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Advanced Non-alcoholic fatty liver disease (NAFLD) is associated with increased risk of cardiovascular disease (CVD).We determine whether combinations of ultrasound graphic steatosis grades, fibrosis scores and apolipoprotein levels add value to CVD risk prediction in NAFLD patients.The retrospective cohort study enrolled 10,453 individuals (3519 NAFLD; 6934 non NAFLD) from 2004 to 2018. Hepatic ultrasound measurements, lipid and apolipoprotein profiles, Fibrosis-4 and the NAFLD fibrosis scores (NFS) were assessed. The primary outcome included both clinical and subclinical CVD.During 116-month follow-up period, there were 957 clinical and 752 subclinical CVD events. NAFLD patients had a higher incidence of CVD than non NAFLD patients as the steatosis degree, NFS, and FIB4 scores increased (25.1% vs 11.9%, Log Rank: p 0.001). For the lipid and apolipoprotein profiles excluding triglyceride or ApoE, subjects with varied steatosis severity in the upper two tertiles had different risk of CVD (p for interaction 0.001). A nomogram model combination of Framingham Risk Score (FRS), NFS and apolipoprotein profiles presented a higher AUC than FRS in a time-dependent ROC curve (0.816 vs 0.752, p 0.001).The novel risk score considering ultrasonography-defined steatosis grades, non-invasive liver fibrosis scores and apolipoprotein profiles accurately predicted the 10-year risk of CVD.

Non-obese nonalcoholic fatty liver disease (NAFLD) is paradoxically associated with improved metabolic and pathological features at diagnosis but worse prognosis relative to obese NAFLD.To compare predictors of disease severity in NAFLD with different body mass index (BMI) categories.All 1509 consecutive NAFLD patients were classified as lean (20.2%), overweight (23.1%) and obese (56.7%). Liver fat content (LFC) and fibrosis were estimated with magnetic resonance imaging-based proton density fat fraction and shear wave elastography respectively.Lipid profiles and uric acid (UA) were significantly increased in parallel with BMI categories (pairwise comparison P 0.001), but insulin resistance (IR) was significantly different between the non-obese and obese groups. For LFC ≥ 10%, increased waist circumference (WC) was an independent predictor in all groups, while UA elevation (P = 0.02) was predictive in the overweight patients, but BMI ≥ 28 kg/mWC was strongly predictive of disease severity in all NAFLD, while UA and BMI plus IR were additional predictors in the overweight and obese NAFLD respectively. Individualized screening strategies should be established for NAFLD according to different BMIs.

Gallbladder cancer (GBC) is one of the most common and aggressive biliary tract diseases with limited therapeutic strategies and poor prognosis. Various therapeutic agents have been demonstrated effective in preclinical models, but high dose requirement and toxicity to normal cells limit their clinical applications. Considering the high concentration of glutathione (GSH) in GBC, we developed a GSH-responsive nanoparticle (NP) system based on biodegradable poly(disulfide amide) (Cys-8E Polymer) for targeted delivery of a BRD4 inhibitor (JQ1), which is known as a promising therapeutic agent for GBC treatment. JQ1-loaded Cys-8E nanoparticles (JQ1@Cys-8E NPs) possessed a high JQ1 loading, preferable stability and redox-responsive release behavior. Additionally, the NPs showed good targeted delivery into GBC tumor spheroids and GBC patient-derived xenograft (PDX) tumors. Specifically, the intracellular GSH in tumors could trigger the release of JQ1, which induced the cell cycle arrest and apoptosis of GBC cells. RNA-sequencing analysis revealed that JQ1@Cys-8E NPs enhanced the effect of JQ1 through inhibiting NF-κB pathway. Importantly, JQ1@Cys-8E NPs significantly suppressed GBC tumor growth in the PDX model of early recurrence. No obvious systemic toxicity and organ damages were observed after treatment with JQ1@Cys-8E NPs. Our results demonstrate the promising therapeutic applications of JQ1@Cys-8E NPs for adjuvant therapy in GBC treatment.

Background H3K27me3 modification inactivates gene transcription by resulting in condensed chromatin. However, the landscape and biological functions of H3K27me3 in breast cancer remain unclear. Methods Fluorescence enzyme assay was used to analyze the cell proliferation. Transwell assay was used to test the ability of migration and invasion in MDA-MB-231 cells with designed treatment. Transfection of exogenous plasmid was used to intervene specific gene expression. Nude mouse tumor xenograft model was employed to detect the effect of GSKJ-4 in vivo. ChIP-Seq analyzed the modification state of H3K27me3 around the TSS of the gene CEMIP. RNA-Seq was used to analyze the mRNA levels after treating with GSKJ-4 in MDA-MB-231 cells. Results Loss of H3K27me3 is specific for aggressive subtypes of breast cancer and may be a useful diagnostic marker. Epigenetic chemical screening identified histone H3K27me3 demethylation inhibition as a therapeutic strategy for triple-negative breast cancer (TNBC). Functional studies and RNA-seq/ChIP-seq data revealed that inactivation of the protein CEMIP (which is translated by oncogene KIAA1199) by increasing H3K27me3 leads to decreased tumor cell growth and migration. Moreover, survival analysis showed that CEMIP was associated with poor outcome in TNBC. Conclusions Our data suggest H3K27me3 loss as an important event in CEMIP mediated breast cancer carcinogenesis and progression. Loss of H3K27me3 is specific for aggressive subtypes of breast cancer and may be a useful diagnostic marker.