Jin-Zhong Dong

Hepatocellular carcinoma associated microRNA expression signature: integrated bioinformatics analysis, experimental validation and clinical significance

microRNA (miRNA) expression profiles varied greatly among current studies due to different technological platforms and small sample size. Systematic and integrative analysis of published datesets that compared the miRNA expression profiles between hepatocellular carcinoma (HCC) tissue and paired adjacent noncancerous liver tissue was performed to determine candidate HCC associated miRNAs. Moreover, we further validated the confirmed miRNAs in a clinical setting using qRT-PCR and Tumor Cancer Genome Atlas (TCGA) dataset. A miRNA integrated-signature of 5 upregulated and 8 downregulated miRNAs was identified from 26 published datesets in HCC using robust rank aggregation method. qRT-PCR demonstrated that miR-93-5p, miR-224-5p, miR-221-3p and miR-21-5p was increased, whereas the expression of miR-214-3p, miR-199a-3p, miR-195-5p, miR-150-5p and miR-145-5p was decreased in the HCC tissues, which was also validated on TCGA dataset. A miRNA based score using LASSO regression model provided a high accuracy for identifying HCC tissue (AUC = 0.982): HCC risk score = 0.180E_miR-221 + 0.0262E_miR-21 - 0.007E_miR-223 - 0.185E_miR-130a. E_miR-n = Log 2 (expression of microRNA n). Furthermore, expression of 5 miRNAs (miR-222, miR-221, miR-21 miR-214 and miR-130a) correlated with pathological tumor grade. Cox regression analysis showed that miR-21 was related with 3-year survival (hazard ratio [HR]: 1.509, 95%CI: 1.079–2.112, P = 0.016) and 5-year survival (HR: 1.416, 95%CI: 1.057–1.897, P = 0.020). However, none of the deregulated miRNAs was related with microscopic vascular invasion. This study provides a basis for further clinical application of miRNAs in HCC.

Curcumin attenuates lipopolysaccharide/d-galactosamine-induced acute liver injury by activating Nrf2 nuclear translocation and inhibiting NF-kB activation.

Curcumin, a polyphenol in curry spice isolated from the rhizome of turmeric, has been reported to possess versatile biological properties including anti-inflammatory, anti-oxidant, antifibrotic, and anticancer activities. In this study, the hepatoprotective effect of curcumin was investigated in lipopolysaccharide (LPS)/d-galactosamine (d-GalN)-induced acute liver injury (ALI) in rats. Experimental ALI was induced with an intraperitoneal (ip) injection of sterile 0.9% sodium chloride (NaCl) solution containing 8μg LPS and 800mg/kg d-GalN. Curcumin was administered once daily starting three days prior to LPS/d-GalN treatment. Results indicated that curcumin could attenuate hepatic pathological damage, decrease serum ALT and AST levels, and reduce malondialdehyde (MDA) content in experimental ALI rats. Moreover, higher dosages of curcumin pretreatment inhibited NF-κB activation and reduced serum TNF-α and liver TNF-α levels induced by LPS/d-GalN ip injection. Furthermore, we found that curcumin up-regulated the expression of nuclear Nrf2 and Nrf2-dependent antioxidant defense genes including heme oxygenase-1 (HO-1), glutamate-cysteine ligase (GCLC), NAD(P)H dehydrogenase, and quinone (NQO-1) in a dose-dependent manner. Our results showed that curcumin protected experimental animals against LPS/d-GalN-induced ALI through activation of Nrf2 nuclear translocation and inhibition of NF-κB activation.

A nomogram for predicting prognostic value of inflammatory response biomarkers in decompensated cirrhotic patients without acute-on-chronic liver failure

Inflammation plays a vital role in liver cirrhosis progression and prognosis.

A diagnostic algorithm for assessment of liver fibrosis by liver stiffness measurement in patients with chronic hepatitis B

Steatosis could affect liver stiffness measurement in patients with nonalcoholic fatty liver disease and chronic hepatitis C. In this study, we aimed to investigate the impact of steatosis on liver stiffness in hepatitis B virus (HBV)‐infected patients and develop a diagnostic algorithm for prediction of liver fibrosis by liver stiffness based on the controlled attenuation parameter. A total of 488 HBV‐infected patients who underwent clinical examination, Fibroscan and liver biopsy were prospectively enrolled. The best liver stiffness measurement (kPa) cut‐offs for significant fibrosis (S≥3) and advanced fibrosis (S≥4) were 8.1 and 10.9, respectively. The best controlled attenuation parameter cut‐off for severe steatosis (≥30%) was 287 dB/m. Among patients with low‐grade fibrosis (S0‐S2/S0‐S3), mean liver stiffness values were significantly higher in subjects with severe steatosis or controlled attenuation parameter ≥287 dB/m compared with those without. Moreover, in subjects with low‐grade fibrosis, a higher rate of false‐positive rate was observed in patients with severe steatosis than those in patients without (F0‐F2: 28.2% vs 9.7%; F0‐F3: 17.0% vs 5.3%), and in patients with CAP≥287 dB/m compared with their counterpart (F0‐F2: 23.7% vs 9.2%; F0‐F3: 14.1% vs 4.8%). Low‐grade fibrosis was accurately identified by γ‐glutamyl transpeptidase‐to‐platelet ratio (GPR) with a cut‐off value of 0.17. In patients with GPR<0.17, similar results were observed. The presence of steatosis may lead to overestimation of fibrosis assessed by liver stiffness measurement in patient with chronic hepatitis B. A diagnostic algorithm for assessing fibrosis using liver stiffness was developed by combining both controlled attenuation parameter and GPR values.

