Predictors of liver fibrosis changes assessed by paired liver biopsies in chronic hepatitis C patients treated with direct-acting antivirals.

BACKGROUND/PURPOSE: There are limited studies performing paired liver biopsies in chronic hepatitis C (CHC) patients treated with direct-acting antivirals (DAA). We aimed to investigate the predictors of liver fibrosis changes assessed by paired liver biopsies in these patients. METHODS: From March 2017 to March 2020, 113 CHC patients were prospectively enrolled to receive DAA therapy at our hospital. Paired liver biopsies were performed at baseline and 12 weeks after the end of treatment. RESULTS: Among the entire cohort, the rate of sustained virological response (SVR) was 100%. Four baseline variables independently predicted fibrosis regression, including age <65 years [odds ratio (OR) = 2.725, p = 0.036], fibrosis stages (METAVIR scores) < 3 (OR = 4.874, p = 0.040), hemoglobin levels ≥12.5 g/dL (OR = 3.538, p = 0.029), and platelet counts ≥160 103/µL (OR = 2.958, p = 0.023). Besides, five independent predictors of fibrosis progression included baseline age ≥66 years (OR = 16.351, p = 0.024), body mass index (BMI) ≥26.5 kg/m2 (OR = 21.666, p = 0.009), sofosbuvir/ribavirin use (OR = 29.465, p = 0.031), platelet counts <119 103/µL (OR = 33.739, p = 0.026), and the absence of alanine aminotransferase (ALT) levels declining from >35 U/L at baseline to ≤35 U/L at 4 weeks after baseline (OR = 284.534, p = 0.026). CONCLUSION: For DAA-treated CHC patients, those with baseline age <65 years, fibrosis stages <3, hemoglobin levels ≥12.5 g/dL, or platelet counts ≥160 103/µL are more likely to attain fibrosis regression. There is a higher risk of fibrosis progression in those with baseline age ≥66 years, BMI ≥26.5 kg/m2, sofosbuvir/ribavirin use, platelet counts <119 103/µL, or the absence of early ALT normalization at 4 weeks after baseline.

KDM4B as a target for prostate cancer: structural analysis and selective inhibition by a novel inhibitor.

The KDM4/JMJD2 Jumonji C-containing histone lysine demethylases (KDM4A-KDM4D), which selectively remove the methyl group(s) from tri/dimethylated lysine 9/36 of H3, modulate transcriptional activation and genome stability. The overexpression of KDM4A/KDM4B in prostate cancer and their association with androgen receptor suggest that KDM4A/KDM4B are potential progression factors for prostate cancer. Here, we report the crystal structure of the KDM4B·pyridine 2,4-dicarboxylic acid·H3K9me3 ternary complex, revealing the core active-site region and a selective K9/K36 site. A selective KDM4A/KDM4B inhibitor, 4, that occupies three subsites in the binding pocket is identified by virtual screening. Pharmacological and genetic inhibition of KDM4A/KDM4B significantly blocks the viability of cultured prostate cancer cells, which is accompanied by increased H3K9me3 staining and transcriptional silencing of growth-related genes. Significantly, a substantial portion of differentially expressed genes are AR-responsive, consistent with the roles of KDM4s as critical AR activators. Our results point to KDM4 as a useful therapeutic target and identify a new inhibitor scaffold.