BACKGROUND Nonalcoholic fatty liver disease(NAFLD)and nonalcoholic steatohepatitis(NASH)seem common after liver transplantation.AIM To investigate incidence and predictors of NAFLD and NASH by employing noninvasive te...BACKGROUND Nonalcoholic fatty liver disease(NAFLD)and nonalcoholic steatohepatitis(NASH)seem common after liver transplantation.AIM To investigate incidence and predictors of NAFLD and NASH by employing noninvasive testing in liver transplant recipients,namely controlled attenuation parameter(CAP)and the serum biomarker cytokeratin 18(CK-18).We also evaluated the diagnostic accuracy of CK-18 and CAP compared to liver histology.METHODS We prospectively recruited consecutive adult patients who received liver transplant at the McGill University Health Centre between 2015-2018.Serial measurements of CK-18 and CAP were recorded.NAFLD and NASH were diagnosed by CAP≥270 dB/m,and a combination of CAP≥270 dB/m with CK-18>130.5 U/L,respectively.Incidences and predictors of NAFLD and NASH were investigated using survival analysis and Cox proportional hazards.RESULTS Overall,40 liver transplant recipients(mean age 57 years;70%males)were included.During a median follow-up of 16.8 mo(interquartile range 15.6-18.0),63.0%and 48.5%of patients developed NAFLD and NASH,respectively.On multivariable analysis,after adjusting for sex and alanine aminotransferase,body mass index was an independent predictor of development of NAFLD[adjusted hazard ratio(aHR):1.21,95%confidence interval(CI):1.04-1.41;P=0.01]and NASH(aHR:1.26,95%CI:1.06-1.49;P<0.01).Compared to liver histology,CAP had a 76%accuracy to diagnose NAFLD,while the accuracy of CAP plus CK-18 to diagnose NASH was 82%.CONCLUSION NAFLD and NASH diagnosed non-invasively are frequent in liver transplant recipients within the first 18 mo.Close follow-up and nutritional counselling should be planned in overweight patients.展开更多
AIM: To investigate whether serum levels of two soluble forms of extracellular cytokeratin 18 (M30-antigen and M65-antigen) may differentiate nonalcoholic steatohepatitis (NASH) from simple steatosis in patients with ...AIM: To investigate whether serum levels of two soluble forms of extracellular cytokeratin 18 (M30-antigen and M65-antigen) may differentiate nonalcoholic steatohepatitis (NASH) from simple steatosis in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: A total of 83 patients with suspected NAFLD and 49 healthy volunteers were investigated. Patients with suspected NAFLD were classified according to their liver histology into four groups: definitive NASH (n = 45), borderline NASH (n = 24), simple fatty liver (n = 9), and normal tissue (n = 5). Serum levels of caspase-3 generated cytokeratin-18 fragments (M30-antigen) and total cytokeratin-18 (M65-antigen) were determined by ELISA. RESULTS: Levels of M30-antigen and M65-antigen were significantly higher in patients with definitive NASH compared to the other groups. An abnormal value (> 121.60 IU/L) of M30-antigen yielded a 60.0% sensitivity and a 97.4% specificity for the diagnosis of NASH. Sensitivity and specificity of an abnormal M65-antigen level (> 243.82 IU/L) for the diagnosis of NASH were 68.9% and 81.6%, respectively. Among patients with NAFLD, M30-antigen and M65-antigen levels distinguished between advanced fibrosis and early-stage fibrosis with a sensitivity of 64.7% and 70.6%, and a specificity of 77.3% and 71.2%, respectively. CONCLUSION: Serum levels of M30-antigen and M65-antigen may be of clinical usefulness to identify patients with NASH. Further studies are mandatory to better assess the role of these apoptonecrotic biomarkers in NAFLD pathophysiology.展开更多
The role of Ese-2, an Ets family transcription factor, in gene regulation is not known. In this study, the interactionbetween Ese-2 and cytokeratin 18 (K18) intron 1 was characterized in lung epithelial cells. Reporte...The role of Ese-2, an Ets family transcription factor, in gene regulation is not known. In this study, the interactionbetween Ese-2 and cytokeratin 18 (K18) intron 1 was characterized in lung epithelial cells. Reporter gene assays showedEse-2 was able to upregulate K18 intron 1 enhanced reporter gene expression by approximately 2-fold. We found thatfull length Ese-2 did not bind DNA strongly, therefore truncated versions of the protein, containing the ETS domain orPointed domain, were created and tested in electrophoresis mobility shift assays. Multiple interactions between the ETSdomain and putative DNA binding sites within K18 intron 1 were observed, which led to the determination of a possibleEse-2 DNA binding consensus sequence. These experiments suggest that Ese-2 could play a role in the regulation ofK18 expression in lung epithelial cells.展开更多
