AIM To evaluate the impact of the Glu167Lys(E167K) transmembrane 6 superfamily member 2(TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus(HIV)/hepatitis C v...AIM To evaluate the impact of the Glu167Lys(E167K) transmembrane 6 superfamily member 2(TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus(HIV)/hepatitis C virus(HCV) co-infected patients.METHODS The study comprised 167 consecutive patients with HIV/HCV coinfection and biopsy-proven chronic hepatitis. A pathologist graded liver fibrosis and necroinflammation using the Ishak scoring system, and steatosis using Kleiner's scoring system. Patients were genotyped for TM6SF2 E167K(rs58542926) by real-time Polymerase chain reaction. The 167 patients, 35 therapy-naive and 132 receiving ART, were prevalently males(73.6%), the median age was 40.7 years and the immunological condition good(median CD4+ cells/mm3 = 505.5).RESULTS The 17 patients with the TM6SF2 E167 K variant, compared with the 150 with TM6SF2-E/E, showed higher AST(P = 0.02) and alanine aminotransferase(P = 0.02) and higher fibrosis score(3.1 ± 2.0 vs 2.3 ± 1.5, P = 0.05). In a multivariate analysis, TM6SF2 E167 K was independently associated with severe fibrosis. The same analysis showed that HCV-genotype 3, present in 42.2% of patients was an independent predictor of severe steatosis. The association of TM6SF2 E167 K with severe steatosis, absent for the whole group of 167 patients, was re-evaluated separately for HCVgenotype 3 and non-3 patients: No factor was independently associated with severe steatosis in the HCV-genotype-3 subgroup, whereas an independent association was observed between severe steatosis and TM6SF2 E167 K in non-3 HCV genotypes. No association between the TM6SF2 E167 K variant and severe liver necroinflammation was observed.CONCLUSION In HIV/HCV coinfection the TM6SF2 E167 K variant is an independent predictor of severe fibrosis, but appears to be independently associated with severe steatosis only for patients with a non-3 HCV genotype.展开更多
This review intends to uncover how information from large-scale genetic profiling(whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease(NAFLD), as well as information from circulatin...This review intends to uncover how information from large-scale genetic profiling(whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease(NAFLD), as well as information from circulating transcriptomics(cell-free mi RNAs) and metabolomics, contributes to the understanding of NAFLD pathogenesis. A further aim is to address the question of whether OMICs information is ready to be implemented in the clinics. The available evidence suggests that any new knowledge pertaining to molecular signatures associated with NAFLD and nonalcoholic steatohepatitis should be promptly translated into the clinical setting. Nevertheless, rigorous steps that must include validation and replication are mandatory before utilizing OMICs biomarkers in diagnostics to identify patients at risk of advanced disease, including liver cancer.展开更多
Cyclin-dependent kinase 4 and 6(CDK4/6)inhibitors combined with endocrine therapy have transformed the treatment of estrogen receptor-positive(ER+)and human epidermal growth factor receptor 2 negative(HER2-)metastatic...Cyclin-dependent kinase 4 and 6(CDK4/6)inhibitors combined with endocrine therapy have transformed the treatment of estrogen receptor-positive(ER+)and human epidermal growth factor receptor 2 negative(HER2-)metastatic breast cancer.However,some patients do not respond to this treatment,and patients inevitably develop resistance,such that novel biomarkers are needed to predict primary resistance,monitor treatment response for acquired resistance,and personalize treatment strategies.Circumventing the spatial and temporal limitations of tissue biopsy,newly developed liquid biopsy approaches have the potential to uncover biomarkers that can predict CDK4/6 inhibitor efficacy and resistance in breast cancer patients through a simple blood test.Studies on circulating tumor DNA(ctDNA)-based liquid biopsy biomarkers of CDK4/6 inhibitor resistance have focused primarily on genomic alterations and have failed thus far to identify clear and clinically validated predictive biomarkers,but emerging epigenetic ctDNA methodologies hold promise for further discovery.The present review outlines recent advances and future directions in ctDNA-based biomarkers of CDK4/6 inhibitor treatment response.展开更多
Objectve To study the new insight into the pathogenesis of ulcerative colitis. Methods Interleukin-6 (IL-6), Interleukin-8 (IL-8) and tumor necrosis factor-α(TNF-α) mRNA expression were assessed in the intestinal mu...Objectve To study the new insight into the pathogenesis of ulcerative colitis. Methods Interleukin-6 (IL-6), Interleukin-8 (IL-8) and tumor necrosis factor-α(TNF-α) mRNA expression were assessed in the intestinal mucosa of active (n=32) and inactive (n=18) phase using in situ hybridization. Immunohistochemistry for different leukocyte subsets was performed in biopsy specimens of the intestinal mucosa from 50 patients with ulcerative colitis and 5 healthy controls.展开更多
