγ) binding activities.Through the biological assays,compounds 18 and 38 were highlighted with K_i values of 12.15 nmol/Land 14.46 nmol/L,respectively.Then structure-activity relationship(SAR) was analyzed to screen privileged structural modifications.Moreover,molecular fitting of these compounds onto the approved drug Rosightazone in the PPARγligand binding domain was performed to elucidate the SAR and explore potential receptor-ligand interactions.These results demonstrate that the 2-thioxo-4-thiazolidinones can be considered as new promising molecular probes with excellent binding activities to PPARγ.
文摘Hilar cholangiocarcinoma,first described by Klatskin in 1965,is a relatively rare tumor arising from the bile ducts.The histomorphological features of hilar cholangiocarcinoma are identical with other extra-and intra-hepatic bile duct carcinomas.The most common disease associated with cholangiocarcinoma is primary sclerosing cholangitis.The development of cholangiocar-cinoma is a multistep process associated with several mutations in oncogenes and tumor-suppressor genes.Based on macroscopic appearance,three distinct subtypes have been described:sclerosing,nodular,and papillary.Microscopically,more than 95%of tumors are adenocar-cinomas.Hilar cholangiocarcinoma is a slowly growing tumor and tends to spread longitudinally along the bile ducts with neural,perineural,and subepithelial extension.Lymph node invasion can be found in 30%–50%patients at the time of diagnosis,but blood-born metastases are rare and usually occur at late stages.