Background: Benign prostate hyperplasia (BPH) is the most common benign disease of the human prostate. The comparison between global versus local changes in spatial patterns of pathological lesions provoked a growing ...Background: Benign prostate hyperplasia (BPH) is the most common benign disease of the human prostate. The comparison between global versus local changes in spatial patterns of pathological lesions provoked a growing interest in some fields such as neuropathology. To date, there is little data on this subject in prostatic pathology. Given the interest of local parameters to distinguish between normal and pathological structures, the present study will apply first and second order stereological tools to find out if the cytokeratin18 (ck18) immunoexpression shows relevant local changes in BPH compared to normal prostate, independently if global estimates were similar in both groups. Methods: To verify if the global and local changes in immuno-expression of ck18 are relevant to ascertain differences between normal (CTR) and BPH cases, the following parameters will be applied: Volume fraction of epithelium immunostained for ck18 (VV ck18), both in global and local estimates;dispersion indices of VV ck18;estimates of local variance of VV ck18 (positional and of scale) using wavelet analysis;and lacunarity analysis to measure the tissue heterogeneity. Then, the set of values from the parameters studied that show significant differences between CTR and BPH will be employed to perform stepwise linear discriminant analyses to determine if locally estimated parameters were able to classify accurately the cases in CTR and BPH groups. Results and Conclusions: The findings of the present study indicate that changes in the expression of ck18 by the hyperplastic prostatic epithelium are not homogeneous. This limits the use of a single biopsy based markers to predict biological behavior in BPH. On the other hand, the local changes in the expression of ck18 are more evident in terms of VV ck18 and its local variability, whereas other parameters that are useful in other pathologies, such as lacunarity, are less relevant In prostatic hyperplasia.展开更多
AIM: To elucidate the possible crosstalk between angiogenesis, cytokeratin-18 (CK-18), and insulin resistance (IR) especially in patients with non-alcoholic steatohepatitis (NASH).METHODS: Twenty-eight patients with N...AIM: To elucidate the possible crosstalk between angiogenesis, cytokeratin-18 (CK-18), and insulin resistance (IR) especially in patients with non-alcoholic steatohepatitis (NASH).METHODS: Twenty-eight patients with NASH and 11 with simple fatty liver disease (FL) were enrolled in this study and underwent clinicopathological examination. The measures of angiogenesis, CK-18, and IR employed were CD34-immunopositive vessels, CK-18immunopositive cells, and homeostasis model assessment of IR (HOMA-IR), respectively. The correlations of these factors with NASH were elucidated.RESULTS: Significant development of hepatic neovascularization was observed only in NASH, whereas almost no neovascularization could be observed in FL and healthy liver. The degree of angiogenesis was almost parallel to liver fibrosis development, and both parameters were positively correlated. Similarly, CK-18expression and HOMA-R were signifi cantly increased in NASH as compared with FL and healthy liver. Furthermore, CK-18 and HOMA-IR were also positively correlated with the degree of neovascularization. CONCLUSION: These results indicate that the crosstalk between angiogenesis, CK-18, and IR may play an important role in the onset and progression of NASH.展开更多
AIM:To examine cytokeratin-18(CK-18) and caspasecleaved CK-18 expression in tumours and correlate with clinicopathological outcomes including tumour regression grade(TRG) response.METHODS:Formalin-fixed human gastro-o...AIM:To examine cytokeratin-18(CK-18) and caspasecleaved CK-18 expression in tumours and correlate with clinicopathological outcomes including tumour regression grade(TRG) response.METHODS:Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays.The first set consisted of 122 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 97 gastric/gastrooesophageal cancer cases exposed to pre-operative platinum-based chemotherapy.Expression of CK-18 and caspase-cleaved CK-18 was investigated using immunohistochemistry.RESULTS:CK18 was commonly expressed in gastrooesophageal tumours(92.6%).Fifty-six point seven percent of tumours previously exposed to neoadjuvant chemotherapy were positive for caspase-cleaved CK-18 expression compared to only 24.6% of tumours not previously exposed to neoadjuvant chemotherapy(P = 0.009).In patients who received neoadjuvant chemotherapy,caspase-cleaved cytokeratin-18 expression correlated with favourable TRG response(TRG 1,2 or 3,P = 0.043).CONCLUSION:This is the largest study to date of CK-18 and caspase-cleaved CK-18 expression in gastrooesophageal tumours.We provide the first evidence that caspase-cleaved CK-18 predicts tumour regression with neoadjuvant chemotherapy.展开更多
基金the Canadian Donation and Transplantation Research Program of the Canadian Society of Transplantation(grant competition 2014)Sebastiani G is supported by a Senior Salary Award from Fonds de la Recherche en Santédu Quebéc(FRQS)(No.#296306).