文摘AIM To evaluate the impact of the Glu167Lys(E167K) transmembrane 6 superfamily member 2(TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus(HIV)/hepatitis C virus(HCV) co-infected patients.METHODS The study comprised 167 consecutive patients with HIV/HCV coinfection and biopsy-proven chronic hepatitis. A pathologist graded liver fibrosis and necroinflammation using the Ishak scoring system, and steatosis using Kleiner's scoring system. Patients were genotyped for TM6SF2 E167K(rs58542926) by real-time Polymerase chain reaction. The 167 patients, 35 therapy-naive and 132 receiving ART, were prevalently males(73.6%), the median age was 40.7 years and the immunological condition good(median CD4+ cells/mm3 = 505.5).RESULTS The 17 patients with the TM6SF2 E167 K variant, compared with the 150 with TM6SF2-E/E, showed higher AST(P = 0.02) and alanine aminotransferase(P = 0.02) and higher fibrosis score(3.1 ± 2.0 vs 2.3 ± 1.5, P = 0.05). In a multivariate analysis, TM6SF2 E167 K was independently associated with severe fibrosis. The same analysis showed that HCV-genotype 3, present in 42.2% of patients was an independent predictor of severe steatosis. The association of TM6SF2 E167 K with severe steatosis, absent for the whole group of 167 patients, was re-evaluated separately for HCVgenotype 3 and non-3 patients: No factor was independently associated with severe steatosis in the HCV-genotype-3 subgroup, whereas an independent association was observed between severe steatosis and TM6SF2 E167 K in non-3 HCV genotypes. No association between the TM6SF2 E167 K variant and severe liver necroinflammation was observed.CONCLUSION In HIV/HCV coinfection the TM6SF2 E167 K variant is an independent predictor of severe fibrosis, but appears to be independently associated with severe steatosis only for patients with a non-3 HCV genotype.
基金Supported by Agencia Nacional de Promoción Científicay Tecnológica,No.PICT 2014-0432,No.PICT 2014-1816 and No.PICT 2015-0551
文摘This review intends to uncover how information from large-scale genetic profiling(whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease(NAFLD), as well as information from circulating transcriptomics(cell-free mi RNAs) and metabolomics, contributes to the understanding of NAFLD pathogenesis. A further aim is to address the question of whether OMICs information is ready to be implemented in the clinics. The available evidence suggests that any new knowledge pertaining to molecular signatures associated with NAFLD and nonalcoholic steatohepatitis should be promptly translated into the clinical setting. Nevertheless, rigorous steps that must include validation and replication are mandatory before utilizing OMICs biomarkers in diagnostics to identify patients at risk of advanced disease, including liver cancer.
文摘Cyclin-dependent kinase 4 and 6(CDK4/6)inhibitors combined with endocrine therapy have transformed the treatment of estrogen receptor-positive(ER+)and human epidermal growth factor receptor 2 negative(HER2-)metastatic breast cancer.However,some patients do not respond to this treatment,and patients inevitably develop resistance,such that novel biomarkers are needed to predict primary resistance,monitor treatment response for acquired resistance,and personalize treatment strategies.Circumventing the spatial and temporal limitations of tissue biopsy,newly developed liquid biopsy approaches have the potential to uncover biomarkers that can predict CDK4/6 inhibitor efficacy and resistance in breast cancer patients through a simple blood test.Studies on circulating tumor DNA(ctDNA)-based liquid biopsy biomarkers of CDK4/6 inhibitor resistance have focused primarily on genomic alterations and have failed thus far to identify clear and clinically validated predictive biomarkers,but emerging epigenetic ctDNA methodologies hold promise for further discovery.The present review outlines recent advances and future directions in ctDNA-based biomarkers of CDK4/6 inhibitor treatment response.
文摘Objectve To study the new insight into the pathogenesis of ulcerative colitis. Methods Interleukin-6 (IL-6), Interleukin-8 (IL-8) and tumor necrosis factor-α(TNF-α) mRNA expression were assessed in the intestinal mucosa of active (n=32) and inactive (n=18) phase using in situ hybridization. Immunohistochemistry for different leukocyte subsets was performed in biopsy specimens of the intestinal mucosa from 50 patients with ulcerative colitis and 5 healthy controls.