Development and validation of a prognostic nomogram for acute-on-chronic hepatitis B liver failure

Determining individual risk of short‐term mortality in patients with acute‐on‐chronic hepatitis B liver failure (ACHBLF) is a difficult task. We aimed to develop and externally validate a prognostic nomogram for ACHBLF patients.

A MELD-based nomogram for predicting 3-month mortality of patients with acute-on-chronic hepatitis B liver failure

BACKGROUND Acute-on-chronic hepatitis B liver failure (ACHBLF) is associated with poor short-term prognosis. The aim of the present study was to construct and validate a model for end-stage liver disease (MELD)-based nomogram for the 3-month mortality estimation for patients with ACHBLF. METHODS A total of 551 patients with ACHBLF were prospectively enrolled from 2 independent medical centers and divided into 2 cohorts of training and validation, respectively. The 3-month mortality was recorded as the outcome. The MELD-based nomogram was constructed to predict the 3-month mortality for ACHBLF using the training group of 335 patients and validated using an independent cohort of 216 patients. The predictive capability of MELD-based nomogram was compared with the MELD score system by calibration analysis, receiver operating characteristics (ROC) and decision curve analysis in both training cohort and validation cohort. RESULTS Multivariate analysis suggested that age, serum sodium, and MELD score were independent prognostic indicators associated with the 3-month mortality for ACHBLF, and therefore used for developing the nomogram. In terms of calibration, the predicted survival by the MELD-based nomogram was found to be extremely in line with the observed 3-month mortality both in training cohort and validation cohort. Additionally, both ROC and decision curve analyses showed that the MELD-based nomogram was better than MELD, MELD-Na, MELDNa, and iMELD for ACHBLF prognosis prediction. The results were confirmed in the external cohort of validation. CONCLUSIONS The MELD-based nomogram provided a user-friendly, accurate and reproducible tool for predicting 3-month mortality of patients with ACHBLF.

Neutrophil-lymphocyte ratio predicts hospital-acquired bacterial infections in decompensated cirrhosis.

BACKGROUND Bacterial infection is a frequent complication and severe burden in cirrhotic patients. We determined the utility of neutrophil-to-lymphocyte ratio (NLR) to predict the hospital-acquired (HA) bacterial infections episode in patients with decompensated cirrhosis. METHODS We retrospectively included 2066 consecutive decompensated cirrhotic patients from two separate tertiary hospitals, divided into training (n=1377) and validation (n=689) set. All data were collected on admission and all overt bacterial infections occurring after >48h of hospital stay were registered. RESULTS The incidence of HA bacterial infections in training and validation cohort was 35.87% and 31.05% respectively. Multivariate analysis showed that total bilirubin (TBil), albumin, white blood cell count (WBC) and NLR were independent predictors of HA bacterial infections. We established a Model_NTWA using these four variables and a Model_TWA which did not include NLR. Areas under the curves (AUC) of Model_NTWA (0.859) and NLR (0.824) were higher than which of Model_TWA (0.713), WBC (0.675), TBil (0.593) and Albumin (0.583). Consistent with training cohort, validation cohort showed similar results. Patients with NLR of at least 4.33 had a significantly lower survival (P<0.001). CONCLUSIONS NLR can be used as a novel noninvasive marker to predict the occurrence of HA bacterial infections in decompensated cirrhotic patients.

Splenic CD11c(low)CD45RB(high) dendritic cells derived from endotoxin-tolerant mice attenuate experimental acute liver failure.

Endotoxin tolerance (ET) is suggested to attenuate the severity of acute liver failure (ALF) in mice, possibly through both innate and adaptive immunity. However, the involvement of regulatory dendritic cells (DCregs) in ET has not been fully elucidated. In this study, their effect on ALF in mice was investigated. Splenic DCregs from ET-exposed mice (ET-DCregs) showed lower expression levels of CD40, CD80, and MHC-II markers and stronger inhibition of allogenic T cells and regulation of IL-10 and IL-12 secretion than splenic DCregs from normal mice (nDCregs). Moreover, the mRNA and protein levels of TNF-α and P65 in splenic ET-DCregs were significantly lower than those in the splenic nDCregs. The survival rate was significantly increased and liver injury was mitigated in mice with ALF treated with splenic ET-DCregs. In addition, A20 expression was decreased in the liver of ALF mice, but elevated after infusion of splenic nDCregs and ET-DCregs, and a much higher elevation was observed after infusing the latter cells. The functionality of splenic DCregs was altered after ET exposure, contributing to protection of the livers against D-GalN/LPS-induced ALF.

NK cells of mice phagocytose hMSCs

mediated inflammatory response in lipopolysaccharide-stimulated bone marrow cell cultures. Although this well-controlled in vitro system partially mimics the real-life IRI scenario, we find it useful in addressing mechanistic questions raised by in vivo observations. We are aware of somewhat conflicting data on inflammasome signaling in other IR-stressed organ systems. Although ASC absence failed to protect mice from renal IRI in one study, others reported that ASC-deficient kidneys were largely resistant against IRI. A more severe epithelial injury after 30-minute renal ischemia in the latter study may have progressed through an ASC-dependent mechanism (versus an ASC-independent pathway after 25-minute ischemia in the former study). There may also be organ-specific differences in inflammasome sensitivity in IR-triggered immune cascades. The fact that the severity of liver IRI peaks at 6 hours of reperfusion in our model, whereas that of kidney IRI lasts for days, may explain these discrepancies as well. Moreover, the liver might be unique in TLR/ inflammasome activation in such a way that endogenous ligands may readily tolerize the hepatic, but not the renal, innate immune environment. As to the role of IL-1b, consistent with our findings, others have provided evidence that IL-1 receptor blockade ameliorated hepatocellular damage in rat liver IRI models.