文摘BACKGROUND Nonalcoholic fatty liver disease(NAFLD)and nonalcoholic steatohepatitis(NASH)seem common after liver transplantation.AIM To investigate incidence and predictors of NAFLD and NASH by employing noninvasive testing in liver transplant recipients,namely controlled attenuation parameter(CAP)and the serum biomarker cytokeratin 18(CK-18).We also evaluated the diagnostic accuracy of CK-18 and CAP compared to liver histology.METHODS We prospectively recruited consecutive adult patients who received liver transplant at the McGill University Health Centre between 2015-2018.Serial measurements of CK-18 and CAP were recorded.NAFLD and NASH were diagnosed by CAP≥270 dB/m,and a combination of CAP≥270 dB/m with CK-18>130.5 U/L,respectively.Incidences and predictors of NAFLD and NASH were investigated using survival analysis and Cox proportional hazards.RESULTS Overall,40 liver transplant recipients(mean age 57 years;70%males)were included.During a median follow-up of 16.8 mo(interquartile range 15.6-18.0),63.0%and 48.5%of patients developed NAFLD and NASH,respectively.On multivariable analysis,after adjusting for sex and alanine aminotransferase,body mass index was an independent predictor of development of NAFLD[adjusted hazard ratio(aHR):1.21,95%confidence interval(CI):1.04-1.41;P=0.01]and NASH(aHR:1.26,95%CI:1.06-1.49;P<0.01).Compared to liver histology,CAP had a 76%accuracy to diagnose NAFLD,while the accuracy of CAP plus CK-18 to diagnose NASH was 82%.CONCLUSION NAFLD and NASH diagnosed non-invasively are frequent in liver transplant recipients within the first 18 mo.Close follow-up and nutritional counselling should be planned in overweight patients.
文摘AIM: To investigate whether serum levels of two soluble forms of extracellular cytokeratin 18 (M30-antigen and M65-antigen) may differentiate nonalcoholic steatohepatitis (NASH) from simple steatosis in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: A total of 83 patients with suspected NAFLD and 49 healthy volunteers were investigated. Patients with suspected NAFLD were classified according to their liver histology into four groups: definitive NASH (n = 45), borderline NASH (n = 24), simple fatty liver (n = 9), and normal tissue (n = 5). Serum levels of caspase-3 generated cytokeratin-18 fragments (M30-antigen) and total cytokeratin-18 (M65-antigen) were determined by ELISA. RESULTS: Levels of M30-antigen and M65-antigen were significantly higher in patients with definitive NASH compared to the other groups. An abnormal value (> 121.60 IU/L) of M30-antigen yielded a 60.0% sensitivity and a 97.4% specificity for the diagnosis of NASH. Sensitivity and specificity of an abnormal M65-antigen level (> 243.82 IU/L) for the diagnosis of NASH were 68.9% and 81.6%, respectively. Among patients with NAFLD, M30-antigen and M65-antigen levels distinguished between advanced fibrosis and early-stage fibrosis with a sensitivity of 64.7% and 70.6%, and a specificity of 77.3% and 71.2%, respectively. CONCLUSION: Serum levels of M30-antigen and M65-antigen may be of clinical usefulness to identify patients with NASH. Further studies are mandatory to better assess the role of these apoptonecrotic biomarkers in NAFLD pathophysiology.
文摘The role of Ese-2, an Ets family transcription factor, in gene regulation is not known. In this study, the interactionbetween Ese-2 and cytokeratin 18 (K18) intron 1 was characterized in lung epithelial cells. Reporter gene assays showedEse-2 was able to upregulate K18 intron 1 enhanced reporter gene expression by approximately 2-fold. We found thatfull length Ese-2 did not bind DNA strongly, therefore truncated versions of the protein, containing the ETS domain orPointed domain, were created and tested in electrophoresis mobility shift assays. Multiple interactions between the ETSdomain and putative DNA binding sites within K18 intron 1 were observed, which led to the determination of a possibleEse-2 DNA binding consensus sequence. These experiments suggest that Ese-2 could play a role in the regulation ofK18 expression in lung epithelial cells.
文摘Background: Benign prostate hyperplasia (BPH) is the most common benign disease of the human prostate. The comparison between global versus local changes in spatial patterns of pathological lesions provoked a growing interest in some fields such as neuropathology. To date, there is little data on this subject in prostatic pathology. Given the interest of local parameters to distinguish between normal and pathological structures, the present study will apply first and second order stereological tools to find out if the cytokeratin18 (ck18) immunoexpression shows relevant local changes in BPH compared to normal prostate, independently if global estimates were similar in both groups. Methods: To verify if the global and local changes in immuno-expression of ck18 are relevant to ascertain differences between normal (CTR) and BPH cases, the following parameters will be applied: Volume fraction of epithelium immunostained for ck18 (VV ck18), both in global and local estimates;dispersion indices of VV ck18;estimates of local variance of VV ck18 (positional and of scale) using wavelet analysis;and lacunarity analysis to measure the tissue heterogeneity. Then, the set of values from the parameters studied that show significant differences between CTR and BPH will be employed to perform stepwise linear discriminant analyses to determine if locally estimated parameters were able to classify accurately the cases in CTR and BPH groups. Results and Conclusions: The findings of the present study indicate that changes in the expression of ck18 by the hyperplastic prostatic epithelium are not homogeneous. This limits the use of a single biopsy based markers to predict biological behavior in BPH. On the other hand, the local changes in the expression of ck18 are more evident in terms of VV ck18 and its local variability, whereas other parameters that are useful in other pathologies, such as lacunarity, are less relevant In prostatic hyperplasia.
文摘AIM: To elucidate the possible crosstalk between angiogenesis, cytokeratin-18 (CK-18), and insulin resistance (IR) especially in patients with non-alcoholic steatohepatitis (NASH).METHODS: Twenty-eight patients with NASH and 11 with simple fatty liver disease (FL) were enrolled in this study and underwent clinicopathological examination. The measures of angiogenesis, CK-18, and IR employed were CD34-immunopositive vessels, CK-18immunopositive cells, and homeostasis model assessment of IR (HOMA-IR), respectively. The correlations of these factors with NASH were elucidated.RESULTS: Significant development of hepatic neovascularization was observed only in NASH, whereas almost no neovascularization could be observed in FL and healthy liver. The degree of angiogenesis was almost parallel to liver fibrosis development, and both parameters were positively correlated. Similarly, CK-18expression and HOMA-R were signifi cantly increased in NASH as compared with FL and healthy liver. Furthermore, CK-18 and HOMA-IR were also positively correlated with the degree of neovascularization. CONCLUSION: These results indicate that the crosstalk between angiogenesis, CK-18, and IR may play an important role in the onset and progression of NASH.
文摘AIM:To examine cytokeratin-18(CK-18) and caspasecleaved CK-18 expression in tumours and correlate with clinicopathological outcomes including tumour regression grade(TRG) response.METHODS:Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays.The first set consisted of 122 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 97 gastric/gastrooesophageal cancer cases exposed to pre-operative platinum-based chemotherapy.Expression of CK-18 and caspase-cleaved CK-18 was investigated using immunohistochemistry.RESULTS:CK18 was commonly expressed in gastrooesophageal tumours(92.6%).Fifty-six point seven percent of tumours previously exposed to neoadjuvant chemotherapy were positive for caspase-cleaved CK-18 expression compared to only 24.6% of tumours not previously exposed to neoadjuvant chemotherapy(P = 0.009).In patients who received neoadjuvant chemotherapy,caspase-cleaved cytokeratin-18 expression correlated with favourable TRG response(TRG 1,2 or 3,P = 0.043).CONCLUSION:This is the largest study to date of CK-18 and caspase-cleaved CK-18 expression in gastrooesophageal tumours.We provide the first evidence that caspase-cleaved CK-18 predicts tumour regression with neoadjuvant chemotherapy.
